Clinical trial NCT02920008
Conditions: Acute Myeloid Leukemia
Keywords: AML, acute myeloid leukemia, guadecitabine, SGI-110, Phase 3
Sponsor: Astex Pharmaceuticals, Inc.
Start date: 2017-03-16; Completion date: 2020-06-01
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multicenter, randomized, open-label, parallel-group study of guadecitabine vs treatment choice (TC). Participants will be randomly assigned in a 1:1 ratio to either guadecitabine or TC. TC options include the 8 high or low intensity, locally available regimens below; or Best supportive Care (BSC) alone:

* High intensity (intermediate or high dose cytarabine \[HiDAC\]; mitoxantrone, etoposide, and cytarabine \[MEC\]; or fludarabine, cytarabine, granulocyte colony stimulating factor \[G-CSF\], +/- idarubicin \[FLAG/FLAG-Ida\]).
* Low intensity (low dose cytarabine \[LDAC\], decitabine, or azacitidine).
* BSC.

Detailed description:
This Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and safety of guadecitabine in adults with previously treated acute myeloid leukemia (AML) will be conducted in approximately 20 countries. There will be a 14-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last approximately 2 years. Duration of individual participant participation will vary, and participants may continue to receive treatment for as long as they continue to benefit.

Approximately 404 participants from approximately 100 study centers will be randomly assigned to either guadecitabine or treatment choice (TC) in a 1:1 ratio (approximately 202 participants per group). TC is as follows:

* High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).
* Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.
* Best Supportive Care (BSC).

Guadecitabine will be given subcutaneous (SC) at a dose of 60 microgram per meter square (mg/m\^2) in 28-day cycles. In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. Cycle 2 will be either the 5-day regimen (Days 1-5) or 10-day regimen (Days 1-5 and 8-12) based on assessment of disease response and hematologic recovery at the end of Cycle 1. In subsequent cycles, guadecitabine treatment will be for 5 days only (Days 1-5).

Arms: arm 1: Guadecitabine will be given SC at a dose of 60 mg/m\^2 in 28-day cycles (delayed as necessary to allow blood count recovery). arm 2: 1. High intensity
2. Low intensity
3. Best supportive care (BSC).
Interventions: intervention 1: guadecitabine intervention 2: Treatment Choice (TC)
Intervention descriptions: intervention 1: In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. In Cycle 2, the guadecitabine dose will be 60 mg/m\^2 for either 10 days (Days 1-5 and 8-12) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by Day ≥28. intervention 2: * High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).
* Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.
* Best Supportive Care (BSC).

Protocol documents:
Prot_000.pdf: 
Astex Pharmaceuticals, Inc. 
Guadecitabine 
Abbreviated Clinical Study Report SGI-110-06 
Confidential Information 
16.1.1 Protocol and Protocol Amendments 
Protocol Amendment 4.0 Global (29 October 2018) 
•
Summary of Changes – Amendment 4.0 Global (29 October 2018)
•
Summary of Changes – Amendment 3.0 Global (14 February 2018)
•
Summary of Changes – Amendment 2.0 Global (29 November 2017)
•
Summary of Changes – Amendment 1.3 Hungary (24 May 2017)
•
Summary of Changes – Amendment 1.2 UK (18 April 2017)
•
Summary of Changes – Amendment 1.1 France (22 March 2017)


Astex Pharmaceuticals, Inc. 
Guadecitabine 
Clinical Protocol SGI-110-06 
Confidential Information 
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29 October 2018 
Clinical Study Protocol — SGI-110-06 
A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine 
(SGI-110) versus Treatment Choice in Adults with Previously Treated 
Acute Myeloid Leukemia 
PROTOCOL TITLE PAGE 
Sponsor: 
Astex Pharmaceuticals, Inc. 
4420 Rosewood Drive, Suite 200 
Pleasanton, CA  94588 
Medical Monitor: 
 
Drug Safety: 
  
 
IND Number: 
102743 
EudraCT Number: 
2015-005256-97 
Study Clinical Phase: 
Phase 3 
Protocol Version: 
Version 4.0 
Version History/Date: 
Original (08 September 2016) 
Amendment 1.1 France (22 March 2017) 
Amendment 1.2 UK (18 April 2017) 
Amendment 1.3 Hungary (24 May 2017) 
Amendment 2.0 Global (29 November 2017) 
Amendment 3.0 Global (14 February 2018) 
Amendment 4.0 Global (29 October 2018) 


Astex Pharmaceuticals, Inc. 
 
Guadecitabine 
Clinical Protocol SGI-110-06 
 
 
Confidential Information 
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29 October 2018 
SPONSOR AND INVESTIGATOR SIGNATURE PAGE 
Astex Pharmaceuticals, Inc. 
4420 Rosewood Drive, Suite 200 
Pleasanton, CA 94588 USA 
Study Acknowledgement 
SGI-110-06: A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine 
(SGI-110) versus Treatment Choice in Adults with Previously Treated  
Acute Myeloid Leukemia  
Version 4.0 (Amendment 4.0, Global), 29 October 2018 
This protocol has been approved by Astex Pharmaceuticals, Inc. The following signature documents this 
approval. 
Medical Monitor  
 
 
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. 
 
Guadecitabine 
Clinical Protocol SGI-110-06 
 
 
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Study Population: 
Approximately 404 adults with previously treated AML. (Enrollment was stopped with approximately 
300 subjects randomly assigned to treatment [Amendment 4].) 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria. 
1. Adult subjects ≥18 years of age who are able to understand study procedures, comply with them, and provide 
written informed consent before any study-specific procedure. 
2. History of cytologically or histologically confirmed diagnosis of AML (except acute promyelocytic 
leukemia) according to the 2008 World Health Organization (WHO) classification (bone marrow [BM] or 
peripheral blood [PB] blast counts ≥20%). 
3. Performance status (Eastern Cooperative Oncology Group; ECOG) of 0-2. 
4. Subjects with AML previously treated with induction therapy using an intensive chemotherapy regimen, 
defined as a regimen including cytarabine and an anthracycline, and who are refractory to induction (primary 
refractory) or in relapse after such induction with or without prior HCT. 
5. Subjects must have either PB or BM blasts ≥5% at time of randomization. 
6. Creatinine clearance or glomerular filtration rate ≥30 mL/min as estimated by the Cockroft-Gault (C-G) or 
other medically acceptable formulas, such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI 
(the Chronic Kidney Disease Epidemiology Collaboration). 
7. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group 
[CTFG]; see protocol for details) 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 of birth control (as described in the 
protocol) and must agree not to become pregnant or father a child (a) while receiving treatment with 
guadecitabine, decitabine, or azacitidine and for at least 3 months after completing treatment and (b) while 
receiving treatment with high-intensity TC or LDAC and for at least 6 months after completing treatment. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria will be excluded from the study: 
1. Known clinically active central nervous system (CNS) or extramedullary AML, except leukemia cutis. 
2. Subjects who are in first relapse after initial induction, if they had a response duration of >12 months from 
date when first response was documented or if they are good candidates for HCT. 
3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 
4. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or 
responding to endocrine therapy.  
5. Grade 3 or higher Graft Versus Host Disease (GVHD), or GVHD on either a calcineurin inhibitor or 
prednisone more than 5 mg/day. (Note: Prednisone at any dose for other indications is allowed.) 
6. Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior decitabine or azacitidine.  
7. Hypersensitivity to decitabine, guadecitabine, or any of their excipients. 
8. Treated with any investigational therapy within 2 weeks of the first dose of study treatment.  
9. Total serum bilirubin >2.5 × upper limit of normal (ULN; except for subjects with Gilbert's Syndrome for 
whom direct bilirubin is <2.5 × ULN), or liver cirrhosis, or chronic liver disease Child-Pugh Class B or C. 
10. 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. 
11. 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. 
12. Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all 
antibiotics; or non-AML-associated pulmonary disease requiring >2 liters per minute (LPM) oxygen, or any 
other condition that puts the subject at an imminent risk of death. 
13. Subjects with high PB blasts >50% AND poor ECOG PS of 2. 


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Guadecitabine 
Clinical Protocol SGI-110-06 
 
 
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Study Treatment: 
Guadecitabine: 60 mg/m2 SC daily on Days 1-5 and Days 8-12 or on Days 1-10 (first cycle).  
Second cycle will be 60 mg/m2 for either 10 days (Days 1-5 and 8-12 or Days 1-10) or 5 days (Days 1-5 only) 
based on assessment of disease response, and hematological recovery by Day ≥28 using the following general 
guidelines:  
• 
Evidence of active leukemia in PB: no need for BM assessment, give second cycle with 10-day regimen with 
no delay.  
• 
No evidence of active leukemia in PB: perform BM assessment and decide on course of action as follows:   
- 
BM blasts ≥5%: give second cycle with the 10-day regimen with no delay. 
- 
BM blasts <5%: assess recovery of PB normal counts as follows:  
• 
Absolute Neutrophil Count (ANC) >500/μL and platelets >50,000/µL: give second cycle with no 
delay using the 5-day regimen.  
• 
ANC <500/µL or platelets <50,000/µL: Delay treatment and repeat PB at least weekly and give 
second cycle either as a 5-day regimen (if both counts recover to a higher level than the limit above 
with no PB blasts); or 10-day regimen (appearance of evidence of active leukemia with PB blasts 
regardless of normal count recovery). 
For Cycles ≥3, guadecitabine will be given for 5 days only (60 mg/m2/day, Days 1-5). These guidelines may be 
modified if it is believed to be in the best interest of the subject according to the treating physician’s best clinical 
judgment. Treatment should be given for at least 6 total 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. 
Treatment Choice (TC): Before randomization, the investigator will assign each subject to one of the following 
TC options. The following doses and schedules are recommended based on prior published reviews and studies 
(Döhner et al 2015; Roboz et al 2014); however, small variations of dose, schedule, route, duration of treatment, 
and dose adjustment guidelines are allowed as long as they follow the locally approved prescribing information or 
institutional standard practice and are documented in the eCRF. TC options include:  
• 
High intensity: 
- 
Intermediate or high dose cytarabine (HiDAC), recommended as 1-1.5 g/m2 every 12 hours or up to 
6 g/m2/day for ≤6 days, maximum 36 g/m2 per cycle. 
- 
Mitoxantrone, etoposide, and cytarabine (MEC): For example: mitoxantrone 6-12 mg/m2 IV 
(recommended 8 mg/m2), etoposide 80-200 mg/m2 IV (recommended 100 mg/m2), and cytarabine 
1000 mg/m2 IV; each daily for 5 days (Days 1-5).  
- 
Fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida): For example: fludarabine 
25-30 mg/m2 IV daily Days 1-5; cytarabine 1-2 g/m2 IV daily for up to 5 days (recommended to be 
given for 4 hours after fludarabine); G-CSF SC daily from Day 6 up to white cell count recovery with or 
without idarubicin 8 mg/m2 IV daily on Days 3 to 5. 
• 
Low intensity: 
- 
Low dose cytarabine (LDAC), 20 mg SC or IV twice daily on Days 1-10.  
- 
Decitabine 20 mg/m2 IV daily on Days 1-5. 
- 
Azacitidine 75 mg/m2 IV or SC daily on Days 1-7. 
• 
BSC only.   
Examples of variations in the above regimens include dose reductions in older subjects (>60 years) or subjects 
with prior HCT for the high intensity regimens; administering FLAG with no G-CSF; small variations in dose 
and days of treatment in the cycle; and giving azacitidine as a 5-2-2 schedule instead of 7 consecutive days.  
Supportive care will be allowed in all study arms according to institutional standard practice. During treatment 
cycles of guadecitabine 10-day regimen and all high intensity regimens in the TC arm, prophylactic broad 
spectrum antibiotics and prophylactic broad spectrum antifungal treatment, with activity against Aspergillus 
species, such as posaconazole and voriconazole are highly recommended.  
Hydroxyurea administration prior to randomization to control high counts is allowed. After randomization, 
subjects in the TC control arms may receive hydroxyurea to control proliferative disease as part of study 
treatment, while subjects in the guadecitabine arm may receive hydroxyurea in the first 30 days of treatment. In 
the guadecitabine arm, earlier treatment cycles (prior to Day 29) are allowed to control high proliferative counts.  






Astex Pharmaceuticals, Inc. 
 
Guadecitabine 
Clinical Protocol SGI-110-06 
 
 
Confidential Information 
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29 October 2018 
Study Duration: 
The expected study duration is approximately 26 months including 18 months for completing enrollment and 
approximately 8 months follow-up before the primary analyses. The study started in Q1 2017. Based on DMC 
recommendation after futility analyses, enrolment was stopped in September 2018. Follow-up for the primary 
analyses will be stopped in Q3 2019 or when the last subject is off study.  
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. 
 
Guadecitabine 
Clinical Protocol SGI-110-06 
 
 
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TABLE OF CONTENTS 
1.0 
INTRODUCTION AND BACKGROUND ....................................................................19 
1.1 
Background of the Disease ....................................................................................19 
1.2 
Treatment Options .................................................................................................20 
1.3 
Guadecitabine ........................................................................................................21 
 
 
 
 
 
 
1.5 
Summary of Clinical Data for Guadecitabine ........................................................23 
1.5.1 
Phase 1-2 Dose Escalation and Dose Expansion Study 
(Study SGI-110-01) ...............................................................................23 
1.5.1.1 
Phase 1 Dose Escalation (Study SGI-110-01) ...............................24 
1.5.1.2 
Phase 2 (SGI-110-01 Dose Expansion) .........................................25 
1.5.2 
Phase 3 Trial in Previously Untreated AML (Study SGI-110-04) ........31 
1.6 
Potential Risks and Benefits to Human Subjects ...................................................31 
2.0 
RATIONALE ...................................................................................................................31 
2.1 
Rationale for the Study ..........................................................................................31 
2.2 
Rationale for Guadecitabine Dose and Regimen ...................................................32 
3.0 
STUDY OBJECTIVES ....................................................................................................32 
3.1 
Primary Objective ..................................................................................................32 
3.2 
Secondary Objectives .............................................................................................32 
 
 
4.0 
INVESTIGATIONAL PLAN .........................................................................................33 
4.1 
Overall Study Design .............................................................................................33 
4.2 
Discussion of Study Design ...................................................................................35 
4.3 
Study Endpoints .....................................................................................................36 
4.3.1 
Primary Endpoint ..................................................................................36 
4.3.2 
Secondary Endpoints .............................................................................37 
4.4 
Data Monitoring Committee ..................................................................................37 
4.5 
Study Steering Committee .....................................................................................37 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................38 
5.1 
Number of Subjects and Centers ............................................................................38 
5.2 
Inclusion Criteria ...................................................................................................38 
5.3 
Exclusion Criteria ..................................................................................................39 
5.4 
Treatment Discontinuation and Withdrawal of Subjects .......................................40 
5.4.1 
Discontinuation from Study Treatment .................................................40 


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Clinical Protocol SGI-110-06 
 
 
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5.4.2 
Withdrawal from the Study ...................................................................40 
5.4.3 
Replacement of Subjects .......................................................................41 
6.0 
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES ............41 
6.1 
Randomization .......................................................................................................41 
6.2 
Blinding..................................................................................................................41 
7.0 
STUDY TREATMENTS .................................................................................................42 
7.1 
Investigational Medicinal Product: Guadecitabine ................................................42 
7.1.1 
IMP Information ...................................................................................42 
7.1.2 
IMP Regimens and Administration .......................................................42 
7.2 
Active Comparator (Treatment Choice) ................................................................44 
7.3 
Guidelines for Adjusting or Withholding Study Treatment ..................................45 
7.3.1 
Guidelines for Guadecitabine ................................................................45 
7.3.2 
Guidelines for Treatment Choice ..........................................................46 
7.4 
Concomitant Treatment .........................................................................................46 
7.4.1 
Supportive, Prophylactic, or Other Treatments ....................................46 
7.4.2 
Prohibited Medications .........................................................................47 
7.5 
Overdose Instructions ............................................................................................47 
8.0 
RISKS/PRECAUTIONS .................................................................................................47 
8.1 
Dose Limiting Toxicities .......................................................................................47 
8.2 
Myelosuppression (Neutropenia, Febrile Neutropenia, Thrombocytopenia, and 
Anemia)..................................................................................................................48 
8.3 
Fertility ...................................................................................................................48 
8.4 
Injection Site Reactions .........................................................................................48 
8.5 
Adverse Events ......................................................................................................49 
9.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................49 
9.1 
Efficacy Assessments .............................................................................................49 
 
 
 
 
9.4 
Safety Assessments ................................................................................................51 
9.5 
Study Procedures ...................................................................................................52 
9.5.1 
Schedule of Events ................................................................................52 
9.5.2 
Screening and Baseline Procedures ......................................................57 
9.5.3 
Treatment Procedures for Cycles 1-3 ....................................................58 
9.5.3.1 
Day 1 (Before Dosing), Cycles 1-3................................................58 
9.5.3.2 
Day 1 (After Dosing), Cycles 1-3 ..................................................59 
9.5.3.3 
Other Dosing Days, Cycles 1-3 .....................................................59 


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Clinical Protocol SGI-110-06 
 
 
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9.5.3.4 
Days 8, 15 and 22, Cycles 1-3 .......................................................59 
9.5.4 
Treatment Procedures for Cycles ≥4 .....................................................60 
9.5.4.1 
Day 1 (Before Dosing), Cycles ≥4 .................................................60 
9.5.4.2 
Day 1 (After Dosing), Cycles ≥4 ...................................................61 
9.5.4.3 
Other Dosing Days in Clinic, Cycles ≥4 ........................................61 
9.5.4.4 
Day 15, Cycles 4 to 6 .....................................................................61 
9.5.5 
Safety Follow-up Visit ..........................................................................61 
9.5.6 
Long-Term Follow-up ...........................................................................62 
9.6 
Unscheduled Visits ................................................................................................63 
9.7 
Missed Evaluations ................................................................................................63 
10.0 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ......63 
10.1 
Definitions..............................................................................................................63 
10.1.1 
Adverse Event (AE) ..............................................................................63 
10.1.2 
Serious Adverse Events (SAEs) ............................................................64 
10.2 
Adverse Event Reporting and Descriptions ...........................................................64 
10.2.1 
Severity .................................................................................................65 
10.2.2 
Relationship to Study Treatment (Suspected Adverse Reactions) ........65 
10.2.3 
Pregnancy and Abortion ........................................................................66 
10.3 
Reporting and Evaluation of Serious Adverse Events ...........................................67 
10.3.1 
Reporting Requirements for Serious Adverse Events (SAEs) ..............67 
10.4 
Follow-up for Adverse Events ...............................................................................68 
11.0 
STATISTICS ....................................................................................................................68 
11.1 
Sample Size ............................................................................................................68 
11.2 
Analysis Sets ..........................................................................................................68 
11.2.1 
All-Subjects Analysis Set ......................................................................68 
11.2.2 
Efficacy Analysis Set ............................................................................69 
11.2.3 
Safety Analysis Set ...............................................................................69 
 
 
 
 
11.3 
Schedule of Analyses .............................................................................................69 
11.4 
Disposition .............................................................................................................70 
11.5 
Analysis of Demographic and Baseline Data ........................................................70 
11.6 
Efficacy Analyses ..................................................................................................70 
11.6.1 
Primary Efficacy Analysis ....................................................................70 
11.6.2 
Secondary Efficacy Analyses ................................................................71 
11.6.2.1 
Event-free Survival (EFS) ..............................................................72 


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11.6.2.2 
Survival rate at 1 Year ...................................................................72 
11.6.2.3 
Number of Days Alive and Out of the Hospital ............................72 
11.6.2.4 
Transfusion Independence Rate .....................................................72 
11.6.2.5 
Complete Response and Complete Response with Partial 
Hematologic Recovery Rates ........................................................73 
11.6.2.6 
Composite CR Rate........................................................................73 
11.6.2.7 
Hematopoietic Cell Transplant Rate ..............................................73 
11.6.2.8 
Duration of Combined CR and CRh ..............................................73 
11.6.2.9 
EQ-5D-5L ......................................................................................74 
11.6.2.10 
Sequence of Statistical Tests for Efficacy Endpoints ....................74 
 
 
11.7 
Safety Analyses ......................................................................................................75 
 
 
 
