Clinical trial NCT02103478
Conditions: Myelodysplastic Syndrome MDS
Keywords: Myelodysplastic Syndrome MDS
Sponsor: Astex Pharmaceuticals, Inc.
Start date: 2014-10-28; Completion date: 2019-12-04
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.

Detailed description:
The trial was designed to define daily doses of the individual components (cedazuridine \[E7727\] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m\^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.

Arms: arm 1: Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m\^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course). arm 2: Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m\^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. arm 3: Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m\^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Interventions: intervention 1: ASTX727 Dose Escalation intervention 2: ASTX727 Dose Confirmation intervention 3: ASTX727 Fixed-Dose Combination
Intervention descriptions: intervention 1: Oral investigational product and approved IV decitabine intervention 2: Randomization cross over design for courses 1 and 2 intervention 3: Fixed-dose investigational product

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
This document is a confidential communication of Astex Pharmaceuticals, Inc. Acceptance of the 
document constitutes agreement by the recipient that the contents will not be disclosed to any 
unauthorized personnel without the prior written authorization of Astex Pharmaceuticals, Inc. 
Clinical Study Protocol — ASTX727-01 
A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of 
ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with 
Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS) 
PROTOCOL TITLE PAGE 
Sponsor: 
Astex Pharmaceuticals, Inc. 
4420 Rosewood Dr., Suite 200 
Pleasanton, CA 94588 
Astex Pharmaceuticals 
 
Medical Monitor: 
Astex Pharmaceuticals 
 
Drug Safety: 
 
IND Number: 
116145 
EudraCT Number: 
2014-005158-20 
Study Clinical Phase: 
Phase 1-2 
Version History/Date: 
Version 1.0: Original (10 January 2014) 
Version 2.0: Amendment 1 (24 November 2014) 
Version 3.0: Amendment 2 (23 September 2015) 
Version 4.0: Amendment 3 (26 July 2016) 
Version 5.0: Amendment 4 (06 April 2017) 
NCT02103478


Astex Pharmaceuticals, Inc. 
 
 
Clinical Protocol ASTX727-01 
 
 
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Version 5.0: 06 April 2017 
SPONSOR AND INVESTIGATOR SIGNATURE PAGE 
Astex Pharmaceuticals, Inc. 
4420 Rosewood Drive, Suite 200 
Pleasanton, CA 94588 USA 
Study Acknowledgement 
A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of 
ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with 
Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS) 
Version 5.0: Amendment 4 (06 April 2017) 
This protocol has been approved by Astex Pharmaceuticals, Inc. The following signature 
documents this approval. 
 
 
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary details 
for me and my staff to conduct this study as described. I will conduct this study as outlined herein 
and will make a reasonable effort to complete the study within the time designated. Further, I agree 
to conduct this study in accordance with Good Clinical Practice and applicable regulatory 
requirements. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Astex Pharmaceuticals, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
 
 
 
Principal Investigator Name (printed) 
 
Signature 
 
 
 
Date 
 
Study Center Number 
 
 
 
Institution Name 
 
Center Location: City, State or Province, Country 
Please forward the original signed Protocol Acceptance Statement to Astex Pharmaceuticals, Inc. 
Retain a copy of this form with the study protocol in your regulatory file. 


Astex Pharmaceuticals, Inc. 
 
 
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PROTOCOL APPROVAL PAGE 
A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of 
ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with 
Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS) 
Version 5.0: Amendment 4 (06 April 2017) 
AUTHORS  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Astex Pharmaceuticals, Inc. 
 
 
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Version 5.0: 06 April 2017 
PROTOCOL APPROVAL PAGE 
A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of 
ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with 
Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS)) 
Version 5.0: Amendment 4 (06 April 2017) 
QA APPROVAL 
 
  
 
 
 
 
 
APPROVED BY 
 
 
 
 
 
 
 
 


Astex Pharmaceuticals, Inc. 
 
