Conditions: Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia
Keywords: MDS CMML decitabine Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia AML
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 227
Healthy volunteers: no

Brief summary:
Multicenter PK study of ASTX727 versus IV decitabine. Adult participants who were candidates to receive IV decitabine were randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m\^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, participants continued to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the participants discontinued treatment or withdrew from the study.

Detailed description:
This Phase 3 study established PK equivalence of ASTX727 to IV decitabine in approximately 227 evaluable participants. Eligible participants were randomized to receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: participants were randomly assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other therapy in Cycle 2.

In the ASTX727 cycle, participants received the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) were done on Days 1, 2, and 5, along with pre-dose PK assessments on Days 1-5 and an assessment at 3 hours post-dose on Day 3. Participants were required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours before and 2 hours after dosing.

In the IV decitabine cycle, participants received a 1-hour infusion of IV decitabine 20 mg/m\^2 Daily×5. Serial PK measurements were done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3.

In Cycles ≥3, participants received the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments were done from Cycle 3 onward.)

Arms:
arm 1: Participants with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m\^2, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. arm 2: Participants with MDS or CMML received IV infusion of decitabine 20 mg/m\^2, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days) followed by ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. arm 3: Participants with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m\^2, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study. arm 4: Participants with AML received IV infusion of decitabine 20 mg/m\^2, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days) followed by ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study.

Interventions: intervention 1: ASTX727 intervention 2: Dacogen
Intervention descriptions: intervention 1: ASTX727 oral tablet intervention 2: Decitabine 20 mg/m\^2 one-hour IV infusion

Protocol document:
SAP_002.pdf: 
Official Title: 
NCT Number: 
NCT03306264
Document Dates:
SAP Version 2.0: 15 October 2021 
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine 
and Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia 
(CMML), and Acute Myeloid Leukemia (AML)


Astex Pharmaceuticals, Inc. 
 
ASTX727 
Clinical Study Report ASTX727-02-D 
 
 
Confidential Information 
16.1.9 
Statistical Analysis Plan 
Statistical Analysis Plan (for AML) version 2.0 (15 October 2021) 
 


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. 
 
 
ASTX727-02 
 
Statistical Analysis Plan (for AML) 
 
 
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and 
Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and 
Acute Myeloid Leukemia (AML) 
 
 
Version: 2.0 
Date: 15 October 2021 
Based on: Protocol Amendment 2.7 Canada, dated 08 March 2021 
 
 


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Statistical Analysis Plan – ASTX727-02 (for AML) 
 
 
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SIGNATURES 
 
AUTHORED BY: 
 
 PhD 
 
 
 
 
 
APPROVED BY: 
 
 MD 
 
PhD 
  
 
 
 MD, PhD 
 
 
 
 
 
DocuSign Envelope ID: 11873C97-13E5-45AF-A7ED-AF4310FB2621
(
DocuSigned by: 
(
DocuSigned by: 
(
DocuSigned by: 


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Statistical Analysis Plan – ASTX727-02 (for AML) 
 
 
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TABLE OF CONTENTS  
SIGNATURES................................................................................................................................2 
VERSION HISTORY ....................................................................................................................5 
ABBREVIATIONS AND DEFINITIONS ...................................................................................6 
1.0 
INTRODUCTION..............................................................................................................8 
1.1 
Acute Myeloid Leukemia ........................................................................................8 
1.2 
Treatment Options ...................................................................................................9 
1.2.1 
ASTX727 ................................................................................................9 
2.0 
STUDY OBJECTIVES ....................................................................................................10 
2.1 
Primary Objective ..................................................................................................10 
2.2 
Secondary Objectives .............................................................................................10 
3.0 
STUDY DESIGN ..............................................................................................................10 
3.1 
Overall Study Design .............................................................................................10 
3.2 
Study Endpoints .....................................................................................................13 
3.2.1 
Primary Endpoint ..................................................................................13 
3.2.2 
Secondary Endpoints .............................................................................13 
4.0 
SAMPLE SIZE .................................................................................................................13 
5.0 
ANALYSIS SETS.............................................................................................................14 
5.1 
All Subject Analysis Set ........................................................................................14 
5.2 
Randomized Subject Analysis Set .........................................................................14 
5.3 
Efficacy Analysis Set .............................................................................................14 
5.4 
Safety Analysis Set ................................................................................................14 
5.5 
Pharmacokinetics Analysis Set ..............................................................................14 
5.6 
Pharmacodynamic Analysis Set .............................................................................14 
6.0 
SCHEDULE OF ANALYSES .........................................................................................15 
7.0 
STATISTICAL ANALYSIS ...........................................................................................15 
7.1 
Subject Disposition ................................................................................................15 
7.2 
Demographic and Other Baseline Characteristics .................................................15 
7.3 
Pharmacokinetics Analyses ...................................................................................16 
7.4 
Pharmacodynamic (LINE-1) Analyses ..................................................................16 
7.5 
Efficacy Variables and Analyses ...........................................................................17 
7.5.1 
Response Rate .......................................................................................17 
7.5.2 
Time to First Response and Time to Best Response .............................18 
7.5.3 
Duration of Response ............................................................................19 
7.5.4 
Transfusion Independence ....................................................................19 
7.5.5 
Overall Survival ....................................................................................19 


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7.5.6 
Survival Rate at 6 Months, One Year and Two Years ..........................20 
7.5.7 
Event-Free Survival ..............................................................................20 
7.5.8 
Progression-free Survival ......................................................................20 
7.6 
Safety Variables and Analyses ...............................................................................20 
7.6.1 
Study Treatment and Exposure .............................................................20 
7.6.2 
Adverse Events .....................................................................................21 
7.6.3 
Concomitant Medications .....................................................................22 
7.6.4 
Laboratory Tests....................................................................................22 
7.6.5 
Vital Signs .............................................................................................22 
7.6.6 
Electrocardiogram (ECG) .....................................................................23 
7.6.7 
ECOG Performance Status ....................................................................23 
7.6.8 
Echocardiogram / Multigated Acquisition (ECHO/MUGA) ................23 
7.6.9 
Physical Examination ............................................................................23 
7.7 
Handling of Missing Data and Other Data Anomalies ..........................................23 
7.8 
Handling of Protocol Deviations ...........................................................................23 
8.0 
SUPPORTING DOCUMENTATION ...........................................................................24 
8.1 
Appendix 1: Astex AML Response Assessment Criteria ......................................24 
8.2 
Appendix 2: Summary of Changes ........................................................................44 
9.0 
REFERENCES .................................................................................................................45 
 
LIST OF TABLES 
Table 1: 
Dosing Schedule by Day and Cycle...........................................................11 
Table 2: 
Modified IWG 2003 AML Response Criteria ...........................................18 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.............................................................................................12 
 


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VERSION HISTORY 
SAP Version 
Approval Date 
Change 
Rationale 
1 
12JUL2021 
Not Applicable 
Protocol Amendment 2.6 Europe, dated 27 
January 2021 
2 
 
Reponse Critreria 
Protocol Amendment 2.7 Canada, dated 08 
March 2021; the original IWG 2003 criteria 
and ELN 2017 criteria for AML response 
assessment  
 


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ABBREVIATIONS AND DEFINITIONS 
ADaM 
Analysis Data Model 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANOVA 
analysis of variance 
AUC 
area under the curve 
BM 
bone marrow 
BSA 
body surface area 
CCSP 
Cardiac Clinical Statistical Plan  
CDA 
cytidine deaminase  
CI 
confidence interval 
CMML 
chronic myelomonocytic leukemia 
CR 
complete response 
CRh 
complete response with partial hematologic recovery 
CRi 
CR with incomplete blood count recovery 
CRp 
CR with incomplete platelet recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic acid 
DNMT 
DNA methyltransferase 
ECG 
electrocardiogram 
ECHO/MUGA echocardiogram / multigated acquisition  
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
ERT 
eResearch Technologies, Inc. 
FAB 
French American British 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
GI 
gastrointestinal 
HCT 
hematopoietic cell transplantation 
HMA 
hypomethylating agent 
IB 
Investigator Brochure 
IPD 
important protocol deviations 
IPSS 
International Prognostic Scoring System 
IV 
intravenous 
IWG 
International Working Group 
LINE-1 
long interspersed nucleotide elements-1 
MDS 
myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCE 
new chemical entity 
NE 
non-evaluable 
NR 
non-responder 
OR 
overall response 
OS 
overall survival 
PAP 
Pharmacometric Analysis Plan 
PB 
peripheral blood 
PD 
pharmacodynamic(s) 


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PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SEER 
US Surveillance, Epidemiology and End Results 
SOC 
system organ class 
TD 
transfusion dependence 
TEAE 
treatment emergent adverse event 
TI 
transfusion independence 
TLFs 
Tables, Listings and Figures 
WHO 
World Health Organization 
 


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1.0 
INTRODUCTION 
Study ASTX727-02 originally included only myelodysplastic syndromes (MDS) and chronic 
myelomonocytic leukemia (CMML) subjects. The Amendment 1.3 Europe (10 December 2018) 
expanded the subject population to include ~70 acute myeloid leukemia (AML) evaluable subjects 
in Europe to obtain pharmacokinetic data in the AML population to allow the PK-bridging 
approach for marketing approval in the EU. This Statistical Analysis Plan (SAP), which is based 
on the ASTX727-02 protocol amendment 2.6 Europe (dated 27 January 2021), will only describe 
analysis of AML subjects included in the ASTX727-02 study (ASTX727-02 SAP [AML]). There 
is a separate SAP which has been approved eaerlier for analysis of only MDS/CMML subjects 
included in the ASTX727-02 study (ASTX727-02 SAP). The ASTX727-02 SAP (AML) details 
the methodology to be used in analyzing the AML subject data and outlines the specifications for 
data to be included in the Tables, Listings and Figures (TLFs) of the Clinical Study Report for 
AML subjects. The analyses specified in this document supersede the high-level analysis plan 
described in the protocol. Analyses and statistical reporting for ASTX727-02 AML subjects, with 
the exception of the analyses that are described in a separate Pharmacometric Analysis Plan (PAP) 
and a separate Cardiac Clinical Statistical Plan (CCSP) for AML subjects, will be conducted by 
Astex Pharmaceuticals Biostatistics department using SAS version 9.4 or higher. 
Pharmacokinetics (PK) analyses of plasma decitabine, cedazuridine, and cedazuridine-epimer are 
described in the PAP and will be conducted by pharmacokinetic specialists and statisticians at 
Certara Strategic Consulting. Analyses of ECG data and exposure vs. QTc Interval assessment are 
described in the CCSP and will be conducted by expert cardiologists and statisticians at eResearch 
Technologies, Inc. (ERT).  
1.1 
Acute Myeloid Leukemia  
In a recent analysis of US Surveillance, Epidemiology and End Results (SEER) data, AML trends 
in relative survival by age were compared over 3 successive decades from 1977 through 2006 for 
19,000 patients at least 65 years of age with AML (Thein et al 2013). Overall, survival improved 
for each successive decade in patients from 65 to 74 years old. In this age range, 12-month survival 
increased from 20% to 25%-30% in the 3 successive cohorts. However, survival rates did not 
significantly improve in patients ≥75 years of age. 
The oldest patients (85 or more years of age) have the lowest survival; older AML patients are 
more likely to have poor-risk cytogenetic abnormalities, which are associated with lower complete 
remission rates. In addition, elderly patients may have comorbid illnesses, poor performance 
status, or diminished organ function, any of which can impair their ability to tolerate antileukemic 
therapy (Cashen et al 2010). Thus, despite ongoing incremental improvements in both AML 
chemotherapy and supportive care since the mid-1970s, mortality following an AML diagnosis 
remains persistently high and with minimal improvement in elderly patients. 


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1.2 
Treatment Options  
Hypomethylating agents (HMAs), such as decitabine and azacitidine, are effective treatment 
modalities for hematologic cancers and are FDA-approved for higher risk MDS and CMML. 
HMAs have also shown promising clinical activity in AML. Consecutive daily dosing for 5 or 
7 days in 28-day cycles are the approved schedules. Continued monthly treatment for patients who 
respond is now the standard of care to avoid early relapse (Cabrero et al 2015). Treatment, which 
may continue for several months or even years, may engender significant hardship due to the 5 to 
7 daily visits required each month, and the 1-hour intravenous (IV) infusion or large-volume 
subcutaneous injections. A possible consequence is non-compliance or premature discontinuation. 
Development of a formulation for oral administration of HMAs has proven difficult due to rapid 
metabolism by cytidine deaminase (CDA) during passage through the gastrointestinal (GI) mucosa 
and liver. To achieve even modest exposures of drug requires administration of large doses, which 
are associated with Grades 3 and 4 GI toxicity (nausea, vomiting, and diarrhea) and high variability 
in exposures (Garcia-Manero et al 2011). Successful development of an oral HMA will ease the 
burden of long-duration parenteral therapy, particularly for those patients who may benefit most. 
1.2.1 
ASTX727 
Astex Pharmaceuticals has developed an oral drug product, ASTX727 (recently approved as 
INQOVI® [current INQOVI Prescribing Information]), which is composed of the new chemical 
entity (NCE) cedazuridine (E7727; 100 mg), a CDA inhibitor (Ferraris et al 2014), and 35 mg 
decitabine. In animal models, dose-dependent increases in decitabine exposures were achieved 
when increasing doses of cedazuridine were administered with oral decitabine (refer to the 
ASTX727 Investigator Brochure [IB]). This interaction effect was demonstrated in CD2F1 mice, 
rhesus monkeys, and in cynomolgus monkeys, supporting the mechanism of action of improved 
pharmacokinetics (PK) for the combination of cedazuridine with oral decitabine. Because 
cedazuridine inhibits CDA in the gut and liver, ASTX727 reduces first pass metabolism of 
decitabine thus enhancing the bioavailability of decitabine and achieving exposure and 
hypomethylation activity similar to IV decitabine at the currently approved dosing schedule of 
20 mg/m2 Daily×5. Decitabine was approved in 2006 by the United States Food and Drug 
Administration (US FDA) as Dacogen® (decitabine) (current Dacogen Prescribing Information), 
administered as a 1-hour IV infusion for the treatment of higher risk patients with MDS and 
CMML. Dacogen was also approved by the EMA in 2012 for treatment of adult patients with AML 
who are not candidates for intensive chemotherapy (current Dacogen Summary of Product 
Characteristics). 
Decitabine is a cytidine analog that profoundly inhibits DNA methylation by incorporating into 
DNA and subsequently forming covalent bonds with DNA methyltransferase (DNMT) (Issa and 
Kantarjian 2009). This enzyme deficiency renders the cell unable to maintain DNA methylation 
after cellular replication, resulting in effective DNA demethylation and re-expression of previously 
silenced genes. The analysis of the methylation of repetitive genomic elements, as in the long 
interspersed nucleotide elements-1 (LINE-1) that are normally heavily methylated, represents a 
pharmacodynamic surrogate marker for global DNA methylation (Yang et al 2004). 


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Statistical Analysis Plan – ASTX727-02 (for AML) 
 
 
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The Astex ASTX727 program's completed Phase 1-2 first-in-human trial, ASTX727-01, was a 
PK-guided dose escalation and dose confirmation study of ASTX727 in patients with MDS and 
CMML intended to define appropriate doses of the individual components of ASTX727 
(cedazuridine + decitabine) so that decitabine exposure after oral administration of ASTX727 is 
comparable to exposure after IV decitabine at the approved daily dose of a 1-hour infusion at 
20 mg/m2. Results showed that ASTX727 enables therapeutic dose-dependent increases in 
decitabine exposure to therapeutic levels and achieves demethylation and clinical activity 
comparable to IV decitabine at the FDA approved 5-day dose regimen using fixed doses of 35 mg 
decitabine and 100 mg cedazuridine (Garcia-Manero 2016; Garcia-Manero et al 2020; current 
Dacogen Prescribing Information). 
The main purpose of the current study is to demonstrate AUC equivalence of ASTX727 to 
IV decitabine. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To establish decitabine AUC equivalence of 5-day dosing between ASTX727 and 
IV decitabine. 
2.2 
Secondary Objectives  
• To assess long-term safety and efficacy (response rate) of ASTX727. 
• To assess LINE-1 demethylation. 
• To assess additional PK parameters. 
3.0 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a Phase 3, multicenter, randomized, open-label, 2-period, 2-sequence crossover study 
comparing decitabine AUC equivalence of ASTX727 and IV decitabine. Adult subjects with 
MDS, CMML, or AML who are candidates to receive IV decitabine will be randomized in a 1:1 
ratio to receive the ASTX727 FDC tablet Daily×5 in Cycle 1, followed by IV decitabine 20 mg/m2 
Daily×5 in Cycle 2, or the converse order (Figure 1). Adequate PK assessments from Cycles 1 and 
2 will be required for subjects to be evaluable for analysis of the primary endpoint.  
The dosing regimen for this study is shown in Table 1. Subjects will receive the ASTX727 FDC 
tablet Daily×5 in Cycle 1, followed by a 1-hour infusion of IV decitabine 20 mg/m2 Daily×5 in 
Cycle 2, or the converse order. In Cycles ≥3, subjects will receive the ASTX727 FDC tablet 
Daily×5 in 28-day cycles. After completion of the 2 treatment cycles, subjects will continue to 
receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, 
or the subject decides to discontinue treatment or withdraw from the study. 


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Table 1: 
Dosing Schedule by Day and Cycle 
Cycle (28 Days)
1 
2 
≥3 
Cycle Day 1 
2 
3 
4 
5 6-28 1 
2 
3 
4 
5 6-28 1 
2 
3 
4 
5 6-28 
If randomized to ASTX727 in 
Cycle 1, then: 
 
   ASTX727 tablet 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
   IV decitabine (20 mg/m2) 
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
If randomized to IV decitabine 
in Cycle 1, then: 
 
   ASTX727 tablet 
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
× 
× 
× 
× 
× 
 
   IV decitabine (20 mg/m2) 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1: 
Study Schema 
 
 
Subject with AML 
Cyde•2' 
R'1ndondn:.rJ l ; J 
TX 2 tablet 
Dally 5 
AS0027t b1 t 
Daily 
AS · 27t bl l 
Dail icS 
con nue dosl -
·ith ASTX727 1un 
~ease pr<1g11ei.-si0m, 1 
u 00!\Pl:abli! toxl 
, Slll'bject dl«.onl ue$ ~reatrliemt, 
or 5tilbjec-t wililildraws from study 
Adequate PK 
,ra Cfdes- i .&2 
m?f!dedf'f>f 
pdmaq· 
,endpoifll 


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3.2 
Study Endpoints  
3.2.1 
Primary Endpoint  
Comparison between ASTX727 and IV decitabine: total 5-day AUC0-24 exposures of decitabine 
after treatment with ASTX727 versus IV decitabine.  
3.2.2 
Secondary Endpoints 
• Safety as assessed by AEs, concomitant medications, physical examination, clinical laboratory 
tests (hematology, serum chemistry, and urinalysis), vital signs, Eastern Cooperative Oncology 
Group (ECOG) performance status, and electrocardiogram (ECG). 
• Maximum %LINE-1 demethylation. 
• Additional secondary PK parameters. 
• Clinical response (complete response [CR], CR with incomplete platelet recovery [CRp], and 
CR with incomplete blood count recovery [CRi] based on modified IWG 2003 AML response 
criteria (Cheson et al 2003) and as in the DACO-016 study (ie, CRp as a subset of CRi) 
(Kantarjian et al 2012). In addition, complete response with partial hematologic recovery 
(CRh) will also be assessed. CRh will be reported as in Kantarjian et al 2017 and as used in 
DiNardo et al 2020. 
• Time to first response, time to best response, and time to CR. 
• Duration of CR and duration of combined CR and CRh, defined respectively as the time 
interval from the first CR to time of relapse and the time interval from the first CR or CRh to 
time of relapse. 
• Red blood cell (RBC) or platelet transfusion independence (TI). 
• Overall survival (OS), defined as the number of days from the date of randomization to the 
date of death from any cause. 
• Survival rates at 6 months, one year, and two years. 
• Event-free survival (EFS), defined as the number of days from the date of randomization to 
the date of treatment failure or death from any cause, whichever occurs first. 
• Progression-free survival (PFS), defined as the number of days from the date of randomization 
to the date disease progression or death from cause, witchever occurs first. 
 
4.0 
SAMPLE SIZE 
In an equivalence test of mean using two one-sided tests on data from a two-by-two crossover 
design, a total sample size of ~70 evaluable subjects achieves 90% power at a 5% significance 
level when the true ratio of the means is 1.0, the coefficient of variation on the original, unlogged 
scale is 0.41, and the equivalence limits of the mean ratio are 0.80 and 1.25. Assuming ~20% of 
subjects may not be evaluable in the study, approximately 85 subjects will need to be randomized. 


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The estimated intra-subject CV from analysis of 5-day AUC in study ASTX727-02 with MDS and 
CMML subjects was approximately 0.32. A conservative intra-subject CV value of 0.41 was used 
above for AML sample size justification. 
5.0 
ANALYSIS SETS 
5.1 
All Subject Analysis Set 
The All Subject Analysis Set will include information from all screened subjects, including those 
who did not meet the study entry criteria. This data set will be used only for screening displays.  
5.2 
Randomized Subject Analysis Set 
The Randomized Subject Analysis Set will include data from all subjects who were randomized 
into the study. Subjects will be included in the treatment group according to their randomly 
assigned treatment. 
5.3 
Efficacy Analysis Set 
The Efficacy Analysis Set will include data from all subjects who received any amount of study 
treatment. All data will be included, and no subjects excluded because of protocol deviations. 
Subjects will be included in the treatment sequence according to their randomly assigned treatment 
sequence. 
5.4 
Safety Analysis Set 
The Safety Analysis Set includes data from all subjects who received any amount of study 
treatment. In the safety analysis, no data exclusion will be allowed because of protocol deviations. 
Subjects will be included in the treatment sequence according to the treatment sequence received. 
5.5 
Pharmacokinetics Analysis Set 
The details of PK analysis sets are covered under a separate Pharmacometric Analysis Plan (PAP) 
document. 
5.6 
Pharmacodynamic Analysis Set 
Subjects will be included in the pharmacodynamic (PD) LINE-1 Analysis Set if they received any 
amount of study treatment and have LINE-1 methylation data at baseline (Day 1) of Cycle 1 or 2 
and on either Day 8 or Day 15 of the respective cycle. 


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6.0 
SCHEDULE OF ANALYSES 
The analysis for submission purpose will be performed after all subjects have completed 6 months 
of follow-up or permanently discontinued treatment prior to 6 months of follow up from their first 
treatment dose. All available data up to the data cutoff will be included in this analysis. An 
additional analysis may be conducted when all subjects have completed the study. No formal 
interim analyses are planned for this study. 
7.0 
STATISTICAL ANALYSIS 
Unless otherwise specified, all statistical tests and confidence intervals (CIs) described in this 
document will be two-sided with alpha = .05. The SAS® statistical package (version 9.4 or a later 
version) will be used for the analyses. 
The first dosing date is defined as the first date the subject received any study treatment. Subject 
disposition, demographics, and baseline characteristics will be summarized by treatment sequence 
and all subjects combined (Total). Adverse events (AEs) will be summarized by actual treatment 
received at the onset of the AE (Section 7.6.2). Efficacy analyses, laboratory tests, vital signs, 
ECG, and ECOG performance status will be summarized by treatment sequence and all subjects 
combined (Total), unless otherwise specified. 
The following data listings by study center and subject ID will be provided: screened subjects 
(with reason for screen failure), disposition (with reasons for discontinuation of treatment and 
withdrawal from study), important protocol deviations, demographic and baseline characteristics, 
study drug administration, individual efficacy data, subjects excluded from the efficacy analysis, 
AEs, all deaths (including primary cause of death), serious adverse events (SAEs), other significant 
AEs (including treatment discontinuation due to AEs), concomitant medications, and the protocol 
specified laboratory measurements. Additional data listings may be generated to support other 
relevant discussions in Clinical Study Report. 
7.1 
Subject Disposition  
Subject disposition including number of subjects randomized (enrolled), treated, and treatment 
discontinuation by reason, as well as reasons for withdrawal from study (ie, death, complete 
consent withdrawal, or lost to follow-up) and subjects ongoing at data-cut will be summarized 
using frequencies and percentages based on information collected on the study case report form 
pages. Subjects in the Randomized Subject Analysis Set will be included in the disposition 
analysis. A separate screening summary, based on the All Subjects Analysis Set, will include the 
number of subjects who were screened, failed screening and the reasons for screen failure. 
7.2 
Demographic and Other Baseline Characteristics 
The Randomized Subject Analysis Set (Section 5.2) will be used to summarize demographic and 
baseline characteristics. The demographic variables consist of age, age category (<18, 18-64, 
65-84, ≥85 years), sex, ethnicity, and race. Baseline characteristics include height, weight, body 


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surface area (BSA), ECOG performance status, prior anticancer therapy if any including prior 
HMA treatment (decitabine or azacitidine), study disease (De Novo AML or Secondary AML), 
secondary AML specify (MDS, Other Antecedent Hematological Disorder, Therapy-related 
AML), FAB classification, time since diagnosis, cytogenetic risk classification, hemoglobin, 
neutrophils, platelets, bone marrow [BM] blast counts (%), peripheral blood [PB] blast counts), 
transfusion dependence (RBC and platelet). Race and ethnicity summaries will be based on the 
levels according to CDISC standards. 
Baseline values are the last value collected before or on the 1st dosing date unless otherwise 
specified. 
Time since diagnosis will be calculated as the (date of 1st dose – 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. Complete details of imputation rules are 
presented in the Astex Data Programming Standards. 
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.  
7.3 
Pharmacokinetics Analyses  
The primary endpoint analysis includes data from the following PK assessment days to calculate 
the 5-day total cycle AUC: 
• ASTX727 AUC0-24: Days 1, 2, and/or 5. 
• IV decitabine AUC0-24: Days 1 and/or 5. 
All details regarding the analyses of the primary and secondary PK endpoints are provided in a 
separate PAP.  
7.4 
Pharmacodynamic (LINE-1) Analyses 
The PD (LINE-1) Analysis Set (Section 5.6) will be used for analyses of LINE-1 methylation. 
Since LINE-1 methylation levels often do not completely return to baseline by Day 28 of Cycle 1, 
and to avoid the confounding effects of differing baselines in Cycle 2 vs Cycle 1, subjects will be 
compared for each of the 2 cycles separately using the baseline values prior to each cycle, thus 
limiting the evaluation to interpatient comparisons in each of the 2 cycles. 
For each of Cycles 1 and 2, LINE-1 methylation data will be summarized descriptively (using 
mean, standard deviation, standard error, median, minimum and maximum) by visit and treatment. 
Descriptive statistics for maximum %LINE-1 demethylation will be summarized by treatment. 
In addition, the 95% CIs for mean maximum %LINE-1 demethylation in Cycles 1 and 2 will be 
provided for ASTX727 and IV decitabine, respectively. The 95% CI for the difference in mean 


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maximum %LINE-1 demethylation between ASTX727 and IV decitabine in Cycles 1 and 2 will 
also be generated based on an analysis of variance (ANOVA) model with treatment as factor. 
7.5 
Efficacy Variables and Analyses 
Efficacy analyses will be based on the Efficacy Analysis Set (Section 5.3). Efficacy variables will 
be summarized using descriptive statistics and there will be no formal comparison analyses 
between treatment sequences. 
7.5.1 
Response Rate 
The evaluation of response (Table 2) will be based on Modified IWG 2003 AML Response Criteria 
(Cheson et al 2003), and include CRp according to the DACO-016 study (Kantarjian et al 2012) 
for that CRp is not any response catergory of IWG 2003 AML Response Criteria (Cheson et al 
2003). Subjects who do not have a valid post-treatment efficacy assessment (ie, no post-treatment 
BM/PB sample or the quality of BM/PB sample is not adequate for an assessment of efficacy) will 
be classified as not evaluable (NE) for response classifications. Subjects who cannot be classified 
into a response category (CR, CRi, or PR) or into the NE category will be classified as non-
responders (NR). According to the recommendations of the European LeukemiaNet (Döhner et al 
2017), progressive disease is defined as >50% increase in marrow blast % from baseline (15% 
increase in cases with <30% marrow blasts at baseline); or >70% marrow blasts over at least 
3 months; or >50% increase in peripheral blasts to ≥25 × 109/L (≥25,000/μL); and stable disease 
is defined as absence of CR, CR subtype, PR and progressive disease for at least 3 months. 
CRh, CR with partial hematologic recovery, 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) (Kantarjian et al 2017). Evaluation of response will be conducted by Astex medical 
monitors assisted by programmed data listings, as detailed in the Astex AML Response Assessment 
Criteria (Section 8.1). 


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Table 2: 
Modified IWG 2003 AML Response Criteria 
Responsea 
ASTX727-02 Specific Criteria 
CR 
ANC ≥1000/μL, Platelets ≥100,000/μL, independence from RBC and platelet transfusions over the 
past week, no leukemic blastsb 
<5% leukemic blasts 
CRi 
All CR criteria except ANC <1000/μL or Platelets <100,000/μL  
 
CRp 
All CR criteria except Platelets <100,000/μL and platelet transfusions over the past week 
 
PR 
All CR criteria except decrease of ≥50% in leukemic blasts to level of 5% to 25% 
ANC=absolute neutrophil count; CR=complete response; CRp=complete response with incomplete platelet 
recovery; CRi=CR with incomplete blood count recovery; PR=partial response.  
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. 
Source: Cheson et al 2003; Kantarjian et al 2012 
For subjects who experience different response levels at different visits, the best response (see 
Table 2) will be used for summary and analyses. Overall objective response will be the number of 
subjects achieving CR, CRi, and PR with each subject counted once according to their best 
response. CRp, a subcategory of CRi will be listed under CRi. Composite response rates, CR + 
CRi (either CR or or CRi), CR + CRi + PR (either CR or CRi or PR), CR + CRh (either CR or 
CRh) and CRh, will also be included in the response analysis. 
Subjects with these different response categories will be listed and summarized using frequency 
counts and proportion of subjects with each category. The 95% Clopper-Pearson confidence 
interval will be provided for each response rate. Subgroup analyses such as by age category 
(<75, ≥75) may be performed.  
7.5.2 
Time to First Response and Time to Best Response 
Both time to first response and time to best response will be calculated and analyzed for subjects 
who achieve a response of CR, CRi (or CRp or CRh), 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, CRi (or CRp 
or CRh), or PR, is achieved. The times to first response and best response will be summarized 
using mean, standard deviation, median, minimum, and maximum. Time to CR will be 
summarized similarly. 