 
11.10 Interim Analysis .....................................................................................................76 
11.11 Procedures for Handling Missing, Unused, and Spurious Data.............................76 
12.0 
STUDY DURATION AND TERMINATION ...............................................................77 
13.0 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ...............................77 
13.1 
Compliance Statement ...........................................................................................77 
13.2 
Informed Consent...................................................................................................77 
13.3 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) ...........77 
14.0 
ADMINISTRATIVE PROCEDURES ...........................................................................78 
14.1 
Sponsor Responsibilities ........................................................................................78 
14.1.1 
Study Supplies .......................................................................................78 
14.1.2 
Investigator Training .............................................................................78 
14.1.3 
Ongoing Communication of Safety Information During the Study ......78 
14.1.4 
Study Monitoring ..................................................................................79 
14.1.5 
Study Assessment of Protocol Deviations and Prohibition of 
Waivers .................................................................................................79 
14.1.6 
Study Auditing and Inspecting ..............................................................79 
14.2 
Investigator Responsibilities ..................................................................................80 
14.2.1 
Subject Screening Log ..........................................................................80 
14.2.2 
Drug Accountability ..............................................................................80 
14.2.3 
Reporting and Recording of Study Data ...............................................80 
14.2.4 
Source Documentation ..........................................................................81 
14.2.5 
Tissue and Blood Sample Collection/Storage .......................................81 
14.2.6 
Records Retention .................................................................................81 


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Clinical Protocol SGI-110-06 
 
 
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14.3 
Clinical Trial Insurance ..........................................................................................82 
14.4 
Study Administrative Letters and Protocol Amendments .....................................82 
15.0 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA ........................83 
16.0 
REFERENCES .................................................................................................................84 
17.0 
APPENDICES ..................................................................................................................89 
 
LIST OF TABLES 
Table 1: 
Summary of Demographic and Baseline Characteristics: 
Relapsed/Refractory AML Subjects (Phase 2, Study SGI-110-01) ...........26 
Table 2: 
Best Response in Subjects with r/r AML (Efficacy Data Set) ...................27 
Table 3: 
Adverse Events Grade ≥3 by Decreasing Incidence (≥10% of Total) in 
Subjects with r/r AML ...............................................................................30 
Table 4: 
30-day and 60-day All-Cause Mortality Rates in Subjects with 
r/r AML ......................................................................................................30 
Table 5: 
Guadecitabine Dosing Adjustment Guideline Based on Peripheral  
Blood Blasts and Counts (for Cycles ≥3) ..................................................45 
Table 6: 
Modified 2003 IWG AML Response Criteria ...........................................50 
Table 7: 
Schedule of Events .....................................................................................53 
Table 8: 
Clinical Laboratory Tests ...........................................................................58 
 
LIST OF FIGURES 
Figure 1: 
Product-Limit Survival Estimates in r/r AML Subjects by Regimen 
(5-Day and 10-Day) ...................................................................................28 
Figure 2: 
Guadecitabine Average LINE-1 Demethylation by Dose and 
Treatment Schedule ...................................................................................29 
Figure 3: 
Study Schema.............................................................................................35 
 
LIST OF APPENDICES 
Appendix 1: 
ECOG performance status .........................................................................90 
Appendix 2: 
Quality of life EQ-5D-5L Sample..............................................................91 
Appendix 3: 
Cytogenetics-Based Risk Classification ....................................................95 
Appendix 4: 
Summary of Changes, Version 4.0 (Amendment 4.0, Global), Relative 
to Protocol Version 3.0 ..............................................................................96 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
adverse event 
ALT 
alanine transaminase (serum glutamic pyruvic transaminase [SGPT]) 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
AUC 
area under the curve 
BCR-ABL 
chronic myelogenous leukemia in blast crisis 
BED 
biologically effective dose 
BM 
bone marrow 
BSA 
body surface area 
BSC 
best supportive care 
CBC 
complete blood count 
CDA 
cytidine deaminase 
CFR 
Code of Federal Regulations 
C-G 
Cockcroft-Gault 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum concentration 
CMML 
chronic myelomonocytic leukemia 
CNS 
central nervous system 
CR 
complete response 
CRc 
composite complete response (CRc=CR+CRi+CRp) 
CRh 
complete response with partial hematologic recovery 
CRi 
CR with incomplete blood count recovery 
CRp 
CR with incomplete platelet recovery 
CRF/eCRF 
case report form/electronic case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLI 
donor lymphocytes infusion 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EMEA 
European Agency for the Evaluation of Medicinal Products 
EQ VAS 
EuroQOL Visual Analogue Scale 
EU 
European Union 
FAB 
French-American-British 
FDA 
Food and Drug Administration 
FIH 
first in human 
FLAG 
fludarabine, cytarabine, and G-CSF  
FLAG-Ida 
fludarabine, cytarabine, G-CSF and idarubicin 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factors 
GLP 
Good Laboratory Practice 
GVHD 
graft versus host disease 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HCT 
hematopoietic cell transplant 
HI 
hematological improvement 


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HiDAC 
high dose cytarabine 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent 
HNSTD 
highest non-severely toxic dose 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee  
IMP 
investigational medicinal product (guadecitabine) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IWG 
International Working Group 
LDAC 
low dose cytarabine 
LINE-1 
long interspersed nucleotide element-1 
LPM 
liters per minute 
mCR 
marrow complete response 
MDRD 
Modification of Diet in Renal Disease 
MDS 
myelodysplastic syndrome 
MEC 
mitoxantrone, etoposide and cytarabine 
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 hospital 
NOAEL 
no observed adverse effect level 
OSHA 
Occupational Safety and Health Administration 
OS 
overall survival 
PB 
peripheral blood 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
QOL 
quality of life 
RBC 
red blood cells 
ROW 
rest of world 
r/r 
relapsed/refractory 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SE 
standard error 
SGI-110 
guadecitabine 
SOC 
System Organ Class 
SSC 
Study Steering Committee 
STD10 
severely toxic dose causing mortality in 10% of animals 
SUSAR 
serious unexpected suspected adverse reaction 
TC 
treatment choice 
TK 
toxicokinetic 
TN 
treatment naive 
ULN 
upper limit of normal 
VAS 
visual analog scale 


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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 Code of Federal Regulations (CFR) 
Parts 11, 50, 54, 56, and 312; the European Union (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 
Background of the Disease 
Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults. In the 
United States, the American Cancer Society estimated that 19,950 new cases of AML will be 
diagnosed in 2016 and approximately 10,430 will die from their disease. The average age of a 
patient with AML is about 67 years; AML is generally a disease of older people and is uncommon 
before age 45 (American Cancer Society 2016). As the population in the United States ages, there 
appears to be an increasing incidence of AML (National Cancer Institute 2016).  
Characteristically AML is a disease associated with termination in cellular differentiation and 
uncontrolled proliferation of clonal immature myeloid precursors (myeloblasts) in the bone 
marrow and blood (Scheinberg et al 2001). AML is differentiated from other hematopoietic 
malignancies by the presence of greater than 20% myeloblasts in the bone marrow or blood. AML 
can be divided into de novo and secondary disease (Scheinberg et al 2001; Appelbaum et al 2001). 
Patients presenting with de novo AML often do not have any identifiable risk factor. Secondary 
causes for AML range from previous myelodysplastic syndrome (MDS), Down syndrome, 
Fanconi 
anemia, 
ataxia-telangiectasia, 
long-term 
treatment 
consequences 
of 
certain 
chemotherapeutic agents, therapeutic or environmental radiation, and exposure to environmental 
hazards (eg, benzene). The common feature of all AML is genetic mutation, which in 70% of 
patients results in visible cytogenetic abnormalities when the leukemia cells are karyotyped. 
In AML, myeloblasts crowd out normal hematopoietic cells in the bone marrow, leaving the 
patient with insufficient erythrocytes, platelets, and neutrophils. The consequent pancytopenias 
cause most of the symptoms of leukemia. Diagnosis is made by pathologic examination of 
peripheral blood (PB) and bone marrow (BM), and no opportunity for early detection exists except 
in patients with antecedent hematologic malignancies or inherited disorders. Diagnosis of AML 
requires a rapid assessment and initiation of treatment. AML leads to death within a few weeks to 
months after diagnosis if left untreated.  
AML is diagnosed and classified according to the World Health Organisation (WHO) 
classification, which considers the genetic, immunophenotypic, biological, and clinical 
characteristics of the disease (Vardiman et al 2009). The WHO classification usually supersedes 
the previously used French-American-British (FAB) classification of AML, which was developed 
based on the morphological and cytological characteristics of the disease (Meenaghan et al 2012). 


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1.2 
Treatment Options 
Traditional, standard therapy consists of 2 phases: induction therapy followed by consolidation or 
intensification therapy (Estey and Döhner 2006). The initial goal in treating AML is to produce 
complete remission with induction chemotherapy. This is followed by consolidation or 
intensification therapy with additional chemotherapy (high-dose cytosine arabinoside or other 
combination regimens) or hematopoietic cell transplant (HCT) with the ultimate goal of cure. The 
standard intensive induction chemotherapy has been the same for decades and mainly comprises 
7 days of Ara-C and 3 days of an anthracycline (daunorubicin or idarubicin), known as the 7+3 
regimen, which produces remission in 70% to 80% of patients for whom the treatment is 
appropriate (Tefferi and Letendre 2012). 
Patients who do not enter remission after 1-2 cycles of this treatment are considered refractory. 
Remission is defined as normal cellularity of the bone marrow, with blast levels of less than 5%, 
and morphologically normal hematopoiesis with a neutrophil count over 1000/µL and a platelet 
count over 100,000/µL (National Comprehensive Cancer Network [NCCN] AML Guidelines 
2014). 
Although up to 80% of AML patients <60 years of age will achieve complete response (CR) with 
intensive chemotherapy, approximately 30% to 40% of these patients will die from their disease 
(Roboz 2011; Estey 2012). The outlook for patients >60 years old is significantly worse. Only 
45% to 50% of older patients achieve complete remission and most remitting patients quickly 
relapse, leading to an overall median survival of approximately 9 months from diagnosis 
(Löwenberg et al 1989; Goldstone et al 2001; Wahlin et al 2001; Ross et al 2015). These figures 
have not improved within the last 3 decades (Roboz 2011; Stalfelt 1994; Alibhai et al 2007). 
The incidence of AML increases with age, with more than 50% of patients with AML being over 
65 years of age (Medeiros 2015). For these older patients, traditional chemotherapy provides 
minimal chance for durable remission, as well as significant toxicity, because of patients’ increased 
risk factors and inability to cope with aggressive treatment (Kuendgen and Germing 2009). 
Induction mortality has been reported to be as high as 20% (Marks 2012).  
Patients unable to achieve a CR with standard induction therapy (refractory AML) or whose 
disease returns after achieving remission (relapsed) are likely to die from their disease (Estey 
2012). Treatment strategy is directed towards getting the patient into remission and then to 
transplant. Otherwise, palliation is the goal. Patients whose first remission lasted longer than one 
year have a good chance at achieving a second remission with standard induction therapy and, if 
the transplant is successful, do almost as well as patients transplanted in first remission 
(Ossenkoppele et al 2016). There are no proven treatment options for subjects with AML refractory 
to intensive remission induction chemotherapy or for subjects who relapse after intensive 
chemotherapy treatment(s), particularly if they fail re-induction with the standard regimen. Safe 
and effective treatments prolonging survival and/or bridging to transplant are urgently needed for 
patients with relapsed or refractory (r/r) AML. 


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Choice of treatment for patients with r/r AML is based mostly on evidence from small studies and 
considers factors such as age, performance status, previous treatment history and responses, 
cytogenetics, access to care, and availability of medications (Roboz et al 2014). There are several 
commonly used salvage regimens, most of which include cytarabine as either a single agent or in 
combination regimens (NCCN AML Guidelines 2014), such as mitoxantrone, etoposide, and 
cytarabine (MEC) (Archimbaud et al 1991; Archimbaud et al 1995) and fludarabine, cytarabine, 
granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida). The hypomethylating agents 
(HMAs) decitabine and azacitidine, though mostly studied in MDS and newly diagnosed AML 
(Kantarjian et al 2012, Fenaux et al 2010, Lubbert et al 2012), are often considered an option for 
frail, older patients with relapsed/refractory AML (Roboz et al 2014). Due to the lack of proven 
treatment for r/r AML, enrollment in a clinical trial is considered an appropriate strategy (NCCN 
AML Guidelines 2014; Roboz et al 2014). 
1.3 
Guadecitabine 
The DNA methylation inhibitors azacitidine and decitabine (also known as HMAs), are approved 
in several jurisdictions for treatment of intermediate and high risk patients with MDS including 
chronic myelomonocytic leukemia (CMML). Guadecitabine is a new chemical entity that 
incorporates decitabine and deoxyguanosine linked by a phosphodiester bond. Unlike decitabine, 
guadecitabine is resistant to deamination by cytidine deaminases (CDAs). Guadecitabine is 
cleaved by intra- and extracellular phosphorylases and other enzymes, releasing decitabine. This 
cleavage in vivo (in primates) results in gradual release of decitabine both extra- and 
intracellularly, thus prolonging decitabine half-life and effective exposure to decitabine.  
Compared with intravenous (IV) decitabine, decitabine from subcutaneous (SC) guadecitabine had 
prolonged exposure and lower maximum concentration (Cmax) (Issa et al 2015). This differentiated 
pharmacokinetic (PK) profile is the proposed basis for potential enhancement of clinical activity 
of guadecitabine.  
Guadecitabine is being evaluated in subjects with hematological malignancies (MDS and AML) 
and solid tumors (ovarian cancer, hepatocellular carcinoma [HCC]). Long interspersed nucleotide 
element-1 (LINE-1) demethylation was demonstrated in AML/MDS subjects treated with 
guadecitabine (Issa et al 2015). Clinical responses in subjects with AML and MDS have been 
observed in the Phase 1-2 study (SGI-110-01) (Issa et al 2015; Kantarjian et al 2013).  
A Phase 3 study (SGI-110-04) of guadecitabine versus treatment choice (TC) is currently ongoing 
in adults with previously untreated AML who are unfit to receive or who are not considered 
candidates 
for 
intensive 
induction 
chemotherapy. 
Another 
Phase 
3 
study 
(SGI-110-07) of guadecitabine versus TC is planned for adults with MDS or CMML who failed 
or relapsed after prior treatment with azacitidine, decitabine, or both. 
 
 
 


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1.5 
Summary of Clinical Data for Guadecitabine 
Guadecitabine has been evaluated in patients with hematological malignancies (MDS and AML) 
and in patients with solid tumors (ovarian cancer and HCC). LINE-1 demethylation, gene-specific 
demethylation, and clinical responses have been observed in patients with AML and MDS (Study 
SGI-110-01), as well as in patients with ovarian cancer and HCC (Studies SGI-110-02 and SGI-
110-03).  
The results from the Phase 1 dose escalation of Study SGI-110-01 and Phase 2 dose expansion of 
Study SGI-110-01 in patients with relapsed or refractory AML (r/r AML) have been summarized 
below. Please refer to the most recent IB for summaries of the other clinical studies.  
1.5.1 
Phase 1-2 Dose Escalation and Dose Expansion Study (Study SGI-110-01) 
Study SGI-110-01 was a first-in-human (FIH), multicenter, randomized study in patients with 
MDS or AML. It was conducted in 2 phases and enrolled 401 subjects. Phase 1 is complete and 
Phase 2 is ongoing.  
• Phase 1 Dose Escalation: 93 subjects with refractory or relapsed MDS or AML treated with 
guadecitabine. 
• Phase 2 Dose Expansion: 308 subjects with MDS or AML treated with guadecitabine. 
All treatment cycles were 28-day cycles in the Phase 1-2 study.  


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1.5.1.1 
Phase 1 Dose Escalation (Study SGI-110-01) 
Phase 1 dose escalation was performed in subjects with refractory or relapsed MDS or AML 
(Issa et al 2015) who had Eastern Cooperative Oncology Group (ECOG) performance status of 
0 to 2 and acceptable liver and kidney function. Co-primary endpoints were maximum tolerated 
dose (MTD) and biologically effective dose (BED).  
Subjects were treated with 3 different dosing schedules (Daily×5, Once Weekly for 3 weeks, and 
Twice Weekly for 3 weeks). Guadecitabine was given SC in 28-day cycles starting at a dose of 
3 mg/m2 once daily on Days 1-5 (Daily×5). Doses were escalated to 125 mg/m2 using the Daily×5 
schedule. The Once-Weekly (Days 1, 8, and 15) dosing schedule was initiated at 6 mg/m2 and was 
escalated to 125 mg/m2. An amendment added the Twice-Weekly (Days 1, 4, 8, 11, 15, 18) dosing 
schedule, which investigated guadecitabine at 60 and 90 mg/m2.  
The MTD was 90 mg/m2/day using the Daily×5 schedule for MDS subjects. The MTD was not 
reached for subjects with AML who were dosed up to 125 mg/m2/day Daily×5. Two subjects with 
MDS developed DLTs at the highest dose (125 mg/m2/day) in the Daily×5 regimen. One subject 
had thrombocytopenia and neutropenia; the other subject had febrile neutropenia, 
thrombocytopenia, and fatal sepsis. 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.  
Potent dose-related DNA demethylation occurred on the Daily×5 regimen. The BED (defined as 
the minimum dose that achieves maximal demethylation of LINE-1 from 3 successive cohorts) 
was 60 mg/m2/day for the Daily×5 schedule. DNA methylation reached a plateau at 60 mg/m2 and 
was similar at 60, 90, and 125 mg/m2 Daily×5. 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.  
A total of 74 subjects with r/r AML were treated with guadecitabine in Phase 1 dose escalation. 
Responses were observed starting at 36 mg/m2. Of 49 subjects treated at 36 mg/m2 or higher in the 
daily and weekly regimens, 5 composite complete responses (CRc: complete response [CR] + 
complete response with incomplete blood count recovery [CRi] + complete response with 
incomplete platelet recovery [CRp]), including 2 CRs, were observed. A total of 19 subjects with 
relapsed/refractory MDS were treated in the Phase 1 study. Six subjects with MDS had clinical 
responses: 2 subjects had marrow complete response (mCR), and 4 had hematological 
improvement (HI; 3 subjects had single-lineage HI and 1 subject had bi-lineage HI).  
The most common Grade 3 or higher adverse events (AEs) were febrile neutropenia (38/93; 41%), 
pneumonia (27/93; 29%), thrombocytopenia (23/93; 25%), anemia (23/93; 25%), and sepsis 
(16/93; 17%). The most common serious AEs (SAEs) were febrile neutropenia (29/93; 31%), 
pneumonia (26/93; 28%), and sepsis (16/93; 17%).  
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 


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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. 
1.5.1.2 
Phase 2 (SGI-110-01 Dose Expansion) 
Phase 2 was a dose-expansion, dose-ranging trial and was opened as a multicenter, open-label, 
randomized comparison of 60 vs 90 mg/m2 guadecitabine SC Daily×5 (once daily on Days 1-5). 
The 60 mg/m2 Daily×5 dose was chosen because it represented the BED from Phase 1, while the 
90 mg/m2 dose was chosen to explore benefit from a higher dose that was still well tolerated in 
both MDS and AML subjects. Subjects were stratified by disease type (treatment-naïve elderly 
AML, relapsed/refractory AML, HMA treatment-naïve MDS, and relapsed/refractory MDS). A 
subsequent amendment, applying only to AML subjects allowed initial intensification with a 
10-day regimen (dosing on Days 1-5 and 8-12) at 60 mg/m2/day for up to 4 cycles, followed by 
continuation of treatment with the Daily×5 regimen. The 10-day regimen was studied first in 
r/r AML subjects and then in treatment-naïve elderly AML subjects. 
Phase 2 in the cohort of subjects with r/r AML is complete and the results for these subjects are 
described below. Key eligibility for r/r AML subjects in Study SGI-110-01 Phase 2 included 
age ≥18 years, confirmed diagnosis of AML, in relapse or refractory following standard treatment, 
and ECOG performance status of 0-2. 
There was no limit on the number of prior regimens, white blood cell (WBC) count, or bone 
marrow (BM) blasts count. Only 1 previous cycle of decitabine or azacitidine was allowed. 
Patients with acute promyelocytic leukemia (M3 classification) were excluded from the study. 
Subjects were randomized to receive either 60 or 90 mg/m2/day guadecitabine once daily on Days 
1-5 of a 28-day cycle. An additional 10-day cohort was added; subjects in this cohort were treated 
with 60 mg/m2/day guadecitabine once daily on Days 1-5 and Days 8-12 of a 28-day cycle for at 
least 2 cycles followed by the 5-day regimen in subsequent cycles. The primary endpoint for r/r 
AML subjects was CRc rate (CRc rate = CR + CRp + CRi). 
A total of 108 subjects were enrolled with r/r AML in Phase 2, of whom 103 subjects received 
treatment. Fifty subjects were randomized and treated with the 5-day regimen (24 and 26 subjects 
received study treatment at 60 or 90 mg/m2 Daily×5, respectively). Fifty-three subjects were 
enrolled 
and 
treated 
with 
guadecitabine 
60 mg/m2 
in 
the 
10-day 
regimen 
(according to protocol amendment 3, without randomization).  
Table 1 presents demographic and baseline characteristics for subjects with r/r AML enrolled and 
treated in Phase 2 Dose Expansion. The median age of subjects was 60 years, 60% of subjects 
were male, and 81% were White. The 10-day group was nearly equally divided between the sexes 
(51% men) compared with the 5-day group (70% men), but all other demographic characteristics 
were similar across treatment groups. Most subjects (73%) had an ECOG status of 1 at baseline 
and had received a median of 2 prior regimens with up to 10 prior regimens including 11% with 