 
Clinical Protocol ASTX727-01 
 
 
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PROTOCOL SYNOPSIS 
Study Number and Title: 
ASTX727-01: A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, 
a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine in Subjects with 
Myelodysplastic Syndromes (MDS)  
Investigational Medicinal Product: 
E7727 oral: 20 mg hard gelatin white opaque capsules 
Decitabine oral: 20 mg hard gelatin Swedish orange capsules; 5 mg hard gelatin light blue capsules  
The fixed-dose combination (FDC) drug form of ASTX727 is a film-coated, oval, white, immediate-release tablet 
containing the combination of E7727 (100 mg) and decitabine (35 mg) for oral administration. 
Clinical Phase: 1-2 
Study Centers Planned/Country: Multicenter: United States, Canada 
Study Objectives:  
Dose Escalation Stage 
Primary Objectives 
• 
Assess safety, tolerability, and pharmacokinetics (PK) of concomitant orally administered decitabine + E7727. 
• 
Identify a dose of oral decitabine + E7727 that together achieve a target mean decitabine AUC comparable to 
that from decitabine given by IV infusion (20 mg/m2) for 1 hour.  
Secondary Objectives 
• 
Determine percent change of LINE-1 demethylation in Course 1 and Course 2. 
• 
Assess preliminary efficacy, as determined by response rate, duration of response, hematological 
improvement, rate of transfusion independence, time to AML, and overall survival. 
• 
Evaluate other PK parameters of decitabine, E7727, and E7727-epimer. 
Exploratory Objectives 
 
  
 
Dose Confirmation Stage 
Primary Objectives 
• 
Confirm the dose of oral decitabine + E7727 identified in the Dose Escalation Stage administered daily×5 that 
achieves mean decitabine AUC (estimated from 5 days of dosing) and LINE-1 DNA demethylation 
comparable to that of IV decitabine 20 mg/m2 daily×5. 
• 
Assess response rate in all subjects.  
Secondary Objectives 
• 
Assess safety and tolerability of oral decitabine + E7727. 
• 
Assess duration of response, hematological improvement, rate of transfusion independence, time to AML, and 
overall survival. 
• 
Evaluate other PK parameters of oral decitabine, E7727, and E7727-epimer (if needed).  
Exploratory Objective 
 
 
Fixed-Dose Combination Stage 
Primary Objectives 
• 
Confirm the ASTX727 FDC tablet achieves mean decitabine AUC (estimated from 5 days of dosing) and 
LINE-1 DNA demethylation similar to that for IV decitabine 20 mg/m2 daily×5. 
• 
Assess response rate in all subjects.  
Secondary Objectives 
• 
Assess safety and tolerability of ASTX727. 
• 
Assess duration of response, hematological improvement, rate of transfusion independence, time to AML, and 
overall survival. 


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• 
Evaluate other PK parameters of ASTX727.  
Exploratory Objective 
 