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7.5.3 
Duration of Response 
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 hematopoietic cell transplantation [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; the median and quartiles of the duration, 
as well as their respective 95% CIs will be provided. Duration of CR or CRp and duration of CR 
will be calculated and analyzed similarly. 
7.5.4 
Transfusion Independence  
Transfusion independence (TI) will be analyzed separately and simultaneously for platelet and 
RBC transfusions. Transfusion dependence (TD) and transfusion independence are defined as follows:  
• Transfusion dependence at baseline: documentation of 2 units or more of transfusion within 
56 days of the first dose of study treatment.  
• Post-treatment transfusion independence: no transfusion for 56 consecutive days or more after 
the first dose of study treatment while maintaining hemoglobin ≥8 g/dL (RBC TI) or 
maintaining platelets ≥20×109/L (platelet TI). 
Post-treatment transfusion independence rate will be calculated separately and simultaneously for 
RBC transfusion independence and platelet transfusion independence as the number of subjects 
who are transfusion independent post treatment (n) among those who were transfusion dependent 
at baseline (N). The 95% Clopper-Pearson CI for transfusion independence rates will be provided. 
The same analyses will be performed for 84-day and 112−day transfusion independence, defined 
as no transfusion for 84 consecutive and 112 consecutive days, respectively, while maintaining 
hemoglobin ≥8 g/dL (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).  
7.5.5 
Overall Survival 
Overall survival (OS) is defined as the number of days from the date the subject was randomized 
to the date of death (regardless of cause). In the absence of documented death at the time of 
anlaysis, the OS time will be censored on the last date the subject is known alive. 
The Kaplan-Meier plot will be provided based on the Efficacy Analysis Set. The median (and 
quartiles) duration of OS and the associated 95% CI will be estimated using the Kaplan-Meier 
method and the log-log transformation for the survival function. In addition, subject follow-up 
time in days will also be summarized. 


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7.5.6 
Survival Rate at 6 Months, 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 and the associated 95% CI will be estimated by Kaplan-Meier procedure 
with the log-log transformation. The survival rates at 6 months and 2 years will be similarly 
summarized. 
7.5.7 
Event-Free Survival  
Event-free survival (EFS) was not described in the study protocol and was added in this SAP. EFS 
is defined as the number of days from the date of randomization to the date of treatment failure 
(disease progression/relapse, discontinue treatment due to disease progression or treatment-related 
adverse event, or alternative anti-leukemia therapy except for HCT) or death from any cause, 
whichever occurs first. In the absence of any of these events at the time of analysis, EFS 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. The Kaplan-Meier plot will be provided 
based on the Efficacy Analysis Set. Estimated median survival time (days) and 95% CIs will also 
be provided if available. 
7.5.8 
Progression-free Survival 
Progression-free (PFS) survival was not described in the study protocol and was added in this SAP. 
PFS is defined as the number of days from the date of randomization to the date of disease 
progression (including relapse) or death from any cause, whichever occurs first. In the absence of 
disease progression or death at the time of analysis, PFS time will be censored on the last date the 
subject is known alive. The Kaplan-Meier plot will be provided based on the Efficacy Analysis 
Set. Estimated median survival time (days) and 95% CIs will also be provided if available.  
7.6 
Safety Variables and Analyses 
Safety Analysis will be performed using the Safety Analysis Set (Section 5.4). Safety is assessed 
by subject-reported and investigator-observed adverse events (AEs), along with physical 
examination, clinical laboratory tests (hematology, chemistries and urinalysis), vital signs, 
concomitant medications, ECOG performance status and ECGs. Exposure to study treatment, 
deaths, and causes of deaths will be tabulated.  
7.6.1 
Study Treatment and Exposure  
The number of cycles completed or partially completed per subject will be summarized using 
descriptive statistics. Frequency count and percentage of dose delayed cycles and dose reduced 
cycles reported by the investigator will be summarized at the subject level and cycle level.  


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7.6.2 
Adverse Events  
Adverse events 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 AEs will be graded using Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
Treatment-emergent AEs (TEAEs) are defined as events that first occurred or worsened on or after 
the date of the first dose of study treatment until 30 days after the last dose of study treatment or 
until the start of a post-treatment alternative anti-leukemia treatment, whichever occurs first, with 
the following exceptions: events that occurred after 30 days beyond the last dose of study treatment 
or the start of a post-treatment alternative anti-leukemia treatment will also be considered 
treatment-emergent if the events are both serious and related to the study treatment. For the purpose 
of determining whether an AE is a treatment-emergent AE, incomplete AE start and stop dates 
will be imputed conservatively following the data programming conventions as detailed in the 
Astex Data Programming Standards. 
All AE data collected in the study database with an AE start date on or before the data cutoff date 
will be included in the data listings, including those that are not treatment emergent. Only TEAEs 
will be included in the AE summary tables. 
An overall safety summary table containing counts and percentages of subjects with any AE, any 
AE Grade ≥3, AE leading to treatment discontinuation, any SAE, and subcategories of SAEs 
(death vs not death) will be produced. 
Related events are those that the Investigator considered to be related to study treatment as 
described in the study protocol. All summaries of AEs will be made separately in the following 
groups: 
• IV decitabine in Cycle 1 or Cycle 2. 
• ASTX727 in Cycle 1 or Cycle 2. 
• ASTX727 in Cycle 3 or later. 
• Total for ASTX727. 
• Total for the AML study. 
The number and percentage of subjects experiencing AEs will be summarized by MedDRA SOCs 
(sorted alphabetically) with PTs sorted alphabetically within each SOC. The number and 
percentage of subjects experiencing AEs will also be summarized by PT and sorted by event 
frequency of the Total for ASTX727 column. Related AEs, serious AEs (SAEs), and related SAEs 
will be summarized similarly. A summary of AEs with fatal outcome, AEs resulting in permanent 
treatment discontinuation, and AEs resulting in treatment delay or dose reduction will also be 
provided. Additional summaries will be generated by SOC, PT and CTCAE grade. For these 


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summaries, if the occurrence of a particular AE for a given subject is reported more than once, the 
event is only counted once with its worst CTCAE grade. 
7.6.3 
Concomitant Medications 
Concomitant medications are medications taken with a start date on or after the date of the first 
dose of study treatment, or those with a start date before the start of the administration of study 
treatment and a stop date on or after the start of the administration of study treatment. Medications 
taken beyond 30 days from the last dose of study treatment or after the start of a post-treatment 
alternative anti-leukemia treatment are not considered concomitant medications, unless they are 
used for treating a related SAE. For the purpose of inclusion in the concomitant medication tables, 
incomplete medication start and stop dates will be imputed conservatively following the data 
programming conventions as detailed in the Astex Data Programming Standards.  
Concomitant medication will be coded by the latest version of WHO Drug Dictionary before the 
data download and summarized by Anatomical Therapeutic Chemical (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. 
7.6.4 
Laboratory Tests  
Laboratory values will also be graded, if possible, by CTCAE v4.03 in conjunction with the 
Harrison (18th edition) lab book normal values (Longo et al 2011). Shift tables will display 
(1) shift from baseline grade to the worst grade during the study, and (2) shift from baseline grade 
to the last grade at the end of study. 
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 ADaM data 
reviewer guide. 
7.6.5 
Vital Signs 
Vital signs will be summarized by visit and treatment group using proportion of subjects with each 
vital sign being too high or too low according to conventionally accepted vital sign normal ranges 
as follows:  
• Pulse rate 110 bpm or greater. 
• Pulse rate 50 bpm or less. 
• Diastolic blood pressure 110 mmHg or greater. 


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• Diastolic blood pressure 55 mmHg or less. 
• Systolic blood pressure 180 mmHg or greater. 
• Systolic blood pressure 80 mmHg or less. 
• Respiration rate 20 breaths/min or greater. 
• Body temperature 39°C or greater. 
7.6.6 
Electrocardiogram (ECG) 
The ECG data will be summarized and presented as part of a separate more extensive analysis that 
will explore the relationship between the change from baseline in QTc intervals and plasma 
concentrations of ASTX727 or IV decitabine. Further details regarding the analyses of the ECG 
data will be provided in the CCSP.  
7.6.7 
ECOG Performance Status 
Shift tables for ECOG from baseline to the worst grade, and from the baseline to the last available 
grade will be provided. 
7.6.8 
Echocardiogram / Multigated Acquisition (ECHO/MUGA) 
This is only done at baseline for reference. Data will be preserved in a Study Data Tabulation 
Model (SDTM) dataset. No particular analysis will be conducted. 
7.6.9 
Physical Examination 
Physical examination data will be preserved in a SDTM dataset. No particular analysis will be 
conducted. 
7.7 
Handling of Missing Data and Other Data Anomalies 
No missing data imputations are planned for the study, except for response assessment as specified 
in Section 7.5.1. Subjects lost to follow-up will be included in statistical analyses to the point of 
the data cut-off date. 
7.8 
Handling of Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team and updated during 
the IPD reviews throughout the study prior to data cut-off date. IPD will be tabulated by IPD 
category and listed by subject. Non-important protocol deviation data will be preserved in a SDTM 
dataset. No particular analysis will be conducted. 
 


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8.0 
SUPPORTING DOCUMENTATION 
8.1 
Appendix 1: Astex AML Response Assessment Criteria  
 
 


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AML Response Assessment Criteria 
 
Objective: To establish AML response assessment criteria guidelines to meet industry standards and match pivotal 
studies  
• Document the original IWG 2003 criteria and ELN 2017 criteria for AML response assessment 
• Document any criteria language needing clarification and/or study-specific modification(s) from the original criteria along with sufficient 
justification and supporting references 
• Standardize AML response assessment in Astex protocols and BDM table output; and Astex medical adjudication 
• Provide sufficient detail for programming to produce desired output 
• Review and document annually and be used for protocol development, training purposes, and generation of SAPs 
 
 
Version Number: 
1.0 
Version Date: 
15 Oct 2021 
Replaced Version Number: 
N/A 
Replaced Version Dated: 
N/A 
 
 
 


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Table of Contents 
IWG 2003 and ELN 2017 AML response assessment ............................................................................................................................................................................... 3 
Appendix A: Recent pivotal studies in AML and reported response Criteria .......................................................................................................................................... 9 
Appendix B: Recent FDA drug approvals in AML and reported CR rates in prescribing information .................................................................................................... 11 
Appendix C: Programming Guidelines ................................................................................................................................................................................................... 12 
Appendix D: Medical adjudication rules ASTX727-02 study .................................................................................................................................................................. 15 
Appendix E: Standard BDM table outputs of response assessment ...................................................................................................................................................... 17 
References ............................................................................................................................................................................................................................................. 19 
 
 
 
 


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IWG 2003 AND ELN 2017 AML RESPONSE ASSESSMENT 
 
AML 
Response 
Assessment 
IWG 2003 AML 
Response Criteria1 
ELN 2017 AML Response 
Criteria2 
Issues Requiring Clarification(s) 
Study-specific Modification(s):  
ASTX727-02 
Complete 
Remission 
(CR) 
• Morphologic leukemia-
free state (MLFS) 
 <5% blasts in an 
aspirate sample with 
marrow spicules and 
with a count of at 
least 200 nucleated 
cells. There should be 
no blasts with Auer 
rods. 
 No residual evidence 
of extramedullary 
leukemia (such as 
CNS or soft tissue 
involvement). 
 The presence of a 
unique phenotype (by 
flow cytometry) 
identical to what was 
found in the 
pretreatment 
specimen (eg, CD34, 
CD7 coexpression) 
should be viewed as 
persistence of 
leukemia. 
• Hemoglobin 
concentration or 
hematocrit has no 
bearing on remission 
status, although the 
patient must be 
independent of 
transfusions. 
• Absence of persistent 
blasts in the peripheral 
• Bone marrow blasts <5% 
• Absence of circulating blasts and 
blasts with Auer rods 
• Absence of extramedullary 
disease  
• ANC ≥1.0x109/L (1000/uL) 
• Platelet count ≥100x109/L 
(100,000/uL) 
 
 
• ≥200 nucleated cells count 
requirement 
• Auer rods is a hematopathology 
determination and not easily 
collected in EDC 
• Extramedullary disease is a 
clinical/radiographic determination 
and not easily collected in EDC 
• Flow cytometry data is a 
hematopathology determination 
and is not easily collected in EDC 
• Transfusion independency 
requirements not specifically 
defined in IWG 2003 and 
transfusion independency is not 
mentioned at all in the ELN 2017 
• Presence of rare peripheral blasts 
may be normal in a regenerative 
marrow (medical adjudication 
required) 
• IWG 2003 ANC requirement is 
written as “more than” but platelet 
requirement is written as “≥” for 
platelet requirement. 
• “Rare peripheral blast” not defined 
numerically in IWG 2003 and not 
mentioned in ELN 2017 
The protocol follows IWG 2003 except:  
• Requires lower threshold of nucleated cell count 
of ≥100  
• Absolute neutrophil count (ANC) ≥1,000/μL  
• Auer rods and extramedullary disease not 
collected in EDC 
• Patient must be independent of RBC transfusion 
and platelet transfusion for a minimum of 1 week 
before each marrow assessment (Sievers et al 
2001; Kantarjian et al 2012)  
 
RECOMMENDATIONS: 
-Medical adjudication - define rule for when cell 
count is not available, near 100 cells but not 100 
cells, only biopsy is available (no aspirate) 
-Use ANC ≥1,000/μL 
-Document in SAP auer rods and extramedullary 
disease is an investigator/hematopathologist 
assessment (not part of medical adjudication) 
-Medical adjudication for cases of CR or CR 
subtype but a RBC or platelet transfusion was 
recorded within 1 week 


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AML 
Response 
Assessment 
IWG 2003 AML 
Response Criteria1 
ELN 2017 AML Response 
Criteria2 
Issues Requiring Clarification(s) 
Study-specific Modification(s):  
ASTX727-02 
blood. A rare peripheral 
blood blast may be 
identified during 
regeneration. 
• Absolute neutrophil 
count (ANC) >1.0 × 
109/L (1000/μL) 
• Platelet count ≥100 × 
109/L (100,000/μL) 
CR with 
incomplete 
blood count 
recovery 
(CRi) 
All CR criteria except for 
residual neutropenia 
(ANC <1.0 × 109/L 
[1000/μL]) OR 
thrombocytopenia 
(platelet count <100 × 109 
/L [100,000/μL]) 
All CR criteria except for residual 
neutropenia (ANC <1.0x109/L 
[1000/uL]) OR thrombocytopenia 
(platelet  count <100x109/L 
[100,000/uL]) 
• CRi subjects did not meet CR 
criteria because either the ANC 
OR platelet count did not meet the 
CR threshold, but the other 
hematologic count did meet the 
CR threshold 
• Examples: ANC 1,200/μL and 
platelet 80,000/μL; or ANC 
800/μL and platelet 120,000/μL 
The protocol defines as “ANC <1,000/μL and no 
leukemic blasts” - criteria is incomplete in the 
protocol but available information is not incorrect 
• No platelet cell count definition 
• No transfusion independence definition 
• In the protocol, CRi is modified and defined as 
the non-CRp subtype of the original CRi IWG 
2003 so subjects are not counted twice 
(Kantarjian et al, 2012) 
 
RECOMMENDATIONS: 
-Use as done in VIALE-A; CRi is collected; CRp is 
not collected.  
CR with 
incomplete 
platelet 
recovery 
(CRp) 
 
 
• CRp is not defined in IWG 2003 
or ELN 2017; CRp was first 
defined by Sievers et al 2001 (as 
referenced in IWG 2003) as 
follows: CR except no platelet 
count recovery requirement (but 
meeting ANC requirement: ANC 
≥1.0x109/L (1000/uL) 
• CRp is a subset of CRi (ie, 
overlaps, thus should not be 
additive in a composite response 
rate) 
• All CR criteria (including ANC 
criterion) except for residual 
thrombocytopenia (platelet<100 × 
109 /L [100,000/μL])  
• Example: ANC 1,200/μL and 
platelet 80,000/μL 
 
 
• The protocol defines as a parallel assessment 
along with CRi, CRp is “ANC ≥1000/μL, 
Platelets <100,000/μL, independence from RBC 
transfusions over the past week, no leukemic 
blasts” 
• In the protocol, CRi is modified and defined as 
the non-CRp subtype of the original CRi IWG 
2003 so subjects are not counted twice 
(Kantarjian et al, 2012) 
 
RECOMMENDATIONS: 
-Approach like DACO-016, which reports CRp as a 
subset of CRi in final data table summary. Note that 
in Kantarjian et al, 2012 paper, the table is presented 
incorrectly. 
-CR+CRp composite are additive for an overall rate 
(Kantarjian et al, 2012 and Sievers et al, 2001)  


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AML 
Response 
Assessment 
IWG 2003 AML 
Response Criteria1 
ELN 2017 AML Response 
Criteria2 
Issues Requiring Clarification(s) 
Study-specific Modification(s): 
ASTX727-02 
CR with 
partial 
hematologic 
recovery 
(CRh) 
•
•
CRh is not defined in IWG 2003 or 
ELN 2017 but can be used as an 
additional CR subtype that 
requires a lower threshold of ANC 
and platelet count recovery 
requirements (Kantarjian et al 
2017)
All CR criteria (IWG 2003 or 
ELN 2017) except for residual 
neutropenia and/or 
thrombocytopenia; but meeting 
minimum ANC ≥0.5 × 109/L
[500/μL]) AND platelet count ≥50 
× 109 /L [50,000/μL])
• CRh should be assessed separately
in those subjects not meeting CR
by IWG 2003 or ELN 2017
criteria (independent of CRi or
CRp)
• SAP defines CRh as a subset of CRi or CRp -
this was transferred over from previous SGI-110
study. No pivotal studies have defined CRh as a
subset of CRi or CRp because subjects may meet
all 3 subtypes of CR, e.g., ANC 1200/μL and
platelet 80,000/μL.
RECOMMENDATIONS: 
-In the SAP, report using CRh as in Kantarjian et al
2017, which may be used as a composite (CR+CRh)
Partial 
remission 
(PR) 
All of the hematologic 
values for a CR but with a 
decrease of at least 50% 
in the percentage of 
blasts to 5% to 25% in the 
bone marrow aspirate. A 
PR may also be assessed 
if the blasts are ≤ 5% but 
Auer rods are present. 
All hematologic criteria of CR; 
decrease of bone marrow blast 
percentage to 5% to 25%; and 
decrease of pretreatment bone 
marrow blast percentage by at least 
50% 
• For IWG 2003, Auer rods is a
hematopathology determination
and not easily collected in EDC
The protocol follows IWG 2003 except: 
• Auer rods are not evaluated for the alternative
PR assessment
Treatment 
failure 
Failure to achieve a CR in 
a Phase 3 trial or less than 
a PR in a Phase 1 or 2 
trial. Resistant disease; 
Death due to 
complications from an 
aplastic or hypoplastic 
marrow; Indeterminate 
causes (death during first 
course of therapy); 
Morphologic relapse; 
Primary refractory disease (no CR or 
CRi after 2 courses of intensive 
induction treatment); death in 
aplasia; death from indeterminate 
cause  
• Treatment failure is not easily
collected in EDC
• Not assessed in most major studies
(Appendix A and Appendix B)
• Not assessed in the protocol


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AML 
Response 
Assessment 
IWG 2003 AML 
Response Criteria1 
ELN 2017 AML Response 
Criteria2 
Issues Requiring Clarification(s) 
Study-specific Modification(s):  
ASTX727-02 
Molecular or cytogenetic 
relapse 
Stable 
disease 
 
Absence of CRMDR-, CR, CRi, PR, 
MLFS; and criteria for progressive 
disease not met (period of SD should 
last for at least 3 months) 
• SD time period requirement is not 
easily collected in EDC 
• Not assessed for this study. Using no response 
(NR) to cover SD/PD as defined in Appendix C.   
 
RECOMMENDATIONS: 
-Medical adjudication SD/PD with available data 
including incomplete marrow/blood data and 
investigator assessment 
-NR=SD+PD+treatment failure 
Progressive 
disease 
 
Evidence for an increase in bone 
marrow blast percentage and/or 
increase of absolute blast counts in 
the blood: 
• >50% increase in marrow blasts 
over baseline (a minimum 15%-
point increase is required in cases 
with <30% blasts at baseline); or 
persistent marrow blast percentage 
of >70% over at least 3 months; 
without at least a 100% 
improvement in ANC to an absolute 
level (>0.5 × 109/L [500/μL], and/or 
platelet count to >50 × 109/L 
[50,000/μL] nontransfused); or 
• >50% increase in peripheral blasts 
to ≥25 × 109/L (≥25,000/μL) (in the 
absence of differentiation syndrome 
or other clinical scenarios); or 
• New extramedullary disease 
• PD assessed by ELN criteria but 
can also be based on clinical 
judgement or incomplete marrow 
or blood evidence of progressive 
disease, which may not be easily 
collected in EDC 
• ANC and platelet requirement is 
confusing and will be difficult to 
assess based on EDC data alone 
(was added to consider exception 
where blast increase can be seen in 
a regenerating marrow) 
• Not assessed for this study. Using no response 
(NR) to cover SD/PD as defined in Appendix C.   
 
RECOMMENDATIONS: 
- Medical adjudication SD/PD with available data 
including incomplete marrow/blood data and 
investigator assessment 
-NR=SD+PD+treatment failure 
Recurrence 
(IWG 2003) 
or Relapse 
(ELN 2017) 
Morphologic relapse after 
attaining CR. 
Reappearance of leukemic 
blasts in the peripheral 
blood or ≥5% blasts in the 
marrow not attributable to 
any other cause. 
Appearance of new 
dysplastic changes should 
• Hematologic relapse (after CRMDR-, 
CR, CRi) defined as bone marrow 
blasts ≥5%; or reappearance of 
blasts in the blood; or development 
of extramedullary disease 
• Molecular relapse (after CRMDR-) 
defined as if studied pretreatment, 
reoccurrence of MRD as assessed 
by RT-qPCR or by MFC 
• Recurrent or relapse is not easily 
collected in EDC because it may 
require the incorporation of 
marrow and peripheral blood 
findings, and hematopathology and 
clinical determination 
  
• In SAP, 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 


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AML 
Response 
Assessment 
IWG 2003 AML 
Response Criteria1 
ELN 2017 AML Response 
Criteria2 
Issues Requiring Clarification(s) 
Study-specific Modification(s):  
ASTX727-02 
also be considered 
relapse. In the setting of 
recent treatment, if there 
are no circulating blasts 
and the bone marrow 
blasts are 5-20%, a repeat 
marrow performed at least 
a week later is necessary 
to distinguish relapse 
from bone marrow 
regeneration. If recurrence 
is confirmed, the date of 
recurrence is defined as 
the first date that more 
than 5% blasts were 
observed in the marrow. 
Reappearance of 
extramedullary disease 
and molecular and/or 
genetic relapse is 
characterized by 
reappearance of the 
respective abnormalities. 
• Auer rods and extramedullary disease not 
collected in EDC 
• Appearance of new dysplastic changes are not 
assessed well (hematopathologist assessment) or 
collected in EDC 
• Repeat marrow requirement in case of 5-20% 
blasts is not necessarily done as part of SOC 
Footnotes:  
1 Cheson et al 2003 (IWG):  
• Early treatment assessment is not included in this table and generally not included in response assessment tables. Per IWG 2003 criteria, evaluation is made ~7-10 days after 
completing the last dose of the initial course of treatment. This evaluation can be used in clinical trials and in clinical practice to obtain an early indication of antileukemic 
activity (e.g., day +14 marrow evaluation after 7+3 induction chemotherapy). May be incorporated in a study as an endpoint or in the treatment schema to guide therapy 
within the cycle. 
• Morphologic leukemia-free state (MLFS) is not included in this table as a stand-alone response criteria but can on occasion be represented separately in a response 
assessment table if the objectives/endpoints of the study warrant reporting this response category which has no criteria for count recovery. See CR for definition of MLFS. 
• Three special categories of morphologic CR should be considered: cytogenic CR (CRc), molecular complete remission (CRm), morphologic complete remission with 
incomplete blood count recovery (CRi). Refer to Cheson et al. for CRc and CRm criteria and recommendations. 
• Treatment failure criteria - refer to Cheson et al. for details. 
 
2 Dohner et al 2017 (ELN):  
• CR without minimal residual disease (CRMRD-) is not included in this table. If MRD is studied pretreatment, CRMRD- is CR with negativity for a genetic marker by RT-
qPCR, or CR with negativity by multiparameter flow cytometry (MFC). MRD evaluation may be incorporated in a study as an endpoint or in the treatment schema to guide 
therapy. If MRD is not evaluated in a study, CR is regardless of MRD status (positive, negative, or unknown). Refer to Dohner et al. for details. 


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AML 
Response 
Assessment 
IWG 2003 AML 
Response Criteria1 
ELN 2017 AML Response 
Criteria2 
Issues Requiring Clarification(s) 
Study-specific Modification(s):  
ASTX727-02 
• Morphologic leukemia-free state (MLFS) is not included in this table as a stand-alone response criteria but can on occasion be represented separately in a response 
assessment table if the objectives/endpoints of the study warrant reporting this response category which has no criteria for count recovery. Per ELN 2017 criteria, requires 
bone marrow blasts <5%, absence of blasts with Auer rods, absence of extramedullary disease, and no hematologic recovery required. 
• Treatment failure criteria - refer to Dohner et al. for details. 


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APPENDIX A: RECENT PIVOTAL STUDIES IN AML AND REPORTED RESPONSE CRITERIA 
Study 
Reported Response Criteria 
Notes 
Kantarjian et al 2012 (DACO-016, 
decitabine monotherapy) 
CR 
CRi 
CRp 
Composite: CR+CRp 
PR 
SD 
PD 
• Uses TI for 1 week 
• Composite rates are best response (each subject 
can only have 1 best response and individual 
rates add up to the composite rate) 
DiNardo et al 2020 (VIALE-A, 
azacitidine+venetoclax) 
CR 
CRi 
CRh 
PD 
CR by initiation of Cycle 2 
Composite: CR+CRi best response but also rate 
by initiation of Cycle 2 
Composite: CR+CRh 
• Uses TI for 56 days between first and last day of 
treatment for this separate endpoint (definition is 
not part of CR determination) 
• Composite rates are best response (each subject 
can only have 1 best response and individual 
rates add up to the composite rate) 
Wei et al 2020 (VIALE-C, 
cytarabine+venetoclax) 
CR 
MRD 
CRi 
CRh 
PR 
Composite: CR+CRi 
Composite: CR+CRh 
Treatment Failure 
• Follows IWG 2003 and ELN 2017 
• CR has RBC TI (no period defined); CRi is 
considered regardless of RBC TI status (written 
as ±RBC transfusion independence) 
• Treatment failure was defined as failure to 
achieve MLFS or higher 
• Composite rates are best response (each subject 
can only have 1 best response and individual 
rates add up to the composite rate) 
Kolitz et al 2020 (Vyxeos) 
CR 
CRi 
Composite: CR+CRi 
• Composite rates are best response (each subject 
can only have 1 best response and individual 
rates add up to the composite rate) 
Dombret et al 2015 (azacitidine 
monotherapy) 
CR 
CRi 
CRc-20 
PR 
SD 
PD 
• CRc-20 was defined as cytogenetic complete 
remission in at least 20 metaphases. 
• SD defined as anything except CR, CRi, disease 
progression, or treatment failure (early death). 