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prior HMA treatment. The median time since diagnosis was 261 days (range 8 to 3214 days). Of 
note are the poor prognostic features of subjects treated in this study (18% of subjects had prior 
HCT and 41% had poor risk cytogenetics). 
Table 1: 
Summary of Demographic and Baseline Characteristics: 
Relapsed/Refractory AML Subjects (Phase 2, Study SGI-110-01) 
5-Day 
 
10-Day 
 
Characteristic 
60 mg/m² 
(N=24) 
90 mg/m² 
(N=26) 
Total 
(N=50) 
 
 60 mg/m² 
(N=53) 
Total 
(N=103) 
Age, yr 
Median 
58.43 
 
65.50 
 
62.34 
 
57.47 
 
60.13 
 
Range 
22.0-77.0 
30.0-81.7 
22.0-81.7 
29.2-82.5 
22.0-82.5 
Gender (n, %) 
Male 
15 
(63) 
20 
(77) 
35 
(70) 
27 
(51) 
62 
(60) 
Female 
9 
(38) 
6 
(23) 
15 
(30) 
26 
(49) 
41 
(40) 
ECOG (n, %) 
0 
2 
(8) 
3 
(12) 
5 
(10) 
9 
(17) 
14 
(14) 
1 
20 
(83) 
20 
(77) 
40 
(80) 
35 
(66) 
75 
(73) 
2 
2 
(8) 
3 
(12) 
5 
(10) 
9 
(17) 
14 
(14) 
Time Since  
Median 
369.5 
 
292.0 
 
342.0 
 
177.0 
 
261.0 
 
 Diagnosis to 
Range 
27-3198 
8-1611
 
8-3198 
 
17-3214 
8-3214 
 
 C1D1 (Days) 
 
 
 
 
 
 
 
 
BM Blasts (%) 
Median 
34.0 
 
35.5 
 
35.0 
 
32.0 
 
33.0 
 
Range 
9-93 
 
2-94 
 
2-94 
 
4-95 
 
2-95 
 
PB Blasts (%) 
Median 
5.0 
 
14.0 
 
10.0 
 
2.5 
 
6.0 
 
Range 
0-95 
 
0-81 
 
0-95 
 
0-99 
 
0-99 
 
WBC (x109/L) 
Median 
1.65 
 
2.12 
 
1.70 
 
2.10 
 
1.80 
 
Range 
0.3-18.7 
0.3-18.6 
0.3-18.7 
0.2-75.5 
0.2-75.5 
Cytogenetics (n, %) n 
24 
 
26 
 
50 
 
53 
 
103 
 
 (Company  
Better Risk 
0 
 
0 
 
0 
 
0 
 
0 
 
 Assessment) 
Int Risk 
12 
(50) 
14 
(54) 
26 
(52) 
26 
(49) 
52 
(50) 
 
Poor Risk 
9 
(38) 
11 
(42) 
20 
(40) 
22 
(42) 
42 
(41) 
Not evaluable 
3 
(13) 
1 
(4) 
4 
(8) 
5 
(9) 
9 
(9) 
Prior Decitabine or Azacitidine (n, %) 
1 
(4) 
2 
(8) 
3 
(6) 
8 
(15) 
11 
(11) 
Prior HCT (n, %) 
5 
(21) 
5 
(19) 
10 
(20) 
9 
(17) 
19 
(18) 
Number of Prior 
Median 
2.5 
 
2.0 
 
2.0 
 
2.0 
 
2.0 
 
 Regimens 
Range 
1-5 
 
1-10 
 
1-10 
 
1-7 
 
1-10 
 
Time Since Last  
n 
24 
26 
50 
53 
103 
 Anti-Leukemia 
<6 Months 
19 
(79) 
20 
(77) 
39 
(78) 
43 
(81) 
82 
(80) 
 Therapy (n, %) 
≥6 Months 
5 
(21) 
5 
(19) 
10 
(20) 
10 
(19) 
20 
(19) 
Unknown 
0 
1 
(4) 
1 
(2) 
0 
1 
(<1) 
AML=acute myelogenous leukemia; BM=bone marrow; C1D1=cycle 1 day 1; ECOG=Eastern Cooperative 
Oncology Group; HMA= hypomethylating agent; PB=peripheral blood; WBC=white blood cell. 
Note 1: Only 2 subjects had more than 1 month prior HMA therapy. 
Source: CSR SGI-110-01-B Table 14.2.1 and, for prior HCT, Appendices 16.2.9.1 and 16.2.11 
Overall, 24 of 103 subjects with AML who were either refractory to prior treatment or relapsed 
after achieving a CR from induction therapy responded to treatment with guadecitabine 
(Table 2). The overall CRc rate was 23.3% (95% CI: 15.5-32.7). Of these 24 responders, 


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14 achieved a best response of CR, 6 achieved a best response of CRi, and 4 achieved a best 
response of CRp.  
The CRc and CR rates of the 10-day regimen were approximately double that of the 5-day regimen 
(10-day CRc and CR rates, 30% and 19%, respectively; 5-day CRc and CR rates, 16% and 8%, 
respectively).  
In the 5-day regimen, the CR and CRc rates were generally not different between 60 and 90 mg/m2 
(8.3% and 7.7% for CR, and 12.5% vs 19.2% for CRc for the 60 and 90 mg/m2 dose groups, 
respectively). 
Of the 24 responders, 5 had prior HCT and 8 had poor cytogenetic risk factors at baseline, and all 
responders who had evaluable LINE-1 data achieved at least -20% LINE-1 demethylation.  
Table 2: 
Best Response in Subjects with r/r AML (Efficacy Data Set) 
Response Rate, n (%) [95% Confidence Interval (CI)] 
5-Day 
 
10-Day 
Total 
(N=103) 
Response Categorya 
60 mg/m² 
(N=24) 
90 mg/m² 
(N=26) 
Total 
(N=50) 
 
60 mg/m² 
(N=53) 
Complete response (CR) 
2 (8.3) 
2 (7.7) 
4 (8.0) 
 
10 (18.9) 
14 (13.6) 
CR with incomplete blood count 
recovery (CRi) 
1 (4.2) 
3 (11.5) 
4 (8.0) 
 
2 (3.8) 
6 (5.8) 
CR with incomplete platelet 
recovery (CRp) 
0 
0 
0 
 
4 (7.5) 
4 (3.9) 
Partial response (PR) 
0 
0 
0 
 
0 
0 
Nonresponder (NR) 
21 (87.5) 
18 (69.2) 
39 (78.0) 
 
36 (67.9) 
75 (72.8) 
Not evaluable (NE)b 
0 
3 (11.5) 
3 (6.0) 
 
1 (1.9) 
4 (3.9) 
CRc rate  
(CR+CRi+CRp) 
3 (12.5) 
[2.7 - 32.4] 
5 (19.2) 
[6.6 – 39.4] 
8 (16.0) 
[7.2 – 29.1] 
 
16 (30.2) 
[18.3 – 44.3] 
24 (23.3) 
[15.5 – 32.7] 
AML=acute myelogenous leukemia; CRc=composite complete response. 
a 
Modified IWG 2003 AML Response Criteria (Cheson et al 2003). 
b 
NE subjects are included in the denominator for response rate calculation. 
Source: CSR SGI-110-01-B Table 14.3.1.1  
Survival data were censored for 19 subjects. Of these 19 subjects, 18 were alive (2 still on 
treatment with guadecitabine) at the time of the data cut-off, and 1 withdrew consent. The overall 
median follow-up was 876 days (29.2 months [95% CI: 25, 32 months]). The median overall 
survival in r/r AML subjects was 197 days (6.6 months [95% CI: 164, 246 days]). Overall 1- and 
2-year survival rates were 28% and 19%, respectively. 
Figure 1 depicts survival estimates by dosing regimen (5-day and 10-day). Median follow-up was 
956 days (31.9 months) for the 5-day regimen and 749 days (25.0 months) for the 10-day regimen. 
Median survival was 214 days (7.1 months) for subjects on the 10-day regimen and 172 days 
(5.7 months) for those on the 5-day regimen. 


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Survival was highly associated with response. Median OS could not be estimated for responders 
(subjects with CRc), and was 168 days (5.6 months) for nonresponders. The longer survival for 
CRc subjects was not dependent on whether or not they went into HCT following response.  
Figure 1: 
Product-Limit Survival Estimates in r/r AML Subjects by Regimen 
(5-Day and 10-Day)  
 
OS=overall survival. 
Source: CSR SGI-110-01-B Table 14.3.4.1 and Figure 14.3.4.4 
 
Guadecitabine effects on global DNA methylation were measured by a quantitative bisulfite 
pyrosequencing method for LINE-1 methylation analysis as previously reported (Yang et al 
2004). Ninety-three subjects with r/r AML provided sufficient samples at different time points to 
assess guadecitabine effects on LINE-1 methylation: 22 treated with 60 mg/m2 on the 5-day 
regimen, 21 with 90 mg/m2 on the 5-day regimen, and 50 with 60 mg/m2 on the 10-day regimen. 
Figure 2 shows the kinetics of LINE-1 demethylation for these 3 groups of subjects. There was not 
a major difference in extent and duration of LINE-1 demethylation between subjects treated on the 
5-day regimen at doses of 60 or 90 mg/m2: the maximum mean (±SE) LINE-1 demethylation 
was -20.6% ± 2.8 for 60 mg/m2 and -22.6% ± 2.8 for 90 mg/m2. Both groups of subjects on the 5-
day regimen re-methylated LINE-1 sequences with the same kinetics. Maximum LINE-1 
demethylation was greater with the 10-day regimen (-30.6% ± 1.6) than with the 5-day regimen. 
Further, for the 10-day regimen, this decrease was sustained until Day 15. 


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Figure 2: 
Guadecitabine Average LINE-1 Demethylation by Dose and 
Treatment Schedule 
 
Source: SGI-110-01-B CSR Table 14.5.1.1 
The majority of subjects (n=80) showed a maximum LINE-1 % decrease from baseline ≥10%. 
Overall maximum LINE-1 demethylation was significantly higher (P=0.0002) in responders 
(-34.89% ±1.78, n=22) than in nonresponders (-23.85% ±1.53, n=69).  
Table 3 presents AEs Grade ≥3 by preferred term (PT) with incidence of ≥10% in either the 5-day 
or 10-day regimens regardless of relationship to study treatment. Overall, the most common 
Grade ≥3 AEs were febrile neutropenia (60%); pneumonia and thrombocytopenia (36% each); and 
anemia (31%). AE incidence was generally higher for the 10-day regimen compared with the total 
5-day regimen. Common AEs Grade ≥3 with an absolute difference in incidence ≥10% higher for 
the 10-day regimen compared with the 5-day regimen, respectively, include febrile neutropenia 
(66% vs 54%), pneumonia (45% vs 26%), thrombocytopenia (51% vs 20%), anemia (43% vs 
18%), neutropenia (28% vs 10%), and sepsis (21% vs 10%). 


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Table 3: 
Adverse Events Grade ≥3 by Decreasing Incidence (≥10% of Total) in 
Subjects with r/r AML 
Number (%) of Subjects 
5-Day 
 
10-Day 
 
Adverse Event 
 60 mg/m² 
(N=24) 
90 mg/m² 
(N=26) 
Total 
(N=50) 
 
60 mg/m² 
(N=53) 
Total 
(N=103) 
Any Event 
20 (83) 
25 (96) 
45 (90) 
50 (94) 
95 (92) 
- Febrile neutropenia 
10 (42) 
17 (65) 
27 (54) 
35 (66) 
62 (60) 
- Pneumonia 
4 (17) 
9 (35) 
13 (26) 
24 (45) 
37 (36) 
- Thrombocytopenia 
5 (21) 
5 (19) 
10 (20) 
27 (51) 
37 (36) 
- Anaemia 
5 (21) 
4 (15) 
9 (18) 
23 (43) 
32 (31) 
- Neutropenia 
2 
(8) 
3 (12) 
5 (10) 
15 (28) 
20 (19) 
- Sepsis 
3 (13) 
2 
(8) 
5 (10) 
11 (21) 
16 (16) 
- Hypokalaemia 
5 (21) 
3 (12) 
8 (16) 
6 (11) 
14 (14) 
- Bacteraemia 
3 (13) 
3 (12) 
6 (12) 
6 (11) 
12 (12) 
- Cellulitis 
4 (17) 
0 
 
4 
(8) 
6 (11) 
10 (10) 
- Leukopenia 
3 (13) 
3 (12) 
6 (12) 
4 
(8) 
10 (10) 
Source: SGI-110-01-B CSR Table 14.4.2.5.1 
The 30- and 60-day all-cause mortality rates (Table 4 were similar across treatments. Early all-
cause mortality was reported in 3.9% and 11.7% of subjects for 30-day and 60-day mortality, 
respectively, which is lower than what would be expected from intensive cytotoxic therapy. The 
consistently higher incidence of Grade ≥3 AEs reported with the 10-day regimen (Table 3) did not 
translate into higher early mortality, suggesting that the increase in toxicity was manageable in the 
context of a fatal disease such as r/r AML. 
Table 4: 
30-day and 60-day All-Cause Mortality Rates in Subjects with 
r/r AML 
 
Number (%) of Subjects 
 
5-Day 
 
10-Day 
 
Mortality 
60 mg/m² 
(N=24) 
90 mg/m² 
(N=26) 
Total 
(N=50) 
 
60 mg/m² 
(N=53) 
Total 
(N=103) 
30-day 
2 
(8.3) 
1 (3.8) 
3 
(6.0) 
 
1 
(1.9) 
4 
(3.9) 
60-day 
4 (16.7) 
2 (7.7) 
6 (12.0) 
 
6 
(11.3) 
12 (11.7) 
Source: SGI-110-01-B CSR Table 14.4.3.1 
Based on these results for r/r AML, we conclude that the recommended regimen comprises the 
previously identified BED of 60 mg/m2/day for 5 days (Days 1-5), with initial intensification 
(first 1-2 cycles) with 10-day dosing (Days 1-5 and 8-12). This regimen, including the initial 
intensification, appears to facilitate a higher response rate which is associated with a trend for 
better overall survival, with more rapid response and more subjects bridged to transplant. Despite 
higher Grade ≥3 AEs in the 10-day regimen, no increase in early mortality was noted with that 
regimen.  


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1.5.2 
Phase 3 Trial in Previously Untreated AML (Study SGI-110-04) 
A Phase 3 study of guadecitabine versus treatment choice is ongoing in adults with previously 
untreated AML who are unfit to receive or who are not considered candidates for intensive 
remission induction chemotherapy. The study is a randomized, open-label, multicenter 
(approximately 100-160 centers) global clinical trial of guadecitabine (60 mg/m2 Daily×5) versus 
treatment choice (cytarabine, decitabine, or azacitidine).  
1.6 
Potential Risks and Benefits to Human Subjects 
For a detailed description of risks, refer to the latest version of the Guadecitabine IB. Commonly 
observed AEs (regardless of relationship to treatment) 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 and any AEs related to myelosuppression and infection such as 
pneumonia and sepsis are expected risks of guadecitabine in this Phase 3 trial in r/r AML.  
Potential benefits of guadecitabine include symptom improvement, improvement in blood counts, 
decreased need for transfusions, delayed disease progression, delayed need for subsequent 
anticancer therapy, and prolongation of survival.  
Risk-benefit considerations favor performance of this trial. This study population has limited 
therapeutic options, and available therapies are of limited utility.  
2.0 
RATIONALE 
2.1 
Rationale for the Study 
Rationale for this study comes from guadecitabine's molecular structure, PK, pharmacodynamics 
(PD), and clinical data. 
Guadecitabine's dinucleotide structure protects the active decitabine metabolite 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 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 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 in subjects with r/r AML, 24 of 103 subjects responded 
to treatment with guadecitabine (Table 2), showing that guadecitabine is clinically active in 


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heavily pretreated subjects with AML. The overall CRc rate was 23.3% (95% CI: 15.5-32.7) and 
the median overall survival in r/r AML subjects was 197 days (6.6 months [95% CI: 164, 
246 days]). In comparison, a recent Phase 3 study comparing a new investigational product 
(elacytarabine) to treatment choice in r/r AML had similar overall response rates to those found 
with guadecitabine (CR+CRi of 23% and 21% for elacytarabine and treatment choice groups, 
respectively) but had lower median survival (3.5 months and 3.3 months for elacytarabine and 
treatment choice groups, respectively) (Roboz et al 2014). 
2.2 
Rationale for Guadecitabine Dose and Regimen 
In the Phase 2 SGI-110-01 Dose Expansion in subjects with r/r AML, there was no difference in 
responses or survival between guadecitabine regimens of 60 and 90 mg/m2 daily for 5 days, so 
60 mg/m2/day was the selected dose. That study in r/r AML subjects also included a 10-day cohort, 
in which subjects were treated initially with a 10-day regimen (Days 1-5 and Days 8-12) for up to 
4 cycles followed by the 5-day regimen in subsequent cycles. A trend for better clinical response 
was observed in the 10-day group versus the 5-day group, and time to response was faster for 
subjects in the 10-day group, with more potent demethylation and more subjects bridged to 
transplant without increase in early mortality.  
For the 10-day regimen, the advantages in CRc and time to response must be balanced against the 
toxicity, as evidenced by higher incidence of AEs than in the 5-day regimen. In particular, the 
incidence of related Grade ≥3 AEs and related SAEs was higher in the 10-day group compared 
with the 5-day group. All-cause mortality (30- and 60-day), however, was similar between the 
regimens, so higher toxicity with the 10-day regimen did not translate to higher mortality. Few 
subjects in either regimen discontinued treatment due to AEs. 
Based on these results for r/r AML, we conclude that the recommended regimen comprises the 
previously identified BED of 60 mg/m2/day for 5 days (Days 1-5), with initial intensification 
(first 1-2 cycles) with 10-day dosing (Days 1-5 and 8-12 or Days 1-10). This regimen, including 
the initial intensification, appears to facilitate rapid response in heavily pretreated AML subjects 
with limited additional toxicity and therefore provides the most favorable benefit/risk in this 
patient population. We recommend limiting the number of cycles of the 10-day regimen to 2 to 
limit the additional Grade ≥3 AEs. 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To assess and compare overall survival (OS) between guadecitabine and treatment choice (TC) in 
adults with previously treated AML. 
3.2 
Secondary Objectives 
To assess and compare effects of guadecitabine and TC in adults with previously treated AML 
with respect to the following variables:  


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• Event-free survival (EFS). 
• Long-term survival. 
• Number of days alive and out of the hospital (NDAOH). 
• Transfusion needs. 
• Complete response (CR) and CR with partial hematologic recovery (CRh) rates. 
• Composite CR rate (CRc). CRc = CR + CR with incomplete blood count recovery (CRi) + CR 
with incomplete platelet recovery (CRp).  
• Bridge to hematopoietic cell transplant (HCT). 
• Health-related quality of life (QOL). 
• Safety. 
 
 
 
 
 
 
. 
4.0 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and 
safety of guadecitabine in adults with previously treated AML. This global study will be conducted 
in approximately 20 countries. The study consists of a 14-day screening period, a treatment period, 
a safety follow-up visit, and a long-term follow-up period. The study is expected to last more than 
2 years. The duration of individual subject participation will vary. Subjects may continue to receive 
treatment for as long as they continue to benefit. 
Approximately 404 subjects from approximately 100 study centers will be randomly assigned to 
either guadecitabine or TC in a 1:1 ratio (approximately 202 subjects per group). (Enrollment was 
stopped with approximately 300 subjects randomly assigned to treatment [Amendment 4].)  
Before randomization, the investigator will assign each subject to one of the following TC options 
based on the subject’s prior treatment received, country approval, and local institutional standards: 
• High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and 
cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida). 
• Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine. 
• Best Supportive Care (BSC). 