 
Study Design and Investigational Plan:  
Study ASTX727-01 will consist of 3 stages: a Dose Escalation Stage, a Dose Confirmation Stage, and a Fixed-Dose 
Combination Stage. 
Dose Escalation Stage 
The Dose Escalation Stage is a single-arm PK-guided 3+3 dose escalation study in subjects with intermediate- or 
high-risk MDS who are candidates for treatment with a hypomethylating agent. At least 3 evaluable subjects will 
be enrolled in each cohort. 
Dosing: 
  Course 1: 
• 
Day -3 (±2 days): Single dose oral decitabine. 
• 
Day 1: Decitabine by 1-hour IV infusion administered at 20 mg/m2. 
• 
Days 2-5: Concomitant oral administration of decitabine + E7727.  
  Course 2: 
• 
Day -3 (± 2 days): Single dose E7727. 
• 
Days 1-5: Concomitant oral administration of decitabine + E7727.  
  Course ≥3: 
• 
Days 1-5: Concomitant oral administration of decitabine + E7727.  
All subjects will continue to receive oral decitabine + E7727 daily×5 of a 28-day course in Course 3 and thereafter 
until the subject has disease progression or unacceptable toxicity, or the subject withdraws consent or is withdrawn 
from the study. 
If no dose limiting toxicities (DLTs) occur in cohort 1 during Course 1, E7727 or oral decitabine will be 
escalated/de-escalated in subsequent cohorts according to protocol Section 4.1.1 until the target mean AUC for oral 
decitabine approaches as close to unity with IV decitabine 20 mg/m2 as possible. 
For the protection of study subjects, a Data and Safety Review Committee (DSRC) will review and evaluate at 
least the 28-day Course 1 safety and PK data from a minimum of 3 evaluable subjects at each dose cohort, and will 
agree on the dose level of oral decitabine and E7727 for the next cohort or agree to expand the current cohort 
(Section 4.4). 
Dose Confirmation Stage 
The Dose Confirmation Stage is a randomized comparison between oral decitabine + E7727 at the doses 
established in the Dose Escalation Stage and IV decitabine 20 mg/m2 1-hour infusion both given daily for 5 days in 
at least 42 evaluable subjects. Subjects will be randomized to the sequence of 
• 
Oral decitabine + E7727 daily×5 in Course 1 followed by IV decitabine daily×5 in Course 2, or 
• 
IV decitabine daily×5 in Course 1 followed by oral decitabine + E7727 daily×5 in Course 2. 
Beginning with Course 3 and all subsequent courses, subjects will receive oral decitabine + E7727 daily×5 of a 
28-day course until the subject has disease progression or unacceptable toxicity, or the subject withdraws consent 
or is withdrawn from the study. 
Fixed-Dose Combination Stage 
This stage is a comparison between a fixed-dose tablet form of ASTX727 and IV decitabine 20 mg/m2. After 
completion of enrollment into the Dose Confirmation Stage, 18-24 evaluable subjects will be randomized into a 
crossover study to confirm that the ASTX727 FDC yields PK exposures and DNA demethylation similar to those 
for IV decitabine. 
Subjects will be randomized in a 1:1 ratio to receive the FDC tablet daily×5 in Course 1 followed by IV decitabine 
daily ×5 in Course 2, or the converse. In Courses ≥3, all subjects will receive the FDC tablet daily ×5 (in a 28-day 
course) until disease progression or unacceptable toxicity or withdrawal from the study.  
Based on (1) data from both the Dose Escalation Stage and Dose Confirmation Stage, which confirmed that the 
combination doses of 100 mg E7727 + 35 mg decitabine emulate the PK and pharmacodynamics (PD) of IV 


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decitabine 20 mg/m2, and (2) availability of the FDC tablet combining these 2 doses, subjects who are still on 
treatment with the separate E7727 and decitabine capsules in the previous study stages will be allowed to transition 
to treatment with the more convenient FDC tablet at the discretion of the investigator but no later than 23 October 
2017. New clinical supplies of the E7727 and decitabine capsules will not be supported after the expiry date 
(31 October 2017) of the current supplies.  
Study Population: 
Number of Subjects 
At least 3 evaluable subjects per cohort will be treated in the Dose Escalation Stage, at least 42 evaluable subjects 
will be treated in the Dose Confirmation Stage, and 18-24 evaluable subjects will be treated in the FDC Stage.  
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria. 
1. 
Able to understand and comply with the study procedures, understand the risks involved in the study, and 
provide written informed consent before the first study-specific procedure. 
2. 
Men or women ≥18 years with IPSS intermediate-1, intermediate-2 or high-risk MDS with peripheral blasts 
or bone marrow blasts <20% in all study stages, including subjects with chronic myelomonocytic leukemia 
(CMML) who are candidates for treatment with a hypomethylating agent. 
3. 
Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see Appendix 3). 
4. 
Subjects with adequate organ function defined as: 
a) Hepatic: Total or direct bilirubin ≤2 X ULN; AST/SGOT and ALT/SGPT ≤2.5 X ULN 
b) Renal: serum creatinine ≤1.5 X ULN or creatinine clearance >50 mL/min/1.73 m2 for subjects with 
creatinine levels above institutional normal 
5. 
For subjects with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD) and 
must be ≥2 weeks off systemic immunosuppressive therapy. 
6. 
Subjects with no major surgery within 2 weeks of first study treatment. 
7. 
Subjects with no cytotoxic chemotherapy within 2 weeks of first study treatment. 
8. 
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 (FSH) levels in the menopausal range. 
9. 
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, double-barrier method (use of a condom AND diaphragm, with 
spermicide), or abstaining from sexual intercourse. 
10. 
Able to swallow the number of capsules required for the treatment assignment within a 10-minute period 
and tolerate 4 hours of fasting. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria will be excluded from the study: 
1. 
Previous treatment with at least 2 courses of decitabine (all stages) or azacitidine (Dose Confirmation 
Stage). 
2. 
Known or suspected hypersensitivity to decitabine or the components of E7727. 
3. 
Treated with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, 
whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically 
significant adverse events from previous treatment with investigational drug or therapy. 
4. 
Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled 
infections. 
5. 
Diagnosis of AML with bone marrow or peripheral blast count ≥20% or other hematological malignancies. 
6. 
Life-threatening illness, medical condition or organ system dysfunction, 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 oral decitabine + E7727 or compromise the integrity of the 
study outcomes. 