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Study 
Reported Response Criteria 
Notes 
Composite: CR+CRi 
• Composite rates are best response (each subject 
can only have 1 best response and individual 
rates add up to the composite rate) 
 
 
 


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APPENDIX B: RECENT FDA DRUG APPROVALS IN AML AND REPORTED CR RATES IN PRESCRIBING INFORMATION 
Study 
Reported CR rates 
Notes 
Midostaurin 
CR (no composite) 
 
Ivosidenib; IDH1i 
CR 
Composite: CR+CRh 
Composite rates are best response (each subject can only have 1 best 
response and individual rates add up to the composite rate) 
Enasidenib; IDH2i 
CR 
Composite: CR+CRh 
Composite rates are best response (each subject can only have 1 best 
response and individual rates add up to the composite rate) 
Vyxeos 
CR (no composite) 
 
 
Gilteritinib 
CR 
Composite: CR+CRh 
Composite rates are best response (each subject can only have 1 best 
response and individual rates add up to the composite rate) 
Venetoclax (for AML) 
CR 
Composite: CR+CRh 
Composite rates are best response (each subject can only have 1 best 
response and individual rates add up to the composite rate) 
 
 
 


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APPENDIX C: PROGRAMMING GUIDELINES 
Table of response AML assessment tatus and programmable measures in ASTX727-02 study   
Response Assessment 
Status 
Programmable Measures*  
Data not evaluable or not easy to capture in EDC (defer to 
hematopathologist and clinical investigator assessment; or 
sponsor medical adjudication) 
CR 
• Marrow blasts: <5% 
• ANC: ≥1000/μL 
• Platelets: ≥100,000/μL 
• No RBC and/or platelet transfusion within 7 
days of BM evaluation 
• Peripheral blasts ≤1%1 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Flow data evaluating blast morphology2  
• Peripheral blasts present at low % (could be due to regeneration)1 
• CR criteria met but transfusion within 7 days of BM evaluation 
due to a medical situation3  
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
CRi  
 
assess independently in 
all non-CR cases except 
progressive disease or 
relapse/recurrence 
• Marrow blasts: <5% 
• ANC: ≥1000/μL OR Platelets: ≥100,000/μL 
• Transfusion: no RBC and/or platelet 
transfusion within 7 days of BM evaluation 
• Peripheral blasts ≤1%1 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Flow data evaluating blast morphology2  
• Peripheral blasts present at low % (could be due to regeneration)1 
• CRi criteria met but transfusion within 7 days of BM evaluation 
due to a medical situation3  
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
CRp 
 
assess independently in 
all non-CR cases except 
progressive disease or 
relapse/recurrence 
• Marrow blasts: <5% 
• ANC: ≥1000/μL 
• Platelets: any platelet count <100  
• Transfusion: no RBC transfusions within 7 
days of BM evaluation (no platelet recovery 
needed so this is independent of platelet 
transfusion status) 
• Peripheral blasts ≤1%1 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Flow data evaluating blast morphology2  
• Peripheral blasts present at low % (could be due to regeneration)1 
• CRp criteria met but transfusion within 7 days of BM evaluation 
due to a medical situation3  
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
CRh 
• Marrow blasts: <5% 
• Auer rods2 


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Response Assessment 
Status 
Programmable Measures*  
Data not evaluable or not easy to capture in EDC (defer to 
hematopathologist and clinical investigator assessment; or 
sponsor medical adjudication) 
 
assess independently in 
all non-CR cases except 
progressive disease or 
relapse/recurrence 
• ANC: ≥500/μL  
• Platelets: ≥50,000/μL 
• Transfusion: no RBC and/or platelet 
transfusions within 7 days of BM evaluation 
• Peripheral blasts ≤1%1 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Flow data evaluating blast morphology2  
• Peripheral blasts present at low % (could be due to regeneration)1 
• CRp criteria met but transfusion within 7 days of BM evaluation 
due to a medical situation3  
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
PR 
 
 
• Marrow blasts: ≥50% reduction of blast % 
from baseline but blast count within 5-25% 
(inclusive of 5% and 25% 
• ANC: ≥1000/μL  
• Platelets: ≥100,000/μL 
• Transfusion: no RBC and/or platelet 
transfusions within 7 days of BM evaluation 
• Peripheral blasts ≤1%1 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Flow data evaluating blast morphology2  
• Peripheral blasts present at low % (could be due to regeneration)1 
• PR criteria met but transfusion within 7 days of BM evaluation 
due to a medical situation3  
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
SD 
• Progression: no progression 
• Response: absence of CR, CR subtype, PR, 
PD 
• Duration: lasting ≥3 months  
• Recurrence/relapse: absent 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
PD 
• Marrow blasts: >50% increase in marrow 
blast % from baseline (a minimum 15% 
increase in cases with <30% marrow blasts 
at baseline); or >70% marrow blasts over at 
least 3 months; or >50% increase in 
peripheral blasts to ≥25 x 109/L 
(≥25,000/μL) 
• Response: absence of CR, CR subtype, PR, 
SD 
• Presence of recurrence/relapse 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Clinical or symptomatic progression (or incomplete data) accepted 
for PD response assessment 
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 


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Response Assessment 
Status 
Programmable Measures*  
Data not evaluable or not easy to capture in EDC (defer to 
hematopathologist and clinical investigator assessment; or 
sponsor medical adjudication) 
• Regardless of ANC, platelets, transfusions4 
NR  
 
not a published criteria 
• Response: defined as absence of CR, CRi 
CRp, CRh, PR (when SD and PD are not 
assessed) 
• Used in place of SD/PD as needed 
Recurrence 
(IWG 2003) or 
Relapse (ELN 
2017) 
• Response: CR or CR subtype achieved 
• Marrow blasts: ≥5% marrow blasts not 
attributable to any other cause after CR 
achieved and sustained on repeat 
assessment (to distinguish relapse from 
regeneration) 
• Auer rods2 
• Extramedullary disease2 
• Minimum 100 nucleated cell count from aspirate3 
• Frank dysplasia not collected in EDC3 
• Marrow blasts ≥5% not attributable to any other cause2 
• Medical adjudication required when BM and CBC data not 
assessed on the same day3 
• Clinical or symptomatic progression (or incomplete data) accepted 
for recurrence or relapse assessment 
1The threshold for the purpose of programming was not defined in IWG 2003 and not mentioned in ELN 2017. Requires medical adjudication if 
present but for programming chose ≤1%. 
2Data not collected. SAP should state that this data is presumed evaluated/assessed by hematopathologist and clinical investigator as routine part of 
assessment. 
3Refer to Appendix D for guidelines for medical adjudication. 
4The ELN 2017 criteria mentions “without at least a 100% improvement” in ANC or platelet count - this is difficult to capture in the EDC or 
evaluate by programming. Omitted this detail in the table since AML is not an indolent disease and progressive disease tends to be obvious with 
other supportive laboratory and clinical data. 
 
*ANC values should extend to thousandths digit (e.g., ANC 0.250 x109/L = 250/uL); Platelet count values should extend to hundreds digit (e.g., 
Platelet 120 x109/L = 120,000/uL). Edit checks/site queries are needed especially if ANC hovers around 1000 or 500/uL and platelet hovers 
around 100,000/uL and 50,000/uL, i.e., where the thresholds for CR and CR subtypes are defined. For example, a reported or derived ANC of 
“0.5” may be 0.499 or 0.505 and this would affect CR assessment (see CRh criterion). 
 
 
 


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APPENDIX D: MEDICAL ADJUDICATION RULES ASTX727-02 STUDY 
This is a working document and may require updating from time to time.  
1. 100 nucleated cells requirement  
a. EDC was not designed correctly to capture whether >100 nucleated cells were evaluated on aspirate 
i. Solution - in EDC, it was asked was the aspirate “sample adequate”?  
1. If yes, use data as quantified by hematopathologist 
2. If answer is blank or “sample not adequate” then options are: 
a. Try to obtain redacted hematopathology report, or 
b. If not possible, send investigator a form that requires them to indicate that the BM evaluation was overall adequate for 
response assessment (e.g., tissue biopsy was used to evaluate blast count and response assessment). File an 
administrative letter or as appropriate. 
2. Peripheral blasts 
a. If ≤1% and other CR/CR subtype criteria met, can assume part of regenerating marrow process 
b. If >1% and other CR/CR subtype criteria met, use at least one follow-up CBC with differentials to confirm CR/CR subtype criteria (blasts should 
lessen over days and become ≤1%) 
3. Transfusions within 1 week of a CR or CR subtype (expecting to be a rare occurrence) 
a. If CR/CR subtype criteria met and there is a documented RBC or platelet transfusion within 1 week, consider clinical circumstances of the 
transfusion - reviewing EDC (AEs, medical hx, concomitant procedures) or asking investigator for details (document and file an administrative 
letter or as appropriate). This will cover the rare circumstance when the subjects are transfused electively for a medical history, AE, or 
procedure. 
4. BM/CBC not on same day (priority of evaluation order) 
a. Evaluate response using BM biopsy and CBC with differential from the same day 
b. If not matched, look for the closest CBC (usually should be ±1 week); assess response using the combination of data and use the later of the two 
dates as first response  
c. If a marrow is done and a CBC >1 week later shows additional count recovery and meets a new response, enter response at date when CBC data 
shows criteria met (ask sites to enter any interim missing weekly labs) 
d. If two CBCs are done with the same # days from the marrow and show the same response, use the marrow date for response assessment; if one 
CBC shows a better response use that CBC and use the date of that CBC  
e. If two CBCs are done with the same # days (±) from the marrow and show the same response, use the marrow date for response assessment; if 
the later CBC shows a better response use that CBC date; if the earlier CBC shows a better response, use the BM biopsy date 
f. 
Note: since CBC with differential on a weekly basis may be critical for proper dating of changes in response assessment (e.g., subject with SD and 
progressing towards a CR), ask sites to add weekly labs even if local labs (pass to DM to query for all missing weekly labs) 
5. No interim BM and CR is achieved on a later CBC 


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a. If MLFS (morphologic leukemia-free state), can assess a CR or CR subtype based on a later CBC with diff showing count recovery to meet criteria  
b. If CR subtype (includes MLFS), can assess a CR based on a later CBC with diff showing count recovery to meet criteria 
c. If PR (blasts 5-20%) or SD, cannot assess a higher response category based on a later CBC with diff without a BM evaluation  
6. Bone Marrow Blasts Percentages 
a. If BM ≥5% is not seen on laboratory values at screening, to be evaluable, there must be evidence in the EDC supporting the AML diagnosis (BM 
≥5%). To rule out the possibility this is a protocol violation (patient does not have a diagnosis of AML), documentation of either 1) any pre-
screening maneuvers that reduced blasts (eg hydroxyurea or single dose of cytarabine or mitoxantrone) or 2) the subject has peripheral 
blasts >20% but not marrow blasts >20%, or 3) the subject presents as a myeloid sarcoma which is a type of AML that grows as a tumor and may 
have a marrow that does not reach AML blast count or is even completely normal. If there is a bone marrow before the screening marrow that 
documents the AML before #1, ask the site to add the data as an unscheduled BM and date it accordingly for proper documentation and 
verification of the AML diagnosis. These are the typical circumstances when subjects with AML have blasts <20% at baseline.  
b.  BM blasts fall from above to below 5% then return above and below 5% again. This may be due to BM rejuvenation. Requires medical 
adjudication to determine if still in best response or relapsing. Answer to this should be apparent over time.  
 
 
 
  
 


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APPENDIX E: STANDARD BDM TABLE OUTPUTS OF RESPONSE ASSESSMENT 
 
(1) using 2003 IWG and Kantarjian et al 2017  
Taking ASTX727-02 AML as a sample: 
ASTX727-02 EMEA AML Submission 
Population: Efficacy Analysis Set 
 
Table xx.x.x 
Analysis of Overall Response 
 
 
 
Sequence A 
(N=xx) 
Sequence B 
(N=xx) 
Total 
(N=xx) 
 
n (%) 
95% CI 
n (%) 
95% CI 
n( %) 
95% CI 
Best Response (1)      
 
 
 
 
 
 
   CR                                 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CRi                                
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
      CRp                              
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   PR                                 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   SD                                
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   PD 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   NE                                 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
 
Composite Response Rates              
 
 
 
 
 
 
   CR + CRi 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CR + CRi + PR  
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CR + CRp  
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CR + CRh         
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
            CRh(2) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
 
The 95% CI is Clopper-Pearson confidence interval. 
CR=complete response; CRp=complete response with incomplete platelet recovery; CRi=CR with incomplete blood count recovery; PR=partial response; SD = Stable Disease; PD = Progressive Disease; 
NE=Not evaluable. Subjects who did not have a valid post-treatment efficacy assessment (ie, no post-treatment BM/PB sample or the quality of BM/PB sample is not adequate for an assessment of efficacy) were 
classified as NE for response classifications.  
(1) Modified 2003 IWG response criteria (Cheson et al. 2003) and DACO-016 CSR was used for CR, CRi, CRp, PR, SD, and PD, and NE. 
(2) Kantarjian et al 2017 was used for the CRh assessment.  
Sequence A: ASTX727 in Cycle 1; IV decitabine in Cycle 2. Sequence B: IV decitabine in Cycle 1; ASTX727 in Cycle 2. 


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Program Location: m:\astx727\02\biostat\phase3_eu\devel\program\tables\t_response1.sas, Data Cut Off: 04JUN2021, Database Extracted: 16JUL2021 
Output: t_14.3.1_response1.rtf (Date Generated: 01SEP2021:13:56), Source Data: ADAMDATA.ADSL, ADRS 
 
(2) ) using 2017 ELN and Kantarjian et al 2017 
<Protocol> 
Population: <Analysis Set> 
 
Table xx.x.x 
Analysis of Overall Response 
 
 
Group 1 
(N=xx) 
... 
(N=xx) 
Total 
(N=xx) 
 
n (%) 
95% CI 
n (%) 
95% CI 
n( %) 
95% CI 
Best Response (1)      
 
 
 
 
 
 
   CR                                 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CRi                                
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   PR                                 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   SD                                
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   PD 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   NE                                 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
 
Composite Response Rates              
 
 
 
 
 
 
   CR + CRi 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CR + CRi + PR  
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
   CR + CRh         
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
            CRh(2) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
xx (xx.x) 
(xx.x, xx.x) 
CR=complete response; CRi=CR with incomplete blood count recovery; PR=partial response; SD = Stable Disease; PD = Progressive Disease; 
NE=Not evaluable. Subjects who did not have a valid post-treatment efficacy assessment (ie, no post-treatment BM/PB sample or the quality of BM/PB sample is not adequate for an assessment of efficacy) were 
classified as NE for response classifications.  
(1) ELN 2017 AML Response Criteria. 
(2) Kantarjian et al 2017 was used for the CRh assessment.  
Group 1: .... 
Program Location: m:\...\devel\program\tables\t_xxx.sas, Data Cut Off: DDMMYYYY, Database Extracted: DDMMYYYY 
Output: t_xx.x.x_xxxx.rtf (Date Generated: DDMMYYYY:HH:MM), Source Data: ADAMDATA.ADSL, ADRS 


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AML Response Assessment Criteria 
Confidential 
 
 
 
 
 
 
Page 19 of 19 
REFERENCES 
2003 IWG: Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin 
Oncol. 2003;21:4642-4649. 
2017 ELN: Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129:424–447. 
CRh: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron 
J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, 
Zimmerman Z, Topp MS. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017 Mar 
2;376(9):836-847. doi: 10.1056/NEJMoa1609783. PMID: 28249141; PMCID: PMC5881572. 
CRp: Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, 
Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in 
patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. 
DACO-016: Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III 
trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients 
with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670–2677. 
ANC counts: Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-425. 
VIALE-A: DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, Koller E, Havelange 
V, Leber B, Esteve J, Wang J, Pejsa V, Hájek R, Porkka K, Illés Á, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong 
WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 
13;383(7):617-629. doi: 10.1056/NEJMoa2012971. PMID: 32786187. 
VIALE-C: Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, 
Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, 
Panayiotidis P. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled 
trial. Blood. 2020 Jun 11;135(24):2137-2145. doi: 10.1182/blood.2020004856. PMID: 32219442; PMCID: PMC7290090.  


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Statistical Analysis Plan – ASTX727-02 (for AML) 
 
 
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15 October 2021 
8.2 
Appendix 2: Summary of Changes 
Rationale for Version 2.0 
Version 2.0 is an update to the AML Response Assessment Criteria. 
Summary of Changes: 
1) Section 3.2.2 The reference for CRp (Kantarjian et al 2012) is added; “ complete response with 
partial hematologic recovery (CRh) will also be assessed as a subset of CRi or CRp” is removed. 
2) Table 2: The criteria for CRi are changed to be consistent with IWG 2003 AML Response 
Criteria (Cheson et al 2003) instead of the protocol. 
3) Section 7.5.1: Progressive disease and stable disease are added based on the European 
LeukemiaNet (Döhner et al 2017). 
4) Section 7.5.2: Changing CRp, CRi to CRi (or CRp) due to that CRp is the subset of CRi 
5) Section 7.5.3: Duration of CR or CRp is added based on DACO-016 (Kantarjian et al 2012). 


Astex Pharmaceuticals, Inc. 
 
ASTX727 
Statistical Analysis Plan – ASTX727-02 (for AML) 
 
 
Confidential Information 
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15 October 2021 
9.0 
REFERENCES 
Cabrero M, Jabbour E, Ravandi F, Bohannan Z, Pierce S, Kantarjian HM, et al. Discontinuation 
of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute 
myelogenous leukemia in complete remission or partial response: retrospective analysis of survival 
after long-term follow-up. Leuk Res. 2015;39(5):520–524. 
Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for 
first-time treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28(4):556–
561. 
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. et al. Revised 
recommendations of the International Working Group for diagnosis, standardization of response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003;21(24):4642–4649.  
Dacogen (decitabine for injection). Prescribing Information. Otsuka America Pharmaceutical, 
Inc.; 2020. Accessed 12 July 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm? 
setid=deb4a13c-855b-4372-9778-6e81da598df6 
Dacogen. Summary of product characteristics. Janssen-Cilag Ltd.; April 2019. Accessed 12 July 
2021. https://www.medicines.org.uk/emc/product/2838/smpc 
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and 
Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 
2020;383(7):617-629.  
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert panel. 
Blood. 2017;129(4):424-447. 
Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, et al. Design, synthesis, and 
pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine 
deaminase. J Med Chem. 2014;57(6):2582–2588. 
Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, MacBeth KJ, et al. Phase I study of oral 
azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid 
leukemia. J Clin Oncol. 2011;29(18):2521–2527. 
Garcia-Manero G, Odenike O, Amrein PC, Steensma DP, DeZern A, Michaelis L, et al. Successful 
emulation of IV decitabine pharmacokinetics with an oral fixed-dose combination of the oral 
cytidine deaminase inhibitor (CDAi) E7727 with oral decitabine, in subjects with myelodysplastic 
syndromes (MDS); Final data of phase 1 study. [Abstract]. Blood. 2016;128:114. 


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Statistical Analysis Plan – ASTX727-02 (for AML) 
Confidential Information 
Page 46 of 46 
15 October 2021 
Garcia-Manero G, Griffiths EA, Steensma DP, Roboz G, Bergeron J, Wells R, et al. Oral 
cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic 
randomized crossover study. Blood. 2020;136(6):674-683. 
INQOVI®. Prescribing Information. Taiho Pharmaceutical Co., Ltd.; 2021. Accessed 12 July 2021. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91a0f80b-f865-4d06-a40d-
4d148d99ee71 
Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res. 2009;15(12):3938–3946. 
Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab 
versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 
2017;376(9):836-847. 
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. 
Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with 
physician advice, of either supportive care or low-dose cytarabine for the treatment of older 
patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670–2677. 
Longo DL et al. 2011. Harrison's principles of internal medicine (18th edition). New York: 
McGraw-Hill Medical Publishing Division.  
Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome of older patients with acute 
myeloid leukemia: an analysis of SEER data over 3 decades. Cancer. 2013;119(15):2720–2727. 
Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A simple method for estimating 
global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 
2004;32(3):e38. 

Prot_000.pdf: 
Official Title: 
NCT Number: 
NCT03306264
Document Dates:
 Protocol Version 2.0: 20 January 2021
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine 
and Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia 
(CMML)


Astex Pharmaceuticals, Inc. 
ASTX727 
Clinical Protocol ASTX727-02 
Confidential Information 
1 
Amendment 2.0 US, 20 January 2021 
Clinical Study Protocol — ASTX727-02 
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and 
Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) 
PROTOCOL TITLE PAGE 
Sponsor: 
Astex Pharmaceuticals, Inc. 
4420 Rosewood Drive, Suite 200 
Pleasanton, CA  94588 
Astex Pharmaceuticals 
MD 
Medical Monitor: 
Astex Pharmaceuticals 
Local Fax: 
 
Clinical Safety and 
E-fax:
Risk Management: 
E-mail:
Global Phone:
IND Number: 
116145 
EudraCT Number: 
2014-005158-20 
Study Clinical Phase: 
Phase 3 
Protocol Version: 
2.0 
Version History/Date: 
Original (06 September 2017) 
Amendment 1.1 Canada (18 January 2018) 
Amendment 1.2 Canada (22 May 2018) 
Amendment 1.3 Europe (10 December 2018) 
Amendment 1.4 Europe (15 April 2019) 


Astex Pharmaceuticals, Inc. 
ASTX727 
Clinical Protocol ASTX727-02 
Confidential Information 
2 
Amendment 2.0 US, 20 January 2021 
Amendment 1.5 Europe (16 May 2019) 
Amendment 1.6 France (26 July 2019) 
Amendment 1.7 Italy (23 August 2019) 
Amendment 1.8 Italy (22 January 2020) 
Amendment 1.9 UK (23 January 2020) 
Amendment 1.10 Czech Republic (24 January 2020) 
Amendment 1.11 Canada (19 February 2020) 
Amendment 1.12 Canada (08 June 2020) 
Amendment 2.0 US (20 January 2021) 
Amendment 2.1 Canada (20 January 2021) 
Amendment 2.2 Czech Republic (20 January 2021) 


Astex Pharmaceuticals, Inc. 
 
ASTX727 
Clinical Protocol ASTX727-02 
 
 
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Amendment 2.0 US, 20 January 2021 
PROTOCOL SYNOPSIS 
Study Number and Title: 
ASTX727-02: A Phase 3, Randomized, Open-Label Crossover Study of ASTX727 (Cedazuridine and Decitabine 
Fixed-Dose Combination) versus IV Decitabine in Subjects with Myelodysplastic Syndromes (MDS) and Chronic 
Myelomonocytic Leukemia (CMML) 
Investigational Drug: ASTX727 (recently approved as INQOVI®) is a film-coated, oval, immediate-release 
tablet of a fixed-dose combination (FDC) of cedazuridine (E7727) (100 mg) and decitabine (35 mg) for oral 
administration. 
Clinical Phase: 3 
Study Centers Planned/Country: Multicenter, North America  
Study Objectives: 
Primary Objective 
• 
To establish decitabine AUC equivalence of 5-day dosing between ASTX727 and IV decitabine. 
Secondary Objectives 
To assess the following: 
• 
Long-term safety and efficacy (response rate) of ASTX727. 
• 
Long interspersed nucleotide elements-1 (LINE-1) demethylation. 
• 
Additional pharmacokinetics (PK) parameters. 
Study Design and Investigational Plan:  
This is a multicenter, randomized, open-label, 2-period, 2-sequence crossover study of ASTX727 versus IV 
decitabine. Adult subjects who are candidates to receive IV decitabine will be randomized in a 1:1 ratio to receive 
the ASTX727 FDC tablet Daily×5 in Cycle 1, followed by IV decitabine 20 mg/m2 Daily×5 in Cycle 2, or the 
converse order. Adequate PK assessments from both cycles will be required for subjects to be evaluable for 
analysis of the primary endpoint. After completion of the first 2 treatment cycles, subjects will continue to receive 
treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, or the subject decides 
to discontinue treatment or withdraw from the study. 
Study Population: 
Inclusion Criteria 
Approximately 132 (at least 118 evaluable) subjects will be enrolled in this study at approximately 60 study 
centers in North America. Subjects must fulfill all of the following inclusion criteria: 
1. Able to understand and comply with the study procedures, understand the risks involved in the study, and 
provide legally effective informed consent before the first study-specific procedure; specifically able to comply 
with the PK assessment schedule during the first 2 treatment cycles. 
2. Men or women ≥18 years who are candidates to receive IV decitabine, ie, subjects with MDS previously treated 
or untreated with de novo or secondary MDS, including all French-American-British subtypes (refractory 
anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with 
excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]), and subjects with MDS 
International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
4. Adequate organ function defined as follows: 
a)  Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); AST/SGOT and ALT/SGPT 
≤2.5 × ULN. 
b)  Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular filtration rate 
>50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal. 
5. No major surgery within 30 days of first study treatment. 
6. Life expectancy of at least 3 months.  
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy 
test at screening. Women of non-childbearing potential are those who have had a hysterectomy or bilateral 
oophorectomy, or who have completed menopause, defined as no menses for at least 1 year AND either age 
≥65 years or follicle-stimulating hormone levels in the menopausal range. 
8. Subjects and their partners with reproductive potential must agree to use effective contraceptive measures 
during the study and for 3 months after the last dose of study treatment. Effective contraception includes 
methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with 
spermicide). 
 


Astex Pharmaceuticals, Inc. 
 
ASTX727 
Clinical Protocol ASTX727-02 
 
 
Confidential Information 
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Amendment 2.0 US, 20 January 2021 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Prior treatment with more than 1 cycle of azacitidine or decitabine.  
2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic 
infection in the 30 days before screening. 
3. Treatment with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever 
is longer, before the first dose of study treatment, or ongoing clinically significant adverse events (AEs) from 
previous treatment. 
4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment. 
5. Concurrent MDS therapies, including lenalidomide, erythropoietin, cyclosporine/tacrolimus, granulocyte-
colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment 
with these agents is permitted, provided that completion is at least 1 week before the first dose of study 
treatment.) 
6. Poor medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled 
infections, or comorbidities that may put the patient at risk of not being able to complete at least 2 cycles of 
treatment. 
7. 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.  
8. Rapidly progressive or highly proliferative disease (total white blood cell count of >15 × 109/L) or other criteria 
that render the subject at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months. 
9. Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive heart failure or 
chronic obstructive pulmonary disease, or other reasons including laboratory abnormalities, which, in the 
investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of 
ASTX727, or compromise completion of the study or integrity of the study outcomes. 
10. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, 
prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject 
has been disease free for at least 2 years. 
11. Hypersensitivity to decitabine, cedazuridine, or any of the excipients in ASTX727 tablets or IV decitabine. 
Study Treatment: 
Investigational medicinal product (IMP): ASTX727 tablet with ~240 mL (8 fluid oz) water Daily×5 every 
28 days. Subjects must fast from food (clear liquids are allowed) 2 hours before and 2 hours after administration. 
No adjustment of dose for weight or body surface area will be made. 
Reference product: IV decitabine 20 mg/m2 as a 1-hour IV infusion Daily×5. 
Study Endpoints: 
Primary Endpoint 
Comparison between ASTX727 and IV decitabine: 
• 
Total 5-day AUC exposures of decitabine after treatment with ASTX727 versus IV decitabine.  
Secondary Endpoints 
• 
Safety as assessed by AEs, concomitant medications, physical examination, clinical laboratory tests 
(hematology and serum chemistry), vital signs, ECOG performance status, and electrocardiogram (ECG). 
• 
Maximum %LINE-1 demethylation. 
• 
Additional secondary PK parameters. 
• 
Clinical response (complete response [CR], marrow complete response [mCR], partial response (PR), and 
hematologic improvement [HI]) based on International Working Group (IWG) 2006 MDS response criteria. 
• 
Red blood cell (RBC) or platelet transfusion independence (TI). 
• 
Leukemia-free survival, defined as the number of days from the date of randomization to the date when bone 
marrow or peripheral blood blasts reach ≥20%, or death from any cause. 
• 
Overall survival (OS), defined as the number of days from the date of randomization to the date of death from 
any cause. 


Astex Pharmaceuticals, Inc. 
 
ASTX727 
Clinical Protocol ASTX727-02 
 
 
Confidential Information 
5 
Amendment 2.0 US, 20 January 2021 
Study Assessments and Procedures: 
Study evaluation visits will occur on Days 1-5, then weekly, in Cycles 1 and 2. Bone marrow samples will be 
collected from subjects at Screening or within 21 days before Cycle 1 Day 1; on or before Day 1 of Cycles 3, 5, 
and 7, then every 3 months in first year and every 6 months thereafter. A manual differential of the myeloid cells 
in bone marrow will be performed with a minimum of 100 cells counted and a specific myeloblast percent 
generated. Complete blood count and differential will be obtained weekly during Cycles 1 and 2 then biweekly in 
Cycles ≥3, with specific output being hemoglobin, platelet count, white blood cell count and percent neutrophils 
(percent polymorphonuclear neutrophils and bands) or an absolute neutrophil count, and percentage of blasts. QTc 
interval will be assessed via routine ECG at Screening and on Day 3 of Cycles 1 and 2. The severity (intensity) of 
AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) for Cancer Clinical Trials, version 4.03.  
Pharmacokinetics Assessments: 
The schedule for PK assessments in Cycles 1 and 2 is as follows:  
• 
ASTX727 cycle: predose on Days 1 through 5; serial collections on Days 1, 2, and 5; collection on Day 3 at 
3 hours. 
• 
IV decitabine cycle: predose on Days 1 and 5; serial collections on Days 1 and 5; collection on Day 3 before 
end of infusion. 
Efficacy Assessments: 
Peripheral blood and bone marrow aspirate or biopsy will be collected and used for response assessments and 
assessment of leukemic transformation. Bone marrow aspirate or biopsy will be performed at Screening (or within 
21 days before Cycle 1 Day 1), on or before Day 1 of Cycles 3, 5, 7, then every 3 months during the first year and 
every 6 months thereafter. Transfusion (blood and platelet) requirements will be recorded monthly. Survival status 
will be monitored and documented throughout the study. 
Pharmacodynamic Assessments 
LINE-1 methylation (in blood) will be measured at the following time points: 
• 
Predose on Day 1 of Cycles 1, 2, and 3. 
• 
Days 8, 15, 22 of Cycles 1 and 2. 
Safety Assessments: 
Safety will be assessed by subject reported and investigator observed AEs, along with concomitant medications, 
physical examination, clinical laboratory tests (hematology, serum chemistry, urinalysis), vital signs, ECOG 
performance status, and ECG. 
Sample Size and Statistical Analyses: 
Sample Size Calculation: 
In a standard 2-period, 2-sequence crossover design under a 1:1 randomization ratio, all treated subjects with 
sufficient PK data will be included in the Primary Endpoint PK Analysis Set. Complete PK will require subjects 
to be successfully dosed and samples to be correctly collected and tested from a minimum of Day 1 and Day 2 or 
5 in the ASTX727 cycle, and Day 1 or 5 in the IV decitabine cycle. The 5-day AUC will be calculated from all 
complete PK data sets in a cycle. A total of 118 subjects in the Primary Endpoint PK Analysis Set included in the 
2 one-sided equivalence tests for the geometric mean ratio of ASTX727 5-day AUC relative to IV decitabine 
5-day AUC will provide 90% power at the statistical significance level of 0.05, when the true ratio of geometric 
means is 1.0, the coefficient of variation (CV) under an unlogged scale is 0.55, and the 90% confidence interval 
(CI) equivalence limits for the ratio of geometric means are 0.8 and 1.25. Assuming 10% of subjects may not be 
evaluable in the study, approximately 132 subjects will need to be randomized. 
Primary Pharmacokinetics Endpoint Analysis: 
The primary endpoint analysis will include data from the following time points to calculate 5-day AUC: 
• 
ASTX727 AUC: Days 1, 2, and 5. 
• 
IV decitabine AUC: Days 1 and 5. 
PK exposure parameters will be estimated for all PK-evaluable subjects based on noncompartmental analysis. The 
primary endpoint of decitabine 5-day AUC will be analyzed in the log scale using the mixed effect model 
including fixed effects of sequence, period, and treatment, and a random effect of subject within sequence. A 90% 
CI for the geometric mean ratio of decitabine 5-day AUC0-t will be obtained by applying the exponential function 
on the 2-sided 90% CI for the difference of mean decitabine 5-day AUC between ASTX727 and IV decitabine in 


Astex Pharmaceuticals, Inc. 
 