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Randomization will be stratified by intensity of preselected TC option (high intensity vs low 
intensity vs BSC), ECOG performance status (0-1 vs 2), baseline cytogenetics (poor risk vs other; 
see Appendix 3), and study center region (North America vs ROW). 
The TC comparator arm options and doses are described in greater detail in Section 7.2 and 
treatment duration will be based on approved prescribing information and institutional standard 
practice. Guadecitabine will be given SC at a dose of 60 mg/m2 in 28-day cycles. For the first cycle 
guadecitabine will be given for 10 days on Days 1-5 and Days 8-12 or on Days 1-10. The second 
cycle will be either the 5-day regimen (Days 1-5) or 10-day regimen (Days 1-5 and 8-12 or 
Days 1-10) based on assessment of disease response and hematological recovery at the end of 
Cycle 1. In subsequent cycles guadecitabine treatment will be for 5 days only (Days 1-5). 
Guadecitabine treatment should be given for at least 6 total 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.  
Treatment cycles are intended to be repeated every 28 days. However, treatment delays are 
permitted to allow normal count hematological recovery in the absence of PB blasts, particularly 
with more intensive treatment such as guadecitabine 10-day regimen, HiDAC, MEC, and 
FLAG/Ida. Visits will occur on treatment days, as necessary. In addition, during the first 3 cycles, 
visits will occur weekly on Days 8, 15, and 22, then on Day 15 in Cycles 4-6. In Cycles >6, visits 
will only occur on treatment days (if necessary), with study specified assessments 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. 
Prior to randomization, administration of hydroxyurea to control high counts is allowed for all 
subjects. After randomization, subjects in the TC arm may receive hydroxyurea to control 
proliferative disease as part of study treatment, while subjects in the guadecitabine arm may 
receive hydroxyurea in the first 30 days of treatment. Subjects randomized to guadecitabine who 
have proliferative disease between cycles may receive subsequent cycles earlier than the standard 
28 days. Subjects with disease progression leading to study therapy discontinuation may receive 
any other alternative anti-leukemia therapy; however, subjects in the TC arm are not allowed to 
cross over to guadecitabine.  
Data will be reviewed by an independent Data Monitoring Committee (DMC) at regular intervals 
primarily to evaluate safety during study conduct. Based on data from 278 randomly assigned 
subjects, the DMC recommended to stop further enrollment into the trial based on futility analysis 
that showed the trial is unlikely to show superiority of guadecitabine over TC for OS. 
Consequently, the study was closed to further enrollment in September 2018 (Amendment 4). 
The primary efficacy endpoint is OS, which will be assessed after at least 315 death events have 
occurred. One formal interim analysis is planned. The interim analysis will be conducted by an 


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independent DMC after approximately half of the required death events have occurred. If OS 
reaches statistical significance in favor of guadecitabine, then the study will be considered positive 
for efficacy. 
Efficacy assessment for the determination of clinical responses will be performed during the first 
6 cycles of treatment as well as during long-term follow-up visits. Subjects should be followed for 
survival information until death, withdrawal of consent, or termination of the clinical trial.  
Figure 3: 
Study Schema 
 
 
4.2 
Discussion of Study Design 
This trial compares the efficacy and safety of guadecitabine to TC in subjects with AML previously 
treated with induction therapy (even if that induction was not given as first-line therapy) using a 


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standard intensive chemotherapy regimen or a similar cytarabine+anthracycline based induction, 
who are refractory to induction or who have relapsed.  
Standard intensive induction chemotherapy comprises 7 days of Ara-C and 3 days of an 
anthracycline (daunorubicin or idarubicin), known as the 7+3 regimen, which produces remission 
in 70%-80% of patients for whom the treatment is appropriate (Tefferi and Letendre 2012). Less 
intensive regimens due to patients’ age and/or comorbidities are acceptable as long as they include 
cytarabine and an anthracycline, including the recently approved CPX-351. For patients with 
relapsed or refractory AML, treatment typically includes diverse regimens of high, medium, and 
low intensity. Cytarabine is included in many of these regimens, either as a single agent or in 
combination regimens. HMAs are also used, as discussed in Section 1.2. 
TC, the control therapy for this study, includes the treatments listed in Section 4.1. These therapies 
have not been compared directly, and regional treatment standards vary. Hence, all of these are 
allowed. TC doses and schedules specified in Section 7.2 are based on prior published reviews and 
studies (Döhner et al 2015; Roboz et al 2014). 
Eligibility criteria for this Phase 3 trial are similar to the eligibility criteria in the preceding 
Phase 1-2 study. This Phase 3 study additionally requires subjects to have BM or PB blasts ≥5% 
at randomization.  
The randomization ratio of 1:1 maximizes study power for the number of subjects and there is no 
ethical reason to deviate from the most efficient study design.  
OS, the primary endpoint, is accepted as a gold standard endpoint to demonstrate clinical benefit 
of cancer therapies. Secondary endpoints complement the primary endpoint. Transfusion 
independence, CR and CRh, days out of hospital, HCT, and quality of life are clinically relevant 
measures of treatment benefit in this population. Safety will be assessed by comparing incidences 
of AEs across treatment groups according to the Common Terminology Criteria for Adverse 
Events (CTCAE) and by 30- and 60-day all-cause mortality.  
This study is open-label. The OS primary endpoint is not prone to observer bias. It would be 
difficult to conduct this trial in a blinded fashion due to differences in treatment schedules and 
routes of administration among treatment choices. The risk of observer bias in assessing clinical 
response as a secondary endpoint can be controlled effectively by an independent central reviewer, 
who will be blinded to treatment assignment (Section 6.2); such review may be conducted if 
central response assessment is deemed important for benefit/risk assessment at the end of the study.  
4.3 
Study Endpoints 
4.3.1 
Primary Endpoint 
• OS, defined as the number of days from date of randomization to date of death. 


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4.3.2 
Secondary Endpoints 
• EFS defined as the number of days from randomization to the earliest of disease progression, 
treatment discontinuation, start of alternative anti-leukemia therapy (except for HCT), or death.   
• Survival rate at 1 year after randomization. (Subjects will also be followed long term to 
estimate 2-year survival rate.)  
• NDAOH. 
• Transfusion independence rate, calculated based on the number of subjects without RBC or 
platelet transfusion for any period of 8 weeks after treatment.  
• CR and CRh rates based on modified IWG 2003 AML Response Criteria. 
• CRc (CR+CRi+CRp) rate. 
• HCT rate. (In subjects who undergo HCT, time to stem cell engraftment and 100-day mortality 
rate post HCT will also be assessed.) 
• Duration of combined CR and CRh, defined as the time from first CR or CRh to time of relapse. 
• Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ 
VAS). 
• Incidence and severity of AEs. 
• 30- and 60-day all-cause early mortality. 
4.4 
Data Monitoring Committee  
An independent Data Monitoring Committee (DMC) will be established for this study. The DMC 
is a 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 continue, 
modify or discontinue the trial. The DMC will review data at regular intervals, primarily to 
evaluate safety during study conduct. The DMC will also conduct an independent interim analysis 
of OS as detailed in Section 11.10 and in a separate DMC Charter.  
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 
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 404 subjects will be enrolled in this study at approximately 100 study centers in 
approximately 20 countries. (Enrollment was stopped with approximately 300 subjects randomly 
assigned to treatment [Amendment 4].) 
5.2 
Inclusion Criteria 
To be eligible for the study, subjects must fulfill all of the following inclusion criteria: 
1) Adult subjects ≥18 years of age who are able to understand study procedures, comply with 
them, and provide written informed consent before any study-specific procedure. 
2) History of cytologically or histologically confirmed diagnosis of AML (except acute 
promyelocytic leukemia) according to the 2008 World Health Organization (WHO) 
classification (BM or PB blast counts ≥20%). 
3) Performance status (ECOG) of 0-2. 
4) Subjects with AML previously treated with induction therapy using an intensive chemotherapy 
regimen, defined as a regimen including cytarabine and an anthracycline, and who are 
refractory to induction (primary refractory) or in relapse after such induction with or without 
prior HCT. 
5) Subjects must have either PB or BM blasts ≥5% at time of randomization. 
6) Creatinine clearance or glomerular filtration rate ≥30 mL/min as estimated by the Cockroft-
Gault (C-G) or other medically acceptable formulas, such as MDRD (Modification of Diet in 
Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration). 
7) Women of child-bearing potential (according to recommendations of the Clinical Trial 
Facilitation Group [CTFG]; see below* for details) 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 of birth control and must agree not to become pregnant or father a child 
(a) while receiving treatment with guadecitabine, decitabine, or azacitidine and for at least 
3 months after completing treatment and (b) while receiving treatment with high-intensity TC 
or LDAC and for at least 6 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. 


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* According 
to 
recommendations 
of 
the 
CTFG 
(http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_ 
Contraception.pdf), a woman is considered of childbearing potential (ie, fertile) following menarche 
and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A man is considered 
fertile after puberty unless permanently sterile by bilateral orchidectomy. 
5.3 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1) Known clinically active CNS or extramedullary AML, except leukemia cutis. 
2) Subjects who are in first relapse after initial induction, if they had a response duration of 
>12 months from the date when first response was documented or if they are good candidates 
for HCT. 
3) BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 
4) Second malignancy currently requiring active therapy, except breast or prostate cancer stable 
on or responding to endocrine therapy.  
5) Grade 3 or higher Graft Versus Host Disease (GVHD), or GVHD on either a calcineurin 
inhibitor or prednisone more than 5 mg/day. (Note: Prednisone at any dose for other indications 
is allowed.) 
6) Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior decitabine 
or azacitidine.  
7) Hypersensitivity to decitabine, guadecitabine, or any of their excipients. 
8) Treated with any investigational therapy within 2 weeks of the first dose of study treatment.  
9) Total serum bilirubin >2.5 × upper limit of normal (ULN) (except for subjects with Gilbert's 
Syndrome for whom direct bilirubin is <2.5 × ULN), or liver cirrhosis, or chronic liver disease 
Child-Pugh Class B or C. 
10) 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. 
11) 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. 
12) Refractory congestive heart failure unresponsive to medical treatment; active infection 
resistant to all antibiotics; or non-AML-associated pulmonary disease requiring >2 liters per 
minute (LPM) oxygen or any other condition that puts the subject at an imminent risk of death. 
13) Subjects with high PB blasts >50% AND poor ECOG PS of 2. 


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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. Medical records or 
publicly available information may be used to document date of death as needed. 
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 even after 
discontinuation from study treatment.  
• Investigators can discontinue subjects from study treatment in case of unacceptable toxicity, 
non-compliance, disease progression requiring alternative therapy, or if the investigator 
determines it is in the subject's best interest.  
• 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 case report form or electronic case report form 
(CRF/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. Subjects should be followed for 
survival information until death, withdrawal of consent, or termination of the clinical trial. Safety 
should be followed for 30 days after the last dose of study treatment, or until the subject starts 
alternative anti-leukemia treatment for AML (except for hydroxyurea as specified in 
Section 7.4.1), whichever happens earlier (see Section 10.4). Collection of AEs and concomitant 
medications may also continue until the decision is made to permanently discontinue study 
treatment. Subjects in the BSC group will be considered to be on study treatment until they have 
disease progression. 
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. 
The term withdrawal of consent should not be used simply because the subject no longer wishes 
to receive randomized treatment or actively continue to return for follow-up assessments or simply 
to justify why efforts are not being made to continue to follow some subjects who have 
discontinued their randomized intervention or wish to participate in another study after 
discontinuing study treatment. Rather, the term should be used only when the subject no longer 
wishes to participate in the trial and no longer authorizes the investigators to make efforts to 
continue to obtain their outcome data. Ideally, if subjects withdraw their consent, it should be done 
in writing. Investigators will be educated and evaluated about the proper use of the term 
withdrawal of consent, and the DMC will regularly assess whether the term is being used properly. 


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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 may 
continue to be available for the follow-up period as described in the approved informed consent 
form (ICF). 
5.4.3 
Replacement of Subjects 
Subjects will not be replaced in this study. Astex Pharmaceuticals may stop the study at any time. 
In this event, Astex will make reasonable efforts to ensure subjects are transitioned off the study 
in an orderly manner. 
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 guadecitabine and TC groups, and will be stratified by 
intensity of preselected TC option (high intensity vs low intensity vs BSC), ECOG performance 
status (0-1 vs 2), baseline cytogenetics (poor risk vs other; see Appendix 3), and study center 
region (North America vs ROW). 
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, evaluation for response may 
be performed by a blinded independent central reviewer. The specific process used for handling 
test samples and reports will be described separately. 


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7.0 
STUDY TREATMENTS 
Guadecitabine is the Investigational Medicinal Product (IMP) (Section 7.1), and the active 
comparator consists of the TC options (Section 7.2).  
7.1 
Investigational Medicinal Product: Guadecitabine 
Guadecitabine (2'-deoxy-5-azacytidylyl-(3'→5')-2'-deoxyguanosine sodium salt) is a dinucleotide 
incorporating decitabine with deoxyguanosine via a 3’→5’ phosphodiester bond.  
7.1.1 
IMP Information 
Guadecitabine (formerly known as SGI-110) 
  
SGI-110 for Injection, 100 mg, 
 
 
  
SGI-110 Diluent for Reconstitution
 
 
 
 
 
 
 
 
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. 
Records of the receipt and dispensing of drug supplies will be kept at the study centers and 
reconciled at the end of the study to provide a complete accounting of all used and unused IMP. 
7.1.2 
IMP Regimens and Administration 
Guadecitabine will be given SC at a dose of 60 mg/m2 in 28-day cycles (delayed as necessary to 
allow blood count recovery, see Section 7.3.1). For the first cycle guadecitabine will be given for 


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10 days on Days 1-5 and Days 8-12, or in the case of apparent progression during the first 5 days, 
guadecitabine can be given on Days 1-10 without interruption.  
The second cycle will be 60 mg/m2 for either 10 days (Days 1-5 and 8-12, or in the case of apparent 
progression, can be Days 1-10) or 5 days (Days 1-5 only) based on assessment of disease response, 
and hematological recovery at the end of Cycle 1, using the following general guidelines:  
• Evidence of active leukemia in PB: no need for BM assessment, give second cycle with 10-day 
regimen with no delay.  
• No evidence of active leukemia in PB: perform BM assessment and decide on course of action 
as follows:   
• BM blasts ≥5%: give second cycle with the 10-day regimen with no delay. 
• BM blasts <5%: assess recovery of PB normal counts as follows:  
• Absolute Neutrophil Count (ANC) >500/µL and platelets >50,000/µL: give second 
cycle with no delay using the 5-day regimen.  
• ANC <500/µL or platelets <50,000/µL: Delay treatment and repeat PB at least weekly 
and give second cycle either as a 5-day regimen (if both counts recover to a higher level 
than the limit above with no PB blasts); or 10-day regimen (appearance of evidence of 
active leukemia with PB blasts regardless of normal count recovery). 
For Cycles ≥3, guadecitabine will be given for 5 days only (60 mg/m2/day, Days 1-5). These 
guidelines may be modified if it is believed to be in the best interest of the subject according to the 
treating physician’s best clinical judgment. Treatment should be given for at least 6 total 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. Guadecitabine treatment benefit may not manifest until at least 2 to 3 cycles and full 
response may need 6 or more cycles (Kropf et al 2015). Maintaining treatment after response is 
essential to avoid quick relapse (Cabrero et al 2015). 
Administer guadecitabine by SC injection, preferably in the abdominal area, upper thigh, or arm. 
The total amount (in mg) of guadecitabine 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 8.4). 
Additional guidelines regarding SC injection will be detailed in the Study Procedures Manual. 
Investigators are prohibited from supplying guadecitabine 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 guadecitabine only from personnel who fully understand the 
procedures for administering the study treatment. 


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7.2 
Active Comparator (Treatment Choice) 
The TC options for this study include high intensity, low intensity and BSC. Before randomization, 
the investigator will assign each subject to one of the following TC options:  
High intensity: 
• Intermediate or high dose cytarabine (HiDAC), recommended as 1-1.5 g/m2 every 12 hours or 
up to 6 g/m2/day for ≤6 days, maximum 36 g/m2 per cycle. 
• MEC: For example: mitoxantrone 6-12 mg/m2 IV (recommended 8 mg/m2), etoposide 80-200 
mg/m2 IV (recommended 100 mg/m2), and cytarabine 1000 mg/m2 IV; each daily for 5 days 
(Days 1-5).   
• FLAG/FLAG-Ida: For example: fludarabine 25-30 mg/m2 IV daily Days 1-5; cytarabine 
1-2 g/m2 IV daily for up to 5 days (recommended to be given for 4 hours after fludarabine); G-
CSF SC daily from Day 6 up to white cell count recovery with or without idarubicin 8 mg/m2 
IV daily on Days 3 to 5. 
Low intensity: 
• LDAC 20 mg SC or IV twice daily on Days 1-10.  
• Decitabine 20 mg/m2 IV daily on Days 1-5. 
• Azacitidine 75 mg/m2 IV or SC daily on Days 1-7. 
Best supportive care (BSC) only: given according to standard and institutional practice (refer to 
Section 7.4.1). 
TC administration guidelines and duration will be based on approved prescribing information and 
institutional standard practice. The above doses and schedules are recommended based on prior 
published reviews and studies (Döhner et al 2015; Roboz et al 2014); however, small variations of 
dose, schedule, route, duration of treatment, and dose adjustment guidelines are allowed as long 
as they follow the locally approved prescribing information or institutional standard practice and 
are documented in the CRF/eCRF. 
Examples of variations in the above regimens include dose reductions in older subjects  
(> 60 years) or subjects with prior HCT for the high intensity regimens; administering FLAG with 
no G-CSF; small variations in dose and days of treatment in the cycle; and giving azacitidine as a 
5-2-2 schedule instead of 7 consecutive days. Hydroxyurea may be added to any of the TC options 
to control highly proliferative disease between cycles. 
If a subject must discontinue pre-assigned TC study treatment, alternative therapy, if given, should 
be determined by the physician or institutional standard practice. Subjects randomly assigned to 
TC study treatment will not be allowed to receive guadecitabine as alternative therapy. HCT is 
allowed as subsequent treatment for subjects who discontinue treatment in any arm, if it is 
determined by the investigator that the subject has become eligible for and may benefit from such 


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treatment. After completion of preassigned TC study treatment, including potential cycles of 
consolidation with or without reduced intensity (including using fewer drugs) of the same regimen, 
the addition of any new anti-leukemia therapy for AML treatment that is different from the 
preassigned TC treatment (with the exception of hydroxyurea to control high WBC count) will be 
considered “alternative” therapy, and as such will require a subject to discontinue from study 
treatment. 
7.3 
Guidelines for Adjusting or Withholding Study Treatment 
7.3.1 
Guidelines for Guadecitabine 
Guadecitabine study therapy is intended to be administered for a minimum of 6 total cycles.  
Dosing for the first 2 cycles is described in Section 7.1.2. Timing of cycle initiation and dose level 
of guadecitabine starting at Cycle 3 will be guided by PB blast and neutrophil/platelet counts after 
the prior cycle, as indicated in Table 5, which describes dose modification based on Day 29 or 
later PB counts.  
Table 5: 
Guadecitabine Dosing Adjustment Guideline Based on Peripheral 
Blood Blasts and Counts (for Cycles ≥3) 
Neutrophils 
 
Platelets 
Peripheral 
Blood Blasts 
Present 
No Peripheral Blood Blasts 
On Day 1 of Next 
Intended Cycle 
Recovery After 
≤1-Week Dose Delay 
Recovery After 
>1-Week Dose Delay 
ANC ≥500/μL 
AND 
Platelets ≥50,000/μL 
Full dose 
(5-day 
regimen) on 
schedule 
Full dose (5-day 
regimen) on schedule 
Full dose (5-day 
regimen) after recovery 
Reduce 1 dose level 
after recovery (5-day 
regimen) 
ANC <500/μL 
OR 
Platelets <50,000/μL 
Consider dose delay or reduction 
For subjects with CRh, CRi or CRp for at least 2 cycles, guadecitabine treatment may be reduced 
1 dose level at a time in each subsequent cycle to allow for normal counts recovery to levels of 
full CR (neutrophils ≥1000/μL and platelets ≥100,000/μL). The highest dose level that achieves 
normal counts recovery should be kept for subsequent cycles. Recommended reduced 
guadecitabine 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. 
Subjects with highly proliferative disease between cycles could receive subsequent cycles earlier 
than the intended 28-day cycle interval (such subsequent cycles could begin any time after 
treatment is completed in the preceding cycle). 
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.  