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7. 
Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical 
cancer, non-metastatic prostate cancer with normal prostate-specific antigen (PSA), or other cancer from 
which the subject has been disease free for at least 3 years. 
8. 
Known history of human immunodeficiency virus (HIV) or if known seropositive for hepatitis C virus 
(HCV) or hepatitis B virus (HBV). 
9. 
Active uncontrolled gastric or duodenal ulcer. 
Study Treatment: 
IV decitabine 20 mg/m2 is to be administered as a 1-hour intravenous infusion per the prescribing information. This 
dose level remains constant throughout the trial. 
The starting dose levels for Cohort 1 in the Dose Escalation Stage are E7727 40 mg and oral decitabine 20 mg. 
Subjects will be fasting on days when receiving study treatment orally. Fasting (no food, milk or alcohol) is 
defined as 2 hours prior to the dose and at least 2 hours post-dose. Only clear liquids such as water, black coffee, 
tea, or fruit juice may be allowed as desired. Administer oral doses with 240 mL (8 fluid oz) of water. Subjects 
should take the investigational medicinal products (IMPs) simultaneously (ie, E7727 followed immediately by oral 
decitabine). The IMPs should be taken at the same time of day (±1 hour) on each dosing day, in at least the first 2 
courses of treatment. When oral decitabine or E7727 is given alone (Day -3 ±2 days of Courses 1 and 2), each will 
be administered at the same dose it is scheduled to be given when the IMPs are combined on subsequent days in 
the same course.  
The ASTX727 FDC tablet is to be administered in the manner described above regarding fasting, administration 
with water, and administration at the same time of day. 
Study Endpoints: 
Dose Escalation Stage 
Primary Endpoint 
• 
Mean decitabine AUC oral/IV: Mean AUC of oral decitabine given with E7727 (Days 2 and/or 5) compared 
with IV decitabine 20 mg/m2 (Day 1). 
• 
Incidence and severity grades of DLTs. 
Secondary Endpoints 
• 
AUC, Cmax, Tmax, and other PK parameters of oral decitabine, E7727, and E7727-epimer. 
• 
Incidence and severity of adverse events and clinically significant abnormal laboratory values 
• 
Mean maximum %LINE-1 demethylation of oral decitabine + E7727 by cohort. 
• 
Overall response rate as measured by the IWG 2006 MDS Response Criteria, duration of response, 
hematological improvement, rate of transfusion independence, time to AML, and overall survival. 
Exploratory Endpoint 
 
 
 
 
Dose Confirmation Stage 
Primary Endpoints 
• 
Mean decitabine AUC (estimated from 5 days of dosing) and mean maximum %LINE-1 demethylation after 
oral decitabine + E7727 compared with IV decitabine 20 mg/m2.  
• 
Response rate in all subjects.   
Secondary Endpoints 
• 
Incidence and severity grades of adverse events (AEs) and clinically significant abnormal laboratory values. 
• 
Duration of response, hematological improvement, rate of transfusion independence, time to AML, and overall 
survival. 
• 
Other PK parameters of oral decitabine, E7727, and E7727-epimer (if needed). 