ASTX727 
Clinical Protocol ASTX727-02 
 
 
Confidential Information 
6 
Amendment 2.0 US, 20 January 2021 
the log scale from the mixed effect model. The study will be claimed positive if the 90% CI for the geometric 
mean ratio is contained within the interval (0.8, 1.25). 
 
Secondary Endpoint Analyses: 
Safety 
The Safety Analysis Set will include all subjects who received any amount of study treatment. Safety will be 
assessed by incidence, grade, and seriousness of AEs. AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) for Cancer Clinical Trials version 4.03. Treatment exposure, AEs including relatedness and severity, 
serious AEs (SAEs), and reasons for treatment discontinuation will be summarized. Concomitant medication will 
be coded using the WHO Drug Dictionary. 
Efficacy 
Efficacy endpoints will be analyzed for subjects in the Efficacy Analysis Set, defined as the set of all subjects who 
received at least one full dose (day) of study treatment. Proportions of clinical responses will be calculated for 
subjects in the Efficacy Analysis Set, while TI rates will be calculated based on subjects who are transfusion 
dependent at baseline. The 95% Wald CIs will be provided for clinical response rates and TI rates. Leukemia-free 
survival and OS will be presented using Kaplan-Meier estimates along with 95% CIs for medians. 
Pharmacokinetics 
Decitabine PK parameters AUC0-inf, Cmax, Tmax, apparent clearance (CL/F), apparent volume of distribution (Vd/F), 
and apparent half-life (t1/2) are of secondary interest and will be reported with AUC0-t where applicable. The PK 
parameters of cedazuridine and cedazuridine-epimer will be also reported. The secondary endpoint analysis will 
also include population PK for evaluation of various covariates and exposure-response.  
Pharmacodynamics 
All treated subjects with evaluable %LINE-1 data will be included for analysis. Evaluable pharmacodynamic (PD) 
samples will include Day 1 and at least Day 8 or Day 15 methylation results. To avoid the confounding effects of 
differing baselines in Cycle 2 vs Cycle 1 observed in study ASTX727-01, subjects will be compared for each of 
the 2 cycles separately, thus limiting the evaluation to interpatient comparisons in each of the 2 cycles. The 95% 
CI for the difference of mean maximum %LINE-1 demethylation between ASTX727 and IV decitabine in Cycle 1 
will be generated using an analysis of variance (ANOVA) model. The 95% CIs for the maximum %LINE-1 
demethylation will also be generated for ASTX727 and IV decitabine, respectively. 
Study Duration and Termination: 
The expected study duration is approximately 18 months (12 months of enrollment and at least 6 months of 
treatment and follow up). The primary analysis will be conducted after all subjects complete the first 2 cycles.  
Compliance Statement: 
The study will be conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) guidelines, principles enunciated in the Declaration of Helsinki, and all human clinical research 
regulations in countries where the study is conducted. 
 
 


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TABLE OF CONTENTS 
1.0 
INTRODUCTION AND BACKGROUND ....................................................................14 
1.1 
Background of the Disease ....................................................................................14 
1.2 
Background of Treatment Options.........................................................................14 
1.3 
Background of ASTX727 ......................................................................................15 
1.4 
Summary of Nonclinical and Preliminary Clinical Data for ASTX727 ................16 
1.4.1 
General Information ..............................................................................16 
1.4.2 
Nonclinical Data ...................................................................................16 
1.4.3 
Clinical Data and Human Pharmacokinetics.........................................17 
1.5 
Summary of Data for Other Study Treatment ........................................................20 
1.6 
Potential Risks and Benefits to Human Subjects ...................................................20 
2.0 
RATIONALE ...................................................................................................................20 
2.1 
Rationale for the Study ..........................................................................................20 
2.2 
Rationale for ASTX727 Dose and Regimen ..........................................................20 
3.0 
STUDY OBJECTIVES ....................................................................................................21 
3.1 
Primary Objective ..................................................................................................21 
3.2 
Secondary Objectives .............................................................................................21 
4.0 
INVESTIGATIONAL PLAN .........................................................................................21 
4.1 
Overall Study Design .............................................................................................21 
4.2 
Discussion of Study Design ...................................................................................23 
4.3 
Study Endpoints .....................................................................................................23 
4.3.1 
Primary Endpoint ..................................................................................23 
4.3.2 
Secondary Endpoints .............................................................................23 
4.4 
Study Steering Committee .....................................................................................24 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................24 
5.1 
Number of Subjects and Centers ............................................................................24 
5.2 
Inclusion Criteria ...................................................................................................24 
5.3 
Exclusion Criteria ..................................................................................................25 
5.4 
Treatment Discontinuation and Withdrawal of Subjects .......................................26 
5.4.1 
Discontinuation from Study Treatment .................................................26 
5.4.2 
Withdrawal from the Study ...................................................................26 
5.4.3 
Replacement of Subjects .......................................................................27 
6.0 
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES ............27 
6.1 
Randomization .......................................................................................................27 
6.2 
Blinding..................................................................................................................27 
7.0 
STUDY TREATMENTS .................................................................................................27 


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7.1 
Investigational Medicinal Product (IMP) – ASTX727 ..........................................27 
7.2 
IV Decitabine .........................................................................................................27 
7.3 
Study Treatment Storage........................................................................................27 
7.4 
Study Treatment Administration ............................................................................28 
7.5 
Late or Missed ASTX727 Doses ...........................................................................29 
7.5.1 
Cycle 1 or 2 ...........................................................................................29 
7.5.2 
Cycles ≥3 ...............................................................................................29 
7.6 
Guidelines for Adjusting or Withholding Study Treatment ..................................29 
7.7 
Concomitant Treatment .........................................................................................30 
7.7.1 
Supportive, Prophylactic, or Other Treatments ....................................30 
7.7.2 
Prohibited Medications .........................................................................31 
8.0 
RISKS/PRECAUTIONS .................................................................................................31 
8.1 
Drug-Drug Interactions ..........................................................................................31 
8.2 
Genotoxicity ...........................................................................................................31 
8.3 
Overdose Instructions ............................................................................................31 
9.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................32 
9.1 
Pharmacokinetics ...................................................................................................32 
9.2 
Efficacy Assessments .............................................................................................34 
9.3 
Pharmacodynamic Assessments ............................................................................34 
9.4 
Safety Assessments ................................................................................................35 
9.5 
Study Procedures ...................................................................................................35 
9.5.1 
Schedule of Events ................................................................................35 
9.5.2 
Screening / Baseline Procedures ...........................................................38 
9.5.3 
Treatment Procedures............................................................................39 
9.5.3.1 
Cycle 1 – Day 1..............................................................................39 
9.5.3.2 
Cycle 1 – Day 2 through Day 4 .....................................................40 
9.5.3.3 
Cycle 1 – Day 5..............................................................................40 
9.5.3.4 
Cycle 1 – Days 8, 15, 22 ................................................................40 
9.5.3.5 
Cycle 2 – Day 1..............................................................................40 
9.5.3.6 
Cycle 2 – Day 2 through Day 4 .....................................................41 
9.5.3.7 
Cycle 2 – Day 5..............................................................................41 
9.5.3.8 
Cycle 2 – Days 8, 15, 22 ................................................................41 
9.5.3.9 
Cycles ≥3 – Day 1 ..........................................................................42 
9.5.3.10 
Cycles ≥3 – Day 15 ........................................................................42 
9.5.4 
Treatment Discontinuation ....................................................................42 
9.5.5 
30-Day Follow Up ................................................................................42 


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9.5.6 
Survival/Conversion to AML ................................................................43 
9.6 
Missed Evaluations ................................................................................................43 
10.0 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ......43 
10.1 
Definitions..............................................................................................................43 
10.1.1 
Adverse Event .......................................................................................43 
10.1.2 
Serious Adverse Events.........................................................................44 
10.2 
Adverse Event Reporting and Descriptions ...........................................................44 
10.2.1 
Severity .................................................................................................45 
10.2.2 
Relationship to Study Treatment (Suspected Adverse Reactions) ........45 
10.2.3 
Pregnancy and Abortion ........................................................................46 
10.3 
Reporting Requirements for Serious Adverse Events (SAEs) ...............................47 
10.4 
Follow-up for Adverse Events ...............................................................................47 
11.0 
STATISTICS ....................................................................................................................48 
11.1 
Sample Size ............................................................................................................48 
11.2 
Analysis Sets to be Analyzed .................................................................................48 
11.2.1 
All Subject Analysis Set .......................................................................48 
11.2.2 
Pharmacokinetics Analysis Sets ............................................................48 
11.2.3 
Efficacy Analysis Set ............................................................................49 
11.2.4 
Safety Analysis Set ...............................................................................49 
11.2.5 
Pharmacodynamics Analysis Set ..........................................................49 
11.3 
Schedule of Analyses .............................................................................................49 
11.4 
Subject Disposition ................................................................................................50 
11.5 
Analysis of Demographic and Baseline Data ........................................................50 
11.6 
Pharmacokinetics Analyses ...................................................................................50 
11.6.1 
Primary Pharmacokinetics Endpoint Analyses .....................................50 
11.6.2 
Other Pharmacokinetics Variables ........................................................51 
11.7 
Efficacy Analyses ..................................................................................................52 
11.7.1 
Clinical Response ..................................................................................52 
11.7.2 
Transfusion Independence ....................................................................52 
11.7.3 
Leukemia-Free Survival ........................................................................52 
11.7.4 
Overall Survival ....................................................................................52 
11.8 
Safety Analyses ......................................................................................................53 
11.9 
Pharmacodynamics Analyses .................................................................................53 
11.10 Interim Analysis .....................................................................................................54 
11.11 Procedures for Handling Missing, Unused, and Spurious Data.............................54 
12.0 
STUDY DURATION AND TERMINATION ...............................................................54 


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13.0 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ...............................54 
13.1 
Compliance Statement ...........................................................................................54 
13.2 
Informed Consent...................................................................................................54 
13.3 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) ...........55 
14.0 
ADMINISTRATIVE PROCEDURES ...........................................................................55 
14.1 
Sponsor Responsibilities ........................................................................................55 
14.1.1 
Study Supplies .......................................................................................56 
14.1.2 
Investigator Training .............................................................................56 
14.1.3 
Ongoing Communication of Safety Information During the Study ......56 
14.1.4 
Study Monitoring ..................................................................................56 
14.1.5 
Study Auditing and Inspecting ..............................................................57 
14.2 
Investigator Responsibilities ..................................................................................57 
14.2.1 
Subject Screening Log ..........................................................................57 
14.2.2 
Study Treatment Accountability ...........................................................57 
14.2.3 
Reporting and Recording of Study Data ...............................................58 
14.2.4 
Source Documentation ..........................................................................58 
14.2.5 
Tissue and Blood Sample Collection/Storage .......................................59 
14.2.6 
Records Retention .................................................................................59 
14.3 
Clinical Trial Insurance ..........................................................................................60 
14.4 
Study Administrative Letters and Protocol Amendments .....................................60 
15.0 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA ........................61 
16.0 
REFERENCES .................................................................................................................62 
17.0 
APPENDICES ..................................................................................................................65 
 
LIST OF TABLES 
Table 1: 
Summary of Cedazuridine (E7727) In Vitro Pharmacology Studies .........16 
Table 2: 
Summary of Cedazuridine (E7727) In Vivo Pharmacology Studies .........16 
Table 3: 
Decitabine AUC – Dose Escalation Stage (Phase 1) of ASTX727-01 ......18 
Table 4: 
AUC Equivalence Analysis Based on 5-Day AUC Estimates – Dose 
Confirmation Stage (Phase 2) of ASTX727-01 .........................................18 
Table 5: 
Dosing Schedule by Day and Cycle...........................................................28 
Table 6: 
Schedule of Pharmacokinetics Assessments – ASTX727 Cycle ...............33 
Table 7: 
Schedule of Pharmacokinetics Assessments – IV Decitabine Cycle .........33 
Table 8: 
Response Categories Based on IWG 2006 MDS Response Criteria .........34 
Table 9: 
Schedule of Events .....................................................................................36 
Table 10: 
Clinical Laboratory Tests ...........................................................................39 


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LIST OF FIGURES 
Figure 1: 
LINE-1 Demethylation in Cynomolgus Monkeys – Cedazuridine 
(E7727) + Oral Decitabine: Three Dose Groups Daily×5 at 2 mg/kg .......17 
Figure 2: 
Individual and Mean Decitabine AUC after ASTX727 Administration 
or IV Decitabine Infusion (N=43) – Dose Confirmation Stage 
(Phase 2) of ASTX727-01 .........................................................................19 
Figure 3: 
Study Schema.............................................................................................22 
 
LIST OF APPENDICES 
Appendix 1: 
ECOG and Karnofsky Performance Status ................................................66 
Appendix 2: 
Common Terminology for Adverse Events v4.0 (CTCAE v4.03) ............67 
Appendix 3: 
Modifications During the COVID-19 Health Emergency .........................68 
Appendix 4: 
Summary of Changes .................................................................................71 
 


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ABBREVIATIONS AND DEFINITIONS 
ADL 
activities of daily living 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ATC 
Anatomical Therapeutic Chemical  
AUC 
area under the curve 
BLQ 
below the limit of quantitation 
CBC 
complete blood count 
CDA 
cytidine deaminase 
CDAi 
CDA inhibitor 
cedazuridine 
International Nonproprietary Name for E7727 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
clearance 
Cmax 
maximum concentration 
CMML 
chronic myelomonocytic leukemia 
CRF/eCRF 
case report form/electronic case report form 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DAC 
Dacogen® 
DNMT 
DNA methyltransferase 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EMEA 
European Agency for the Evaluation of Medicinal Products 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
HDPE 
high density polyethylene 
HI 
hematologic improvement 
HI-E 
erythroid response  
HI-N 
neutrophil response 
HI-P 
platelet response 
HMA 
hypomethylating agent 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee  
IMP 
investigational medicinal product (the specific Astex drug product under study) 
IND 
Investigational New Drug 
int 
intermediate 
IPSS 
International Prognostic Scoring System 


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IRB 
Institutional Review Board 
IV 
intravenous 
IWG 
International Working Group 
LINE-1 
long interspersed nucleotide elements-1 
mCR 
marrow complete response 
MDS 
myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
multiple gated acquisition scan 
NCE 
new chemical entity 
NCI 
National Cancer Institute 
OS 
overall survival 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
Preferred Term 
RBC 
red blood cell 
SAE 
serious adverse event 
SOC 
System Organ Class 
SD 
standard deviation 
SSC 
Study Steering Committee 
SUSAR 
serious unexpected suspected adverse reaction 
t1/2 
half life 
TEAE 
treatment-emergent adverse event 
TI 
transfusion independence 
tmax 
time to reach maximum concentration 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
Vd/F 
apparent volume of distribution 
WHO 
World Health Organization 


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The study will be conducted in accordance with the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines; 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 
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell 
disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic 
progenitors and associated with cytopenias affecting one or more of the three lineages (Bennett 
1982; Cheson et al 2000; Heaney and Golde 1999; Kantarjian and Estey 2001). Most MDS patients 
are elderly, and their prognosis (with high-risk factors) is poor (Garcia-Manero 2015). Patients 
often present with complications related to anemia (fatigue), neutropenia (infections), or 
thrombocytopenia (bleeding). In addition, variable blast expansion, and, less commonly, 
leukocytosis are observed. MDS may evolve into acute myeloid leukemia (AML) in 10% to 70% 
of patients. 
Prognosis for MDS patients is poor: patients die either from complications associated with 
cytopenias (infections and bleeding) or from transformation to AML. In practice, "lower risk" 
MDS patients may be distinguished from "higher risk" MDS patients by their degree of pre-
leukemic blast expansion, responses to therapeutic agents, disease outcomes, and prognosis  
(Bejanyan and Sekeres 2011). These factors have allowed the establishment of an International 
Prognostic Scoring System (IPSS) to predict survival and progression to AML (Greenberg et al 
1997) as well as aiding treatment decisions. 
Based on the IPSS scoring system, patients with lower risk (IPSS low risk or intermediate  
[int]-1) MDS (approximately 70% of patients) have an expected median survival of 3.5 to 
5.7 years. Median survival for higher risk patients (int-2 and high-risk MDS) ranges from 0.4 to 
1.2 years (Greenberg et al 1997). 
1.2 
Background of Treatment Options 
Hypomethylating agents (HMAs), such as decitabine and azacitidine, are effective treatment 
modalities for hematologic cancers and are FDA-approved for higher risk MDS and chronic 
myelomonocytic leukemia (CMML). HMAs have also shown promising clinical activity in AML. 
Consecutive daily dosing for 5 or 7 days in 28-day cycles are the approved schedules. Continued 
monthly treatment for patients who respond is now the standard of care to avoid early relapse 
(Cabrero et al 2015). Treatment, which may continue for several months or even years, may 
engender significant hardship due to the 5 to 7 daily visits required each month, and the 1-hour 
intravenous (IV) infusion or large-volume subcutaneous injections. A possible consequence is 
non-compliance or premature discontinuation. Development of a formulation for convenient oral 
administration of HMAs has proven difficult due to rapid metabolism by cytidine deaminase 
(CDA) during passage through the gastrointestinal (GI) mucosa and liver. To achieve even modest 


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exposures of drug requires administration of large doses, which are associated with Grades 3 and 
4 GI toxicity (nausea, vomiting, and diarrhea) and high variability in exposures (Garcia-Manero 
et al 2011). Successful development of an oral HMA will alleviate the significant inconvenience 
of long-duration parenteral therapy, particularly for those patients who may benefit most. 
1.3 
Background of ASTX727 
Astex Pharmaceuticals has developed an oral drug product, ASTX727 (recently approved as 
INQOVI® [current INQOVI Prescribing Information]), which is composed of the new chemical 
entity (NCE) cedazuridine (E7727; 100 mg), a CDA inhibitor (Ferraris et al 2014), and 35 mg 
decitabine. In animal models, dose-dependent increases in decitabine exposures were achieved 
when increasing doses of cedazuridine were administered with oral decitabine (refer to the 
ASTX727 Investigator Brochure [IB]). This interaction effect was demonstrated in CD2F1 mice, 
rhesus monkeys, and in cynomolgus monkeys, supporting the mechanism of action of improved 
pharmacokinetics (PK) for the combination of cedazuridine with oral decitabine. Because 
cedazuridine inhibits CDA in the gut and liver, ASTX727 reduces first pass metabolism of 
decitabine thus enhancing the bioavailability of decitabine and achieving exposure and 
hypomethylation activity similar to IV decitabine at the currently approved dosing schedule of 
20 mg/m2 Daily×5. Decitabine was approved in 2006 by the United States Food and Drug 
Administration (US FDA) as Dacogen® (decitabine) (current Dacogen Prescribing Information), 
administered as a 1-hour IV infusion for the treatment of higher risk patients with MDS and 
CMML.  
Decitabine is a cytidine analog that profoundly inhibits DNA methylation by incorporating into 
DNA and subsequently forming covalent bonds with DNA methyltransferase (DNMT) (Issa and 
Kantarjian 2009). This enzyme deficiency renders the cell unable to maintain DNA methylation 
after cellular replication, resulting in effective DNA demethylation and re-expression of previously 
silenced genes. The analysis of the methylation of repetitive genomic elements, as in the long 
interspersed nucleotide elements (LINE-1) that are normally heavily methylated, represents a 
pharmacodynamic surrogate marker for global DNA methylation (Yang et al 2004). 
The Astex ASTX727 program's completed Phase 1-2 first-in-human trial, ASTX727-01, was a 
PK-guided dose escalation and dose confirmation study of ASTX727 in patients with MDS and 
CMML intended to define appropriate doses of the individual components of ASTX727 
(cedazuridine + decitabine) so that decitabine exposure after oral administration of ASTX727 is 
comparable to exposure after IV decitabine at the approved daily dose of a 1-hour infusion at 
20 mg/m2. Results showed that ASTX727 enables therapeutic dose-dependent increases in 
decitabine exposure to therapeutic levels and achieves demethylation and clinical activity 
comparable to IV decitabine at the FDA approved 5-day dose regimen using fixed doses of 35 mg 
decitabine and 100 mg cedazuridine (Garcia-Manero 2016, Garcia-Manero et al 2020; current 
Dacogen Prescribing Information). 
The main purpose of the current study is to demonstrate AUC equivalence of ASTX727 to IV 
decitabine. 


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1.4 
Summary of Nonclinical and Preliminary Clinical Data for ASTX727 
1.4.1 
General Information 
General information on ASTX727 is located in Section 7.1 of this protocol. ASTX727 is an oral 
fixed-dose combination tablet containing cedazuridine (E7727, a CDA inhibitor) and decitabine. 
1.4.2 
Nonclinical Data 
Refer to the ASTX727 IB for more detailed nonclinical information on the components of 
ASTX727 (cedazuridine + decitabine). A summary is given below. 
In vitro safety pharmacology studies performed with various concentrations of cedazuridine are 
summarized in Table 1. 
Table 1: 
Summary of Cedazuridine (E7727) In Vitro Pharmacology Studies 
Title 
System 
Key Findings for Cedazuridine (E7727) 
Effect of E7727 on the Half-life of Gemcitabine 
in the Presence of CDA in 100 mM pH 7.4 
Tris-HCl Buffer at 37°C 
Stability study  
Gem T½ +CDA ≤36 min 
Gem T½ +CDA +E7727 ≥66 h 
Determination of IC50 and Binding Constant 
(Ki) of MGI 25208 
Human recombinant 
CDA 
IC50 = 400 nM, Ki = 400 nM 
Determination of E7727 and ER-876437 IC50 
against human recombinant Cytidine 
Deaminase (CDA) 
Human recombinant 
CDA 
IC50 = 281 ± 100 nM 
Measurement of antiproliferative activity of 
E7727 in HCC827, NCI-H820, NCI-H1650, 
EVSA-T, MDA-MB-231, HCT-116, HL60, and 
THP-1 cell lines 
Human cell lines 
No significant inhibition of any cell line 
tested 
In vivo pharmacology studies performed to determine the effect of cedazuridine on anticancer 
activity of oral decitabine are summarized in Table 2. 
Table 2: 
Summary of Cedazuridine (E7727) In Vivo Pharmacology Studies 
Title 
System 
Key Findings for Cedazuridine (E7727) 
Effect of E7727 on in vivo anticancer activity of 
oral decitabine against CD2-F1 mouse L1210 
disseminated model 
L1210 mouse ALL 
disseminated model 
All 3 dose levels of E7727 (1, 10, and 
100 mg/kg) + 0.4 mg/kg oral decitabine 
have significant antitumor activity 
Effect of E7727 on in vivo anticancer activity of 
oral decitabine against KG-1 human AML 
disseminated model 
KG-1 human AML 
disseminated model 
All 3 doses of E7727 (1, 10, and 
100 mg/kg) + 0.3 mg/kg oral decitabine 
have significant antitumor activity 
The pharmacodynamics (PD) of oral decitabine + cedazuridine were demonstrated in a one-cycle 
study in cynomolgus monkeys in which decitabine was administered at 2 mg/kg with cedazuridine 
doses of 1, 3, or 6 mg/kg Daily×5, followed by 23 days of no dosing. Demethylation of LINE-1 


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sequences was seen for all 3 treatment groups, with the maximum demethylation of -17.4% 
to -24.5% achieved at Day 11. 
Figure 1: 
LINE-1 Demethylation in Cynomolgus Monkeys – Cedazuridine 
(E7727) + Oral Decitabine: Three Dose Groups Daily×5 at 2 mg/kg 
 
Source: Oganesian et al 2013. 
Safety pharmacology studies conducted to date do not highlight an off-target concern for 
cardiovascular or other organ systems. 
1.4.3 
Clinical Data and Human Pharmacokinetics 
Refer to the ASTX727 IB for more detailed clinical information. A summary is given below. 
In the Phase 1 (dose escalation) part of study ASTX727-01, oral cedazuridine and decitabine were 
administered concomitantly and each escalated separately to identify a dose combination that 
delivers oral decitabine AUC similar to that for 1-hour IV decitabine infusion at 20 mg/m2. Five 
different dose combinations were evaluated, with Cohort 4 (100 mg cedazuridine and 40 mg 
decitabine) achieving 144% of IV decitabine AUC, while the Cohort 5 expansion at 100 mg 
cedazuridine and 30 mg decitabine produced 85% of IV decitabine AUC (Table 3).  


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Table 3: 
Decitabine AUC – Dose Escalation Stage (Phase 1) of ASTX727-01 
Subjects Who Completed Cycle 1 (N=43); Data are Geometric Mean (CV%) 
 
Oral Dosea (mg) 
 
AUClast by Day (ng*h/mL) 
Geometric Mean (CV%) 
 5-Days Total  
AUClast 
% of AUC 
(Oral/IV) 
Cohort DAC cedazuridine N 
D −3 
D2 
D5 
IV D1 
 Oral 
IV 
1 
20 
40 
6 11.4 (98) 
46.8 (139) 
74.0 (95) 
174 (51) 
 
345 
872 
40 
 
 
 
5b 
8.67 (50) 
32.0 (60) 
56.7 (36) 
151 (38) 
 
260 
753 
35 
2 
20 
60 
6 
8.21 (63) 
32.8 (47) 
77.5 (33) 
180 (34) 
 
346 
899 
39 
3 
20 
100 
6 
8.72 (75) 
57.5 (51) 
106 (46) 
198 (40) 
 
482 
992 
49 
4 
40 
100 
6 32.2 (73) 175 
(46) 
234 (59) 
155 (44) 
 1120 
775 
144 
5 
30 
100 
19c 16.8 (66) 
87.3 (65) 
153 (50) 
170 (35) 
 
701 
852 
85 
DAC=Dacogen 
a 
Oral dosing was not body weight or body surface area adjusted. IV dose was 20 mg/m2 in all cohorts. 
b 
Data presented with one subject in Cohort 1 excluded as an extreme outlier. 
c 
IV used n=18 as one subject was excluded as an extreme outlier.  
Source: DE DAC  AUClast_(n=43 and n=42 w Cht1=5)_EOP. 
Based on this outcome, a dose combination of 100 mg cedazuridine with 35 mg decitabine (ie, 
intermediate dose between 30 mg and 40 mg) was selected for the Phase 2 randomized, crossover 
(dose confirmation) stage, wherein full-cycle AUC exposures from oral ASTX727 were compared 
with full-cycle IV AUC. Based on data from 43 subjects, ASTX727 achieved 95.5% of IV AUC 
and met the equivalence test based on a 90% confidence interval (CI) and margins of 0.8-1.25 
(Table 4 and Figure 2).  
Table 4: 
AUC Equivalence Analysis Based on 5-Day AUC Estimates – Dose 
Confirmation Stage (Phase 2) of ASTX727-01 
 
 
 
Adjusted 
Geometric  
Means 
Ratio of Adjusted Geometric Means 
Population 
N 
Treatment 
Estimate 
90% Confidence 
Interval 
PK Analysis Set 
43 
cedazuridine + decitabine 
769.194 
0.955 
( 0.806, 1.133) 
IV decitabine 
805.130 
-- 
 
Source: PK_Bioavailability.rtf. 