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7.3.2 
Guidelines for Treatment Choice 
For scheduling and dose adjustment of TC therapies, refer to the latest locally approved Prescribing 
Information for each therapy (eg, Cytarabine PI 2015) in the relevant region. Schedule of TC 
administration may be slightly adjusted in accordance with local standard practice (eg, dosing 
delay due to hospital closure on weekends or holidays). Dose adjustments should be made 
according to institutional standards and relevant locally approved Prescribing Information.  
7.4 
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, or 
start of new anti-leukemia treatment for AML (except for hydroxyurea as specified in 
Section 7.4.1), whichever is first. Collection of concomitant medications may also continue until 
the decision is made to permanently discontinue study treatment (in the event that this decision 
occurs more than 30 days after the last dose of study treatment). Prior anti-AML and anti-MDS 
therapy should be documented regardless of timing with randomization. Include supportive or 
palliative treatment whether prescription or nonprescription. Include start and stop dates and 
indication.  
7.4.1 
Supportive, Prophylactic, or Other Treatments 
Supportive care will be allowed in all study arms according to institutional standard practice. 
Hydroxyurea may be added to any of the TC options to control proliferative disease as part of 
study treatment. Hydroxyurea is allowed after randomization in the guadecitabine arm in the first 
30 days of treatment. If it is given to guadecitabine subjects after the first 30 days, it should be 
recorded as a deviation but the subject can still continue on guadecitabine study treatment. 
Intrathecal treatment to control CNS disease is allowed for all subjects as a concomitant treatment. 
Supportive care includes, but is not limited to treatment with hydroxyurea, blood transfusions 
(RBCs or platelets), growth factors including erythropoiesis stimulating agents (ESAs), 
granulocyte stimulating factors (GSFs), iron chelating therapy, and broad spectrum antibiotics 
and/or antifungals. The investigator is permitted to prescribe supportive treatment(s) at his or her 
discretion. Give supportive treatment according to the institutional standard practice or other 
established standard of care guidelines. Investigators are also allowed to give donor lymphocytes 
infusion (DLI) if it is part of their standard practice in certain subjects with r/r AML. Any 
supportive or other concomitant treatment should be documented in the provided CRFs/eCRFs.  
During treatment cycles of guadecitabine 10-day regimen and all high intensity regimens in the 
TC arm, prophylactic broad spectrum antibiotics and prophylactic broad spectrum antifungal 
treatment, with activity against Aspergillus species, such as posaconazole and voriconazole are 
highly recommended.  


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Once the subject is permanently discontinued from their study treatment due to progression, 
unacceptable toxicity, bridged to transplant, or any other reason, all subsequent anti-leukemia 
therapy including HCT or hydroxyurea will be recorded as subsequent anti-AML therapy.  
7.4.2 
Prohibited Medications 
Other anticancer therapies, unless specified in the protocol (eg, endocrine therapy described in 
exclusion criteria), 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. 
7.5 
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 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 
For guadecitabine, refer to the most recent version of the IB for the most current risks and 
precautions for guadecitabine, as well as a complete list of AEs considered expected with 
guadecitabine therapy. For risks and benefits of TC therapies, refer to the latest locally approved 
Prescribing Information for each therapy. 
Since guadecitabine is an investigational drug, unexpected and potentially clinically significant 
AEs or SAEs may occur with its use. All subjects treated with guadecitabine should be closely 
monitored. The active metabolite of guadecitabine is decitabine so all events expected with 
decitabine would also be considered expected for guadecitabine (Dacogen Prescribing 
Information). 
Guadecitabine should not be given to women who are pregnant or to subjects with known 
sensitivity to decitabine. 
8.1 
Dose Limiting Toxicities 
DLTs related to myelosuppression occurred in 2 subjects with MDS in the Phase 1 Dose Escalation 
(SGI-110-01) at a dose of 125 mg/m2 SC Daily×5 and included thrombocytopenia (Grade 4), 
neutropenia (Grade 4), and sepsis (Grade 5). There were no DLTs in subjects with AML. 


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8.2 
Myelosuppression (Neutropenia, Febrile Neutropenia, Thrombocytopenia, and 
Anemia) 
Myelosuppression is the primary toxicity associated with administration of guadecitabine and its 
effects after 5 consecutive days of administration are maximal between Days 15 and 22 in a cycle 
with recovery in 1 to 3 weeks. With the 10-day regimen (dosing on Days 1-5 and 8-12 or on 
Days 1-10) the nadir is lower and lasts longer than with the 5-day regimen. Pancytopenia is a 
hallmark of AML and MDS and may aggravate or obscure the effects of guadecitabine. However, 
if a clinical response occurs and normal hematopoietic cells repopulate the bone marrow, 
neutropenia and thrombocytopenia may abate. 
Complete blood and platelet counts should be performed as needed to monitor counts. Since 
myelosuppression and infection events are also manifestations of the underlying disease of AML, 
careful investigator judgment regarding relationship to treatment is important to guide the decision 
whether to dose delay, dose reduce, or both. The cyclic nature of myelosuppression 
(reduction of counts between Day 8-15 and trend to recover by Day 22-28 or later) could be more 
indicative of a drug effect, while persistent low counts regardless of treatment is probably more 
indicative of a disease effect that needs to be treated without dose delay. Investigators should use 
their clinical judgment guided by the recommendations for dose adjustment for guadecitabine 
described above (see Section 7.3.1), and should use the guidelines of dose adjustment for TC 
options as per their local prescribing information and standard practice. 
8.3 
Fertility 
Use of decitabine, the active metabolite of guadecitabine, alters fertility and is mutagenic. Because 
of the possibility of infertility, men should seek advice on cryopreservation of sperm, and women 
of childbearing potential should seek consultation regarding oocyte cryopreservation before study 
treatment is started. 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 of birth control and must agree not to become pregnant or father a child while receiving 
treatment with guadecitabine for at least 3 months after completing treatment. Investigators should 
advise study subjects to seek advice on sperm and oocyte cryopreservation related to TC options 
as per their local prescribing information and standard practice.  
8.4 
Injection Site Reactions 
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 guadecitabine SC administration and are mostly Grade 1 or 2. 
Care must be taken to avoid intradermal injection. If injection site pain is reported, it could be 
avoided or diminished by slow SC injection and the application of ice packs to the injection site 
both before and after injection. If injection site pain is still clinically significant at subsequent 


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injections despite slow injection and use of ice packs, pretreatment with topical or systemic 
analgesics can be considered. In case of injection site pain when injection volume is greater than 
1 mL, consider splitting the dose into 2 injections. 
8.5 
Adverse Events 
Most AEs observed in the Phase 1-2 clinical trial are common in the AML/MDS population. 
Common AEs, regardless of relationship to guadecitabine, observed in the AML/MDS populations 
(r/r AML, treatment-naïve [TN] AML, TN MDS, r/r MDS, N=308 [Phase 2 Dose Expansion]) 
treated with guadecitabine (60-90 mg/m2 Daily×5 or 60 mg/m2 10-day regimen in AML only) 
include injection site AEs, febrile neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, 
anemia, and constipation. The most common SAEs were febrile neutropenia, pneumonia, and 
sepsis.  
MDS and AML subjects commonly have severely compromised bone marrow and blood counts. 
Severe or prolonged myelosuppression has been reported as related to guadecitabine, particularly 
at high doses when the drug may exert cytotoxic effects.  
Refer to Section 7.3.1 for guidelines to adjust study treatment dose. 
9.0 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Efficacy Assessments 
Efficacy will be assessed by evaluation of survival (OS, EFS, and survival rates at 1 and 2 years), 
transfusion needs for RBC and platelets (independence and number of transfusions), response (CR, 
CRh, CRc, CRi, CRp, and partial response [PR]), HCT rate, NDAOH, and health-related QOL.  
Survival: Survival will be monitored and documented throughout the study. Survival status will 
be monitored and recorded as long as possible during the long-term follow-up period. 
Transfusions/Hospitalizations: All blood and platelet transfusions will be documented and used 
to determine transfusion independence and to calculate the number of 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. Transfusion requirements will be recorded 
every month in the first 6 months then at every study visit until disease progression. All hospital 
admissions will be documented and used to determine NDAOH every month in the first 6 months 
then at every study visit until disease progression. For subjects who discontinue study treatment 
before Cycle 6, transfusions/hospitalizations will be assessed monthly until 6 months after the start 
of study treatment, then at every study visit until disease progression. 
Response Assessments: Clinical response is based on both PB sampling and BM aspirate or 
biopsy assessments. If BM aspirate is not available and only BM biopsy slides are provided, slides 
should include touch prep slides. In cycles where a BM sample is not collected, the most recent 
previous BM sample will be used for response assessment.    


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PB will be assessed at baseline and at specified time points in each cycle (see Table 7). BM aspirate 
or biopsy will be performed at screening and then at the end of Cycles 1, 3, and 6, unless PB shows 
persistence of ≥5% leukemic blasts that excludes the possibility of a marrow response. After Cycle 
6, BM assessment, BM aspirate or biopsy (with touch prep slides) 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 may be done centrally by the independent blinded central reviewer based on 
BM assessment and PB counts, using the modified 2003 IWG AML response criteria (Cheson et 
al 2003; Table 6).  
Table 6: 
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 
CRh 
Same as CR but with ANC >500/μL and Platelets 
>50,000/μL 
<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 blasts 
<5% leukemic blasts 
Partial 
response 
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 
because 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; CRh=complete response with partial hematologic 
recovery; CRp=complete response with incomplete platelet recovery; CRi=CR with incomplete blood count 
recovery. 
Source: Cheson et al 2003 with modification to define CRh 
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. 
• CR; CRp and CRi, including the subset of subjects with CRh; partial response. 
• Composite CR (CRc=CR+CRp+CRi). 
Subjects who did not have a sufficient post-treatment efficacy assessment (eg, no BM or PB 
assessment) will be classified as nonevaluable for response presentations. These subjects will be 
included in the denominator of the intent-to-treat (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. 


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HCT Rate: In subjects who undergo HCT, time to stem cell engraftment and 100-day mortality 
rate post HCT will be assessed. Time to engraftment will be calculated from the day of transplant 
to the first day of 3 consecutive days of PB ANC of >500/µL. 
Quality of Life: Health-related QOL will be assessed using the EQ-5D™, which is a standardized 
instrument for use as a measure of health outcome. QOL assessments will consist of the EQ-5D 
level health questionnaire (EQ-5D-5L) and the EQ VAS which will be administered before 
treatment on Day 1 of each cycle for 6 cycles and then at every study visit until disease progression; 
for subjects who discontinue study treatment before Cycle 6, QOL will be assessed monthly until 
6 months after the start of study treatment, then at every study visit until disease progression. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
9.4 
Safety Assessments 
Documented safety assessments will include AEs, concomitant medications, physical examination 
findings, vital signs, electrocardiogram (ECG) measurements, ECOG performance status, and 
clinical laboratory parameters (hematology and chemistry), according to the schedule of events. 


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9.5 
Study Procedures 
9.5.1 
Schedule of Events 
Table 7 presents the complete schedule of events, 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 
IRB/IEC according to policy. 
 






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d  
Study treatment: For details on all treatment regimens, see Section 7.0. TC duration will be based on approved prescribing information and institutional 
standard practice. For the TC arm, small variations of dose, schedule, route, duration of treatment, and dose adjustment guidelines are allowed as long as 
they follow the locally approved prescribing information or institutional standard practice and are documented in the eCRF. BSC subjects are to follow the 
same 28-day cycle schedule as other subjects, despite not receiving cyclical treatment. Treatment delays are permitted to allow normal hematological count 
recovery in the absence of PB blasts at the investigator’s discretion. Delays due to logistical reasons should be limited to 7 days. 
e  
Guadecitabine treatment: Cycle 1 will be on Days 1-5 and 8-12 or Days 1-10 (10-day regimen). Cycle 2 will be either the 10-day regimen or the 5-day 
(Days 1-5) regimen, based on assessment of disease response and hematological recovery by Day ≥28, as specified in Section 7.1.2. Cycle 3 will be the 
5-day regimen (Days 1-5).  
f  
Screening (and Randomization): Screening must occur within 14 days before randomization, except that BM aspirate/biopsy may be collected within 
28 days before Cycle 1 Day 1. Cytogenetics should be prior to randomization and may be more than 14 days prior to randomization (see Appendix 3 for 
cytogenetics-based risk classification). Randomization should occur as close as possible to Cycle 1 Day 1 and may occur on Cycle 1 Day 1. The time 
between randomization and first treatment should not be more than 1 week. 
g  
Physical examination: Includes weight and examination of body systems according to institutional standards. A complete physical examination is required. 
Cycle 1 Day 1 physical examination does not need to be repeated if it was done at screening within 4 days of Cycle 1 Day 1. 
h  
Vital signs: Assess before dosing on every dosing day in the clinic (based on the subject’s assigned treatment regimen), after subject has rested in the sitting 
position for at least 3 minutes. Subjects in BSC arm: After screening, assess vital signs on Day 1 of every cycle, and at the safety follow-up visit. 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 
signs assessment is not required. 
i  
12-Lead ECG (triplicate): Conduct predose and 1-2 hours postdose only on Day 1 of Cycle 1, and at safety follow-up visit. Subjects in BSC arm: Conduct 
ECG (in triplicate) on Cycle 1 Day 1, and at the safety follow-up visit. Acquire and review 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.  
j  
Health-related QOL: Administer EQ-5D-5L and EQ VAS before treatment on Day 1 of each cycle for 6 cycles, then at every study visit until disease 
progression. For subjects who discontinue treatment before Cycle 6, administer EQ-5D-5L and EQ VAS monthly until 6 months after the start of study 
treatment, then at every study visit until disease progression.  
k  
Weight and BSA calculation: Weigh subjects on Day 1 of each cycle. BSA recalculation is only required if weight changes ±10% or more from the last 
calculation. 
l  
Concomitant medications: Document all medications taken within 14 days before randomization to 30 days after the last dose of study treatment, or start of 
new anti-leukemic treatment for AML (except for hydroxyurea as specified in Section 7.4.1), whichever is first. 
m  
Hematology: Include complete blood count with WBC differential (a manual count should be conducted if there is suspicion of PB blasts). Day 1 
hematology for all cycles does not need to be repeated if done within 4 days of 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 Laboratory Manual.  
n  
Serum chemistry: Refer to Table 8. 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 Laboratory Manual. 
o  
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. 




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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 forward the appropriate documentation to the 
attention of the sponsor according to the Study Procedures Manual.  
Bone marrow aspirate/biopsy samples may be collected within 28 days before Cycle 1 Day 1. 
Within 14 days before randomization, 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. Document concurrent medical signs and symptoms to establish baseline 
conditions. 
• Record prior anti-leukemic therapies, including start and stop dates, best response and duration 
of response. 
• Record all medications taken within 14 days before randomization. 
• Complete physical exam including height and 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.  
• Serum or urine pregnancy test: for women of child-bearing potential only. Results must be 
negative for the subject to be eligible for enrollment into the study. 
• ECOG performance status (Appendix 1).  
• Height measurement (for BSA calculation). 
• All study-procedure-related AEs from the time of informed consent. 
• Blood and urine sample collection for clinical laboratory tests (Table 8). 
• 
. 
• Adequate BM aspirate slide or biopsy to include touch prep slide, collected within 28 days 
before starting study treatment. 
• Cytogenetic assessments performed at any time before randomization. 
• Document all blood and platelet transfusions (blood product transfused and units) performed 
within 56 days before randomization. 
• Investigator's confirmation of eligibility. Perform all necessary procedures and evaluations to 
document that the subject meets each eligibility criterion. 


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• Study treatment randomization, after eligibility is confirmed. Randomize as close as possible 
to the first dose of study treatment (on Cycle 1 Day 1). Treatment should start as soon as 
possible after randomization, and in all cases within 1 week. 
Table 8: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Serology 
Complete blood count (CBC) 
 - Hemoglobin 
 - Hematocrit 
 - RBC counts 
 - WBC counts 
 - Platelets 
WBC differential (a manual 
count should be conducted if 
there is suspicion of PB 
blasts) 
 - Blasts 
 - Promyelocytes 
 - Myelocytes 
 - Metamyelocytes 
 - Monoblasts 
 - Promonocytes 
 - Neutrophils 
 - Band neutrophils 
 - Segmented neutrophils 
 - Eosinophils 
 - Basophils 
 - Lymphocytes 
 -Monocytes 
- Albumin 
- Alkaline phosphatase 
- ALT 
- AST 
- 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 Procedures for Cycles 1-3 
The following text represents assessments and procedures for Cycles 1, 2, and 3, unless otherwise 
specified (eg, PK and ECG assessments are done only in Cycle 1). Refer to Table 7. 
After randomization, visits will occur on every treatment day, as necessary. In addition, visits will 
occur on Days 8, 15 and 22 of the first 3 cycles of therapy. Additional visits, based on treatment 
effect and blood counts may be done at the investigator’s discretion. 
9.5.3.1 
Day 1 (Before Dosing), Cycles 1-3 
• Complete physical examination (does not need to be repeated if was done ≤4 days before Cycle 
1 Day 1). 
• Vital signs. 
• ECOG performance status (Appendix 1). 
• 12-lead ECG (triplicate) (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and 
QT/QTc, morphology and overall interpretation), Cycle 1 only. 


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• Health-related QOL (Appendix 2). 
• Weight and BSA calculation (use height from screening; BSA recalculation is only required if 
weight changes ±10% or more from last calculation). 
• Cycle 1: All study-procedure-related AEs and concomitant medications.   
• Cycles 2-3: All AEs and concomitant medications. 
• Sample collection for laboratory assessments, including: 
• Hematology (see Table 8) (does not need to be repeated if done ≤4 days before Day 1). 
• Serum chemistry (see Table 8) (does not need to be repeated if done ≤4 days before Day 1). 
• Serum or urine pregnancy test for women of child-bearing potential only (for Cycle 1 Day 
1 does not need to be repeated if done at screening within 7 days of C1D1). 
• BM aspirate/biopsy required at the end of Cycle 1 (ie, Day 1 of Cycle 2) unless PB shows 
persistence of ≥5% leukemic blasts that excludes the possibility of a marrow response.  
• 
 
• 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 Day 1 of previous 
cycle. 
9.5.3.2 
Day 1 (After Dosing), Cycles 1-3 
• 12-lead ECG (triplicate), in Cycle 1 only, 1 to 2 hours postdose. ["Postdose" ECG not required 
for subjects randomized to the BSC arm.] 
• 
 
 
 
 
 
• Cycle 1: All treatment-emergent AEs and concomitant medications. 
9.5.3.3 
Other Dosing Days, Cycles 1-3 
• Vital signs (before dosing). 
• All AEs and concomitant medications. 
• 
 
 
 
 
9.5.3.4 
Days 8, 15 and 22, Cycles 1-3 
The following procedures will be performed on Days 8 (±2), 15 (±3), and 22 (±3) of Cycles 1-3. 
• Vital signs (to be performed before dosing on Day 8, if applicable).  


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• All AEs and concomitant medications. 
• Hematology (see Table 8). 
9.5.4 
Treatment Procedures for Cycles ≥4 
Table 7 shows assessments and procedures for Cycles ≥4. For Cycles 4-6, visits will occur on 
every treatment day (as necessary) and on Days 1 and 15. In Cycles >6, only treatment day visits 
are required (if necessary), with study-specified assessments required 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 and long-term follow-up 
thereafter. 
9.5.4.1 
Day 1 (Before Dosing), Cycles ≥4 
• Complete physical examination. 
• Vital signs. 
• ECOG performance status (Appendix 1). 
• Health-related QOL (Appendix 2). 
• Weight and BSA calculation (use height from screening; BSA recalculation is only required if 
weight changes ±10% or more from last calculation). 
• All AEs and concomitant medications. 
• Sample collection for laboratory assessments, including: 
• Hematology (see Table 8). 
• Serum chemistry (see Table 8).  
• Serum or urine pregnancy test for women of child-bearing potential only.  
• BM aspirate/biopsy required at the end of Cycles 3 and 6 (ie, on or before Day 1 of Cycles 4 
and 7) unless PB shows persistence of ≥5% leukemic blasts that excludes the possibility of a 
marrow response. Subjects who discontinue treatment before Cycle 6 Day 1 and before 
documented progression must undergo response assessment until disease progression or 
relapse is confirmed. After Cycle 6, repeat BM aspirate/biopsy every 3 months for the first 
year on study, then every 6 months thereafter until PB or BM assessment shows disease 
progression or relapse. 
• 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 Day 1 of the previous 
cycle. 