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Exploratory Endpoint 
• 
. 
Fixed-Dose Combination Stage 
Primary Endpoints 
• 
Mean decitabine AUC and mean maximum %LINE-1 demethylation after ASTX727 administration compared 
with IV decitabine 20 mg/m2.  
• 
Response rate in all subjects. 
Secondary Endpoints 
• 
Incidence and severity grades of AEs and clinically significant abnormal laboratory values. 
• 
Duration of response, hematological improvement, rate of transfusion independence, time to AML, and overall 
survival. 
• 
Other PK parameters of ASTX727. 
Exploratory Endpoint 
• 
. 
Study Assessments and Procedures (see Section 9.0 and Table 3 through Table 6 for details): 
• 
Screening Assessments: Baseline assessment of eligibility criteria, physical examination and medical history 
including demographics, hematology, chemistry, urinalysis, ECG, ECHO/MUGA, and bone marrow aspirate 
or biopsy. 
• 
Efficacy Assessments: Efficacy assessments (via bone marrow aspirate or biopsy) will be based on the IWG 
2006 MDS Response Criteria for MDS.  
• 
PK: AUC, Cmax, Tmax, and other PK parameters of decitabine, E7727, and E7727-epimer. 
• 
Pharmacodynamics: In all subjects, global LINE-1 DNA methylation will be assessed at Screening, and at 
specified times (see Schedule of Events) after Course 1, and Course 2.  
Safety Assessments: Safety will be assessed by subject reported and Investigator observed AEs along with 
physical examination clinical laboratory tests (hematology, chemistries, and urinalysis) and ECG. DLTs will be 
determined during the first course of treatment as defined in Section 4.5 (Dose Escalation Stage only). 
Subjects ongoing in the Dose Escalation Stage or Dose Confirmation Stage who transition from the E7727 + 
decitabine capsules to the ASTX727 FDC tablet will continue with all study assessments and procedures as 
indicated for the FDC Stage. 
Sample Size and Statistical Analyses: 
Sample Size for Dose Escalation Stage 
At least 3 evaluable subjects will be treated in each cohort to allow sufficient decitabine PK (AUC) data 
comparison between IV decitabine at the approved dose of 20 mg/m2 (Course 1 Day 1) and the different dose 
levels of oral decitabine + E7727 (decitabine AUC Day 2 and/or Day 5 after oral administration). Up to 6 
additional evaluable subjects may be enrolled in a cohort before PK and safety results from at least the first 3 
subjects in that cohort become available. When the AUC range for a 3-subject cohort is between 0.90-1.10 of IV 
decitabine, and no more than 1 DLT has occurred, additional evaluable subjects may be added to reach up to 12 -18 
subjects in that cohort) to confirm the AUC range at 0.90-1.10 and to confirm safety at no more than 1 DLT in 6 
subjects. If AUC and safety are confirmed in those 12 subjects, the Dose Confirmation Stage of the trial will be 
opened. Otherwise, the dose of E7727 or decitabine will be titrated further (escalated or de-escalated) based on 
AUC and safety until the AUC is confirmed at 0.90-1.10 and safety is confirmed at no more than 1 DLT in 
6 subjects. 
Sample Size for Dose Confirmation Stage 
Approximately 42 evaluable subjects are planned for enrollment into the Dose Confirmation Stage at the final 
recommended dose combination. Data from these subjects will be primarily used to assess decitabine AUC and 
LINE-1 demethylation, using a standard 2 x 2 cross-over design (the first 2 courses), between IV decitabine 
20 mg/m2 daily×5 and the final recommended doses of oral decitabine + E7727. 