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Figure 2: 
Individual and Mean Decitabine AUC after ASTX727 Administration 
or IV Decitabine Infusion (N=43) – Dose Confirmation Stage 
(Phase 2) of ASTX727-01 
 
Source: DC DAC AUC (n=43)_by Day_EOP_Fig 12. 
After dosing with ASTX727, decitabine AUC exposures were higher on Days 2-5 vs Day 1 of 
dosing. However, Day 5 decitabine exposures appeared to be the same as on Day 2; this was 
consistent with the similar and consistent presence of trough cedazuridine levels predose on Days 2 
through 5, which also explains the lower exposure on Day 1 due to absence of any cedazuridine 
exposure before the first dose of ASTX727. To account for the lower exposures on Day 1, the 
estimated total AUC from 5 days of dosing with IV decitabine was compared with the AUC from 
5 days of dosing with ASTX727 imputed from a 5-day model.  
The variability of decitabine AUC exposures was slightly higher after administration of the oral 
combination, compared with IV infusion. This was expected, as IV dosing is adjusted for body 
surface area, whereas the oral dose was fixed for all subjects regardless of body weight. Despite 
the somewhat higher variability for decitabine AUC after the oral combination, the AUC 
equivalence analysis showed that the oral combination achieved a mean decitabine AUC ratio of 
0.955 with the 90% CI of 0.806, 1.133 based on N=43 subjects. 
Recently, the first PK analysis from Phase 3 study ASTX727-02 based on 123 treated subjects 
with MDS and CMML with complete PK data was presented. PK data from the first 2 cycles 
comparing oral ASTX727 to IV decitabine showed 5-day cycle decitabine AUC0-24 oral/IV ratio 
of 98.9% with a very narrow 90% CI of 92.7% to 105.6%, confirming equivalent decitabine 
exposure between oral and IV with high confidence (Garcia-Manero et al 2019). There were no 
subjects in whom there was no systemic decitabine exposure after oral ASTX727. 
Day 1
Day 2
Day 5
IV 
DAC AUClast (h*ng/mL)
10
100
1000
xxxxx
xxxxx
xxxxx
Oral ASTX727 Mean
xxxxx
 IV DAC Mean
Day of Dosing 
161


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1.5 
Summary of Data for Other Study Treatment 
The comparator product to be used in this trial is IV decitabine, for which the mechanism of action, 
prescribing information, and critical clinical data are provided in the FDA-approved Dacogen 
package insert (current Dacogen Prescribing Information). 
1.6 
Potential Risks and Benefits to Human Subjects 
No safety issues have been identified to date with ASTX727 that are inconsistent with the safety 
profile of IV decitabine. Blood levels of ASTX727 (at 100 mg cedazuridine and 35 mg decitabine) 
in study ASTX727-01 have been shown to be similar to levels seen after 1-hour IV infusion with 
20 mg/m2 decitabine. Risks of ASTX727 in humans are described further in Section 8.0. For more 
detailed information, please refer to the IB for ASTX727. 
Most cancer patients prefer oral to injectable drug formulations (Liu et al 1997); an oral HMA will 
alleviate the inconvenience of potential long-duration parenteral therapy as well as the hardship 
involved with the clinic visits associated with a drug that must be administered intravenously. This 
is of particular importance considering the prevalence of this disease in the elderly and the need 
for continued monthly treatment potentially for years, particularly for those patients who respond 
to treatment and benefit the most. An oral drug may also improve compliance with 5 days/month 
treatment. 
2.0 
RATIONALE 
2.1 
Rationale for the Study 
This Phase 3 study will establish AUC equivalence of ASTX727 to IV decitabine in a randomized, 
crossover design in approximately 118 evaluable subjects comparing 5-day AUC from Cycle 1 
and Cycle 2 as the primary endpoint. Preliminary data from study ASTX727-01 show that 
ASTX727 enhances oral bioavailability of decitabine, permitting the achievement of exposures 
similar to IV decitabine at the currently approved dosing schedule of 20 mg/m2 Daily×5 using 
similar doses of oral decitabine (35 mg). 
2.2 
Rationale for ASTX727 Dose and Regimen 
Data from the Dose Escalation Stage (Phase 1) of study ASTX727-01 show that a fixed dose of 
100 mg cedazuridine, and decitabine doses of 30 mg and 40 mg, achieved an AUC of 85% and 
144% respectively of that of IV decitabine over 5 days of dosing (Table 3). The Dose Confirmation 
Stage (Phase 2) was therefore conducted using the combination of cedazuridine 100 mg with 
decitabine 35 mg as an intermediate dose between the 30 mg and 40 mg evaluated in Phase 1. That 
dose combination achieved 95% of IV decitabine AUC and reached the 90% equivalence margin 
of 0.80-1.25 (Table 4). Dosing of ASTX727 in Phases 1 and 2 of study ASTX727-01 was 
conducted using separate capsules of cedazuridine and decitabine administered concomitantly to 
titrate dose. A new FDC tablet formulation was manufactured after the doses of the 2 components 
(100 mg cedazuridine and 35 mg decitabine) were established and is under investigation in Phase 2 


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of ASTX727-01. A study in cynomolgus monkeys (BioDuro Study Report APL-FFS-PK-
20160512-01) has shown that PK data were similar between the FDC tablet and the capsule 
formulations. 
Protocol ASTX727-01 was then amended primarily to confirm the PK data, using the new FDC 
tablet formulation in 24 subjects using a crossover design (FDC Stage) as in the Dose Confirmation 
Stage. Preliminary data from the FDC stage of ASTX727-01 show the 5-day AUC ratio of 
approximately 1.05 between ASTX727 tablets and IV decitabine. 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
• To establish decitabine AUC equivalence of 5-day dosing between ASTX727 and IV 
decitabine. 
3.2 
Secondary Objectives 
To assess the following: 
• Long-term safety and efficacy (response rate) of ASTX727. 
• LINE-1 demethylation. 
• Additional pharmacokinetics (PK) parameters. 
4.0 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 3, multicenter, randomized, open-label, 2-period, 2-sequence crossover study 
comparing decitabine AUC equivalence of ASTX727 and IV decitabine. Adult subjects with MDS 
or CMML who are candidates to receive decitabine will be randomized in a 1:1 ratio to receive 
the ASTX727 FDC tablet Daily×5 in Cycle 1, followed by IV decitabine 20 mg/m2 Daily×5 in 
Cycle 2, or the converse order (Figure 3). Adequate PK assessments from Cycles 1 and 2 will be 
required for subjects to be evaluable for analysis of the primary endpoint. After completion of the 
first 2 treatment cycles, subjects will continue to receive treatment with ASTX727 in 28-day cycles 
until disease progression, unacceptable toxicity, or the subject decides to discontinue treatment or 
withdraw from the study. 
Assessment of efficacy and safety of ASTX727 in the patient population requires multiple cycles 
and is critical to measure all the secondary clinical endpoints (response rate, transfusion 
independence, survival, and adverse events). The only way to be able to measure these important 
clinical endpoints of the study, is for patients to receive ASTX727 from Cycle 3 onwards after 
completing the PK component in the first 2 cycles.  
As of the effective date of this protocol amendment, the COVID-19 health emergency is altering 
the way clinical studies are being conducted, such that alternative measures are being implemented 


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to ensure the safety of subjects and maintain the integrity of clinical trial data. Appendix 3 provides 
information regarding potential modifications to the conduct of the study. 
Figure 3: 
Study Schema 
 
 


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4.2 
Discussion of Study Design 
The clinical efficacy and safety of decitabine in MDS and CMML have been established 
previously, with a favorable benefit-risk that led to approval for treatment of these conditions. The 
approach for establishing the safety and effectiveness of ASTX727 is based on a PK bridging 
approach in which the primary study endpoint is 5-day cumulative AUC equivalence between 
ASTX727 and IV decitabine at the approved 5-day dose regimen. Data from study ASTX727-01 
showed that similar daily dose exposure profiles between the IV and orally administered drug 
resulted in similar clinical activity and safety, consistent with the known profile of decitabine IV. 
Demonstration that the mean 5-day cumulative exposure of decitabine from oral ASTX727 is 
equivalent to the approved IV regimen would predict similar clinical performance from the two 
drugs. The crossover design of the first 2 cycles in the current study allows robust PK analysis. 
The washout period between the 2 cycles (ie, Days 6-28) is appropriate, and no decitabine or 
cedazuridine is expected to be present predose at Cycle 2 Day 1. Continuation of ASTX727 
treatment from Cycle 3 onwards would confirm longer term activity and safety of the oral 
compound. Assessment of efficacy and safety are not conditional upon achieving the PK primary 
endpoint in this study, but are an independent component for acquiring data necessary to support 
marketing application (PK, efficacy, and safety data of ASTX727 at the selected fixed doses of 
100 mg cedazuridine and 35 mg decitabine). The treatment of subjects with ASTX727 at the 
selected doses in this study is supported by data from Phase 1 and Phase 2 (Garcia-Manero et al 
2020; Savona et al 2019) that showed that ASTX727 at these doses produce equivalent exposure 
to IV decitabine at 20 mg/m2 and achieves comparable efficacy and safety in a Phase 2 study in 
MDS and CMML. 
4.3 
Study Endpoints 
4.3.1 
Primary Endpoint 
Comparison between ASTX727 and IV decitabine: 
• Total 5-day AUC exposures of decitabine after treatment with ASTX727 versus IV decitabine. 
4.3.2 
Secondary Endpoints 
• Safety as assessed by AEs, concomitant medications, physical examination, clinical laboratory 
tests (hematology, serum chemistry, and urinalysis), vital signs, Eastern Cooperative Oncology 
Group (ECOG) performance status, and electrocardiogram (ECG). 
• Maximum %LINE-1 demethylation. 
• Additional secondary PK parameters. 
• Clinical response (complete response [CR], marrow complete response [mCR], partial 
response (PR), and hematologic improvement [HI]) based on International Working Group 
(IWG) 2006 MDS response criteria. 
• Red blood cell (RBC) or platelet transfusion independence (TI). 


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• Leukemia-free survival, defined as the number of days from the date of randomization to the 
date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. 
• Overall survival (OS), defined as the number of days from the date of randomization to the 
date of death from any cause. 
4.4 
Study Steering Committee 
The Study Steering Committee (SSC) will comprise the principal investigators (or designees), 
medical monitor, study director, PK director, and other study team members as appropriate and 
will review available clinical data on a predetermined schedule. The SSC may recommend changes 
to the study based on emerging data.  
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects and Centers 
Approximately 132 (at least 118 evaluable) subjects will be enrolled in this study at approximately 
60 study centers in North America. 
5.2 
Inclusion Criteria 
To be eligible for the study, subjects must fulfill all of the following inclusion criteria: 
1) Able to understand and comply with the study procedures, understand the risks involved in the 
study, and provide legally effective informed consent before the first study-specific procedure; 
specifically able to comply with the PK assessment schedule during the first 2 treatment cycles. 
2) Men or women ≥18 years who are candidates to receive IV decitabine, ie, subjects with MDS 
previously treated or untreated, with de novo or secondary MDS, including all French-
American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, 
refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, 
and CMML), and subjects with MDS IPSS int-1, -2, or high-risk MDS. 
3) ECOG performance status of 0 to 1. 
4) Adequate organ function defined as follows: 
a) Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); AST/SGOT and 
ALT/SGPT ≤2.5 × ULN. 
b) Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular 
filtration rate >50 mL/min/1.73 m2 for subjects with creatinine levels above institutional 
normal. 
5) No major surgery within 30 days of first study treatment. 
6) Life expectancy of at least 3 months. 


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7) Women of child-bearing potential must not be pregnant or breastfeeding and must have a 
negative pregnancy test at screening. Women of non-childbearing potential are those who have 
had a hysterectomy or bilateral oophorectomy, or who have completed menopause, defined as 
no menses for at least 1 year AND either age ≥65 years or follicle-stimulating hormone levels 
in the menopausal range. 
8) Subjects and their partners with reproductive potential must agree to use effective 
contraceptive measures during the study and for 3 months after the last dose of study treatment. 
Effective contraception includes methods such as oral contraceptives or double-barrier method 
(eg, use of a condom AND diaphragm, with spermicide). 
5.3 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1) Prior treatment with more than 1 cycle of azacitidine or decitabine.  
2) Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, 
or systemic infection in the 30 days before screening. 
3) Treatment with any investigational drug or therapy within 2 weeks of study treatment, or 
5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically 
significant adverse events (AEs) from previous treatment.  
4) Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study 
treatment. 
5) Concurrent MDS therapies, including lenalidomide, erythropoietin, cyclosporine/tacrolimus, 
granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating 
factor, etc. (Prior treatment with these agents is permitted, provided that completion is at least 
1 week before the first dose of study treatment.) 
6) Poor medical risk because of other conditions such as uncontrolled systemic diseases, active 
uncontrolled infections, or comorbidities that may put the patient at risk of not being able to 
complete at least 2 cycles of treatment. 
7) 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. 
8) Rapidly progressive or highly proliferative disease (total white blood cell count of 
>15 × 109/L) or other criteria that render the subject at high risk of requiring intensive cytotoxic 
chemotherapy within the next 3 months. 
9) Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive 
heart failure or chronic obstructive pulmonary disease, or other reasons including laboratory 
abnormalities, which, in the investigator's opinion, could compromise the subject's safety, 
interfere with the absorption or metabolism of ASTX727, or compromise completion of the 
study or integrity of the study outcomes. 


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10) Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ 
cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other 
cancer from which the subject has been disease free for at least 2 years. 
11) Hypersensitivity to decitabine, cedazuridine, or any of the excipients in ASTX727 tablets or 
IV decitabine. 
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. 
Astex Pharmaceuticals may stop the study at any time. In this event, Astex will make reasonable 
efforts to ensure subjects are appropriately transitioned off study. 
5.4.1 
Discontinuation from Study Treatment 
Contact the Astex medical monitor before discontinuing treatment for a given subject.  
Subjects who discontinue study treatment at any time will be followed for safety (Section 10.2). 
Subjects will be followed for survival/conversion to AML according to Section 9.5.6. 
• 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.  
Notwithstanding the above, every attempt should be made for subjects to complete at least the first 
2 cycles of treatment and the corresponding PK assessments to minimize the number of non-
evaluable subjects and safeguard the integrity of the study primary endpoint. 
In all cases, the reason(s) for discontinuation from study treatment must be recorded in the source 
document and on the relevant page of the subject's electronic case report form (eCRF).  
5.4.2 
Withdrawal from the Study 
Subjects may withdraw consent for the study at any time; the specific reason for withdrawal must 
be obtained. It is important to obtain follow-up information, according to standard medical 
practice, on any subject who prematurely withdraws from the study. Every effort must be made to 
obtain at least the assessments that are critical for efficacy or safety evaluation (eg, disease 
response, survival, safety assessments), unless the subject withdraws consent from further follow up.  


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5.4.3 
Replacement of Subjects 
Enrollment of subjects will continue until the required number of 118 evaluable subjects is 
reached. 
6.0 
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES 
After providing legally effective informed consent, subjects will be screened at each study center 
for assessment of study eligibility. Eligibility will be further confirmed by the medical monitor 
prior to randomization of the subject. At screening, each subject will be assigned a unique number 
(subject identification [ID] number) consisting of 6 digits; the first 3 digits will reflect the study 
center number, followed by a 3-digit number corresponding to the individual subject. The ID will 
be used to identify the subject throughout the study and will be entered on all study documents. 
6.1 
Randomization 
Eligible subjects will be randomly assigned to Cycle 1 study treatment in a ratio of 1:1 to receive 
ASTX727 or IV decitabine. Subjects will cross over to the other therapy in Cycle 2. Treatment 
assignment will be determined through a computer-generated randomization schedule and 
accessed through an interactive voice response system. Subjects should receive study treatment as 
soon as possible after randomization. 
6.2 
Blinding 
This is an open-label study. Treatment assignment will be unblinded. 
7.0 
STUDY TREATMENTS 
7.1 
Investigational Medicinal Product (IMP) – ASTX727 
ASTX727 (recently approved as INQOVI®) is a film-coated, oval, immediate-release FDC tablet 
containing the combination of cedazuridine (100 mg) and decitabine (35 mg) for oral 
administration. The tablets are packed as a 5-count in an opaque high-density polyethylene 
(HDPE) bottle with a child resistant closure. Please see the ASTX727 IB and Pharmacy Manual 
(provided by Astex) for more information. 
7.2 
IV Decitabine 
Decitabine, 20 mg/m2 IV will be used as the reference product. Decitabine is approved for IV 
infusion in the US and will be sourced locally at the US study centers. Decitabine for IV infusion 
will be provided by the sponsor as an IMP in territories where it is not currently approved for use. 
7.3 
Study Treatment Storage 
ASTX727 tablets should be stored on site as indicated in the study-specific Pharmacy Manual 
according to institutional policy and the Sponsor's requirements. ASTX727 tablets for outpatient 
administration should be dispensed by the study pharmacist according to institutional policy and 


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in accordance with the Sponsor's requirements. Instructions regarding transport from pharmacy to 
home and at-home storage instructions should be given to the study subject, as applicable. 
Decitabine should be stored according to institutional policy and storage instructions provided in 
the US product package insert (current Dacogen Prescribing Information). 
Records of the receipt and dispensing of study 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 drug 
supplies. 
7.4 
Study Treatment Administration 
The dosing regimen for this study is shown in Table 5. Subjects will receive the ASTX727 FDC 
tablet Daily×5 in Cycle 1, followed by a 1-hour infusion of IV decitabine 20 mg/m2 Daily×5 in 
Cycle 2, or the converse order. In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 
28-day cycles. 
Reconstitution of decitabine for IV administration will be performed by the institutional 
pharmacists according to the US package insert. 
Subjects will be required to fast from food for 4 hours on days in all cycles when receiving 
ASTX727. Fasting begins at least 2 hours prior to and ends 2 hours after dosing. Subjects will take 
ASTX727 with ~240 mL (8 fluid oz) of water. Clear liquids such as water, black coffee, or tea 
may be allowed as desired together with any concomitant medication that is needed to be given to 
the subject. ASTX727 should be taken at the same time of day (8 AM ±1 hour) on each dosing 
day during the first 2 cycles.  In subsequent cycles, ASTX727 should be taken at the same time of 
day (±1 hour) on dosing days. For late or missed (or vomited) doses, see Section 7.5. 
Table 5: 
Dosing Schedule by Day and Cycle 
Cycle (28 Days) 
1 
2 
≥3 
Cycle Day 1 
2 
3 
4 
5 6-28 1 
2 
3 
4 
5 6-28 1 
2 
3 
4 
5 6-28 
If randomized to ASTX727 in 
Cycle 1, then: 
 
   ASTX727 tablet 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
   IV decitabine (20 mg/m2) 
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
If randomized to IV decitabine 
in Cycle 1, then: 
 
   ASTX727 tablet  
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
× 
× 
× 
× 
× 
 
   IV decitabine (20 mg/m2) 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE: On days of ASTX727 administration, subjects should take the FDC tablet at the same time each day 
±1 hour (8 AM during the first 2 cycles). 
 


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7.5 
Late or Missed ASTX727 Doses 
7.5.1 
Cycle 1 or 2 
In the ASTX727 cycle (1 or 2), subjects should take the FDC tablet at the same time of day (8 AM 
± 1 hour) on each day of ASTX727 administration. If the tablet is taken within 3 hours after 8 AM, 
proceed with dosing and PK sample collection (if applicable) according to Table 6. (A dose 
administered within 3 hours after 8 AM will not be considered a protocol deviation.) If the tablet 
is taken more than 3 hours after 8 AM, the PK for that day may not be evaluable. Contact the 
medical monitor for instructions regarding whether the PK sampling schedule may be adjusted on 
the following days (if applicable). 
If the subject vomits within 6 hours after dosing on a dosing day, the PK for that day and the 
following day (if applicable) may not be evaluable. Contact the medical monitor for instructions 
regarding whether the PK sampling schedule may be adjusted in remaining days of dosing (if 
applicable). 
7.5.2 
Cycles ≥3 
If an ASTX727 dose is not taken at the intended time on a dosing day, the dose should be taken 
immediately if the subject remembers by 6:00 PM that day. After 6:00 PM, the dose should be 
skipped, and dosing should resume the following day at the intended time. Subjects should 
complete all 5 daily doses; if a dose is missed, the dosing period will extend by one day for every 
missed dose to complete the 5 daily doses. A vomited dose should not be retaken. Dosing should 
resume on the next dosing day and continue for the remaining dosing days in the cycle. If the 
subject experienced repeated vomiting after dosing in Cycles 1 or 2, a prophylactic antiemetic 
should be considered for the subsequent cycles. 
7.6 
Guidelines for Adjusting or Withholding Study Treatment 
It is important that Cycles 1 and 2 are given at full dose (safely) to allow for proper assessment of 
exposure after ASTX727 and IV decitabine administration. Contact the Astex medical monitor if 
considering reducing the dose in the first 2 cycles. 
Dose delays up to 2 weeks for recovery of blood counts from drug-related myelosuppression are 
acceptable. Delays beyond 2 weeks in the first 2 cycles must be approved by the medical monitor. 
Subjects whose therapy is interrupted during dosing days of ASTX727 in the first 2 cycles may 
not be evaluable for assessment of the primary endpoint unless treatment can be restarted on a later 
date (after agreement by the medical monitor) in a manner that will allow AUC assessment (see 
Section 11.2.2 and Section 11.6). Dosing should be delayed in the presence of non-hematologic 
toxicities (serum creatinine equal or greater than 2 mg/dL; SGPT or bilirubin equal or greater than 
2 times the ULN), or active or uncontrolled infection until these toxicities are resolved. 
Beginning with Cycle 3, dose delays to allow recovery of blood counts from drug-related 
myelosuppression are allowed at the discretion of the investigator. If there is a need for dose 


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reduction starting from Cycle 3, ASTX727 treatment may be reduced to 4 days. Additional dose 
reductions may be applied by further reducing treatment to 3 days. Dose reductions should be 
considered if myelosuppression is suspected to be drug-related rather than disease-related. 
Transient reductions in blood counts on Day 15 (expected maximal drug effect) followed by a 
recovery trend by Day 28 may be indicative of a drug-related effect, whereas stable counts or 
improvements in counts by Day 15 followed by reduction by Day 28 is indicative of a disease 
effect that is being improved by the drug on Day 15. In the event of drug-related count suppression, 
a dose reduction in consultation with the medical monitor may be considered to allow the patient 
to achieve a complete or partial response. 
7.7 
Concomitant Treatment 
Record on the concomitant medication eCRF all treatments a subject receives, including 
supportive or palliative treatment whether prescription or over the counter, vitamin and mineral 
supplements, herbs, and medications taken for procedures (eg, biopsy). Also record antacids, 
proton pump inhibitors, and H2 antagonists. Specifically record start/stop dates, name of treatment, 
and indication for use. 
7.7.1 
Supportive, Prophylactic, or Other Treatments 
The investigator is permitted to perform diagnostic testing and to prescribe supportive treatment(s) 
at his or her discretion. Appropriate hydration and supportive care (eg, antiemetics and blood and 
platelet transfusions) may be administered according to study center standards. Ensure the subject 
is adequately hydrated. 
All supportive treatment including units of blood and platelet transfusions must be recorded on the 
eCRF. Aggressive surveillance, prophylaxis, and the treatment of bacterial, fungal, viral, and 
opportunistic infections are essential to prevent morbidity and mortality. 
Antibiotics may be used to prevent or manage febrile neutropenia according to institutional 
standard practice. Febrile neutropenia is defined as temperature at least 38.5°C when the absolute 
neutrophil count (ANC) is <1000 cells/μL. Febrile subjects are to be evaluated by physical 
examination, complete blood count (CBC) with differential, chest x-ray, urine culture, and blood 
culture. Subjects with febrile neutropenia or frank infection are to be hospitalized for temporizing 
antibiotic coverage, consistent with local pathogen sensitivities until an infectious agent is 
identified. Antibiotic prophylaxis (at least a quinolone unless either medically contraindicated or 
contrary to institutional standard practice) is strongly recommended for subjects with documented 
ANC <0.5×109/L or expected to experience ANC <0.5×109/L for any duration during the first 
2 cycles. In subsequent cycles, antibiotic prophylaxis is strongly recommended for subjects 
expecting to experience ANC <0.5×109/L for more than 7 days or per local institutional guidelines. 
The medical monitor should be consulted in cases where specific antibiotics are contraindicated. 
Fungal prophylaxis is strongly recommended for subjects expected to experience ANC <0.5×109/L 
for more than 7 days during any cycle or per local institutional guidelines. 


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Hematopoietic growth factors will not be routinely used. However, short-term use of G-CSF for 
febrile neutropenia is permitted at the discretion of the treating physician and should be guided by 
accepted practice or institutional guidelines. 
7.7.2 
Prohibited Medications 
Prohibited concomitant therapies while on study are as follows: chemotherapy, immunotherapy, 
or any experimental therapy.  
Also prohibited are other nucleosides or drugs that are metabolized by CDA (including cytarabine, 
gemcitabine, azacitidine, vidarabine, zalcitabine, zidovudine, telbivudine, didanosine, zalcitabine, 
stavudine, lamivudine, abacavir, emtricitabine, entecavir, apricitabine, idoxuridine, trifluridine, 
tenofovir and adefovir). 
8.0 
RISKS/PRECAUTIONS 
Refer to the ASTX727 IB for the most current risks and precautions, as well as a list of AEs 
considered expected with ASTX727 therapy. As with any IMP, subjects may experience reactions 
or complications that are unknown and are therefore unpredictable. 
8.1 
Drug-Drug Interactions 
The primary activity of cedazuridine is the inhibition of CDA, which enhances the bioavailability 
of orally administered decitabine. Therefore, drugs known to be metabolized by CDAs should not 
be given (such drugs include cytarabine, gemcitabine, azacytidine, vidarabine, zalcitabine, 
zidovudine, telbivudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, 
entecavir, apricitabine, idoxuridine, trifluridine, tenofovir and adefovir) on days when ASTX727 
is administered and for 24 hours thereafter. As new agents may come to market during the trial, 
confer with the medical monitor if questions arise. 
ASTX727 is not expected to produce cytochrome P450 (CYP)-mediated drug-drug interaction, as 
ASTX727 has shown no potential to inhibit or induce human CYP enzymes in vitro. 
8.2 
Genotoxicity 
ASTX727 is shown to be genotoxic, which could cause fetal harm. Therefore, subjects with 
reproductive potential must use methods of contraception during the study (as described in 
Section 5.0) and for 3 months after the last dose of study treatment. Subjects should promptly 
notify the investigator if they, or their partner, become pregnant during this period. If a female 
subject becomes pregnant during the treatment period, she must discontinue study treatment 
immediately (see Section 10.2.3). 
8.3 
Overdose Instructions 
Record the actual dose of study treatment administered in the source document and on the Dosing 
eCRF. Record any adverse clinical signs and symptoms associated with a potential overdose on 


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the AE eCRFs. Report signs and symptoms of a potential overdose that meet SAE criteria (defined 
in Section 10.1.2) on the SAE form within 24 hours (see Section 10.3). Treat any AE (including 
SAEs) based on standard care for the specific signs and symptoms.  
No data are available regarding overdosage of ASTX727. Based on the clinical experience of 
decitabine, an overdosage of ASTX727 may result in more profound or prolonged 
myelosuppression and its consequences such as infection, or bleeding, or GI toxicity, and subjects 
should be managed accordingly. No antidote has yet been developed for overdose of ASTX727. 
9.0 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Pharmacokinetics 
The schedules for PK assessments during the ASTX727 and IV decitabine cycles are provided in 
Table 6 and Table 7, respectively. Pharmacokinetics will be evaluated on Days 1 through 5 during 
the cycle of ASTX727 administration (serial collections on Days 1, 2, and 5, trough levels on Days 
1-5, and once on Day 3), and on Days 1, 3, and 5 during the cycle of IV decitabine administration. 
Adequate PK assessments in both Cycles 1 and 2 (see Section 11.2.2) will be required for subjects 
to be evaluable for the primary study endpoint. 
During the IV decitabine cycle, the contralateral arm should be used for PK blood draws. No blood 
draws for PK assessments should be done from the arm used for IV decitabine infusion.  
Detailed instructions for PK sample collection will be provided separately from the protocol. The 
total blood volume planned for Cycle 1 + Cycle 2 = ~171 mL. The blood draw schedule may be 
modified by Astex. 


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Table 6: 
Schedule of Pharmacokinetics Assessments – ASTX727 Cycle 
 
ASTX727 Cycle 
Cycle Day 
1 
2 
3 
4 
5 
6-28 
Pre-dose (within 90 min before dosing) 
× 
×a 
×a,b 
× 
× 
 
TIME AFTER ORAL DOSE 
 
15 min (± 2 min) 
× 
× 
 
 
× 
 
30 min (± 2 min) 
× 
× 
 
 
× 
 
1 hour (± 3 min) 
× 
× 
 
 
× 
 
1.5 hours (± 3 min) 
× 
× 
 
 
× 
 
2 hours (± 3 min) 
× 
× 
 
 
× 
 
3 hours (± 5 min) 
× 
× 
×b 
 
× 
 
4 hours (± 5 min) 
× 
× 
 
 
× 
 
6 hours (± 10 min) 
× 
× 
 
 
× 
 
8 hours (± 10 min) 
× 
× 
 
 
× 
 
24 hours (± 60 min)a 
×a 
×a 
 
 
 
 
a  The pre-dose time point is the same as the 24-hour time point on the previous day; the 24-hour time point is the same as 
the pre-dose time point on the following day. 
b  Time-matched PK assessment for QTc on Day 3: ECG is to be done predose and at 3 hr ± 5 min. PK blood draw should 
be done immediately after completion of ECG for QTc. 
NOTE: Volume per blood draw = 3 mL. Total blood volume planned for the ASTX727 cycle = ~99 mL.  
NOTE: Every effort should be made to collect PK samples within the specified sampling windows. 
Table 7: 
Schedule of Pharmacokinetics Assessments – IV Decitabine Cycle 
IV Decitabine Cycle 
Cycle Day
1 
2 
3 
4 
5 
6-28 
Pre-dose (within 90 min before dosing) 
× 
 
×b 
 
× 
 
TIME AFTER START OF 
INFUSION 
TIME AFTER END OF 
INFUSION 
 
15 min (± 2 min) 
 
× 
 
 
 
× 
 
30 min (± 2 min) 
 
× 
 
 
 
× 
 
1 hour (59 min ± 1 min)a 
 
×a 
 
×b 
 
×a 
 
1 hour 5 min (± 1 min) 
5 min (± 1 min)c 
× 
 
 
 
× 
 
1.5 hours (± 3 min) 
30 min (± 3 min) 
× 
 
 
 
× 
 
2 hours (± 3 min) 
1 hour (± 3 min) 
× 
 
 
 
× 
 
3 hours (± 5 min) 
2 hours (± 5 min) 
× 
 
 
 
× 
 
4 hours (± 5 min) 
3 hours (± 5 min) 
× 
 
 
 
× 
 
6 hours (± 10 min) 
5 hours (± 10 min) 
× 
 
 
 
× 
 
8 hours (± 10 min) 
7 hours (± 10 min) 
× 
 
 
 
× 
 
a  Obtain the 1-hour PK sample immediately prior to the end of infusion (59 min ± 1 min). 
b  Time-matched PK assessment for QTc on Day 3: ECG is to be done predose and within 10 min before end of infusion. 
PK blood draw should be done immediately after completion of ECG for QTc but before the end of the infusion. 
c  The clock for 5 min post-infusion should begin when the infusion is finished. 
NOTE: Blood draws for PK should be made from the contralateral arm (arm not used for IV infusion). Volume per blood 
draw = 3 mL. Total blood volume planned for the IV decitabine cycle = ~72 mL.  
NOTE: Every effort should be made to collect PK samples within the specified sampling windows. 
 