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9.5.4.2 
Day 1 (After Dosing), Cycles ≥4 
• 
 
 
 
 
9.5.4.3 
Other Dosing Days in Clinic, Cycles ≥4 
• Vital signs (before dosing). 
• All AEs and concomitant medications. 
9.5.4.4 
Day 15, Cycles 4 to 6 
Day 15 for Cycles 4 to 6 has a visit window of ±3 days. 
• All AEs and concomitant medications. 
• Hematology (see Table 8). 
9.5.5 
Safety Follow-up Visit 
Subjects will attend a safety follow-up visit after study treatment has been permanently 
discontinued. The safety follow-up visit must occur 30 (+7) calendar days after the last dose of 
study treatment or before the subject starts another anti-leukemia therapy for AML (except for 
hydroxyurea as specified in Section 7.4.1), whichever occurs first.  
Each subject should be followed, 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 10.3).  
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 (Appendix 1). 
• 12-lead ECG (triplicate). 
• Health-related QOL (Appendix 2). 
• All AEs and concomitant medications. 
• Sample collection for clinical laboratory tests, including: 
• Hematology (see Table 8) 
• Serum chemistry (see Table 8) 


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• 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 they were last 
recorded. 
• Subsequent anti-leukemic therapy (regimen and start date); for HCT, include time to stem cell 
engraftment. 
• Disease progression status: Subjects who discontinue study treatment before documented 
disease progression must undergo response assessments (PB or BM aspirate/biopsy) until 
disease progression or relapse is confirmed.  
If the subject is not able to attend the clinic for the safety follow-up visit, the visit may be conducted 
by telephone to collect at minimum AE information, hospitalization information, transfusion 
information, subsequent anti-leukemic therapy, QOL responses, and survival status. If a decision 
is made to permanently discontinue study treatment ≥30 (+7) days after the last dose, then the 30-
day safety follow-up visit should be performed as soon as possible on the day the discontinuation 
decision is made or as soon as possible thereafter.  
9.5.6 
Long-Term Follow-up 
Long-term follow-up starts after subjects discontinue study treatment. Long-term follow-up visits 
will occur monthly (±7 days) 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 after the start 
of study treatment, long-term follow-up visits will be every 3 months (±2 weeks) until death. The 
first long-term follow-up visit should occur 1 month or 3 months (whichever applies) after the 
safety follow-up visit or after the last dose of study treatment, whichever applies. Long-term 
follow-up visits may be conducted by telephone if needed. 
At the monthly long-term follow-up visits, the following assessments are required unless they are 
refused by the subject. However, at a minimum, information on survival status must be collected.  
• Health-related QOL (Appendix 2). 
• Hematology and/or BM aspirate/biopsy: Subjects who discontinue study treatment before 
documented disease progression must undergo response assessments (PB or BM 
aspirate/biopsy) until disease progression or relapse is confirmed. 
• 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-leukemic therapy (regimen and start date); for HCT, include time to stem cell 
engraftment. 
• Survival follow-up (must be collected). 


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At the quarterly long-term follow-up visits, the following assessments are required unless they 
are refused by the subject. However, at a minimum, information on survival status must be 
collected. 
• Health-related QOL (Appendix 2) until disease progression. 
• Hematology and/or BM aspirate/biopsy: Subjects who discontinue study treatment before 
documented disease progression must undergo response assessments (PB or BM 
aspirate/biopsy) until disease progression or relapse is confirmed. 
• 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 until 
disease progression. 
• Subsequent anti-leukemic therapy (regimen and start date); for HCT, include time to stem cell 
engraftment. 
• Survival follow-up (must be collected).  
9.6 
Unscheduled Visits 
Additional visits (not specified in Table 7) 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. For guadecitabine dosing, if a dose is missed 
on one or more days, it should be administered as soon as possible to complete the full 5-day 
course (see Section 7.3.1). For TC dosing, if a dose is missed, it should be made up in a manner 
consistent with institutional standards (see Section 7.3.2). 
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 serious adverse event (SAE). If there are 
specific AEs that are always part of disease progression, these do not need to be reported as AEs 


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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 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 or until the subject starts new anti-AML treatment, including new investigational 
treatment, whichever occurs first. Collection of AEs may also continue until the decision is made 
to permanently discontinue study treatment. Related SAEs should be collected until the end of the 
study or the subject’s death. Record screening procedure-related AEs that occur before the start of 
study treatment. 


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Record all AEs 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 CTCAE version 4.03 for grading the severity (intensity) of AEs. 
The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for 
each referenced AE and provides guidance not listed. 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. 
• 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.  


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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. 
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 fax 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 guadecitabine who become pregnant must 


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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. 
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. 


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10.4 
Follow-up for Adverse Events 
Follow all AEs and SAEs that are encountered during the protocol-specified AE reporting period 
until (1) they are resolved, or (2)  the investigator assesses the subject as stable and the event 
follows a clinically expected outcome, or (3) the subject is lost to follow-up, discontinues long-
term follow up (except for survival), 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 
In order to provide power of at least 90% to detect a difference in hazard ratio of approximately 
0.692 (median OS of 4.5 months for the TC arm versus 6.5 months for the guadecitabine arm) 
using a stratified 2-sided log-rank test at an overall 0.05 alpha level given the 1:1 randomization, 
the trial will require 315 death events. Assuming that the enrolment will be non-uniform over an 
18 month period (with additional follow up of 8 months) during which 3 to 29 subjects per month 
(3, 6, 9, 12, 15, 18, 21, 24, 27, and 29) are expected to be enrolled in the first 10 months in 
increasing order followed by 30 subjects per month in months 11-18, with the proportion of 
subjects dropping out each month equal to 0.012, then approximately 404 subjects need to be 
randomized. If, after a follow up of 12 months from the last subject randomized, the 315 death 
events have not occurred, the primary analysis will be conducted at 12 months from last subject 
randomized (if 277 or more death events have occurred), or after at least 277 death events have 
been observed (corresponding to 86% power). Based on DMC recommendation to stop further 
enrollment, the time of primary analyses is shifted to occur after approximately 12 months 
follow-up from the last subject randomly assigned to treatment or after the last subject is off study. 
11.2 
Analysis Sets 
11.2.1 
All-Subjects Analysis Set 
The All-Subjects Analysis Set will contain information from all screened subjects, including those 
who did not meet the study entry criteria or did not receive a study treatment. 


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11.2.2 
Efficacy Analysis Set 
Efficacy analyses will be based on the 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, the primary analysis sets will include only the 
data collected during the first 6 months of the study because, during this study period, subjects are 
assessed monthly whether or not they are still on study treatment. Secondary analysis sets may 
also include additional data (eg, data collected over the entire study). 
11.2.3 
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. 
 
 
 
 
 
  
 
 
 
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 was planned to be conducted by the DMC when 
approximately half of the required 315 death events have occurred. However, at the DMC meeting 
on 12 September 2018, after approximately one-third of the required 315 death events had 
occurred, the DMC recommended to discontinue enrollment based on futility, so no further interim 
analysis will be conducted. 
To achieve a mature analysis of OS and also keep the study duration within a reasonable period, 
the primary analysis was to be conducted either after 315 death events (corresponding to a 90% 
power) have occurred within 12 months from the date of the last subject randomization, or at 


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12 months from last subject randomized (if 277 or more death events occurred by then), or after at 
least 277 death events (corresponding to an 86% power) have been observed. Refer to 
Section 11.1; the time of primary analyses is shifted to occur after approximately 12 months 
follow-up from the last subject randomly assigned to treatment or after the last subject is off study. 
11.4 
Disposition 
Subject disposition including numbers screened, randomized, treated, treatment discontinuation 
by reason, and withdrawal from study by reason will be summarized for each treatment group 
(guadecitabine and TC) and both treatment groups combined. Sample sizes for Efficacy and Safety 
Analysis Sets will be clearly identified. The All-Subjects Analysis Set will be used for 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 Analysis Sets will be used for the summaries. The 
summaries will be done for each treatment group (guadecitabine and TC) and both treatment 
groups combined. 
11.6 
Efficacy Analyses 
Efficacy analyses will be presented by treatment group (guadecitabine vs TC) 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 315 deaths 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 for analysis of each endpoint in the 
hierarchical testing, accounting for the alpha spent in the interim analysis. The stratification factors 
used in the analyses will be the randomization stratification factors unless it is necessary to collapse 
some strata due to analysis difficulties caused by too many strata. The rule for collapsing strata 
will be specified in the statistical analysis plan. 
If the primary endpoint reaches statistical significance in favor of guadecitabine, the study will be 
considered positive in efficacy. 
11.6.1 
Primary Efficacy Analysis 
OS is the primary endpoint and is defined as the number of days from the day the subject was 
randomized to the date of death (regardless of cause). Subjects without a documented death date 
will be censored on the last date known to be alive. 


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OS will be displayed using a Kaplan-Meier estimate and will be compared between the 2 treatment 
groups using a log-rank test stratified by the randomization stratification factors with an overall 
2-sided alpha level of 0.05. In order to control the overall type I error rate at 0.05 
(2-sided), the nominal alpha to be used in the final analysis will be calculated accounting for the 
alpha already spent at the interim analysis.  
In addition, the hazard ratio and the 95% CI will be estimated using a Cox proportional-hazard 
model with treatment as the independent variable and stratified by the same randomization 
stratification factors as used for the log-rank test. 
11.6.2 
Secondary Efficacy Analyses 
Response will be assessed in each cycle using both PB and BM. In cycles where BM is not 
available, the most recent prior BM will be used.  
Secondary efficacy endpoints are the following and will be defined in more detail in the statistical 
analysis plan: 
• EFS defined as the number of days from randomization to the earliest date of disease 
progression, treatment discontinuation, start of alternative anti-leukemia therapy (except for 
HCT), or death.  
• Survival rate at 1 year after randomization (subjects will also be followed long term to estimate 
2-year survival rate).  
• NDAOH. 
• Transfusion independence rate. 
• CR and CRh rates based on modified IWG 2003 AML Response Criteria, as described in 
Section 9.1. 
• CRc (CR+CRi+CRp) rate, as described in Section 9.1. 
• HCT rate (in subjects who undergo HCT, time to stem cell engraftment and 100-day mortality 
rate post HCT will also be assessed). 
• Duration of combined CR and CRh, defined as the time from first CR or CRh to time of relapse. 
• Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ 
VAS). 
If statistical significance is achieved for OS, hierarchically EFS, 1-year survival rate, NDAOH, 
transfusion independence rate, combined CR+CRh rate, CRc rate, and HCT rate will be compared 
between the two treatment groups as addressed in Section 11.6.2. The alpha level for the secondary 
endpoints involved in statistical testing depends on results of previous hierarchical testing and on 
whether early termination of the study occurs after the interim analysis.  


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11.6.2.1 
Event-free Survival (EFS) 
EFS is defined as the number of days from randomization to the earliest of disease progression, 
treatment discontinuation, start of alternative anti-leukemia therapy (except for HCT), or death. 
Disease progression is defined as earliest occurrence of one of the following: 
• For subjects with CR, CRh, CRi, or CRp, the confirmed (at least 2 PB samples at least 1 week 
apart) appearance of ≥5% leukemic blasts in PB, OR ≥5% leukemic blasts in the BM. 
• For all other subjects, when PB or BM shows evidence of continued increase in blasts % that 
necessitates alternative therapy. 
EFS will be displayed using a Kaplan-Meier estimate and will be compared between the two 
treatment groups using a log-rank test stratified by the randomization stratification factors. EFS 
time will be censored on the last date the subject is known to be alive without an EFS event. 
11.6.2.2 
Survival rate at 1 Year 
One-year survival rate is defined as the survival rate at the end of the first year from randomization. 
One-year survival rate for each treatment group will be estimated by the Kaplan-Meier procedure. 
Hypothesis testing will be based on the stratified Kaplan-Meier estimates and standard errors 
estimated by Greenwood formula. Subjects who do not have death in record will be censored on 
the last date known to be alive. The stratification factors will be the same as those used in the OS 
analysis. The survival rate at 2 years will also be determined. 
11.6.2.3 
Number of Days Alive and Out of the Hospital 
The date of each hospital admission and discharge will be collected for each subject. The number 
of days when subjects are still alive and out of hospital during the first 6 months of the study will 
be summarized by treatment group and compared between the 2 treatment groups using an analysis 
of variance model, which includes treatment group and all randomization stratification factors in 
the model.  
11.6.2.4 
Transfusion Independence Rate 
Transfusion independence rate is calculated as number of subjects without RBC or platelet 
transfusion for any period of 8 weeks after treatment divided by the total number of subjects 
included in the efficacy analysis. The transfusion independence rate will be compared between the 
2 treatment groups using a Cochran Mantel-Haenszel test stratified by the randomization 
stratification factors. In addition, the Mantel-Haenszel weighted difference in transfusion 
independence rate between the 2 treatment groups and the associated CI will be provided. 


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11.6.2.5 
Complete Response and Complete Response with Partial Hematologic Recovery 
Rates 
The CR and CRh rates will be calculated individually and combined as the number of subjects 
with a best response of CR or CRh divided by the total number of subjects included in the efficacy 
analysis. The CR, CRh, and combined CR+CRh rates will be compared between the 2 treatment 
groups using a Cochran Mantel-Haenszel test stratified by the randomization stratification factors. 
In addition, the Mantel-Haenszel weighted difference in CR, CRh, and combined CR+CRh rates 
between the 2 treatment groups and the associated CI will be provided.  
11.6.2.6 
Composite CR Rate 
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 stratified by the 
stratification variables. In addition, the Mantel-Haenszel weighted difference in CRc rate between 
the 2 treatment groups and the associated CI will be provided. 
11.6.2.7 
Hematopoietic Cell Transplant Rate 
The HCT rate will be calculated as the number of subjects who received an HCT after 
randomization divided by the total number of subjects included in the efficacy analysis. The HCT 
rate will be compared between the 2 treatment groups using a Cochran Mantel-Haenszel test 
stratified by the randomization stratification factors. In addition, the Mantel-Haenszel weighted 
difference in HCT rate between the 2 treatment groups and the associated CI will be provided. 
Time-to-stem-cell engraftment is calculated, for subjects who received an HCT after 
randomization, from the day of transplant to the first day of 3 consecutive days of PB ANC of 
>500/µL. Time-to-stem-cell engraftment will be summarized by treatment group.  
One hundred-day post-HCT mortality rate (regardless of cause) will be calculated for subjects who 
received an HCT after randomization, and summarized by treatment group. 
11.6.2.8 
Duration of Combined CR and CRh 
Duration of combined CR and CRh (in number of days) will be calculated from the first time a CR 
or CRh is observed to time of relapse (defined as the earliest time point whereby BM assessment 
or PB assessment indicate relapse/disease progression due to confirmed reappearance of ≥5% 
leukemic blasts in PB or ≥5% leukemic blasts in BM). The duration of combined CR and CRh will 
be censored at the last available time point at which a relapse/disease progression was not 
observed. Duration of combined CR and CRh will be estimated using the Kaplan-Meier method 
for subjects who achieved a CR or CRh during the study. To take the proportion of responders into 
consideration when analyzing duration of combined CR and CRh, a separate analysis including all 
subjects will be conducted with a 0 day event duration assigned to subjects who did not achieve a 
CR or CRh. 


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11.6.2.9 
EQ-5D-5L 
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). The EQ-5D-5L index value 
and VAS and their respective changes from baseline will be summarized by visit. Only the data 
collected in the first 6 months of the study will be included in this analysis. In addition, the changes 
from baseline of EQ-5D-5L index value, and separately EQ VAS, will be analyzed using a mixed 
model approach for repeated measures.  
11.6.2.10 Sequence of Statistical Tests for Efficacy Endpoints 
The primary endpoint OS will be tested first. If the test for OS is positive, hypothesis testing will 
proceed for the secondary endpoints in the following order: 
• EFS. 
• Survival rate at 1 year after randomization.  
• NDAOH during the first 6 months. 
• Transfusion independence rate. 
• Combined CR+CRh rate. 
• CRc (CR+CRi+CRp) rate. 
• HCT rate. 
A positive test result of the earlier endpoint serves as a gatekeeper (Westfall and Krishen 2001) 
for analysis of the next endpoint. Other secondary efficacy endpoints (duration of CR and Health 
Related QOL) will be used as supportive evidence of the beneficial treatment effect. Differences 
of treatment effect for these endpoints and associated 95% CIs, if applicable, will be constructed. 
11.6.3 
Subgroup and Exploratory Analyses 
Subgroup analyses will be performed to explore how OS is influenced by baseline variables and 
the individual TC therapy administered, and to evaluate the treatment effect at different levels of 
each of these variables. The Kaplan-Meier analysis and Cox model will be performed by subgroup 
levels of the baseline variables and each TC therapy listed below: 
• Age (<75, ≥75). 
• Baseline cytogenetic risk (poor-risk, others; see Appendix 3). 
• ECOG performance status (0-1, 2). 
• Number of prior regimens (≤2, >2). 
• Prior HCT (yes, no). 
• Baseline BM blasts (≤40%, >40%). 


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• Baseline total WBC counts (≤20,000/μL, >20,000/μL). 
• Study center region (North America, Europe, Asia-Pacific, Other). 
• Race (White, Black, Asian, Other). 
• Presence of baseline specific gene mutations or gene expressions for each gene (yes, no). 
• Individual preselected TC (high intensity, low intensity, BSC). 
• Additional subgroups may also be further described in the Statistical Analysis Plan. 
11.7 
Safety Analyses 
The Safety Analysis Set will be used for all safety analyses. Safety will be assessed by subject-
reported and investigator-observed AEs and 30- and 60-day all-cause mortality, along with clinical 
laboratory tests (hematology, chemistries), concomitant medications, physical examination, vital 
signs, ECOG performance status and ECGs. Safety will also be assessed by exposure to 
guadecitabine or TC, reasons for discontinuation, deaths, and causes of deaths. 
AEs will be mapped to the appropriate System Organ Class (SOC) and PT according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Severity of AEs will be graded using CTCAE 
version 4.03. All AEs collected during the study will be presented in data listings. Treatment-
emergent AEs will also be analyzed with summary tables. Treatment emergent AEs are defined as 
events that first occurred or worsened after the first dose of study drug given on Cycle 1 Day 1 
(C1D1) until 30 days after the last dose of study treatment or the start of an alternative anti-
leukemia treatment for AML (except for hydroxyurea as specified in Section 7.4.1), whichever 
occurs first, as to be defined in more detail in the statistical analysis plan. The summary 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. 
Thirty- (30) and 60-day all-cause mortality rates will be calculated as number of deaths, regardless 
of cause, within 30 or 60 days from the first study dose (C1D1) divided by the total number of 
subjects included in the safety analysis set. The 30- and 60-day mortality rates and their 95% CIs 
will be provided for each treatment group.  
Laboratory values will be graded, if applicable, by CTCAE in conjunction with Harrison 
(18th edition) lab book normals (Longo et al 2011). Shift tables will be provided for each graded 
laboratory test.  
Concomitant medications are the medications taken with a start date on or after the start of the 
administration of the study drug (C1D1), or those with a start date before the start of study drug 


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administration (C1D1) and a stop date on or after the start of study drug administration (C1D1), 
as to be defined in more detail in the statistical analysis plan. 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. 
Vital sign measurements 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. 
Physical examination, ECOG and ECG findings will be listed in data listings or analyzed with 
summary tables.  
 
 
 
  
 
 
 
 
 
 
 
 
 
11.10 Interim Analysis 
One interim analysis of OS is planned with a maximum spendable alpha of 0.01. This interim 
analysis was be conducted by the independent DMC after approximately half of the required 
315 death events have occurred. The nominal alpha values for the interim and final 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 0.04998, respectively. The actual 
alpha value to be used in the final analysis will depend on the actual alpha spent for the interim 
analysis. An interim futility analysis was conducted by the DMC at approximately one-third of the 
required 315 events, guided by the O’Brien-Fleming “lower boundary” that rules out the minimally 
important difference (hazard ratio of approximately 0.80). 
Refer to Section 11.3 for the schedule of analyses. 
11.11 Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed, except as specified. Data from subjects 
lost to follow-up will be included in statistical analyses to the point of their last evaluation.  


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12.0 
STUDY DURATION AND TERMINATION 
The expected study duration is approximately 26 months including 18 months for completing 
enrollment and approximately 8 months follow-up before the primary analyses. The study started 
in Q1 2017. Based on DMC recommendation after futility analyses, enrolment was stopped in 
September 2018. Follow up for the primary analyses will be stopped in Q3 2019 or when the last 
subject is off study.  
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 principles of 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 subject’s source document 
(including the date), and the informed consent form must be signed and dated, 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. 


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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. 
• 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 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. 


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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. 
• 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 guadecitabine 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 Assessment of Protocol Deviations and Prohibition of Waivers 
Representatives of Astex Pharmaceuticals will assess protocol deviations to determine whether 
any deviation should be reported to regulatory authorities as a serious breach of GCP and the 
protocol. No protocol waivers will be granted.  
14.1.6 
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. 


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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 
Drug Accountability 
An initial supply of guadecitabine 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. Thereafter, the study pharmacist is responsible for 
ordering a resupply. 
Keep all supplied study drug 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 any study drug 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. 
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 supplied study drug and other study 
material is destroyed or returned to the sponsor on completion of the study. If the supplied study 
drug 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. Supplied 
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, 


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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. 
• 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. 
 
 
 
 
  
 
 
 
 
 
  
14.2.6 
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 


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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. 
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 and seek approval from relevant regulatory authorities before 
implementation where applicable. 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. 