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Sample Size for Fixed-Dose Combination Stage 
In an equivalence test of the mean decitabine AUCs of the ASTX727 FDC tablet compared with IV decitabine, 
data from the 18-24 evaluable subjects in a standard 2 x 2 crossover design will provide 75%-88% power at a 10% 
significance level using 2 one-sided tests when the true ratio of means is 1.0, the coefficient of variation under an 
unlogged scale is 0.55, and the equivalence limits for the ratio of means are 0.65 and 1.539. The sample size of 
18-24 evaluable subjects in the same 2 x 2 crossover design achieves 78%-86% power to detect non-inferiority in 
the comparison of mean maximum %LINE-1 demethylation from baseline between the FDC tablet and IV 
decitabine using a one-sided t-test when the margin of non-inferiority is -0.075, the true mean difference is 0, the 
standard deviation is 0.15, and the significance level is 0.1. 
Efficacy Analyses: 
Response rates and rates of hematologic improvement will be calculated as defined by the IWG 2006 MDS 
Response Criteria. Rates of transfusion independence will be calculated based on the number of transfusion-
dependent subjects who had no transfusion for at least 56 days during treatment.  
Overall survival will be defined as the number of days from the day the subject received the first dose of study 
treatment to the date of death (regardless of cause). Time to AML will be the number of days from the day the 
subject received the first dose of study treatment to the date of MDS progression to AML as defined by ≥20% 
blasts in bone marrow or peripheral blood, or death. 
Pharmacokinetics/Pharmacodynamics Analyses: 
PK parameters will be summarized descriptively using mean, standard deviation, median and range by dose cohort 
and course/days, and by stage of the study if deemed necessary. PK values obtained after oral decitabine + E7727 
will be compared with those after IV decitabine on an intra-subject basis and also by dose/cohort average basis. In 
addition, the decitabine AUC values obtained from the 2 x 2 crossover part of the study will be analyzed for 
comparability of means using the CI method (Section 11.8.1). 
Pharmacodynamic (LINE-1 demethylation data) and biomarkers will be summarized descriptively (using mean, 
standard deviation, median and range for continuous variables and counts and percentages for categorical 
variables) by dose cohort and course/days, and by stage of the study. In addition, the mean maximum %LINE-1 
demethylation from baseline obtained from the 2 x 2 crossover design part of the study will be analyzed for non-
inferiority of means (oral decitabine + E7727 compared with IV decitabine) using the CI method (Section 11.8.2).  
Safety Analyses: 
Adverse events will be summarized using counts and percentages by MedDRA System Organ Class (SOC) and 
Preferred Term (PT) and by CTCAE grades. DLTs will be identified in each dose cohort (as defined in Section 4.5) 
and listed separately to assist in determining the desired dose level for the combination of oral decitabine + E7727 
in the Dose Escalation Stage. Concomitant medications will be summarized by WHO Drug Therapeutic subgroup 
and generic name. Clinical laboratory values will be listed and reviewed. 
Interim Analysis: 
No formal interim analysis is planned for this study. However, ongoing data review will be performed by the Data 
and Safety Review Committee (DSRC) as described in Section 4.4.  
Study Duration and Termination:  
The expected study duration is as follows: 
Dose Escalation Stage ≈12 months 
Dose Confirmation Stage ≈12 months 
Fixed-Dose Combination Stage ≈ 12 months 
The study is expected to begin (ie, first subject enrolled) in 2Q14. 
Compliance Statement: 
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines, US Title 21 CFR Parts 11, 50, 54, 56, and 312; and the principles enunciated in 
the Declaration of Helsinki and all human clinical research regulations in the countries where the study is to be 
conducted. 


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TABLE OF CONTENTS 
SPONSOR AND INVESTIGATOR SIGNATURE PAGE ........................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
PROTOCOL APPROVAL PAGE ...............................................................................................4 
PROTOCOL SYNOPSIS ..............................................................................................................5 
TABLE OF CONTENTS ............................................................................................................11 
LIST OF TABLES .......................................................................................................................15 
LIST OF FIGURES .....................................................................................................................15 
LIST OF APPENDICES .............................................................................................................15 
ABBREVIATIONS AND DEFINITIONS .................................................................................16 
1.0 
INTRODUCTION AND BACKGROUND ...................................................................18 
1.1 
Background of the Disease ....................................................................................18 
1.2 
Background of Treatment Options.........................................................................18 
1.3 
Summary of Nonclinical and Clinical Data for Oral Decitabine + E7727 ............19 
1.3.1 
General Information ..............................................................................19 
1.3.2 
Nonclinical Data....................................................................................19 
1.3.3 
Clinical Data and Human Pharmacokinetics (PK) ................................21 
1.4 
Potential Risks and Benefits to Human Subjects ...................................................22 
2.0 
RATIONALE ...................................................................................................................22 
2.1 
Rationale for the Study ..........................................................................................22 
2.2 
Rationale for Oral Decitabine + E7727 Dose and Study Treatment Regimen ......23 
3.0 
STUDY OBJECTIVES ....................................................................................................24 
3.1 
Dose Escalation Stage - Primary Objectives .........................................................24 
3.2 
Dose Escalation Stage - Secondary Objectives .....................................................24 
3.3 
Dose Escalation Stage - Exploratory Objectives ...................................................24 
3.4 
Dose Confirmation Stage - Primary Objectives.....................................................24 
3.5 
Dose Confirmation Stage - Secondary Objectives.................................................24 
3.6 
Dose Confirmation Stage - Exploratory Objective ................................................24 
3.7 
Fixed-Dose Combination Stage - Primary Objectives ...........................................24 
3.8 
Fixed-Dose Combination Stage - Secondary Objectives .......................................25 
3.9 
Fixed-Dose Combination Stage - Exploratory Objective ......................................25 
4.0 
INVESTIGATIONAL PLAN .........................................................................................25 
4.1 
Overall Study Design .............................................................................................25 
4.1.1 
Dose Escalation Stage ...........................................................................25 
4.1.2 
Dose Confirmation Stage ......................................................................29 
4.1.3 
Fixed-Dose Combination Stage ............................................................30 