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9.2 
Efficacy Assessments 
The response criteria for evaluation of MDS are based on the International Working Group (IWG) 
criteria published by Cheson et al (2006) modified as shown in Table 8. 
Complete response (CR), marrow CR (mCR), partial response (PR), and hematologic 
improvement (HI) will be determined based on peripheral blood counts and bone marrow 
aspirate/biopsy at the scheduled assessment days. Red blood cell (RBC) or platelet TI for at least 
56 consecutive days will be determined in subjects who are transfusion dependent at baseline of 
study ASTX727-02. Leukemia free survival is defined as the number of days from the date of 
randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or the date 
of death from any cause. Overall survival is determined from the date of randomization to the date 
of death from any cause. 
Table 8: 
Response Categories Based on IWG 2006 MDS Response Criteria 
Complete Response (CR): the following for at least 4 weeks 
Peripheral: normal peripheral counts with persistent granulocyte count ≥1.0 x 109/L, platelet ≥100 x 109/L, and 
Hgb ≥11 g/dL. 
Marrow: normal bone marrow with persistent marrow blasts ≤5%; persistent dysplasia will be noted. 
Partial Response (PR): the following for at least 4 weeks 
Peripheral: normal peripheral counts with granulocyte count ≥1.0 x 109/L, platelet count ≥100 x 109/L, and Hgb 
≥11g/dL. 
Marrow: normal bone marrow and marrow blasts >5% but were reduced by 50% or more. 
Marrow Complete Response (mCR): the following at least for 4 weeks 
Reduction of bone marrow blasts to ≤5% and decrease by 50% or more with or without normalization of peripheral 
counts. 
Hematological Improvement (HI): lasts at least 8 weeks 
Erythroid Response (HI-E): 
Major Response: Hemoglobin increase ≥1.5 g/dL in the absence of RBC 
transfusions. 
Platelet Response (HI-P): 
Major Response: Absolute increase of platelet count from <20 to >20 X 109/L and 
by at least 100%, or if more than 20 x 109/L, by an absolute 
increase of at least 30 x 109/L in the absence of platelet 
transfusions. 
Neutrophil Response (HI-N): Major Response: granulocyte increase ≥100%, and by an absolute increase ≥0.5 x 
109/L. 
a  Abnormal baseline counts should be assessed within one week prior to therapy, not influenced by transfusions (no 
transfusion for at least 1 week). 
 
9.3 
Pharmacodynamic Assessments 
Pharmacodynamic assessments will be based on %LINE-1 demethylation in blood, which will be 
measured at the following time points: 
• Predose on Day 1 of Cycles 1, 2, and 3. 
• Days 8, 15, 22 of Cycles 1 and 2. 


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9.4 
Safety Assessments 
Safety will be assessed by subject reported and investigator observed AEs, along with physical 
examination, clinical laboratory tests (hematology, chemistry, urinalysis), ECOG performance 
status, and electrocardiogram (ECG). Time-matched PK assessments for QTc will be performed 
at specified time points on Day 3 of Cycles 1 and 2, as described in Table 6. 
9.5 
Study Procedures 
The procedures to be performed in this study are described in detail in this section. 
9.5.1 
Schedule of Events 
Table 9 presents the complete schedule of events for this study, with details following in text. 
Additional information on the study procedures is provided in the Study Procedures Manual.  
Clinical and diagnostic laboratory evaluations are detailed throughout the study. The purpose of 
obtaining these detailed measurements is to ensure adequate assessments of safety and tolerability. 
Clinical evaluations and laboratory studies may be performed more frequently if clinically 
indicated. 
Note any deviation from protocol procedures. Investigators are responsible for implementing 
appropriate measures to prevent the recurrence of violations and deviations and to report to their 
Institutional Review Board / Independent Ethics Committee (IRB/IEC) according to policy. 
 


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Table 9: 
Schedule of Events 
Cycle (28 Days)
1 
2 
≥3 
 
 
Cycle Day 1 
2 
3 
4 
5 
8, 15, 
22 
1 
2 
3 
4 
5 
8, 15, 
22 
1 
2 
3 
4 
5 
15 
Trtmt 
Disc.a 
30-Day 
F/U 
Study treatment administration (Table 5) 
× 
× × × 
× 
 
× 
× 
× 
× 
× 
 
× 
× 
× 
× 
× 
 
 
 
Procedures 
Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent; IPSS risk category, eligibility 
confirmation 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/(symptom-directed PE)b 
× 
(×) 
 
 
 
 
 
(×) 
 
 
 
 
 
(×) 
 
 
 
 
 
× 
(×) 
Height  
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight / BSA calculationc 
× 
× 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
 
 
 
 
 
 
Vital signsd 
× 
× 
× × × 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
 
 
× 
 
ECOG statuse 
× 
 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
 
 
 
 
× 
× 
12-lead ECGf 
× 
 
 
× 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGAg 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments/adverse eventsh 
× 
× 
× × × 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
 
 
× 
× 
Transfusion requirementsi 
× 
× 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
 
 
 
 
× 
× 
Pharmacokinetics assessments (Table 6 and Table 7) 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyj 
× 
(×) 
 
 
 
 
× 
× 
 
 
 
 
× 
× 
 
 
 
 
× 
× 
 
Chemistryk 
× 
 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
Urinalysisl  
× 
 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
 
 
 
 
× 
 
Serum or urine pregnancy testm 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
 
%LINE-1 demethylation (blood)n 
 
× 
 
 
 
 
× 
× 
 
 
 
 
× 
×n 
 
 
 
 
 
 
 
Bone marrow aspirate/biopsyo 
× 
 
 
 
 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 


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NOTE: Days 8, 15, 22 assessments are permitted within ± 1 day.  
a  
Treatment discontinuation: If subject withdraws consent from the study or discontinues treatment, record the reason and complete the indicated procedures. See Section 9.5.6 
for following subjects for survival/conversion to AML. 
b  
Physical Exam (PE): A complete PE includes examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system 
and genitourinary system (if applicable). On Cycle 1 Day 1, PE may be symptom-directed if a full PE was completed within 4 days prior. 
c  
Weight/BSA calculation: Use actual body weight at Screening for BSA calculation. After Screening, collect body weight only (no BSA needed). 
d  
Vital signs: Predose. Assess predose on indicated days, and at treatment discontinuation, after the subject has rested sitting for at least 3 minutes. Include resting 
systolic/diastolic blood pressure, resting respiration rate, resting heart rate, and body temperature. 
e  
ECOG status: Assess at Screening and predose on Day 1 of Cycles ≥2. 
f  
12-Lead ECG (single tracing only, unless clinically significant abnormality for which triplicate ECG is preferred for confirmation, eg, QTc >500 msec). ECG specifically for 
QTc must be done at Screening and predose on Day 3 of Cycles 1 and 2. Time-matched PK assessment for QTc (Cycles 1 and 2 only): to be done at 3 hr ± 5 min during the 
ASTX727 cycle, and within 10 min before end of infusion during the IV decitabine cycle (see Table 6 and Table 7, respectively). PK blood draw should be done immediately 
after completion of ECG for QTc but before the end of the infusion. Either the Bazett's or Fridericia's formula may be used to calculate the QTc interval but must be used 
consistently throughout the study. 
g  
Echocardiogram(ECHO)/ multiple gated acquisition scan (MUGA): May be done within 28 days before first dose of study treatment. 
h  
Concomitant treatments/adverse events: Collect concomitant treatments and adverse events at Screening and throughout the study. Include start date when known. 
i  
Transfusion requirements: Report transfusions received since previous assessment time point. Final assessment is at the 30-Day Follow-Up Visit. 
j  
Hematology: Collect weekly through Cycle 2, at Days 1 and 15 in Cycles ≥3, and at treatment discontinuation. Hematology done during Screening within 1 week before the 
start of study treatment does not need to be repeated on Cycle 1 Day 1. Complete blood count and differential, with specific output being hemoglobin, platelet count, white 
blood cell count and percent neutrophils (percent polymorphonuclear neutrophils and bands) or an absolute neutrophil count, and percentage of blasts. Additional laboratory 
assessments may be done at the investigator's discretion for clinical intervention.  
k  
Chemistry: At Screening, predose on Day 1 of Cycles ≥2, and at treatment discontinuation. Must include glucose, calcium, magnesium, albumin, total protein, sodium, 
potassium, CO2, chloride, BUN, creatinine, lactate dehydrogenase, alkaline phosphatase, ALT, AST, total bilirubin, direct bilirubin only if total bilirubin is elevated above 
the protocol inclusion criterion. Additional laboratory assessments may be done at the investigator's discretion for clinical interventions. 
l  
Urinalysis: At Screening, predose on Day 1 of Cycles ≥2, and at treatment discontinuation. Dipstick only (microscopic analysis required only to follow up abnormal findings 
or if dipstick not performed). See Table 10. 
m  Pregnancy test: At Screening and at treatment discontinuation. Serum or urine; only for women of child-bearing potential. 
n  
LINE-1 demethylation: Obtain whole blood sample predose on Day 1 of Cycles 1 and 2 (as baseline), Days 8, 15, 22 of Cycles 1 and 2; and Day 1 of Cycle 3. 
o  
Bone marrow aspirate or biopsy: At Screening or within 21 days before Cycle 1 Day 1; on or before Day 1 of Cycles 3, 5, 7, and then every 3 months in first year and every 
6 months thereafter. Bone marrow aspirate or biopsy differential will be performed according to local standard practice. A bone marrow biopsy can be done if no aspirate is 
available. A manual differential of the myeloid cells in bone marrow will be performed with a minimum of 100 cells counted and a specific myeloblast percent generated. 
Bone marrow aspirate or biopsy differential may include the following: total cells counted, metamyelocytes, lymphocytes, normoblasts, myeloid and erythroid maturation, 
blasts, segmented neutrophils, plasma cells, megakaryocytes, presence of dysplasia, promyelocytes, eosinophils, monocytes, M:E ratio, cellularity: % cellularity; 
hypocellular, hypercellular, normocellular; myelocytes, basophils, pronormoblasts, and other. An anonymized report of all bone marrow testing results will be recorded on 
the electronic Case Report Form. A portion of bone marrow aspirates will be used for assessing disease-associated gene mutations. Cytogenetics will be reviewed on the 
screening bone marrow and should include at least 20 clones. If cytogenetics are abnormal, they must be reviewed again in subsequent bone marrow aspirates or biopsies. 


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9.5.2 
Screening / 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.  
Within 14 days before treatment administration (or as specified below or in Table 9), perform the 
following study procedures and tests: 
• Legally effective informed consent. The ICF must be signed and dated by the subject before 
any study-specific samples are collected or study-specific procedures are initiated.  
• Investigator's confirmation of eligibility. Perform all necessary procedures and evaluations to 
document that the subject meets each eligibility criterion. 
• Assess IPSS and any prior cancer treatments. 
• Complete medical history, including demographics. Record disease history, including the date 
of initial diagnosis. Document concurrent medical signs and symptoms to establish baseline 
conditions. 
• Randomization (confirm with medical monitor): see Section 6.1. 
• Complete physical exam (PE) including height and weight, and examination of body systems.  
• Obtain height and weight; perform BSA calculation. Use Screening BSA for calculation of IV 
decitabine dose (for IV decitabine cycle). 
• Vital signs include resting systolic/diastolic blood pressure, resting respiration rate, resting 
heart rate, and body temperature.  
• ECOG performance status (see Appendix 1).  
• 12-lead ECG: single tracing only unless clinically significant abnormality for which triplicate 
ECG is preferred for confirmation, eg, QTc >500 msec; rhythm, atrial rate, ventricular rate, 
PR interval, QRS duration, and QT/QTc, and overall interpretation. Either the Bazett's or 
Fridericia's formula may be used to calculate the QTc interval but must be used consistently 
throughout the study. 
• ECHO or MUGA: may be performed up to 28 days before study treatment. 
• Record concomitant medications. 
• Transfusion requirements: record transfusions received since previous assessment time point: 
up to 56 days prior if data are available. 
• Collect blood samples for hematology and serum chemistry, and urine sample for urinalysis. 
• 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. 


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• Collect bone marrow aspirate or biopsy (must be collected within 21 days before first dose of 
study treatment).  
Table 10: 
Clinical Laboratory Tests  
Hematology 
Serum Chemistry 
Urinalysis 
Pregnancy Test 
-Complete blood count 
(CBC) and differential 
(hemoglobin, platelet 
count, white blood cell 
count and percent 
neutrophils (percent 
polymorphonuclear 
neutrophils and bands) 
or an absolute 
neutrophil count, and 
percentage of blasts) 
 
 
-Glucose 
-Calcium 
-Magnesium  
-Albumin 
-Total protein 
-Sodium 
-Potassium 
-CO2 
-Chloride 
-BUN 
-Creatinine 
-Lactate dehydrogenase 
-Alkaline phosphatase 
-ALT 
-AST 
-Total bilirubin 
-Direct bilirubin (only if total 
bilirubin is elevated)  
-Dipstick only (microscopic 
analysis required only to 
follow up abnormal findings 
or if dipstick not performed) 
-Specific gravity 
-pH 
-Protein 
-Glucose 
-Ketones 
-Leukocyte esterase 
-Blood 
-Microscopic urinalysis 
-Color 
-Clarity 
-Urine or serum 
Note: The frequency of these assessments is given in Table 9. 
 
9.5.3 
Treatment Procedures 
9.5.3.1 
Cycle 1 – Day 1 
• Perform the following procedures before administration of study treatment: 
o Complete PE (may be a symptom-directed PE if a full PE was completed within 4 days of 
this visit). 
o Body weight. 
o Vital signs. 
o Record concomitant medications and adverse events. 
o Record transfusion requirements. 
o Collect blood samples for hematology. NOTE: hematology done during Screening within 
1 week before the start of study treatment does not need to be repeated on Cycle 1 Day 1. 
o Obtain whole blood sample for %LINE-1 demethylation. 
o Pharmacokinetics assessment. 
• Perform the following procedures at the specified time points: 
o Pharmacokinetics assessments. 


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9.5.3.2 
Cycle 1 – Day 2 through Day 4 
• Perform the following procedures before administration of study treatment: 
o Vital signs. 
o ECG including QTc interval – Day 3 only. 
o Record concomitant medications and adverse events. 
o Pharmacokinetics assessment – only Day 3 during IV decitabine cycle. 
• Perform the following procedures at the specified time points: 
o Pharmacokinetics assessments: Day 2 (if ASTX727 given this cycle), and Day 3. 
o ECG with QTc interval on Day 3 as specified in Table 6 or Table 7, depending upon 
treatment cycle. 
9.5.3.3 
Cycle 1 – Day 5 
• Perform the following procedures before administration of study treatment: 
o Vital signs. 
o Record concomitant medications and adverse events. 
o Pharmacokinetics assessments. 
• Perform the following procedures at the specified time points: 
o Pharmacokinetics assessments. 
9.5.3.4 
Cycle 1 – Days 8, 15, 22 
• Assessments are permitted within ± 1 day: 
o Vital signs. 
o Record concomitant medications and adverse events. 
o Collect blood samples for hematology. 
o Obtain whole blood sample for %LINE-1 demethylation assessment. 
9.5.3.5 
Cycle 2 – Day 1 
• Perform the following procedures before administration of study treatment: 
o Complete PE including weight/BSA (may be a symptom-directed PE). 
o Body weight. 
o Vital signs. 
o ECOG performance status (Appendix 1). 


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o 12-lead ECG: single tracing only. 
o Record concomitant medications and adverse events. 
o Record transfusion requirements. 
o Collect blood samples for hematology and chemistry, and perform urinalysis. 
o Obtain whole blood sample for %LINE-1 demethylation assessment. 
• Pharmacokinetics assessments. 
9.5.3.6 
Cycle 2 – Day 2 through Day 4 
• Perform the following procedures before administration of study treatment: 
o Vital signs. 
o ECG including QTc interval – Day 3 only. 
o Record concomitant medications and adverse events. 
o Pharmacokinetics assessment – only Day 3 during IV decitabine cycle. 
• Perform the following procedures at the specified time points: 
o Pharmacokinetics assessments: Day 2 (only if ASTX727 given this cycle), and Day 3. 
o ECG with QTc interval as specified in Table 6 or Table 7, depending upon treatment cycle. 
9.5.3.7 
Cycle 2 – Day 5 
• Perform the following procedures before administration of study treatment: 
o Vital signs. 
o Record concomitant medications and adverse events. 
• Pharmacokinetics assessments. 
9.5.3.8 
Cycle 2 – Days 8, 15, 22 
• Assessments are permitted within ± 1 day: 
o Vital signs. 
o Record concomitant medications and adverse events. 
o Collect blood samples for hematology. 
o Obtain whole blood sample for %LINE-1 demethylation assessment. 


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9.5.3.9 
Cycles ≥3 – Day 1 
• Perform the following procedures before administration of study treatment: 
o Complete PE including weight (may be a symptom-directed PE). 
o Body weight. 
o Vital signs. 
o ECOG performance status (Appendix 1). 
o Record concomitant medications and adverse events. 
o Record transfusion requirements. 
o Collect blood samples for hematology and chemistry, and perform urinalysis. 
o Obtain whole blood sample for %LINE-1 demethylation assessment (Cycle 3 only). 
o Collect bone marrow aspirate or biopsy.  
9.5.3.10 
Cycles ≥3 – Day 15 
• Collect blood samples for hematology. 
9.5.4 
Treatment Discontinuation 
Confer with the Astex medical monitor before discontinuing treatment for a given subject. 
If the subject withdraws consent from the study or is discontinued from study treatment at any 
time before finishing Cycles 1 and 2, complete the following procedures: 
• Complete PE. 
• Vital signs. 
• ECOG performance status (Appendix 1). 
• Record concomitant medications and adverse events. 
• Record transfusion requirements. 
• Record the specific reason the subject terminated treatment. 
• Collect blood samples for hematology and serum chemistry, and urine sample for urinalysis. 
• Serum or urine pregnancy test: for women of child-bearing potential only. 
9.5.5 
30-Day Follow Up  
The 30-Day Follow-up Visit must occur 30 (+5) days after the last dose of study treatment or 
within 3 days before starting new anti-cancer treatment (do not record medications taken during 
new treatment), whichever is sooner. This visit may be conducted in person or by telephone. For 


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30-Day Follow-up via telephone, assess as much as possible but at a minimum assess AEs. Also 
record any new therapy for the subject's disease.  
• Symptom-directed PE. 
• ECOG performance status (Appendix 1). 
• Record concomitant medications and adverse events. 
• Record transfusion requirements. 
9.5.6 
Survival/Conversion to AML 
Follow all subjects for survival/conversion to AML who have stopped study treatment. Contact 
subject every 3 months until death or withdrawal of consent or the close of the trial. This 
assessment may be conducted by telephone. 
9.6 
Missed Evaluations 
Evaluations should occur within the visit window specified by the protocol, as applicable. 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. 
10.0 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Adverse Event 
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 
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). 


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10.1.2 
Serious Adverse Events 
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. 
10.2 
Adverse Event Reporting and Descriptions 
Record any AEs related to screening procedures that occur before the start of study treatment. 
Record new AEs from the start of study treatment to the earliest of the following, as applicable: 
• Until 30 days after the last dose of study treatment, or 
• Until the subject starts new MDS/CMML treatment, including new investigational treatment. 
Record in the eCRF all AEs from any source (eg observed by study personnel, reported by the 
subject, or from the subject’s medical record). 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?").  


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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 v4.03 (Appendix 2) 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.  
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 


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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 Clinical Safety and Risk Management 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 ASTX727 who become pregnant must 
immediately discontinue study treatment. The investigator should counsel the subject, discussing 
any risks of continuing the pregnancy and any possible effects on the fetus. 
Report any abortion and the reason for it, whether therapeutic, elective, or spontaneous, to Astex 
Pharmaceuticals Clinical Safety and Risk Management within 24 hours, through the SAE reporting 
process (Section 10.3). 


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10.3 
Reporting Requirements for Serious Adverse Events (SAEs) 
All SAEs regardless of causality will be reported by the investigator to Astex Pharmaceuticals 
Clinical Safety and Risk Management (or via a designee) 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. 
Enter all SAEs (initial and follow-up information) into the electronic data capture (EDC) database 
within 24 hours of awareness. The EDC system will automatically send the SAE report via the 
Safety Gateway to Astex Pharmaceuticals Clinical Safety and Risk Management. Astex 
Pharmaceuticals may request follow-up and other additional information from the investigator (eg, 
hospital admission or discharge notes, laboratory results). Additional source documents can be 
emailed to the address below. If the EDC system is not accessible for any reason, the SAE form 
will need to be completed and sent to Astex Pharmaceuticals Clinical Safety and Risk 
Management. When the EDC system becomes available, the information on the SAE form shall 
be entered into EDC. 
Astex Pharmaceuticals Clinical Safety and Risk Management Contact Information 
Primary Contact Email 
DrugSafety@astx.com 
 
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 Clinical Safety and Risk Management, 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 Clinical 
Safety and Risk Management or designee will report to the relevant regulatory authorities and 
forward a formal notification describing the SUSAR to investigators, according to regulatory 
requirements. Each investigator must then notify his or her IRB/IEC of the SUSAR as required by 
local regulatory authorities and in accordance with IRB/IEC policy. 
10.4 
Follow-up for Adverse Events 
Follow all AEs and SAEs that are encountered during the protocol-specified AE reporting period 
(1) to resolution, (2) until the investigator assesses the subject as stable and the event is following 
a clinically expected outcome, or (3) until the subject is lost to follow-up or withdraws consent. 


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11.0 
STATISTICS 
Statistical analyses will be performed by Astex Pharmaceuticals or its designee. 
Data summaries and listings will be generated using SAS version 9.4 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 
A preliminary analysis of 5-day AUC in study ASTX727-01 shows an estimate of intra-subject 
CV of 0.5. A conservative CV value of 0.55 was chosen to calculate the sample size. 
A total of 118 subjects in the Primary Endpoint PK Analysis Set (Section 11.2.2) included in the 
2 one-sided equivalence tests for the geometric mean ratio of ASTX727 5-day AUC relative to IV 
decitabine 5-day AUC will provide 90% power at the statistical significance level of 0.05, when 
the true ratio of geometric means is 1.0, the CV under an unlogged scale is 0.55, and the 90% CI 
equivalence limits for the ratio of geometric means are 0.8 and 1.25. Assuming 10% of subjects 
may not be evaluable in the study, approximately 132 subjects will need to be randomized. 
11.2 
Analysis Sets to be Analyzed 
11.2.1 
All Subject Analysis Set 
The All Subject Analysis Set will include information from all screened subjects, including those 
who did not meet the study entry criteria or who did not receive a study treatment. This data set 
will be used only for disposition in which all screened subjects are accounted. 
11.2.2 
Pharmacokinetics Analysis Sets 
Two PK analysis sets will be used for analysis of PK data, as described below. 
The Primary Endpoint PK Analysis Set will be used for calculating decitabine 5-day AUC0-t and 
bioequivalence statistical analysis. This analysis set will include decitabine daily AUC0-t from 
subjects who are successfully dosed in Cycles 1 and 2 (see below) and who meet the following 
criteria for both ASTX727 and IV decitabine dosing. 
ASTX727 successful dosing: received full dose of ASTX727 within 3 hours of the intended dosing 
time, and no vomiting within 6 hours of dosing. 
• Subjects in this analysis set will have at least 2 days of evaluable decitabine AUC0-t 
measurements in the ASTX727 cycle, ie, Day 1 and either Day 2 or Day 5: 


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o For Day 1 to be included, subjects must have been successfully dosed on Day 1. 
o For Day 2 to be included: subjects must have been successfully dosed on Day 1 and Day 2. 
o For Day 5 to be included: subjects must have been successfully dosed on Day 4 and Day 5.  
IV decitabine successful dosing: received the full dose as a 1-hour infusion. 
• Subjects in this analysis set will have at least 1 evaluable day of decitabine AUC0-t 
measurement in the IV decitabine cycle, either Day 1 or Day 5. 
The Overall PK Analysis Set will be used for calculating PK parameters, including decitabine 
daily AUC0-t, which will be used to derive the primary PK endpoint of decitabine cumulative 5-day 
AUC0-t exposures, and other secondary PK parameters for decitabine, cedazuridine, and 
cedazuridine-epimer. This analysis set will include subjects who may or may not be included in 
the Primary PK Analysis set and who meet the following criteria: 
• Received any amount of study treatment. 
• Complied with the protocol sufficiently to ensure PK samples were collected as intended. 
• Provided sufficient samples to measure available plasma concentrations for decitabine, 
cedazuridine, and cedazuridine-epimer. 
11.2.3 
Efficacy Analysis Set 
The Efficacy Analysis Set will include data from all subjects who received at least one full dose 
(day) of study treatment. All data will be included, and no subjects excluded because of protocol 
violations. Subjects will be included in the treatment group according to their randomly assigned 
treatment. 
11.2.4 
Safety Analysis Set 
The Safety Analysis Set will include all subjects who received any amount of study treatment. All 
data will be included, and no subjects will be excluded because of protocol violations. 
11.2.5 
Pharmacodynamics Analysis Set 
Subjects will be included in the PD Analysis Set if they have received at least one dose of study 
treatment and have %LINE-1 methylation data at baseline (Day 1) of Cycle 1 or 2 and on either 
Day 8 or Day 15 of the respective cycle.  
11.3 
Schedule of Analyses 
Pharmacokinetics for the primary study endpoint, PD, and safety analyses will be performed after 
all evaluable subjects have completed Cycles 1 and 2. Additional secondary endpoint analyses will 
be performed after all subjects discontinue treatment or complete at least 6 cycles of treatment. 


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11.4 
Subject Disposition 
The number and percentage (n, %) of subjects enrolled, treated, lost to follow up, and withdrawn 
(with reason) will be summarized. Sample size for the Efficacy Analysis Set, Safety Analysis Set, 
PK Analysis Set, and PD Analysis Set will be clearly identified for each treatment sequence. All 
subjects in the All Subject Analysis Set will be included in the disposition analysis. 
11.5 
Analysis of Demographic and Baseline Data 
Subject demographic and baseline characteristics will be summarized by mean, standard deviation 
(SD), median, minimum, and maximum for continuous variables; and by counts and percentages 
for categorical variables. Summaries will be provided separately for each treatment sequence and 
both sequences combined. The Efficacy Analysis Set will be used for the summaries. 
11.6 
Pharmacokinetics Analyses 
A detailed description of the PK analyses is in the Pharmacokinetic Analysis Plan. A brief 
description follows below. 
11.6.1 
Primary Pharmacokinetics Endpoint Analyses 
The primary PK endpoint analyses will be performed in the order presented below. 
Calculation of daily decitabine AUC0-t 
The Overall PK Analysis Set will be used for calculation of decitabine AUC0-t. Decitabine AUC0-t 
by Cycle and Day will be calculated by the linear up/log down non-compartmental method using 
the measured concentration-time values above the quantitation limit using Phoenix® WinNonlin.  
In the case of a missed sample collection, enough data should be available for reliable calculation 
of the parameter AUC0-t. To be considered reliable for calculation of AUC0-t without imputation 
of missing data, a plasma PK profile should contain more than 5 consecutive data points with a 
quantifiable concentration value, including at least 3 data points beyond the Tmax, and %AUCextrap 
( (1－[AUC0-t/AUC0-inf])×100) should not exceed 20% for each individual profile. 
Individual values of decitabine daily AUC0-t will be used for generating the Primary Endpoint PK 
Analysis Set from evaluable subjects as described above. A listing of individual values of 
decitabine daily AUC0-t Cycle and Day, and non-model-based descriptive statistics will be 
provided. However, decitabine daily AUC0-t from subjects who are not evaluable to be included in 
the Primary Endpoint PK Analysis Set will be identified in the listing but will not be included in 
descriptive statistics; the reason for exclusion will be provided. 
Calculation of decitabine 5-day AUC0-t 
The Primary Endpoint PK Analysis Set will be used to calculate decitabine 5-day cumulative 
AUC0-t exposures after ASTX727 treatment. The following assumptions will be used: 


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• Steady state is reached on Day 2 of dosing with ASTX727.  
• Based on steady state achievement on Day 2, decitabine AUC0-t from Day 2 and Day 5 would 
be representative of daily AUC0-t on Days 2 through Day 5 in a putative 5-day dosing with 
ASTX727.  
Therefore, to calculate total 5-day oral decitabine AUC0-t exposures using PK data from 3 days 
sequential PK sampling, Day 1 AUC0-t (first ASTX727 dose) will be added to (Day 2 AUC0-t + 
Day 5 AUC0-t) × 2. If AUC0-t on Day 2 is not available, it will be replaced by AUC0-t on Day 5; the 
converse is also true.  
To calculate decitabine 5-day AUC0-t exposures after IV decitabine, (Day 1 AUC0-t + Day 5 
AUC0-t) / 2 will be multiplied by 5, based on Dacogen prescribing information (current Dacogen 
Prescribing Information) that there was no accumulation on Day 5 vs Day 1 for a 5-day infusion. 
If AUC0-t on Day 1 is not available, it will be replaced by AUC0-t on Day 5; the converse is also 
true.  
Bioequivalence statistical analysis of decitabine 5-day AUC0-t between ASTX727 and IV 
decitabine treatments 
Decitabine AUC0-t equivalence analysis will be performed on the Primary Endpoint PK Analysis 
Set. 
The primary endpoint, decitabine 5-day AUC0-t, will be analyzed in the log scale using a mixed 
effect model including fixed effects of sequence, period, and treatment, and a random effect of 
subject within sequence (EMA 2010; EMA 2015). The factors to be included in the model will be 
based on the actual treatment sequence. A 90% CI for the geometric mean ratio of 5-day AUC0-t 
will be obtained by applying the exponential function on the 2-sided 90% CI for the difference of 
mean 5-day AUC0-t between ASTX727 and IV decitabine in the log scale from the mixed effect 
model. The decitabine AUC0-t equivalence will be established if the 90% CI for the geometric 
mean ratio is contained within the interval (0.8, 1.25).  
11.6.2 
Other Pharmacokinetics Variables 
Calculation of other secondary PK parameters will be performed on the Overall PK Analysis Set. 
Pharmacokinetics parameters will be calculated by noncompartmental analysis methods from the 
concentration-time data using Phoenix® WinNonlin®. 
Decitabine PK parameters AUC0-inf, Cmax, Tmax, clearance (CL/F), apparent volume of distribution 
(Vd/F), and apparent half life (t1/2) are of secondary interest and will be reported together with 
AUC0-t where applicable. The PK parameters of cedazuridine and cedazuridine-epimer will be also 
reported. 
Individual values will be listed for each PK parameter by treatment and analyte, and the following 
(non-model-based) descriptive statistics will be provided: number of subjects with non-missing 


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data, arithmetic mean, standard deviation, arithmetic percent, median, minimum, maximum, 
geometric mean, and geometric percent CV. Note that CL/F and Vd/F will be calculated only for 
decitabine and cedazuridine and will not be calculated for cedazuridine-epimer.  
A population PK analysis for evaluation of various covariates and exposure-response will also be 
performed. 
11.7 
Efficacy Analyses 
Unless otherwise specified, the Efficacy Analysis Set will be used for all efficacy analyses. 
Efficacy endpoints will be analyzed as one treatment group regardless of randomization. 
11.7.1 
Clinical Response 
Complete response, mCR, PR, and HI (also HI-E, HI-P, and HI-N separately) will be summarized 
for all subjects in the Efficacy Analysis Set. The rate of each response status and its 95% Wald 
CIs will be provided, respectively. 
11.7.2 
Transfusion Independence 
Transfusion independence (TI) will be analyzed separately for platelet and RBC TI, the latter 
defined as no RBC transfusion for 56 consecutive days while maintaining hemoglobin ≥8 g/dL. 
Platelet TI is defined as no platelet transfusion for 8 consecutive weeks, while maintaining platelets 
≥20×109/L. Transfusion independence rates will be calculated based on subjects who are in the 
Efficacy Analysis Set and who were transfusion dependent at baseline. The 95% Wald CIs will be 
provided separately for the RBC and platelet TI rates. 
11.7.3 
Leukemia-Free Survival 
The number of days from randomization to the date when bone marrow or peripheral blood blasts 
reach ≥20%, or death from any cause, will be measured for subjects in the Efficacy Analysis Set. 
Subjects who do not have events in leukemia-free survival will be censored on the last date of bone 
marrow or peripheral blood blasts assessment, whichever is later. Subjects who have bone marrow 
or peripheral blood blasts ≥20% at baseline will be censored at the date of randomization. 
Leukemia-free survival will be presented using a Kaplan-Meier estimate. The 95% CI for the 
median of leukemia-free survival will be provided using the Kaplan-Meier procedure. 
11.7.4 
Overall Survival 
Overall survival 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 they were known to be alive. Overall survival will be presented using a Kaplan-Meier 
estimate. The 95% CI for median OS will be provided using the Kaplan-Meier procedure. 