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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 in the study shall be listed as lead authors on manuscripts and reports of study 
results. 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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Appelbaum FR, Rowe JM, Radich J, Dick JE. 2001. Acute myeloid leukemia. Hematology Am 
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Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. 2003. Revised 
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Chuang JC, Warner SL, Vollmer D, Vankyalapati H, Redkar S, Bearss DJ, et al. 2010. S110, a 
5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo 
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Fang F, Munck J, Tang J, Taverna P, Wang Y, Miller DF, et al. 2014. The novel, small-molecule 
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Lubbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U, et al. 2012. A multicenter 
phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia 
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Westfall PH, Krishen A. 2001. Optimally weighted, fixed sequence and gatekeeper multiple 
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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 16 August 2016) 
 


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APPENDIX 2: 
QUALITY OF LIFE EQ-5D-5L SAMPLE 


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APPENDIX 3: 
CYTOGENETICS-BASED RISK CLASSIFICATION 
Cytogenetics-based risk classification is based on National Comprehensive Cancer Network 
(NCCN) Guidelines® (2014) as follows: 
Risk Status Based on Cytogeneticsa 
Risk Status 
Cytogenetics 
Better-risk 
inv(16)b,c or t(16;16)b 
t(8;21)b 
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)d 
a 
The molecular abnormalities included in this table reflect those for which validated assays are available in 
standardized commercial laboratories. Given the rapidly evolving field, risk stratification should be modified 
based on continuous evaluation of research data. Other novel genetic mutations have been identified that may 
have prognostic significance. 
b 
 Other cytogenetic abnormalities in addition to these findings do not alter better risk status. 
c 
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. 
d 
For Philadelphia+ AML t(9;22), manage as myeloid blast crisis in chronic myeloid leukemia, with addition of 
tyrosine kinase inhibitors. 
Sources: NCCN Guidelines: Acute Myeloid Leukemia. Version.2. 2014. NCCN.org 
 






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SAP_001.pdf: 
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Abbreviated Clinical Study Report SGI-110-06 
 
 
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Statistical Analysis Plan  
Statistical Analysis Plan (22 July 2020) 


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-110-06 
 
Statistical Analysis Plan 
 
A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine 
(SGI-110) versus Treatment Choice in Adults with Previously Treated 
Acute Myeloid Leukemia 
 
 
Date: 22 July 2020 
Based on: Protocol Amendment 4.0 
 
 
 


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Authored by: 
  
Study Biostatistician  
 
 
Approved by: 
  
VP, Biostatistics and Data Management 
  
Senior Vice President, Clinical Development 
  
President & Chief Medical Officer 
 
 
 


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TABLE OF CONTENTS 
1.0 
INTRODUCTION..............................................................................................................6 
1.1 
Acute Myeloid Leukemia ........................................................................................6 
1.2 
Treatment Options ...................................................................................................6 
1.3 
Guadecitabine ..........................................................................................................7 
2.0 
STUDY OBJECTIVES ......................................................................................................7 
2.1 
Primary Objective ....................................................................................................7 
2.2 
Secondary Objectives...............................................................................................7 
 
 
3.0 
STUDY DESIGN ................................................................................................................8 
3.1 
Overall Study Design ...............................................................................................8 
3.2 
Study Endpoints .....................................................................................................10 
3.2.1 
Primary Efficacy Endpoint ....................................................................10 
3.2.2 
Secondary Efficacy Endpoints ..............................................................10 
3.2.3 
Safety Endpoints ...................................................................................11 
4.0 
SAMPLE SIZE .................................................................................................................11 
5.0 
ANALYSIS SETS.............................................................................................................12 
5.1 
Efficacy Analysis Set .............................................................................................12 
5.2 
Safety Analysis Set ................................................................................................12 
 
 
 
 
6.0 
SCHEDULE OF ANALYSES .........................................................................................12 
7.0 
STATISTICAL ANALYSIS ...........................................................................................13 
7.1 
Subject Disposition ................................................................................................14 
7.2 
Demographic and Other Baseline Characteristics .................................................14 
7.3 
Efficacy Variables and Analyses ...........................................................................15 
7.3.1 
Primary Efficacy Endpoint and Analyses .............................................15 
7.3.2 
Secondary Efficacy End Points and Analyses ......................................16 
7.3.3 
Test Sequence and Procedures of Statistical Tests for Efficacy 
Endpoints ..............................................................................................22 
 
 
7.3.5 
Dealing with Technical Issues Caused by Small Cell Count ................23 
7.4 
Safety Variables and Analyses ...............................................................................23 
7.4.1 
Study Treatment Exposure ....................................................................24 
7.4.2 
Adverse Events......................................................................................25 
7.4.3 
30- and 60-Day All-cause Mortality .....................................................25 


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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 
 
 
 
 
7.7 
Interim Analyses and Data Monitoring..................................................................28 
7.8 
Handling of Missing Data and Other Data Anomalies ..........................................28 
7.9 
Handling of Protocol Deviations ...........................................................................28 
8.0 
REFERENCES .................................................................................................................29 
 
LIST OF TABLES 
Table 1: 
2003 IWG AML Response Criteria ...........................................................19 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.............................................................................................10 
 


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ABBREVIATIONS AND DEFINITIONS
AE 
adverse event 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
BM 
bone marrow 
BSA 
body surface area 
BSC 
best supportive care 
CDA 
cytidine deaminase 
CI 
confidence interval 
Cmax 
maximum concentration 
CR 
complete response 
CRc 
composite CR  
(CRc = CR + CRp + CRi) 
CRh 
Complete response with partial 
hematologic recovery 
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 
EFS 
event-free survival 
EQ VAS 
EuroQol visual analogue scale 
FLAG/FLAG-Ida  fludarabine, cytarabine, G-
CSF, +/- idarubicin 
HCT 
hematopoietic cell transplant 
HiDAC 
high dose cytarabine 
HMA 
hypomethylating agent 
HR 
hazard ratio 
ITT 
intent-to-treat 
IV 
intravenous 
IWG 
International Working Group 
LDAC 
low-dose cytarabine 
MDS 
myelodysplastic syndromes 
MEC 
mitoxantrone, etoposide, and 
cytarabine 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
NCCN 
National Comprehensive Cancer 
Network 
NDAOH 
number of days alive and out of 
the hospital 
NE 
nonevaluable 
NR 
nonresponder 
OR 
odds ratio 
OS 
overall survival 
PB 
peripheral blood 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
QOL 
quality of life 
QTc 
heart rate corrected QT interval 
RBC 
red blood cell 
ROW 
rest of world 
Remission 
equivalent to “response” 
Response 
equivalent to “remission” 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SGI-110 
guadecitabine 
SOC 
system organ class 
TC 
treatment choice 
WBC 
white blood cell 
 
 


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1.0 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on SGI-110-06 protocol version 4.0, dated 
29 October 2018. Based on data from 278 randomly assigned subjects, the Data Monitoring 
Committee (DMC) recommended stopping further enrollment into the trial based on futility 
analysis that indicated the trial was unlikely to show superiority of guadecitabine over treatment 
choice (TC) for overall survival (OS). Consequently, the study was closed to further enrollment in 
September 2018 (protocol amendment 4).  
Analyses and statistical reporting for SGI-110-06 will be conducted by Astex Pharmaceuticals 
Biostatistics department with the interim analysis results as reported by the study’s DMC. The 
analyses specified in this document supersede the high-level analysis plan described in the 
protocol. 
1.1 
Acute Myeloid Leukemia  
Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults. The 
average age of a patient with AML is about 68 years; AML is generally a disease of older people 
and is uncommon before age 45 (American Cancer Society 2020).  
AML is differentiated from other hematopoietic malignancies by the presence of greater than 20% 
myeloblasts in the bone marrow or blood. In AML, myeloblasts crowd out normal hematopoietic 
cells in the bone marrow, leaving the patient with insufficient erythrocytes, platelets, and 
neutrophils. The consequent pancytopenia causes most of the symptoms of leukemia. Diagnosis is 
made by pathologic examination of peripheral blood (PB) and bone marrow (BM), and no 
opportunity for early detection exists except in patients with antecedent hematologic malignancies 
or inherited disorders. Diagnosis of AML requires a rapid assessment and initiation of treatment. 
AML leads to death within a few weeks to months after diagnosis if left untreated. 
1.2 
Treatment Options  
The standard intensive induction chemotherapy for AML has been the same for decades. Although 
up to 80% of AML patients <60 years of age will achieve complete response (CR) with intensive 
chemotherapy, approximately 30% to 40% of these patients will die from their disease (Roboz 
2011; Estey 2012). The outlook for patients >60 years old is significantly worse. Only 45% to 50% 
of older patients achieve complete remission and most remitting patients quickly relapse. 
Patients unable to achieve a CR with standard induction therapy (refractory AML) or whose 
disease returns after achieving remission (relapsed) are likely to die from their disease (Estey 
2012). There are no proven treatment options for subjects with AML refractory to intensive 
remission induction chemotherapy or for subjects who relapse after intensive chemotherapy 
treatment(s), particularly if they fail re-induction with the standard regimen.  
There are several commonly used salvage regimens, most of which include cytarabine as either a 
single agent or in combination regimens (NCCN AML Guidelines 2014). The hypomethylating 


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agents (HMAs) decitabine and azacitidine, though mostly studied in myelodysplastic syndromes 
(MDS) and newly diagnosed AML (Kantarjian et al 2012, Fenaux et al 2010, Lubbert et al 2012), 
are often considered an option for frail, older patients with relapsed/refractory AML (Roboz et al 
2014). Due to the lack of proven treatment for r/r AML, enrollment in a clinical trial is considered 
an appropriate strategy (NCCN AML Guidelines 2014; Roboz et al 2014). 
1.3 
Guadecitabine 
Guadecitabine is a new chemical entity that incorporates decitabine and deoxyguanosine linked by 
a phosphodiester bond. Unlike decitabine, guadecitabine is resistant to deamination by cytidine 
deaminases (CDAs). Compared with intravenous (IV) decitabine, decitabine from subcutaneous 
(SC) guadecitabine had prolonged exposure and lower maximum concentration (Cmax) (Issa et al 
2015). This differentiated pharmacokinetic (PK) profile is the proposed basis for potential 
enhancement of clinical activity of guadecitabine. 
Clinical responses in subjects with AML (including relapsed/refractory AML) and MDS have been 
observed in the Phase 1-2 study (SGI-110-01) (Issa et al 2015; Kantarjian et al 2013). The median 
overall survival was estimated to be 6.6 months for subjects with r/r AML (SGI-110-01). 
Two additional Phase 3 studies (SGI-110-04 and SGI-110-07) of guadecitabine versus treatment 
choice (TC) were conducted. SGI-110-04 was in adults with previously untreated AML who were 
unfit to receive or who were not considered candidates for intensive induction chemotherapy. 
SGI-110-07 (currently ongoing) is in adults with MDS or CMML who failed or relapsed after prior 
treatment with azacitidine, decitabine, or both. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To assess and compare overall survival (OS) between guadecitabine and treatment choice (TC) in 
adults with previously treated AML. 
2.2 
Secondary Objectives 
To assess and compare effects of guadecitabine and TC in adults with previously treated AML 
with respect to the following variables: 
• Event-free survival (EFS). 
• Long-term survival. 
• Number of days alive and out of the hospital (NDAOH). 
• Transfusion needs. 
• Complete response (CR) and CR with partial hematologic recovery (CRh) rates. 
• Composite CR rate (CRc). CRc = CR + CR with incomplete blood count recovery (CRi) + CR 
with incomplete platelet recovery (CRp). 


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• Bridge to hematopoietic cell transplant (HCT). 
• Health-related quality of life (QOL). 
• Safety. 
 
 
 
 
 
 
 
3.0 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and 
safety of guadecitabine in adults with previously treated AML. Approximately 404 subjects from 
approximately 100 study centers were planned to be randomly assigned to either guadecitabine or 
TC in a 1:1 ratio (approximately 202 subjects per group): 
• Guadecitabine: 60 mg/m2 in 28-day cycles (either given for 10 days on Days 1-5 and Days 8-12 
or on Days 1-10 [Cycle 1], for either a 5-day regimen [Days 1-5] or a 10-day regimen [Days 1-5 
and Days 8-12 or on Days 1-10] for Cycle 2, based on assessment of disease response and 
hematological recovery at the end of Cycle 1, and then for 5 days only [Days 1-5] for 
Cycles >2). 
• TC (high intensity, low intensity, and best supportive care) 
Before randomization, the investigator assigns each subject to one of the following TC options 
based on the subject’s prior treatment received, country approval, and local institutional standards: 
• High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and 
cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida). 
• Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine. 
• Best supportive care (BSC). 
Randomization was stratified by intensity of preselected TC option (high intensity vs low intensity 
vs BSC), Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2), baseline 
cytogenetics (poor risk vs other), and study center region (North America vs rest of world [ROW]). 
Subjects with a different selection of TC intensity may expect a different treatment outcome, with 
younger and healthy subjects usually being treated with a higher intensity TC and experiencing a 
better treatment response and longer survival. Subjects who have a poor performance status (2) 
tend to have a worse survival than subjects with a good performance status (0 or 1). Similarly, 
subjects with a poor-risk cytogenetics generally do not respond to treatment well and have a shorter 


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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 sought to minimize imbalance between treatment groups 
within strata and was designed to reduce bias and improve power of the study.  
Selection of one of the TCs was 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).  
Peripheral blood (PB) was assessed at Screening and on Day 1 of each cycle for response 
evaluation. Bone marrow (BM) aspirate or biopsy was performed at screening and then at the end 
of Cycles 1, 3, and 6 unless PB showed persistence of ≥5% leukemic blasts that excluded the 
possibility of a marrow response. After Cycle 6, BM assessment, BM aspirate, or biopsy (with 
touch prep slides) was repeated every 3 months for the first year on study and then every 6 months 
thereafter until PB or BM assessment showed disease progression or relapse. 
Figure 1 below summarizes the study design. 


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Figure 1: 
Study Schema 
 
 
3.2 
Study Endpoints 
3.2.1 
Primary Efficacy Endpoint 
• OS, defined as the number of days from date of randomization to date of death. 
3.2.2 
Secondary Efficacy Endpoints 
• EFS defined as the number of days from randomization to the earliest date of, treatment 
discontinuation (for reasons other than initiation of HCT), start of alternative anti-leukemia 
therapy (except for HCT), or death. 
• Survival rate at 1 year after randomization. (Subjects will also be followed long term to 
estimate 2-year survival rate.) 


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• NDAOH. 
• Transfusion independence rate, calculated based on the number of subjects with neither red 
blood cell (RBC) nor platelet transfusion for any period of 8 weeks after treatment. 
• CR rate based on modified International Working Group (IWG) 2003 AML Response Criteria 
and CRh rate as described in the US FDA approved Prescribing Information of enasidenib and 
ivosidenib.  
• CRc (CR+CRi+CRp) rate. 
• HCT rate. (In subjects who undergo HCT, time to stem cell engraftment and 100-day mortality 
rate post HCT will also be assessed.) 
• Duration of combined CR and CRh, defined as the time from first CR or CRh to time of relapse. 
• Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ 
visual analogue scale [VAS]). 
3.2.3 
Safety Endpoints 
Safety was assessed by subject-reported and investigator-observed AEs and 30- and 60-day all-
cause mortality, along with clinical laboratory tests (hematology, chemistries), concomitant 
medications, physical examination, vital signs, ECOG performance status, and ECGs.  
4.0 
SAMPLE SIZE 
In order to provide power of at least 90% to detect a difference in hazard ratio of approximately 
0.692 (median OS of 4.5 months for the TC arm versus 6.5 months for the guadecitabine arm) 
using a stratified 2-sided log-rank test at an overall 0.05 alpha level given the 1:1 randomization, 
the trial will require 315 death events. Assuming that the enrollment would be non-uniform over 
an 18 month period during which 3 to 29 subjects per month (3, 6, 9, 12, 15, 18, 21, 24, 27, and 
29) were expected to be enrolled in the first 10 months in increasing order followed by 30 subjects 
per month in months 11-18, with the proportion of subjects dropping out each month equal to 
0.012, then approximately 404 subjects would need to be randomized. If after a follow up of 
12 months from the last patient randomized, the 315 death events had not occurred, the primary 
analysis would be conducted at 12 months from last subject randomized (if 277 or more death 
events have occurred), or after at least 277 death events had been observed (corresponding to 86% 
power). Based on DMC recommendation to stop further enrollment, the time of primary analyses 
was shifted to occur after approximately 12 months follow-up from the last subject randomly 
assigned to treatment or after the last subject is off study. 


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5.0 
ANALYSIS SETS 
5.1 
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, 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 monthly whether or not they are still on study treatment. Secondary analysis, if 
performed, may also include data beyond the first 6 months of the study (eg, over the entire study 
period until disease progression). 
5.2 
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 a subject receives more than one type of study treatment during the study, 
the subject will be included in the treatment group according to the treatment received most 
frequently. In the unlikely event a subject receives the same number of cycles of two different 
treatments the subject will be included in the treatment group according to the treatment received 
first. 
 
 
 
 
 
 
  
 
 
 
 
6.0 
SCHEDULE OF ANALYSES 
Data listings and summary tables were 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 were generated by 


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Axio Research LLC, an independent contract research organization (CRO) supporting the DMC 
activities.  
One formal interim analysis of OS was planned to be conducted by the DMC when approximately 
half of the required 315 death events have occurred.  
At the Sponsor’s request, an additional earlier interim analysis of futility was conducted by the 
DMC at one of the scheduled DMC meetings on 12 September 2018 when approximately one-
third of the required 315 death events had occurred. This interim analysis was added due to the 
emerging information showing a lack of significant survival benefit over the TC arm (similar to 
the Low Intensity TC in this study) from a similar trial conducted by the Sponsor in treatment-
naive AML subjects using the same drug product in which the study failed to meet the primary 
endpoint (SGI-110-04 study). This meeting resulted in a DMC recommendation to the Sponsor 
that enrollment in Study SGI-110-06 should be discontinued based on futility. 
Since the enrollment was stopped prior to reaching the planned number of death events for the 
formal interim analysis of OS as described in the protocol, the formal interim analysis was 
cancelled.  
As a result, the time of primary analyses was shifted to occur after approximately 12 months 
follow-up from the last subject randomly assigned to treatment or after the last subject is off study. 
A cutoff date of 20 January 2020 was planned to support the primary analysis and subjects who 
were no longer receiving study treatment were not followed for survival beyond the cutoff date. 
The database lock based on the 20 January 2020 cutoff date was delayed due to the COVID-19 
pandemic and a final database lock will be conducted which will include all data from all subjects 
up to the time they discontinued from the study or completed participation in SGI-110-06 and 
enrolled into the extension study, SGI-110-12. This final study database will include data beyond 
the 20 January 2020 data cutoff date for subjects who were still participating in SGI-110-06. To 
avoid bias related to the changes in data collection after 20 January 2020, key primary and 
secondary endpoints such as overall survival, event-free survival, survival rate at 1 year after 
randomization, transfusion independence rate, response rates and duration of response will be 
based on data up to the planned data cutoff date, while analyses of all other efficacy and safety 
endpoints will be based on all data included in the final study database. 
7.0 
STATISTICAL ANALYSIS 
Unless otherwise specified, treatment comparisons will be performed between the guadecitabine 
group and the TC group. Additional comparisons of guadecitabine with each TC option in the 
patients randomized under that preselected TC option may be performed as appropriate. 
Procedures will be employed to control the alpha error associated with testing multiple endpoints 
(see Section 7.3.3). The statistical test to be employed for each comparison is specified below. The 
SAS® statistical package (SAS Institute Inc., Cary, NC, USA, version 9.4 or a later version) will 
be used for the analyses. 


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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, individual efficacy data, subjects excluded from the 
efficacy analysis, AEs, medications, and the relevant laboratory measurements. Additional data 
listings may be generated to support other relevant discussions in CSR.  
The baseline value for a particular variable is generally the last value collected prior to the Cycle 1 
Day 1 (C1D1) study visit. For subjects who were randomized but did not receive study treatment, 
the baseline value is defined as the last value collected prior to randomization. For variables 
collected on Day 1 of Cycle 1 (C1D1) without explicit timing, the C1D1 values will be used as the 
baseline values since the protocol requires these tests or procedures to be performed prior to 
dosing. 
7.1 
Subject Disposition 
Subject disposition including numbers randomized, treated, and treatment discontinuation by 
reason, as well as the reasons for withdrawal from study will be summarized by treatment group 
using frequencies and percentages based on information collected on the relevant study case report 
form pages. The number of subjects screened, screen failures and reasons for failure will be 
summarized. The number of subjects randomized will also be tabulated by region, country, study 
site/investigator and treatment group. The number of subjects in each analysis set will be 
summarized by treatment group, when applicable. In addition, subject eligibility information 
including characteristics related to inclusion and exclusion criteria collected during screening will 
be summarized by treatment group. 
Duration of follow-up will be calculated as the (date of the data cutoff − date of randomization) 
and will be summarized using mean, standard deviation, median, minimum, and maximum. 
7.2 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics include, but are not limited to age, sex, ethnicity, race, 
geographical region, response to initial intensive induction therapy, time since AML diagnosis, 
height, weight, body surface area (BSA), ECOG performance status, number and type of prior 
cancer therapies, 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, TP53, FLT3-ITD, NPM1, ASXL-1, 
RUNX-1, and CEBPA biallelic. 
Categories of response to initial intensive induction therapy are defined as follows: 
• Refractory is defined as refractory to induction where a subject did not have CR, CRp, or CRi 
to the first line induction regimen.  
• First relapse refers to subjects who had just one prior regimen and had a response (CR, CRp, 
CRi, or PR) to the first line induction regimen.  