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4.2 
Discussion of Study Design ...................................................................................32 
4.3 
Study Endpoints .....................................................................................................32 
4.3.1 
Dose Escalation Stage – Primary Endpoint ..........................................32 
4.3.2 
Dose Escalation Stage – Secondary Endpoints .....................................33 
4.3.3 
Dose Escalation Stage – Exploratory Endpoints ...................................33 
4.3.4 
Dose Confirmation Stage – Primary Endpoints ....................................33 
4.3.5 
Dose Confirmation Stage – Secondary Endpoints ................................33 
4.3.6 
Dose Confirmation Stage – Exploratory Endpoint ...............................33 
4.3.7 
Fixed-Dose Combination Stage – Primary Endpoints ..........................33 
4.3.8 
Fixed-Dose Combination Stage – Secondary Endpoints ......................33 
4.3.9 
Fixed-Dose Combination Stage – Exploratory Endpoints ....................34 
4.4 
Data and Safety Review Committee (DSRC) ........................................................34 
4.5 
Definition of Dose-Limiting Toxicities .................................................................35 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................35 
5.1 
Number of Subjects and Centers ............................................................................35 
5.2 
Inclusion Criteria ...................................................................................................36 
5.3 
Exclusion Criteria ..................................................................................................36 
5.4 
Withdrawal of Subjects ..........................................................................................37 
5.4.1 
Withdrawal from Study Treatment .......................................................37 
5.4.2 
Withdrawal from the Study ...................................................................38 
5.4.3 
Follow-up Procedures after Withdrawal (from Treatment and/or the 
Study) ....................................................................................................38 
5.4.4 
Replacement of Subjects .......................................................................38 
6.0 
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES ............38 
6.1 
Enrollment..............................................................................................................38 
6.2 
Randomization .......................................................................................................39 
6.3 
Blinding..................................................................................................................39 
7.0 
STUDY TREATMENTS .................................................................................................39 
7.1 
Investigational Medicinal Products (IMPs) ...........................................................40 
7.1.1 
Drug Form and Labeling .......................................................................40 
7.1.2 
Storage...................................................................................................40 
7.1.3 
Product Reconciliation ..........................................................................40 
7.1.4 
Study Treatment Administration ...........................................................40 
7.1.5 
Missed Doses ........................................................................................41 
7.2 
Active Comparator or Placebo ...............................................................................41 
7.3 
Guidelines for Adjusting or Withholding Study Treatment ..................................41 