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11.8 
Safety Analyses 
The Safety Analysis Set will be used for all safety analyses. Safety will be assessed by subject 
reported and investigator observed AEs, along with concomitant medications, physical 
examination, clinical laboratory tests (hematology and serum chemistry), vital signs, ECOG 
performance status and ECG. Safety will also be assessed by exposure to ASTX727 or IV 
decitabine, reasons for discontinuation, deaths, and causes of deaths.  
AEs will be mapped to the appropriate System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). Severity of AEs will 
be graded using CTCAE version 4.03 (Appendix 2). All AEs collected during the study will be 
presented in data listings. Treatment-emergent AEs (TEAEs) are defined as events that first occur 
or worsen after the subject receives study drug on C1D1 until 30 days after the last dose of study 
treatment, or the start of an alternative anti-cancer treatment for MDS/CMML or subsequent 
leukemia, whichever occurs first, 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 based on the treatment period when the events occur: 
• By maximum severity.  
• Incidence by SOC (by severity grade and overall). 
• Incidence rate by PT (by severity grade and overall) within each SOC. 
Laboratory values will be graded, if possible, by CTCAE in conjunction with the Harrison (18th 
edition) laboratory normal reference ranges. 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 
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 (Anatomical 
Therapeutic Chemical [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. 
11.9 
Pharmacodynamics Analyses 
Subjects in the PD Analysis Set will be included in the PD analyses. To avoid the confounding 
effects of differing baselines in Cycle 2 vs Cycle 1 observed in study ASTX727-01, subjects will 
be compared for each of the 2 cycles separately, thus limiting the evaluation to interpatient 
comparisons in each of the 2 cycles. 


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The 95% CI for the difference of mean maximum %LINE-1 demethylation between ASTX727 
and IV decitabine in Cycles 1 and 2 will be generated using an analysis of variance (ANOVA) 
model. The 95% CIs for mean maximum %LINE-1 demethylation will also be generated for 
ASTX727 and IV decitabine, respectively. Descriptive statistics including arithmetic mean, SD, 
median, and range will be summarized by visit and actual treatment. Descriptive statistics for 
maximum %LINE-1 demethylation will also be summarized by actual treatment. 
11.10 Interim Analysis 
No interim analysis is planned for this study. 
11.11 Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed, except as specified in the Statistical 
Analysis Plan. Data from subjects lost to follow-up will be included in statistical analyses to the 
point of the last evaluation. 
12.0 
STUDY DURATION AND TERMINATION 
The expected study duration is approximately 18 months (12 months enrollment and at least 
6 months of treatment and follow up) and is expected to start in late 2017 or early 2018. 
13.0 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
13.1 
Compliance Statement 
The study will be conducted in accordance with the ICH GCP guidelines; principles enunciated in 
the Declaration of Helsinki; and all human clinical research regulations in countries where the 
study is conducted. 
13.2 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, federal regulations US 
21 CFR Part 50, and ICH GCP guidelines and any other local regulations. The investigator, or a 
person delegated by the investigator, must explain the medical aspects of the study, including the 
nature of the study and the treatment, orally and in writing, in such a manner that the subject is 
aware of potential benefits and risks. Subjects must be informed that participation is voluntary and 
that they may withdraw from the study at any time, without prejudice. Subjects must provide 
legally effective informed consent. 
The informed consent process must be conducted, documented in the source document (including 
the date), and the form must be signed, before the subject undergoes any study-specific procedures. 


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13.3 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) 
The investigator must submit the protocol, any protocol amendments, and the informed consent 
form (ICF) for the proposed study, along with any other required documents to the study center's 
duly constituted IRB/IEC for review and approval. The investigator must also ensure that the 
IRB/IEC reviews the progress of the study on a regular basis and, if necessary, renews its approval 
of the study on an annual basis. A copy of each IRB/IEC approval letter must be forwarded to the 
sponsor before the study is implemented. Documentation of subsequent reviews of the study must 
also be forwarded to the sponsor. 
14.0 
ADMINISTRATIVE PROCEDURES 
14.1 
Sponsor Responsibilities 
Astex Pharmaceuticals reserves the right to terminate the study and remove all study materials 
from a study center at any time. Astex Pharmaceuticals and the investigators will assure that 
adequate consideration is given to the protection of the subjects' interests. Specific circumstances 
that may precipitate such termination are: 
• Request by Health Authority to terminate the study 
• Unsatisfactory subject enrollment with regard to quality or quantity 
• 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 


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14.1.1 
Study Supplies 
The sponsor will supply following materials to each study center: 
• Initial supply of ASTX727 tablets. 
• IV decitabine to study centers outside the US (Section 14.2.2). 
• IB for ASTX727. 
• Approved labeling for Dacogen. 
• eCRFs and other data collection tools as applicable. 
Refer to the ASTX727-02 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 ASTX727 and are unexpected (see Section 10.1.2), as appropriate. The 
investigator must forward this documentation to the IRB/IEC, as described in Section 10.2. 
The sponsor will also notify the investigator about any other significant safety findings that could 
alter the safety profile of ASTX727 from that 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 SSC (Section 4.4) such as limiting the eligibility criteria or reducing the 
ASTX727 dose or dosing schedule. 
14.1.4 
Study Monitoring 
Representatives of Astex Pharmaceuticals will monitor the study. Routine monitoring visits will 
be conducted to: 
• Assure compliance with the study protocol and appropriate regulations. 


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• 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 eCRFs and source documents to ensure that reported study data are accurate, 
complete, and verifiable from source documents. 
• Verify that study drugs are stored properly and under the proper conditions, that they are in 
sufficient supply, and that receipt, use, and return of study drug at the study centers is 
controlled and documented adequately. 
• Verify that the investigator and study center personnel remain adequately qualified throughout 
the study. 
• Verify that the research facilities, including laboratories and equipment, are maintained 
adequately to safely and properly conduct the study. 
14.1.5 
Study Auditing and Inspecting 
The sponsor may audit the study conduct, compliance with the protocol, and accuracy of the data 
in one or more centers.  
The investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections by 
the sponsor, IRB/IEC, government regulatory bodies and Astex Pharmaceuticals Quality 
Assurance personnel or its designees by providing direct access to source data/documents after 
appropriate notification from sponsor. 
14.2 
Investigator Responsibilities 
14.2.1 
Subject Screening Log 
The investigator must keep a record that lists all subjects who signed an informed consent and the 
reason for non-inclusion if they were not ultimately randomized or treated. 
14.2.2 
Study Treatment Accountability 
An initial supply of ASTX727 tablets will be provided to all study centers, and resupplies will be 
handled through an automated inventory management system. Study centers in the US are 
expected to supply commercially available IV decitabine. Astex will supply IV decitabine to study 
centers in territories where it is not approved for use. 
Keep study treatments in a locked, limited-access room. The study treatments must not be used 
outside the context of the protocol. Under no circumstances should the investigator or other study 
center personnel supply the study treatments to other investigators, subjects, or clinics or allow 


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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 ASTX727 and decitabine 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 study treatments and other study 
material are destroyed or returned to the sponsor on completion of the study. If the study treatments 
are destroyed at the study center, there should be documentation of destruction at the study center. 
The sponsor and/or representatives will verify final drug accountability. 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 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 eCRF. Incomplete or inconsistent data on the 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 eCRFs or other documents or subject records provided to Astex Pharmaceuticals, 
identify subjects by code (subject number, initials, date of birth) and not by names. The principal 
investigator should maintain documents not for submission to Astex Pharmaceuticals, (eg, 
subjects' signed informed consent) in strict confidence. 
14.2.4 
Source Documentation 
The investigator must maintain adequate and accurate source documents upon which eCRFs for 
each subject are based. They are to be separate and distinct from eCRFs, except for cases in which 
the sponsor has predetermined that direct data entry into specified pages of the subject's 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 eCRFs. 


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• 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. 
14.2.5 
Tissue and Blood Sample Collection/Storage 
Tissue and blood samples collected as part of routine medical care or as part of protocol procedures 
may be stored and analyzed for pharmacokinetic or pharmacodynamic analyses. 
After the study, samples may be used for additional investigation to help identify factors that may 
influence response to therapy. Such samples will be used in compliance with guidelines defined 
by FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover 
Human Specimens that are Not Individually Identifiable (issued 25 April 2006) and European 
Agency for the Evaluation of Medicinal Products (EMEA) Reflection Paper on Pharmacogenomic 
Samples, Testing and Data Handling (EMEA 2007). 
14.2.6 
Records Retention 
The investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the clinical trial agreement entered into with the sponsor in 
connection with this study. The investigator will maintain all records and documents pertaining to 
the study including, but not limited to, those outlined above (see Section 14.2.4) for a period of at 
least 2 years after FDA approval of the drug or at least 2 years after withdrawal of the IND under 
which this study was conducted, whichever is longer. In countries outside the US, records must be 
kept for the period of time required by the US FDA as a minimum, and record retention should 
also comply with the local country regulatory requirements, if longer retention times are required 
than in the US. Mandatory documentation includes copies of study protocols and amendments, 
financial disclosures, each FDA Form 1572, IRB/IEC approval letters, signed ICFs, drug 
accountability records, SAE forms transmitted to Astex Pharmaceuticals, subject files (source 
documentation) that substantiate entries in 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. 


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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 SSC 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. 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 and accruals of eligible subjects and data in the study shall be listed as lead 
authors on manuscripts and reports of study results. The sponsor's medical monitor, study director 
and/or lead statistician may also be included in the list of authors. This custom can be adjusted 
upon mutual agreement of the authors and Astex Pharmaceuticals. In addition, other than clinical 
pharmacology studies in healthy volunteers or Phase 1 studies, all clinical studies must be 
registered with ClinicalTrials.gov. 


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16.0 
REFERENCES 
Bejanyan N, Sekeres MA. The revolution of myelodysplastic syndromes. Ther Adv Hematol. 
2011;2(1):33–43. 
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for 
the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51(2):189–199. 
BioDuro Study Report APL-FFS-PK-20160512-01. Comparison of Pharmacokinetic Profiles of 
Decitabine and E7727 after Single Oral Administration of ASTX727 in FDC Tablets or in 
Capsules using a Crossover Design.  
Cabrero M, Jabbour E, Ravandi F, Bohannan Z, Pierce S, Kantarjian HM, et al. Discontinuation 
of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute 
myelogenous leukemia in complete remission or partial response: retrospective analysis of survival 
after long-term follow-up. Leuk Res. 2015;39(5):520–524. 
Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an 
international working group to standardize response criteria for myelodysplastic syndromes. 
Blood. 2000;96(12):3671–3674. 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood. 2006;108:419-425. 
Dacogen®. Prescribing Information. Otsuka America Pharmaceutical, Inc.; 2020. Accessed 11 
November 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=deb4a13c-855b-
4372-9778-6e81da598df6  
European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). 
Guideline on the Investigation of Bioequivalence. London, UK. CPMP/EWP/QWP/1401/98 Rev. 
1/ Corr. 2010. 
European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). 
Questions & Answers: positions on specific questions addressed to the Pharmacokinetics Working 
Party (PKWP). EMA/618604/2008 Rev 13. 2015. 
European Medicines Agency. Committee for Human Medicinal Products (CHMP). Reflection 
Paper 
on 
Pharmacogenomic 
Samples, 
Testing 
and 
Data 
Handling. 
Doc. 
Ref. 
EMEA/CHMP/PGxWP/201914/2006. 15 November 2007. 
Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, et al. Design, synthesis, and 
pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine 
deaminase. J Med Chem. 2014;57(6):2582–2588. 


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Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, MacBeth K, et al. Phase 1 study of oral 
azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid 
leukemia. J Clin Oncol. 2011;29(18):2521–2527. 
Garcia-Manero G. Myelodysplastic syndromes: 2015 update on diagnosis, risk-stratification and 
management. Am J Hematol. 2015;90(9):832-841. 
Garcia-Manero G, Odenike O, Amrein PC, Steensma DP, DeZern A, Michaelis L, et al. Successful 
emulation of IV decitabine pharmacokinetics with an oral fixed-dose combination of the oral 
cytidine deaminase inhibitor (CDAi) E7727 with oral decitabine, in subjects with myelodysplastic 
syndromes 
(MDS); 
Final 
data 
of 
phase 
1 
study. 
[Abstract]. 
Blood. 
2016;128:114. 
Garcia-Manero G, McCloskey J, Griffiths EA, Yee KW, Zeidan AM, Al-Kali A, et al. 
Pharmacokinetic exposure equivalence and preliminary efficacy and safety from a randomized 
cross-over Phase 3 study (ASCERTAIN) of an oral hypomethylating agent ASTX727 
(cedazuridine/decitabine) 
compared 
to 
IV 
decitabine 
[ASH 
Abstract]. 
Blood. 
2019;134(Supplement_1):846. 
Garcia-Manero G, Griffiths EA, Steensma DP, Roboz G, Bergeron J, Wells R, et al. Oral 
cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic 
randomized crossover study. Blood. 2020;136(6):674-683. 
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system 
for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–2088. 
Heaney ML, Golde DW. Myelodysplasia. N Engl J Med. 1999;340(21):1649–1660. 
INQOVI®. Prescribing Information. Taiho Pharmaceutical Co., Ltd.; 2020. Accessed 03 December 
2020. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91a0f80b-f865-4d06-a40d-
4d148d99ee71 
Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res. 2009;15(12):3938–3946. 
Kantarjian H, Estey E. Myelodysplastic syndromes. 6th ed. DeVita VT, Hellman S, Rosenberg 
SA, editors: Lippincott Williams & Wilkins. 2001. 
Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative 
chemotherapy. J Clin Oncol. 1997;15:110–115. 
Oganesian A, Redkar S, Taverna P, Joshi-Hangal R, Azab M, et al. Preclinical data in cynomolgus 
(cyn) monkeys of ASTX727, a novel oral hypomethylating agent (HMA) composed of low-dose 
oral decitabine combined with a novel cytidine deaminase inhibitor (CDAi) E7727 [ASH 
Abstract]. Blood. 2013;122(21): Abstract 2526. 


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Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, et al. An oral 
fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a 
multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019;6(4):e194–e203. 
Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A simple method for estimating 
global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 
2004;32(3):e38. 


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17.0 
APPENDICES 
 


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APPENDIX 1: 
ECOG AND KARNOFSKY PERFORMANCE STATUS 
Score 
ECOG Description 
Score 
Karnofsky Description 
0 
Fully active, able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints. 
90 
Able to carry on normal activities; minor 
signs or symptoms of disease. 
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. 
80 
Normal activity with effort. 
70 
Care for self. Unable to carry on normal 
activity or do active 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. 
60 
Requires occasional assistance; cares for 
most needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
40 
Disabled: requires special care and 
assistance. 
30 
Severely disabled: hospitalization indicated 
though death not imminent. 
4 
Completely disabled. Cannot carry on any  
self-care. Totally confined to bed or chair. 
20 
Very sick: hospitalization necessary. 
Active support treatment necessary. 
10 
Moribund. 
5 
Dead. 
0 
Dead. 
Sources: 
ECOG Performance Status — http://www.ecog.org/general/perf_stat.html (accessed 29 August 2017). 
Karnofsky Performance Status — http://oncologypro.esmo.org/Guidelines-Practice/Practice-Tools/Performance-
Scales (accessed 29 August 2017). 
 
 


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APPENDIX 2: 
COMMON TERMINOLOGY FOR ADVERSE EVENTS V4.0 
(CTCAE V4.03) 
For the NCI-CTCAE version 4.03, refer to the following: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  (accessed 05 December 2020) 
 
 
 


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APPENDIX 3: 
MODIFICATIONS DURING THE COVID-19 HEALTH 
EMERGENCY 
General Information  
This section describes modifications to the study protocol which will be implemented to allow 
flexibility in conducting this study during the current COVID-19 public health emergency or re-
emergence of the same, while maintaining safety of trial subjects, maintaining compliance with 
GCP, and minimizing risks to trial integrity. These modifications are intended to remain in effect 
only for the duration of the public health emergency related to COVID-19 and only in instances 
where the study cannot be conducted per the protocol.  
Any modifications to the study protocol must be discussed with the Astex medical monitor before 
implementing.  
Study Status  
In extenuating circumstances (eg, during the COVID-19 pandemic), Astex may implement all or 
some of the following modifications:  
• Temporarily pause recruitment of new trial subjects.  
• Extend the duration of the study.  
• Postpone activation of study centers that have not been initiated.  
• Transfer of study subjects to investigational study centers away from high-risk zones or closer 
to their home.  
• Conversion of physical visits to telephone or video visits.  
• Modification to ensure that only strictly necessary visits are performed at study centers.  
• Allow laboratory test and/or diagnostic tests to be conducted at a local laboratory/facility 
authorized/certified to perform such tests.  
• Remote monitoring source data review/verification, where permitted by regulations.  
• Changes to the per-protocol informed consent process in accordance with IRB/IEC and 
Institutional guidelines.  
COVID-19 Benefit/Risk Assessment  
The safety of each trial subject is of primary importance. Astex will continually reassess the risks 
of conducting this clinical trial against the anticipated benefit for trial subjects as the COVID-19 
situation evolves and implement and document changes accordingly.  
It is possible that local circumstances may lead to a local change in risk assessment (eg, an 
escalation of the pandemic within a certain region); therefore, the need to implement additional 


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measures may arise. Investigators may be asked to complete a risk assessment questionnaire 
provided by Astex. This assessment should be documented in the investigator’s site master file 
and communicated to Astex.  
Modifications to Study Conduct  
Alternative Methods for Obtaining Informed Consent  
Alternative methods for obtaining informed consent may be used for re-consenting subjects if 
necessary and must be appropriately documented in each subject’s chart. Alternative methods 
include but are not limited to contacting the trial subject via telephone or video-calls and obtaining 
oral consent, supplemented with e-mail confirmation, etc, as per IRB/IEC and Institutional policies 
or guidelines.  
Alternative Methods for IMP Shipment  
In extenuating circumstances (eg, during the COVID-19 pandemic) where standard approaches to 
dispensing study drug to subjects are not possible, alternative methods for dispensing study drug 
to subjects may be used. Astex will work with individual sites to find acceptable alternative 
arrangements (eg, shipment of study drug from study center pharmacies to subjects) that assure 
compliant control of study drug and acceptable safety monitoring. Alternative methods for drug 
dispensing must be reviewed by Astex before implementing.  
Study Visits and Procedures  
Protocol-mandated visits and laboratory/diagnostic testing may be modified as follows (and 
documented as protocol deviations):  
• Study subjects may use local laboratories for standard laboratory testing (eg, hematology, 
serum/plasma chemistry, and urinalysis)  
• Telemedicine visits (ie, conducted via telephone and/or video calls, or in-person Telehealth 
Visits with a health professional) may be permitted in lieu of in-person visits to monitor AEs 
and subject safety.  
• Telemedicine visits must be approved by Astex and aligned with institutional practice and local 
regulations.  
• Telemedicine visits must be appropriately documented in source documents.  
• Additional details regarding how to conduct telemedicine visits will be provided by Astex.  
In-person visits are required to assess eligibility, perform baseline assessments, and for primary 
outcome measures. Telemedicine visits would generally not be permitted for the following 
procedures unless approved by Astex:  
• Screening and/or pre-dose Cycle 1 Day 1 assessments to determine eligibility.  


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• Visits with blood sample collection for PK analysis.  
• Bone marrow collection.  
• Day 1 cycle visits when a subject is in early cycles of the protocol-defined treatment. 
 
 


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APPENDIX 4: 
SUMMARY OF CHANGES 
Rationale for Amendment 2.0 
Amendment 2 is a global amendment that is being applied to the original protocol. Due to later 
amendments to generate regional protocols, Amendment 2.0 is now the US protocol. 
Summary of Changes: 
Minor edits to the text for clarity are not included below, but are provided in the redline version of 
the protocol (provided as a separate document).  
1. Addition of information on marketing approval of ASTX727 as INQOVI® (35 mg 
decitabine/100 mg cedazuridine) (Synopsis, Section 1.3, and Section 7.1). 
2. Addition of language describing modifications to study conduct implemented due to the 
current COVID-19 health emergency (Section 4.1 and Appendix 3). 
3. Removal of restriction on ingestion of medication that may affect gastric pH for 4 hours before 
and 4 hours after ASTX727 dosing because PK results have shown this is not required 
(Synopsis, Section 7.4, and Section 7.7.2). 
4. Description of informed consent is changed from “written informed consent” to “legally 
effective informed consent” (Synopsis, Section 5.2, Section 6.0, Section 9.5.2, and 
Section 13.2). 
5. Further details and guidance on antibiotic prophylaxis are provided at the request of a health 
authority (Section 7.7.1). 
6. Exclusion criterion for “Hypersensitivity to decitabine, cedazuridine, or any of the excipients 
in ASTX727 tablets or IV decitabine” is added at the request of a health authority (Synopsis 
and Section 5.3). 
7. A brief summary of PK results from the MDS subjects in this study is added at the request of 
a health authority (Section 1.4.3). 
8. A paragraph emphasizing the importance of multiple cycles of treatment after completion of 
Cycles 1 and 2 is added at the request of a health authority (Section 4.1). 
9. An explanation that assessment of efficacy and safety is independent of the PK endpoints is 
added at the request of a health authority (Section 4.2). 
10. Instructions regarding what to do in the event of a vomited dose are added at request of a health 
authority (Section 7.5.2). 
11. Instructions that dosing should be delayed in presence of certain non-hematologic toxicities 
are added at the request of a health authority (Section 7.6). 


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12. Prohibition of nucleosides or drugs metabolized by CDA is extended from days that ASTX727 
is administered to entire duration of study treatment at the request of a health authority, and a 
non-inclusive list of such drugs is (Section 7.7.2). 
13. ASTX727 is identified as genotoxic, based on the current INQOVI Prescribing Information 
(Section 8.2). 
14. Description of AE reporting is updated to align with current practice (Section 10.2). 
15. SAE reporting requirements are updated to align with current practice that includes automated 
sending of SAE reports through the Safety Gateway (Section 10.3). 
16. Administrative changes including a name change for Astex Drug Safety to “Astex Clinical 
Safety and Risk Management”, reference to current labelling information, updating hyperlinks, 
and addition of references as applicable. 
 

SAP_001.pdf: 
Official Title: 
NCT Number: 
NCT03306264
Document Dates:
SAP Version 1.0: 27 February 2019 
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine 
and Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia 
(CMML) 


Astex Pharmaceuticals, Inc. 
ASTX727 
Clinical Study Report ASTX727-02-B 
Confidential Information 
16.1.9 Documentation of Statistical Methods 
Statistical Analysis Plan Version 1.0 (27 February 2019) 
 
 


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. 
ASTX727-02 
Statistical Analysis Plan  
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and 
Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) 
Version : Final 1.0 
Date: 27 February 2019 
Based on: Protocol Version 1.0, dated 06 September 2017 


Astex Pharmaceuticals, Inc. 
ASTX727 
Statistical Analysis Plan – ASTX727-02 
Confidential Information 
Page 2 of 24 
27 February 2019 
AUTHORED BY: 
, PhD 
 
APPROVED BY: 
, MD 
 
, PhD 
 
, MD, PhD 
 
, MD  
 
Doc1USigne<11 by: 
Doc1USignM by: 
f 
DOCIUSignedl by: 


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Statistical Analysis Plan – ASTX727-02 
Confidential Information 
Page 3 of 24 
27 February 2019 
TABLE OF CONTENTS  
ABBREVIATIONS AND DEFINITIONS ...................................................................................5 
1.0 
INTRODUCTION..............................................................................................................7 
1.1 
Myelodysplastic Syndromes ....................................................................................7 
1.2 
Treatment Options ...................................................................................................7 
1.2.1 
ASTX727 ................................................................................................8 
2.0 
STUDY OBJECTIVES ......................................................................................................9 
2.1 
Primary Objective ....................................................................................................9 
2.2 
Secondary Objectives...............................................................................................9 
3.0 
STUDY DESIGN ................................................................................................................9 
3.1 
Overall Study Design ...............................................................................................9 
3.2 
Study Endpoints .....................................................................................................11 
3.2.1 
Primary Endpoint ..................................................................................11 
3.2.2 
Secondary Endpoints .............................................................................12 
4.0 
SAMPLE SIZE .................................................................................................................12 
5.0 
ANALYSIS SETS.............................................................................................................12 
5.1 
All Subject Analysis Set ........................................................................................12 
5.2 
Randomized Subject Analysis Set .........................................................................12 
5.3 
Efficacy Analysis Set .............................................................................................13 
5.4 
Safety Analysis Set ................................................................................................13 
5.5 
Pharmacokinetics Analysis Set ..............................................................................13 
5.6 
Pharmacodynamic Analysis Set .............................................................................13 
6.0 
SCHEDULE OF ANALYSES .........................................................................................13 
7.0 
STATISTICAL ANALYSIS ...........................................................................................13 
7.1 
Subject Disposition ................................................................................................14 
7.2 
Demographic and Other Baseline Characteristics .................................................14 
7.3 
Pharmacokinetics Analyses ...................................................................................15 
7.4 
Pharmacodynamic (LINE-1) Analyses ..................................................................15 
7.5 
Efficacy Variables and Analyses ...........................................................................15 
7.5.1 
Response Rate .......................................................................................15 
7.5.2 
Transfusion Independence ....................................................................17 
7.5.3 
Leukemia-Free Survival ........................................................................18 
7.5.4 
Overall Survival ....................................................................................18 
7.6 
Safety Variables and Analyses ...............................................................................18 
7.6.1 
Study Treatment and Exposure .............................................................19 
7.6.2 
Adverse Events......................................................................................19 


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7.6.3 
Concomitant Medications .....................................................................20 
7.6.4 
Laboratory Tests....................................................................................20 
7.6.5 
Vital Signs .............................................................................................21 
7.6.6 
Electrocardiogram (ECG) .....................................................................21 
7.6.7 
ECOG Performance Status ....................................................................21 
7.6.8 
Echocardiogram / Multigated Acquisition (ECHO/MUGA) ................21 
7.6.9 
Physical Examination ............................................................................21 
7.7 
Handling of Missing Data and Other Data Anomalies ..........................................21 
7.8 
Handling of Protocol Deviations ...........................................................................22 
8.0 
REFERENCES .................................................................................................................23 
LIST OF TABLES 
Table 1: 
Dosing Schedule by Day and Cycle...........................................................10 
Table 2: 
IWG 2006 MDS Response Criteria ...........................................................16 
LIST OF FIGURES 
Figure 1: 
Study Schema.............................................................................................11 