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• >1 relapse refers to subjects who had at least 2 prior regimens and had a response. 
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.  
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 
Unless otherwise specified, all efficacy analyses will be based on the Efficacy Analysis Set. This 
section describes the analyses conducted at the final and primary analysis time point after at least 
12 months follow-up from the last subject randomly assigned to treatment. The stratification 
factors used in the analyses will be the randomization stratification factors unless it is necessary to 
collapse some strata due to analysis difficulties caused by too many strata. The rule for collapsing 
strata are detailed in Section 7.3.5. If the strata are collapsed for the analysis of the primary 
endpoint, the collapsed strata will be applied to stratified analyses for all subsequent endpoints. 
7.3.1 
Primary Efficacy Endpoint and Analyses 
OS is the primary efficacy endpoint and is defined as the time, in days, from the subject 
randomization date to the date of death (regardless of cause).  
Survival time in days = (date of death or censoring − date of randomization) 
In the absence of death at the time of analysis, the survival time will be censored on the last date 
the subject is known to be alive. Subjects who do not have post-baseline information will be 
censored at the date of randomization. 
OS curves will be estimated using the Kaplan-Meier method and formally compared between the 
two treatment groups using a 2-sided stratified log-rank test, stratified by the randomization 
stratification factors.  
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 
OS will be tested at an overall alpha level of 0.05, as further described in Section 7.3.3. If this 
primary endpoint reaches statistical significance at this level in favor of guadecitabine, then the 
study will be considered positive for efficacy.  


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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.  
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.  
The following sensitivity analyses will be conducted for the primary efficacy endpoint of OS for 
evaluating robustness of the treatment effect: 
1) 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 OS, based on treatment actually received as 
described in Section 5.2, 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) An 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 (except hematopoietic cell transplant [HCT]).  
7.3.2 
Secondary Efficacy End Points and Analyses 
Secondary efficacy endpoints include EFS, survival rate at 1 year and 2 years after randomization, 
NDAOH, transfusion independence rate, combined CR + CRh rate, CRc rate and HCT rate, 
duration of combined CR and CRh, and the EQ-5D-5L descriptive system and the EQ VAS.  
7.3.2.1 
Event-Free Survival 
Event-free survival (EFS) is defined as the time, in days, from the subject randomization date to 
the earliest of treatment discontinuation (for reasons other than initiation of HCT), start of 
alternative anti-leukemia therapy (other than HCT), or death.  
In the absence of any of these events at the time of analysis, event-free survival time will be 
censored on the last date the subject is known alive. Subjects who do not have post-baseline 
information will be censored at the date of randomization. 
EFS curves will be estimated using the Kaplan-Meier method and formally compared between the 
two treatment groups using a 2-sided log-rank test, stratified by the randomization stratification 
factors. EFS will be tested at an overall alpha level of 0.05, as further described in Section 7.3.3.  
The median (and quartiles) duration of EFS and the associated 95% CI for each treatment arm will 
be estimated using the Kaplan-Meier method and the log-log transformation for the event-free 
survival function.  


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7.3.2.2 
Survival Rate at One-Year and Two-Years 
One-year survival rate is defined as the survival rate at the end of the first year from randomization. 
One-year survival rate for each treatment group will be estimated by Kaplan-Meier procedure as 
addressed in Section 7.3.1. Hypothesis testing will be based on the stratified Kaplan-Meier 
estimates and standard errors estimated by the Greenwood formula using the log-log 
transformation of the OS function at an overall alpha level of 0.05, as further described in 
Section 7.3.3. Subjects who do not have death in record will be censored on the last date known to 
be alive. The stratification factors will be the same as those used in the OS analysis.  
The survival rate at 2 years will be similarly summarized. 
7.3.2.3 
Number of Days Alive and Out of the Hospital  
The date of each hospital admission and discharge were collected for each subject for at least 
6 months (and until disease progression for subjects who had not progressed during the first 
6 months or until the subject died or withdrew consent prior).  
The duration of each individual hospital stay in days (regardless of the reason for hospitalization) 
is calculated as: 
Duration of individual hospital stay = date of discharge − date of admission 
For a subject who was 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 the durations of all 
individual hospital stays occurring between date of randomization 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: 
NDAOH6M = 180 − total duration of all hospital stays − number of death days before Day 180 
For subjects who died within the first 6-month period, the number of death days before Day 180 
is calculated as: 
Number of death days = (date of Day 180 − date of death)  
For subjects who died on or after Day 180 the number of death days before Day 180 will be set 
to 0. 
For subjects who were 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 NDAOH6M will be summarized by treatment group and comparisons between the 2 treatment 
groups will be performed using an analysis of variance (ANOVA) model at an overall alpha level 


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of 0.05, as further described in Section 7.3.3. The variables used for stratification at randomization 
will be included in the analysis of variance model as fixed factors.  
7.3.2.4 
Transfusion Independence Rate 
Transfusion independence rate is calculated as number of subjects with neither RBC nor platelet 
transfusion for any period of 8 weeks after the initiation of treatment (or C1D1 visit date for 
subjects randomized to BSC or randomization for subjects not treated) and up to treatment 
discontinuation divided by the total number of subjects included in the efficacy analysis. The 
transfusion independence rate will be compared between the 2 treatment groups using a Cochran 
Mantel-Haenszel test stratified by the randomization stratification factors at an overall alpha level 
of 0.05, as further described in Section 7.3.3. In addition, the Mantel-Haenszel weighted difference 
in transfusion independence rate between the 2 treatment groups and the associated CI will be 
provided. 
The individual RBC and platelet transfusion independence rates will also be presented. 
7.3.2.5 
Criteria for Response Assessment 
The 2003 AML IWG Response Criteria (summarized in Table 1) are used to identify AML 
subjects with CR, CRp, CRi, or partial response (PR). CRh will also be assessed as a subset of CRi 
or CRp who have partial hematologic recovery and is defined as <5% of blasts in the bone marrow, 
no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/μL and 
ANC >500/μL). Evaluation of response will be conducted by Astex medical monitors assisted by 
programmed data listings. 


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Table 1: 
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 who did not receive any study treatment, or who do not have a valid post-treatment (or 
post C1D1 visit date for BSC) efficacy assessment (ie, no post-treatment BM/PB sample or the 
quality of BM/PB sample is not adequate for an assessment of efficacy) will be classified as not 
evaluable (NE) for response classifications. These subjects will be included in the denominator of 
the ITT analysis for calculation of response rates. Subjects who cannot be classified into a response 
category (CR, CRp, CRi, CRh, or PR) or into the NE category will be classified as non-responders 
(NR) for a given evaluation time point. For subjects who experience different response levels at 
different visits, the best response in the order of CR, CRp, CRi, and PR will be used for summary 
and analyses. Subjects who progress (see Section 7.3.2.1 for definition) prior to experiencing a 
response (CR, CRp, CRi, CRh, or PR) will be included in the NR category. The best response (CR, 
CRp, CRi, PR, NR, or NE) based on the investigators will be summarized in a table displaying the 
number and percentage of subjects who meet the criteria for each endpoint. CRh, which is a 
subcategory of CRp and Cri, will be summarized similarly.  
7.3.2.6 
Complete Response and Complete Response with Partial Hematologic Recovery 
Rates  
The CR and CRh rates are calculated individually and combined as the number of subjects who 
achieve a best response of CR or CRh, divided by the total number of subjects included in the 
efficacy analysis. The CR, CRh, and combined CR+CRh rates will be compared between the 
2 treatment groups using a Cochran Mantel-Haenszel test, stratified by the randomization 
stratification factors, at an overall alpha level of 0.05, as further described in Section 7.3.3. In 
addition, the 2-sided 95% CI for the Mantel-Haenszel weighted difference in CR, CRh, and 
combined CR+CRh rates between the 2 treatment groups will be provided. 


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7.3.2.7 
Composite CR Rate  
The CRc rate is calculated as the number of subjects who achieve 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, stratified by 
the randomization stratification factors, at an overall alpha level of 0.05, as further described in 
Section 7.3.3. In addition, the 2-sided 95% CI for the Mantel-Haenszel weighted difference in CRc 
rate between the 2 treatment groups will be provided. 
7.3.2.8 
HCT 
The HCT rate will be calculated as the number of subjects who received an HCT after 
randomization divided by the total number of subjects included in the efficacy analysis. The HCT 
rate will be compared between the 2 treatment groups using a Cochran Mantel-Haenszel test 
stratified by the randomization stratification factors, at an overall alpha level of 0.05, as further 
described in Section 7.3.3. The Mantel-Haenszel weighted difference in HCT rate between the 
2 treatment groups and the associated CI will also be provided. 
Time-to-stem-cell engraftment is calculated, for subjects who received an HCT after 
randomization, from the day of transplant to the day of engraftment, as recorded in the CRF. The 
day of engraftment is the first day of 3 consecutive days of PB absolute neutrophil counts of 
>500/μL. The number and percent of subjects who received HCT and subsequently achieved stem-
cell engraftment will be summarized by treatment group. The time-to-stem-cell engraftment will 
also be summarized by treatment group using mean, standard deviation, median, minimum, and 
maximum for subjects who have achieved stem-cell engraftment.  
In addition, 100-day post-HCT mortality rate (regardless of cause) will be calculated for subjects 
who received an HCT after randomization and summarized by treatment group. The mortality rate 
will be number of subjects who died from any cause within 100 days of HCT divided by the total 
number of subjects who received HCT. HCT subjects who had no survival status data on or after 
100 days post HCT will be excluded from the analysis. 
7.3.2.9 
Duration of Combined CR and CRh 
A combined duration of CR and CRh (in number of days) will be calculated from the first time a 
CR or CRh is observed to the date of the earliest of the following 3 events: (1) relapse (defined as 
the earliest time point whereby BM assessment or PB assessment by the investigator indicate 
relapse/disease progression due to confirmed reappearance of leukemic blasts in PB or ≥5% 
leukemic blasts in BM, or clinical progression determined by the investigator), (2) start of 
alternative therapy (except HCT) or (3) death. In the absence of any event, the combined duration 
of CR and CRh will be censored at the last available time point (BM assessment, PB assessment, 
or safety/long-term follow-up visit) at which an event was not observed. Duration of combined 
CR and CRh will be analyzed using the Kaplan-Meier method for subjects who achieved a CR or 
CRh during the study and compared between the two treatment groups using a non-stratified log-


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rank test. The median and quartiles of duration of complete response, as well as their respective 
95% CIs will be provided. Duration of CR will be calculated and analyzed similarly. 
To take the proportion of responders into consideration when analyzing duration of combined CR 
and CRh, a separate analysis including all subjects will be conducted with a 0-day event duration 
assigned to subjects who did not achieve a CR or CRh. The median and quartiles of duration of 
complete response, as well as their respective 95% CIs will be provided. 
In addition, both time to first response and time to best response will be calculated and analyzed 
for subjects who achieve a response of CR, CRp, CRi, or PR. Time to first response is defined as 
the time, in days, from the date of first treatment (C1D1) to the first date when any response is 
achieved. Time to best response is similarly defined as the time, in days, from the date of first 
treatment (C1D1) to the first date when a subject’s best response, in the order of CR, CRp, CRi, 
or PR, is achieved. The times to first response and best response will be summarized by treatment 
group using mean, standard deviation, median, minimum, and maximum. Time to CR will be 
summarized similarly. 
7.3.2.10 
EQ-5D-5L Descriptive System Total Score and the EQ VAS 
The EQ-5D-5L descriptive system scores and the EQ VAS were collected for each subject for a 
minimum 6 months unless the subject died or withdrew 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). Since there are only a limited number of countries 
which have rules available for calculating EQ-5D-5L index values, the rules for England (Devlin 
et al 2016) will be used for all subjects from all countries in this study. These analyses will include 
only the data collected for each subject during the first 6 months of study participation. 
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), 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 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.  


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7.3.3 
Test Sequence and Procedures of Statistical Tests for Efficacy Endpoints 
To control the alpha errors associated with testing the multiple endpoints, the primary endpoint, 
OS, will be tested first. If OS reaches statistical significance in favor of guadecitabine, a 
hierarchical analysis of secondary endpoints will proceed in the following pre-specified order: 
1) EFS. 
2) Survival rate at 1 year after randomization. 
3) NDAOH during the first 6 months. 
4) Transfusion independence rate. 
5) Combined CR + CRh rate 
6) CRc (CR+CRi+CRp) rate. 
7) HCT rate. 
A statistically significant test result in favor of guadecitabine for a given endpoint serves as a 
gatekeeper (Westfall and Krishen 2001) for the testing of statistical significance to proceed to a 
subsequent secondary endpoint. The overall alpha error rate is controlled at the 0.05 level by 
following the above testing sequence and procedures.  
The efficacy endpoints of duration of combined CR and CRh and Health Related QOL will be 
used as supportive evidence of the beneficial treatment effect and will therefore, not be included 
in the hierarchical testing to control alpha error. Differences of treatment effect for these endpoints 
and associated 95% CIs, if applicable, will be constructed. 
7.3.4 
Subgroup 
 Analysis  
Subgroup analyses will be performed to explore how the treatment effect on OS is influenced by 
baseline variables, extent of treatment received, and the individual TC therapy administered. To 
evaluate the treatment effect at different levels of each of these variables, the Kaplan-Meier 
analysis and Cox model will be performed separately by each level of each variable as follows:  
• Age (<65, ≥65). 
• Age (<75, ≥75). 
• Sex (Male, Female). 
• Baseline cytogenetic risk (poor-risk, others). 
• Baseline ECOG performance status (0-1, 2). 
• Response to initial intensive induction therapy (refractory, first relapse, >1 relapse). 
• Prior HCT (yes, no). 
• Baseline BM blasts (≤40%, >40%). 


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• Baseline PB blasts (≤30%, >30%). 
• Baseline total WBC counts (≤20,000/μL, >20,000/μL). 
• Study center region (North America, ROW). 
• Race (White, Black, Asian, Other). 
• Presence of baseline genetic mutations or gene expressions for each gene such as FLT3-ITD, 
NPM1, CEBPA biallelic, TP53, ASXL-1, and RUNX-1 (yes, no). 
• Treatment cycles received (<4 cycles vs ≥4 cycles). 
• Treatment cycles received (<6 cycles vs ≥6 cycles). 
• Individual preselected TC (high intensity, low intensity, BSC).  
The treatment effect (HR and 95% CI) for each of these subgroups will be displayed on Forest 
plots. 
Subjects with missing a value for a variable used to define a subgroup will be excluded from that 
subgroup analysis except for subgroups with an "Other" category. In those subgroups, subjects 
with missing values will be included in the Other category.  
 
 
7.3.5 
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 pre-selected TC options (combine 2 or more of the TC comparators: high intensity, 
low intensity and BSC). 
2) Collapse study center regions (combine North America and ROW) and collapse pre-selected 
TC options. 
7.4 
Safety Variables and Analyses 
Unless otherwise specified, 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 5.2). For all safety analyses, summaries by treatment group (guadecitabine and 
TC) will be provided. Additional displays of study treatment exposure and adverse events may be 
generated for each preselected TC option. Data will be summarized by guadecitabine and each TC 
option within a given preselected TC option. 
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 


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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 (or CxD1 visits completed for subjects 
randomized to BSC), dose cycles delayed, and dose reduced cycles will be summarized by 
treatment group and will be based on dose administrations, dose reductions, and dose delays 
identified by the study site and collected on the study drug administration CRFs. Delayed cycles 
will be identified and reported by the study site. For LDAC, MEC, and FLAG, dose-reduced cycles 
will be identified and reported by the study site while for the guadecitabine, azacitidine, decitabine, 
and HiDAC treatment groups, a dose-reduced cycle will be defined as a cycle in which: 
•  the planned dose for cycles ≥2 is less than planned dose for Cycle 1, OR 
• the actual total dose (mg) for any day in the cycle is ≥25% reduction from planned dose (mg) 
calculated from BSA and planned dose (mg/m2), OR  
• the number of days of dosing in cycle is less than expected.  
Summaries of delayed cycles and dose reduced cycles will be provided at both subject and cycle 
levels. 
Dose intensity, presented as the incidence of subjects receiving <80% of their intended dose, will 
be summarized by cycle for the guadecitabine treatment group. Dose intensity will be calculated 
as the actual total dose divided by planned total dose for each treatment cycle.  
Both completed or partially completed dose cycles are counted in these summaries. For BSC, 
cumulative dose, delayed cycles, dose-reduced cycles, and dose intensity will not be summarized.  


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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 (or the C1D1 visit date for subjects randomized to BSC) until 30 days 
after the last dose of study treatment (or until the Safety Follow-up visit date for subjects 
randomized to BSC), 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 after the Safety Follow-up visit date for subjects randomized to BSC), 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 dates will be imputed conservatively. 
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 resulting in permanent treatment discontinuation, AE resulting in drug 
interruption, AE resulting in dose reduction, any serious AE (SAE), and subcategories of SAEs 
(fatal and non-fatal) 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 by decreasing frequency within each SOC. The number 
and percentage of subjects experiencing AEs will also be summarized by PT and sorted by event 
frequency. Related AEs, AEs Grade ≥3, related AEs Grade ≥3, serious AEs, related serious AEs, 
AEs with an outcome of death, AEs resulting in permanent treatment discontinuation, AEs 
resulting in drug interruption, and AEs resulting in dose reduction will be summarized similarly. 
In addition, AEs, related AEs, and SAEs will be summarized by SOC, PT, and CTCAE grade 
where subjects with multiple occurrences of the same AE will be counted once with its worst 
CTCAE grade.  
7.4.3 
30- and 60-Day All-cause Mortality 
The 30- and 60-day all-cause mortality will be calculated as the proportions of subjects who have 
died within 30 or 60 days of study treatment initiation based on each subject’s date of death relative 
to C1D1 (ie, date of death minus date of C1D1). Subjects who die 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 


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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.  
In addition, a summary of all deaths, by cause of death (AE, progressive disease, other) and 
treatment group will be provided for the Efficacy Analysis Set (all randomized subjects) 
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 (or the C1D1 visit date for subjects randomized to BSC), or those 
with a start date before C1D1 and a stop date on or after C1D1. Medications taken beyond 30 days 
from the last dose of study treatment (or after the Safety Follow-up visit date for subjects 
randomized to BSC), 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. 
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 (including 
G-CSF, GM-CSF and ESAs), anti-infective medications (including but not limited to anti-
bacterials, anti-mycotics, anti-mycobacterials, anti-virals, 
and immunoglobulins), and 
hydroxyurea given to reduce high counts during study treatment and not as part of a subsequent 
anti-leukemia treatment. These concomitant medications will be tabulated separately. 
Transfusions will be described separately as part of the efficacy analyses (Section 7.3.2.4). 
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 
study’s Analysis Data Model (ADaM) specifications. 
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 (Kratz et al 2012). 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. 
Summaries will also be provided of the incidence of all new or worsening laboratory abnormalities 
(any CTCAE grade) and new or worsening CTCAE Grade ≥3 laboratory abnormalities by 


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parameter. A listing of potential Hy’s Law cases will be provided. In addition, for selected 
laboratory parameters, a figure of mean values by visit will be generated. 
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:  
• Heart rate ≥110 bpm. 
• Heart 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 at the safety 
follow-up visit), the mean of the available triplicate electrocardiogram values is entered in the 
CRF. For the ECG parameters (heart rate, PR interval, QRS duration, QT interval, and QTcF), the 
value and respective changes from baseline will be summarized by visit using mean, standard 
deviation, median, minimum, and maximum. Summaries will also be provided of the maximum 
post-baseline absolute QTcF and the maximum post-baseline increase in QTcF. 
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 
Relevant physical examination data may be presented in a data listing. 
 
  
 
 
 


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.  
7.7 
Interim Analyses and Data Monitoring 
Data were reviewed by an independent DMC at regular intervals primarily to evaluate safety 
during study conduct. The DMC operates independently from the Sponsor and the clinical 
investigators. 
An interim futility analysis was conducted by the DMC at approximately one-third of the required 
315 events, guided by the O’Brien-Fleming “lower boundary” that rules out the minimally 
important difference (hazard ratio of approximately 0.80). Based on the results of the interim 
futility analyses, the DMC recommended that enrollment in Study SGI-110-06 should be 
discontinued based on futility.  
7.8 
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. 
7.9 
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. 
Protocol deviations related to the COVID-19 pandemic will be noted in the system and an 
additional summary table of important protocol deviations related to COVID-19 will be generated. 


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8.0 
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