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ABBREVIATIONS AND DEFINITIONS 
ADaM 
Aanalysis Data Model 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANOVA 
analysis of variance 
AUC 
area under the curve 
BM 
bone marrow 
BSA 
body surface area 
CCSP 
Cardiac Clinical Statistical Plan  
CDA 
cytidine deaminase  
CI 
confidence interval 
CMML 
chronic myelomonocytic leukemia 
CR 
complete response 
CRF 
case report form/electronic case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic acid 
DNMT 
DNA methyltransferase 
ECG 
electrocardiogram 
ECHO/MUGA Echocardiogram / Multigated Acquisition  
ECOG 
Eastern Cooperative Oncology Group 
ERT 
eResearch Technologies, Inc. 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
GI 
gastrointestinal 
HI 
hematological improvement 
HI-E 
erythroid response  
HI-N 
neutrophil response 
HI-P 
platelet response 
HMA 
hypomethylating agent 
IB 
Investigator Brochure 
IPD 
important protocol deviations 
IPSS 
International Prognostic Scoring System 
IV 
intravenous 
IWG 
International Working Group 
LINE-1 
long interspersed nucleotide elements-1 
mCR 
marrow complete response 
MDS 
myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCE 
new chemical entity 
NE 
non-evaluable 
NR 
non-responder 
OR 
overall response 
OS 
overall survival 
PAP 
Pharmacometric Analysis Plan 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 


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PR 
partial response 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SOC 
system organ class 
TD 
transfusion dependence 
TEAE 
treatment emergent adverse event 
TI 
transfusion independence 
TLFs 
Tables, Listings and Figures 
WHO 
World Health Organization 
 


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1.0 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the ASTX727-02 protocol (dated 06 September 
2017). It details the methodology to be used in analyzing the data and outlines the specifications 
for data to be included in the Tables, Listings and Figures (TLFs). The analyses specified in this 
document supersede the high-level analysis plan described in the protocol. Analyses and statistical 
reporting for ASTX727-02, with the exception of the analyses that are described in a separate 
Pharmacometric Analysis Plan (PAP) and a separate Cardiac Clinical Statistical Plan (CCSP), will 
be conducted by Astex Pharmaceuticals Biostatistics department using SAS version 9.4 or higher. 
Pharmacokinetics (PK) analyses of plasma decitabine, cedazuridine, and cedazuridine-epimer are 
described in the PAP and will be conducted by pharmacokinetic specialists and statisticians at 
Certara Strategic Consulting. Analyses of ECG data and exposure vs. QTc Interval assessment are 
described in the CCSP and will be conducted by expert cardiologists and statisticians at eResearch 
Technologies, Inc. (ERT).  
1.1 
Myelodysplastic Syndromes 
Myelodysplastic syndromes (MDS) are a heterogenous group of hematopoietic stem cell disorders 
characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitors and 
associated with cytopenias affecting one or more of the three lineages (Bennett 1982; Cheson et al 
2000; Heaney and Golde 1999; Kantarjian and Estey 2001). Most MDS patients are elderly, and 
their prognosis (with high-risk factors) is poor. Patients often present with complications related 
to anemia (fatigue), neutropenia (infections), or thrombocytopenia (bleeding). In addition, variable 
blast expansion, and, less commonly, leukocytosis are observed. MDS may evolve into acute 
myeloid leukemia (AML) in one-third of patients (Shukron et al 2012). 
MDS patients die either from complications associated with cytopenias (infections and bleeding) 
or from transformation to AML. In practice, "lower risk" MDS patients may be distinguished from 
"higher risk" MDS patients by their degree of pre-leukemic blast expansion, responses to 
therapeutic agents, disease outcomes, and prognosis (Benjanyan and Sekeres 2011). These factors 
have allowed the establishment of an International Prognostic Scoring System (IPSS) to predict 
survival and progression to AML (Greenberg et al 1997) as well as aiding treatment decisions. 
Based on the IPSS scoring system, patients with lower risk (IPSS low risk or intermediate-1) MDS 
(approximately 70% of patients) have an expected median survival of 3.5 to 5.7 years. Median 
survival for higher risk patients (intermediate-2 and high-risk MDS) ranges from 0.4 to 1.2 years 
(Greenberg et al 1997). 
1.2 
Treatment Options 
Hypomethylating agents (HMAs), such as decitabine and azacitidine, are effective treatment 
modalities for hematologic cancers and are FDA-approved for higher risk MDS and chronic 
myelomonocytic leukemia (CMML). HMAs have also shown promising clinical activity in AML. 
Consecutive daily dosing for 5 or 7 days in 28-day cycles are the approved schedules. Continued 


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monthly treatment for patients who respond is now the standard of care to avoid early relapse 
(Cabrero et al 2015). Treatment, which may continue for several months or even years, may 
engender significant hardship due to the 5 to 7 daily visits required each month, and the 1-hour 
intravenous (IV) infusion or large-volume subcutaneous injections. A possible consequence is 
non-compliance or premature discontinuation. Development of a formulation for oral 
administration of HMAs has proven difficult due to rapid metabolism by cytidine deaminase 
(CDA) during passage through the gastrointestinal (GI) mucosa and liver. To achieve even modest 
exposures of drug requires administration of large doses, which are associated with Grades 3 and 
4 GI toxicity (nausea, vomiting, and diarrhea) and high variability in exposures (Garcia-Manero 
et al 2011). Successful development of an oral HMA will ease the burden of long-duration 
parenteral therapy, particularly for those patients who may benefit most. 
1.2.1 
ASTX727 
Astex Pharmaceuticals is developing an oral drug product, ASTX727, which is composed of the 
new chemical entity (NCE) cedazuridine (E7727), a CDA inhibitor (Ferraris et al 2014), and 
decitabine. In animal models, dose-dependent increases in decitabine exposures were achieved 
when increasing doses of cedazuridine were administered with oral decitabine (refer to the 
ASTX727 Investigator Brochure [IB]). This interaction effect was demonstrated in CD2F1 mice, 
rhesus monkeys, and in cynomolgus monkeys, supporting the mechanism of action of improved 
pharmacokinetics (PK) for the combination of cedazuridine with oral decitabine. Because 
cedazuridine inhibits CDA in the gut and liver, ASTX727 reduces first pass metabolism of 
decitabine thus enhancing the bioavailability of decitabine and achieving exposure and 
hypomethylation activity similar to IV decitabine at the currently approved dosing schedule of 20 
mg/m2 Daily×5.  
Decitabine is a cytidine analog that profoundly inhibits DNA methylation by incorporating into 
DNA and subsequently forming covalent bonds with DNA methyltransferase (DNMT) (Issa and 
Kantarjian 2009). This enzyme deficiency renders the cell unable to maintain DNA methylation 
after cellular replication, resulting in effective DNA demethylation and re-expression of previously 
silenced genes. The analysis of the methylation of repetitive genomic elements, as in the long 
interspersed nucleotide elements-1 (LINE-1) that are normally heavily methylated, represents a 
pharmacodynamic surrogate marker for global DNA methylation (Yang et al 2004). 
The Astex ASTX727 program's Phase 1-2 first-in-human trial, ASTX727-01, is a PK-guided dose 
escalation and dose confirmation study of ASTX727 in patients with MDS and CMML intended 
to define appropriate doses of the individual components of ASTX727 (cedazuridine + decitabine) 
so that decitabine exposure after oral administration of ASTX727 is comparable to exposure after 
IV decitabine at the approved daily dose of a 1-hour infusion at 20 mg/m2. Preliminary results 
show that ASTX727 enables therapeutic dose-dependent increases in decitabine exposure to 
therapeutic levels and achieves demethylation and clinical activity comparable to IV decitabine at 
the FDA approved 5-day dose regimen using fixed doses of 35 mg decitabine and 100 mg 
cedazuridine (Garcia-Manero 2016, Dacogen Prescribing Information 2014). 


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The main purpose of the current study is to demonstrate decitabine AUC equivalence after 
administration of ASTX727 and IV decitabine. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To establish decitabine AUC equivalence of 5-day dosing between ASTX727 and IV 
decitabine. 
2.2 
Secondary Objectives  
• To assess long-term safety and efficacy (response rate) of ASTX727. 
• To assess LINE-1 demethylation. 
• To assess additional PK parameters. 
3.0 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a Phase 3, multicenter, randomized, open-label, 2-period, 2-sequence crossover study 
comparing decitabine AUC equivalence of ASTX727 and IV decitabine. Adult subjects with MDS 
or CMML who are candidates to receive decitabine will be randomized in a 1:1 ratio to receive 
the ASTX727 fixed-dose combination (FDC) tablet Daily×5 in Cycle 1, followed by IV decitabine 
20 mg/m2 Daily×5 in Cycle 2, or the converse order (Figure 1). Adequate PK assessments from 
Cycles 1 and 2 will be required for subjects to be evaluable for analysis of the primary endpoint.  
The dosing regimen for this study is shown in Table 1. Subjects will receive the ASTX727 FDC 
tablet Daily×5 in Cycle 1, followed by a 1-hour infusion of IV decitabine 20 mg/m2 Daily×5 in 
Cycle 2, or the converse order. In Cycles ≥3, subjects will receive the ASTX727 FDC tablet 
Daily×5 in 28-day cycles. After completion of the 2 treatment cycles, subjects will continue to 
receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, 
or the subject decides to discontinue treatment or withdraw from the study. 


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Table 1: 
Dosing Schedule by Day and Cycle 
Cycle (28 Days) 
1 
2 
≥3 
Day 1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
If randomized to ASTX727 in 
Cycle 1, then: 
 
     ASTX727 tablet 
× 
× 
× 
× 
× 
 
 
 
 
 
× 
× 
× 
× 
× 
     IV decitabine (20 mg/m2) 
 
 
 
 
 
× 
× 
× 
× 
× 
 
 
 
 
 
If randomized to IV decitabine in 
Cycle 1, then: 
 
     IV decitabine (20 mg/m2) 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
     ASTX727 tablet  
 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 


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Figure 1: 
Study Schema 
 
 
3.2 
Study Endpoints  
3.2.1 
Primary Endpoint  
Comparison between ASTX727 and IV decitabine: total 5-day AUC0-24 exposures of decitabine 
after treatment with ASTX727 versus IV decitabine.  
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3.2.2 
Secondary Endpoints 
• Safety as assessed by AEs, concomitant medications, physical examination, clinical laboratory 
tests (hematology, serum chemistry, and urinalysis), vital signs, Eastern Cooperative Oncology 
Group (ECOG) performance status, and electrocardiogram (ECG). 
• Maximum %LINE-1 demethylation. 
• Additional secondary PK parameters. 
• Clinical response (complete response [CR], marrow complete response [mCR], partial 
response (PR), and hematologic improvement [HI]) based on International Working Group 
(IWG) 2006 MDS response criteria. 
• Red blood cell (RBC) or platelet transfusion independence (TI). 
• Leukemia-free survival, defined as the number of days from the date of randomization to the 
date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. 
• Overall survival (OS), defined as the number of days from the date of randomization to the 
date of death from any cause. 
4.0 
SAMPLE SIZE 
The sample size calculation for this study was based on preliminary analysis of 5-day AUC in 
study ASTX727-01, which showed an estimate of intra-subject CV of 0.5. A conservative CV 
value of 0.55 was chosen to calculate the sample size. 
A total of 118 subjects in the Primary Endpoint PK Analysis Set (Section 5.5) included in the 
2 one-sided equivalence tests for the geometric mean ratio of ASTX727 5-day AUC relative to IV 
decitabine 5-day AUC will provide 90% power at the statistical significance level of 0.05, when 
the true ratio of geometric means is 1.0, the CV under an unlogged scale is 0.55, and the 90% CI 
equivalence limits for the ratio of geometric means are 0.8 and 1.25. Assuming 10% of subjects 
may not be evaluable in the study, approximately 132 subjects will need to be randomized. 
5.0 
ANALYSIS SETS 
5.1 
All Subject Analysis Set 
The All Subject Analysis Set will include information from all screened subjects, including those 
who did not meet the study entry criteria. This data set will be used only for screening displays.  
5.2 
Randomized Subject Analysis Set 
The Randomized Subject Analysis Set will include data from all subjects who were randomized 
into the study. Subjects will be included in the treatment group according to their randomly 
assigned treatment. 


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5.3 
Efficacy Analysis Set 
The Efficacy Analysis Set will include data from all subjects who received any amount of study 
treatment. All data will be included, and no subjects excluded because of protocol deviations. 
Subjects will be included in the treatment sequence according to their randomly assigned treatment 
sequence. 
5.4 
Safety Analysis Set 
The Safety Analysis Set includes data from all subjects who received any amount of study 
treatment. In the safety analysis, no data exclusion will be allowed because of protocol deviations. 
Subjects will be included in the treatment sequence according to the treatment sequence received. 
5.5 
Pharmacokinetics Analysis Set 
The details of PK analysis sets are covered under a separate Pharmacometric Analysis Plan (PAP) 
document. 
5.6 
Pharmacodynamic Analysis Set 
Subjects will be included in the PD LINE-1 Analysis Set if they received any amount of study 
treatment and have LINE-1 methylation data at baseline (Day 1) of Cycle 1 or 2 and on either Day 
8 or Day 15 of the respective cycle. 
6.0 
SCHEDULE OF ANALYSES 
Two formal analyses are planned for this study:  
The first analysis will be performed after all evaluable subjects have completed Cycles 1 and 2 
and will include analyses of all PK endpoints, maximum %LINE-1 demethylation, and all 
available safety and clinical response rate data up to the data cutoff date for the first analysis.  
A second analysis will be performed after all subjects have completed 6 months of follow-up or 
permanently discontinued treatment prior to 6 months of follow up from their first treatment dose. 
Comprehensive analyses of all efficacy (response rate, transfusion independence, leukemia-free 
survival, and overall survival), and safety will be performed using all available data up to the data 
cutoff for the second analysis.  
No formal interim analyses are planned for this study. 
7.0 
STATISTICAL ANALYSIS 
Unless otherwise specified, all statistical tests and confidence intervals (CIs) described in this 
document will be two-sided with alpha = .05. The SAS® statistical package (version 9.4 or a later 
version) will be used for the analyses. 


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The first dosing date is defined as the first date the subject received any study treatment. Subject 
disposition, demographics, and baseline characteristics will be summarized by treatment sequence 
and all subjects combined (Total). Adverse events (AEs) will be summarized by actual treatment 
received at the onset of the AE (Section 7.6.2). Efficacy analyses, laboratory tests, vital signs, 
ECG, and ECOG performance status will be summarized by treatment sequence and all subjects 
combined (Total), unless otherwise specified. 
The following data listings by study center and subject ID will be provided: screened subjects 
(with reason for screen failure), disposition (with reasons for discontinuation of treatment and 
withdrawal from study), important protocol deviations, demographic and baseline characteristics, 
study drug administration, individual efficacy data, subjects excluded from the efficacy analysis, 
AEs, all deaths (including primary cause of death), serious adverse events (SAEs), other significant 
AEs (including treatment discontinuation due to AEs), concomitant medications, and the protocol 
specified laboratory measurements. Additional data listings may be generated to support other 
relevant discussions in Clinical Study Report. 
7.1 
Subject Disposition  
Subject disposition including number of subjects randomized (enrolled), treated, and treatment 
discontinuation by reason, as well as reasons for withdrawal from study (ie, death, complete 
consent withdrawal, or lost to follow-up) and subjects ongoing at data-cut will be summarized 
using frequencies and percentages based on information collected on the study case report form 
pages. Subjects in the Randomized Subject Analysis Set will be included in the disposition 
analysis. A separate screening summary, based on the All Subjects Analysis Set, will include the 
number of subjects who were screened, failed screening and the reasons for screen failure. 
7.2 
Demographic and Other Baseline Characteristics 
The Randomized Subject Analysis Set (Section 5.2) will be used to summarize demographic and 
baseline characteristics. The demographic variables consist of age, age category (<18, 18-64, 
65-84, ≥85 years), sex, ethnicity, race, and country. Baseline characteristics include height, weight, 
BSA, ECOG performance status, prior anticancer therapy if any including prior HMA treatment 
(decitabine or azacitidine), study disease (MDS or CMML), IPSS risk category, time since 
diagnosis, cytogenetic risk classification, disease pathology (eg, hemoglobin, neutrophils, 
platelets, bone marrow [BM] blast counts (%), peripheral blood blast counts), transfusion 
dependence (RBC and platelet). Race and ethnicity summaries will be based on the levels 
according CDISC standards. 
Baseline values are the last value collected before or on the 1st dosing date unless otherwise 
specified. 
Time since diagnosis will be calculated as the (date of 1st dose – 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.  


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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.  
7.3 
Pharmacokinetics Analyses  
The primary endpoint analysis includes data from the following PK assessment days to calculate 
the 5-day total cycle AUC: 
• ASTX727 AUC0-24: Days 1, 2, and/or 5. 
• IV decitabine AUC0-24: Days 1 and/or 5. 
All details regarding the analyses of the primary and secondary PK endpoints are provided in a 
separate PAP.  
7.4 
Pharmacodynamic (LINE-1) Analyses 
The PD (LINE-1) Analysis Set (Section 5.6) will be used for analyses of LINE-1 methylation. 
Since LINE-1 methylation levels often do not completely return to baseline by Day 28 of Cycle 1, 
and to avoid the confounding effects of differing baselines in Cycle 2 vs Cycle 1, subjects will be 
compared for each of the 2 cycles separately using the baseline values prior to each cycle, thus 
limiting the evaluation to interpatient comparisons in each of the 2 cycles. 
For each of Cycles 1 and 2, LINE-1 methylation data will be summarized descriptively (using 
mean, standard deviation, standard error, median, minimum and maximum) by visit and treatment. 
Descriptive statistics for maximum %LINE-1 demethylation will be summarized by treatment. 
In addition, the 95% CIs for mean maximum %LINE-1 demethylation in Cycles 1 and 2 will be 
provided for ASTX727 and IV decitabine, respectively. The 95% CI for the difference in mean 
maximum %LINE-1 demethylation between ASTX727 and IV decitabine in Cycles 1 and 2 will 
also be generated based on an analysis of variance (ANOVA) model with treatment as factor. 
7.5 
Efficacy Variables and Analyses 
Efficacy analyses will be based on the Efficacy Analysis Set (Section 5.3). Efficacy variables will 
be summarized using descriptive statistics and there will be no comparison analyses between 
treatment sequences. 
7.5.1 
Response Rate 
The evaluation of response (Table 2) is based on IWG 2006 MDS Response Criteria (Cheson et al 
2006) and conducted by medical review of peripheral blood, bone marrow, and transfusion data.  


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Table 2: 
IWG 2006 MDS Response Criteria 
Complete Response (CR): the following for 4 weeks 
Peripheral: Normal peripheral counts with persistent granulocyte count ≥1.0×109/L, platelet 
≥100×109/L and Hgb ≥11 g/dL. No blasts. 
Marrow: Normal bone marrow with persistent marrow blasts ≤5%. Persistent dysplasia will 
be noted. 
Partial Response (PR): the following for 4 weeks 
Peripheral: Normal peripheral counts with granulocyte count ≥1.0×109/L, platelet count 
≥100×109/L, and Hgb ≥11 g/dL. No blasts. 
Marrow: Normal bone marrow and marrow blasts >5%, but were reduced by 50% or more. 
Marrow Complete Response (mCR): the following for 4 weeks 
Reduction of bone marrow blasts to ≤5% and decrease by 50% or more without normalization 
of peripheral counts. 
Hematological Improvement (HI): lasts at least 8 weeks 
Erythroid Response (HI-E): 
Major 
Response: 
Hemoglobin increase ≥1.5 g/dL in the absence of 
RBC transfusion. 
Platelet Response (HI-P): 
Major 
Response: 
Absolute increase of platelet count from <20 to 
>20×109/L and by at least 100%, or if more than 
20×109/L, by an absolute increase of at least 
30×109/L in the absence of platelet transfusion. 
Neutrophil Response (HI-N): Major 
Response: 
Granulocyte increase ≥100%, and by an absolute 
increase ≥0.5×109/L. 
The details of the response criteria are presented in (Cheson et al 2006). 
Response categories listed in Table 2, as well as the start and stop date of a subject’s best response 
(CR, PR, mCR, and HI) will be determined by medical review. Baseline values of neutrophils, 
hemoglobin and platelets used for response evaluation are the average of all values obtained during 
screening up to and including the first dosing date. If there is only one value available before 
treatment then it will be used as the baseline value. 
The following rates of best response will be estimated using sample proportions and 95% Wald CI 
based on the number of subjects in the Efficacy Analysis Set: 
• CR. 
• PR. 
• mCR. 
• HI (HI-E, HI-P or HI-N). 
o HI-E. 
o HI-P. 


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o HI-N. 
• Overall response (OR [CR+PR+mCR+HI]). 
• mCR with HI. 
Subjects with these different response categories, as well as non-responders (NR) and non-
evaluable (NE) subjects will be listed and summarized using frequency counts and proportion of 
subjects with each category of best response (each subject will be counted once with best response, 
in the following hierarchy: CR, followed by PR, followed by mCR, followed by HI). In the HI 
category, subjects will be listed in each HI category they achieved, so subjects may be counted 
under multiple HI categories). The category of mCR with HI is a subset of mCR subjects who also 
achieved HI. Subjects who did not have a valid post-treatment efficacy assessment will be 
classified as NE for response classifications. These subjects will be included in the denominator 
of the efficacy analysis for calculation of different response rates.  
For the first analysis (see Section 6.0), the responses will be summarized for all subjects regardless 
of the length of follow-up at the time of the data cutoff date. Response will also be summarized 
based on the subjects with mature response data from those subjects in the Efficacy Analysis Set 
who have completed at least 6 months of follow-up or who have permanently discontinued 
treatment prior to 6 months of follow up from their first treatment dose. 
For the second analysis (see Section 6.0), duration of best response (CR, PR, and mCR) will be 
summarized.  
7.5.2 
Transfusion Independence  
Transfusion independence (TI) will be analyzed separately for platelet and RBC transfusions. 
Transfusion dependence (TD) and transfusion independence are defined as follows:  
• Transfusion dependence at baseline: documentation of 2 units or more of transfusion within 
56 days of the first dose of study treatment.  
• Post-treatment transfusion independence: no transfusion for 56 consecutive days or more after 
the first dose of study treatment while maintaining hemoglobin ≥8 g/dL (RBC TI) or 
maintaining platelets ≥20×109/L (Platelet TI). 
Post-treatment transfusion independence rate will be calculated separately for RBC transfusion 
independence and platelet transfusion independence as the number of subjects who are transfusion 
independent post treatment (n) among those who were transfusion dependent at baseline (N). The 
95% Wald CI for transfusion independence rates will be provided. The same analyses will be 
performed for 84-day and 112-day transfusion independence, defined as no transfusion for 
84 consecutive and 112 consecutive days, respectively, while maintaining hemoglobin ≥8 g/dL 
(RBC TI) or maintaining platelets ≥20×109/L (Platelet TI).  


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7.5.3 
Leukemia-Free Survival 
Leukemia-free survival is defined as the number of days from the date of randomization to the date 
of MDS progression to AML or death.  
The date of MDS progression to AML or death will be defined based on the earliest date of 
following: 
• Death date. 
• AML conversion date defined as the earliest date of the following: 
o AML conversion date on the Conversion to AML CRF page. 
o The first date when a record of ≥20% blasts in bone marrow was reported or 2 consecutive 
records of ≥20% blasts in peripheral blood were reported. 
Subjects who have bone marrow or peripheral blood blasts ≥20% at baseline will be censored at 
the date of randomization, and subjects without a time to AML event as described above will be 
censored on the date of last contact.  
The Kaplan-Meier plot will be provided based on the Efficacy Analysis Set. Estimated median 
leukemia-free survival and 95% CIs will also be provided if available. 
7.5.4 
Overall Survival 
Overall survival is defined as the number of days from the date the subject was randomized to the 
date of death (regardless of cause). Subjects without documentation of death will be censored on 
the last date of contact or the last date subject was confirmed alive on the Study Discontinuation 
CRF page, whichever is later. 
The Kaplan-Meier plot will be provided based on the Efficacy Analysis Set. Estimated median 
survival time (days) and 95% CIs will also be provided if available. In addition, subject follow-up 
time in days will also be summarized. 
7.6 
Safety Variables and Analyses 
Safety Analysis will be performed using the Safety Analysis Set (Section 5.4). Safety was assessed 
by subject-reported and investigator-observed adverse events (AEs), along with physical 
examination, clinical laboratory tests (hematology, chemistries and urinalysis), vital signs, 


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concomitant medications, ECOG performance status and ECGs. Exposure to study treatment, 
deaths, and causes of deaths will be tabulated.  
7.6.1 
Study Treatment and Exposure  
The number of cycles completed or partially completed per subject will be summarized using 
descriptive statistics. Frequency count and percentage of dose delayed cycles and dose reduced 
cycles reported by the investigator will be summarized at the subject level and cycle level.  
7.6.2 
Adverse Events  
Adverse events 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 AEs will be graded using Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
Treatment-emergent AEs (TEAEs) are defined as events that first occurred or worsened on or after 
the date of the first dose of study treatment until 30 days after the last dose of study treatment or 
until the start of a post-treatment alternative anti-cancer treatment for MDS/ CMML and 
subsequent AML, whichever occurs first, with the following exceptions: events that occurred after 
30 days beyond the last dose of study treatment or the start of a post-treatment alternative anti-
cancer treatment for MDS/CMML and subsequent AML will also be considered treatment-
emergent if the events are both serious and related to the study treatment. For the purpose of 
determining whether an AE is a treatment-emergent AE, incomplete AE start and stop dates will 
be imputed conservatively following the data programming standards as detailed in the Aanalysis 
Data Model (ADaM) data reviewer guide. 
All AE data collected in the study database with an AE start date on or before the data cutoff date 
will be included in the data listings, including those that are not treatment emergent. Only TEAEs 
will be included in the AE summary tables. 
An overall safety summary table containing counts and percentages of subjects with any AE, any 
AE Grade ≥3, AE leading to treatment discontinuation, any SAE, and subcategories of SAEs 
(death vs not death) will be produced. 
Related events are those that the Investigator considered to be related to study treatment as 
described in the study protocol. All summaries of AEs will be made separately in the following 
groups: 
• IV decitabine in Cycle 1 or Cycle 2. 
• ASTX727 in Cycle 1 or Cycle 2. 
• ASTX727 in Cycle 3 or later. 
• Total for ASTX727. 


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• Total for Phase 3. 
The number and percentage of subjects experiencing AEs will be summarized by MedDRA SOCs 
(sorted alphabetically) with PTs sorted alphabetically within each SOC. The number and 
percentage of subjects experiencing AEs will also be summarized by PT and sorted by event 
frequency of the Total for ASTX727 column. Related AEs, serious AEs (SAEs), and related SAEs 
will be summarized similarly. A summary of AEs with fatal outcome, AEs resulting in permanent 
treatment discontinuation, and AEs resulting in treatment delay or dose reduction will also be 
provided. Additional summaries will be generated by SOC, PT and CTCAE grade. For these 
summaries, if the occurrence of a particular AE for a given subject is reported more than once, the 
event is only counted once with its worst CTCAE grade. 
7.6.3 
Concomitant Medications 
Concomitant medications are medications taken with a start date on or after the date of the first 
dose of study treatment, or those with a start date before the start of the administration of study 
treatment and a stop date on or after the start of the administration of study treatment. Medications 
taken beyond 30 days from the last dose of study treatment or after the start of a post-treatment 
alternative anti-cancer treatment for MDS/CMML and subsequent AML are not considered 
concomitant medications, unless they are used for treating a related SAE. For the purpose of 
inclusion in the concomitant medication tables, incomplete medication start and stop dates will be 
imputed conservatively.  
Concomitant medication will be coded by the latest version of WHO Drug Dictionary before the 
data download and summarized by Anatomical Therapeutic Chemical (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. 
7.6.4 
Laboratory Tests  
Laboratory values will also be graded, if possible, by CTCAE v4.03 in conjunction with the 
Harrison (18th edition) lab book normal values (Longo et al 2011). Shift tables will display 
(1) shift from baseline grade to the worst grade during the study, and (2) shift from baseline grade 
to the last grade at the end of study. 
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 ADaM data 
reviewer guide. 


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7.6.5 
Vital Signs 
Vital signs will be summarized by visit and treatment group using proportion of subjects with each 
vital sign being too high or too low according to conventionally accepted vital sign normal ranges 
as follows:  
• Pulse rate 110 bpm or greater. 
• Pulse rate 50 bpm or less. 
• Diastolic blood pressure 110 mmHg or greater. 
• Diastolic blood pressure 55 mmHg or less. 
• Systolic blood pressure 180 mmHg or greater. 
• Systolic blood pressure 80 mmHg or less. 
• Respiration rate 20 breaths/min or greater. 
• Body temperature 39°C or greater. 
7.6.6 
Electrocardiogram (ECG) 
The ECG data will be summarized and presented as part of a separate more extensive analysis that 
will explore the relationship between the change from baseline in QTc intervals and plasma 
concentrations of ASTX727 or IV decitabine. Further details regarding the analyses of the ECG 
data will be provided in the CCSP.  
7.6.7 
ECOG Performance Status 
Shift tables for ECOG from baseline to the worst grade, and from the baseline to the last available 
grade will be provided. 
7.6.8 
Echocardiogram / Multigated Acquisition (ECHO/MUGA) 
This was only done at baseline for reference. Data will be preserved in a Study Data Tabulation 
Model (SDTM) dataset. No particular analysis will be conducted. 
7.6.9 
Physical Examination 
Physical examination data will be preserved in a SDTM dataset. No particular analysis will be 
conducted. 
7.7 
Handling of Missing Data and Other Data Anomalies 
No missing data imputations are planned for the study, except as specified. Subjects lost to follow-
up will be included in statistical analyses to the point of the data cut-off date. 


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7.8 
Handling of Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team and updated during 
the IPD reviews throughout the study prior to data cut-off date. IPD will be tabulated by IPD 
category and listed by subject. Non-important protocol deviation data will be preserved in a SDTM 
dataset. No particular analysis will be conducted. 


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8.0 
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