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7.4 
Concomitant Treatment .........................................................................................42 
7.4.1 
Supportive or Other Treatments ............................................................42 
7.4.2 
Prohibited Medications .........................................................................43 
7.5 
Overdose Instructions ............................................................................................43 
8.0 
RISKS/PRECAUTIONS .................................................................................................43 
8.1 
Drug-Drug Interactions ..........................................................................................44 
8.2 
Genotoxicity ...........................................................................................................44 
9.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................44 
9.1 
Efficacy Assessments.............................................................................................44 
9.2 
Pharmacokinetic/Pharmacodynamic/Biomarker Assessments ..............................44 
9.2.1 
Pharmacokinetics (PK)..........................................................................44 
9.2.2 
Pharmacodynamics ...............................................................................46 
9.3 
Safety Assessments ................................................................................................47 
9.4 
Study Procedures ...................................................................................................47 
9.4.1 
Schedule of Events ................................................................................47 
9.4.2 
Screening and Baseline Procedures ......................................................52 
9.4.3 
Treatment and Follow-up Procedures ...................................................53 
9.4.4 
Course 2, Days 1-5 – All Stages ...........................................................57 
9.4.5 
Course 2, Days 8, 15, and 22 – All Stages ............................................58 
9.5 
Missed Evaluations ................................................................................................60 
9.6 
Response Criteria ...................................................................................................60 
10.0 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ......61 
10.1 
Definitions..............................................................................................................61 
10.1.1 
Adverse Event (AE) ..............................................................................61 
10.1.2 
Serious Adverse Events (SAEs) ............................................................61 
10.2 
Adverse Event Reporting and Descriptions ...........................................................62 
10.2.1 
Severity .................................................................................................62 
10.2.2 
Relationship to Study Treatment (Suspected Adverse Reactions) ........63 
10.2.3 
Pregnancy and Abortion ........................................................................64 
10.3 
Reporting and Evaluation of Serious Adverse Events ...........................................64 
10.3.1 
Reporting Requirements for Serious Adverse Events (SAEs) ..............64 
10.4 
Follow-up for Adverse Events ...............................................................................65 
11.0 
STATISTICS ....................................................................................................................65 
11.1 
Sample Size ............................................................................................................65 
11.1.1 
Dose Escalation Stage ...........................................................................65 
11.1.2 
Dose Confirmation Stage ......................................................................66 


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11.1.3 
Fixed-Dose Combination Stage ............................................................66 
11.2 
Data Sets to be Analyzed .......................................................................................67 
11.2.1 
All Enrolled Subjects ............................................................................67 
11.2.2 
Efficacy .................................................................................................67 
11.2.3 
Safety.....................................................................................................67 
11.2.4 
Pharmacokinetics ..................................................................................67 
11.2.5 
Pharmacodynamics and Biomarker Analyses .......................................67 
11.3 
Schedule of Analyses .............................................................................................67 
11.4 
Analysis of Subject Disposition .............................................................................68 
11.5 
Analysis of Demographic and Baseline Data ........................................................68 
11.6 
Efficacy Analyses ..................................................................................................68 
11.7 
Safety Analyses ......................................................................................................69 
11.8 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses ....................................69 
11.8.1 
Pharmacokinetic Analyses ....................................................................69 
11.8.2 
Pharmacodynamic/Biomarker Analyses ...............................................70 
11.9 
Interim Analysis .....................................................................................................70 
11.10 Procedures for Handling Missing, Unused, and Spurious Data.............................71 
12.0 
STUDY DURATION AND TERMINATION ...............................................................71 
13.0 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ...............................71 
13.1 
Compliance Statement ...........................................................................................71 
13.2 
Informed Consent...................................................................................................71 
13.3 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) ...........71 
14.0 
ADMINISTRATIVE PROCEDURES ...........................................................................72 
14.1 
Sponsor’s Responsibilities .....................................................................................72 
14.1.1 
Study Supplies .......................................................................................72 
14.1.2 
Investigator Training .............................................................................72 
14.1.3 
Ongoing Communication of Safety Information during the Study .......72 
14.1.4 
Study Monitoring ..................................................................................73 
14.1.5 
Study Auditing and Inspecting ..............................................................73 
14.2 
Investigator’s Responsibilities ...............................................................................74 
14.2.1 
Subject Screening Log ..........................................................................74 
14.2.2 
Decitabine, E7727, and FDC Tablet Accountability ............................74 
14.2.3 
Reporting and Recording of Study Data ...............................................74 
14.2.4 
Source Documentation ..........................................................................75 
14.2.5 
Tissue and Blood Sample Collection/Storage .......................................75 
14.2.6 
Records Retention .................................................................................75 


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14.3 
Clinical Trial Insurance..........................................................................................76 
14.4 
Study Administrative Letters and Protocol Amendments .....................................76 
15.0 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA ........................76 
16.0 
REFERENCES .................................................................................................................78 
17.0 
APPENDICES ..................................................................................................................80 
 
LIST OF TABLES 
Table 1: 
In Vitro Safety Pharmacology Studies .......................................................20 
Table 2: 
In Vivo Pharmacology Studies ..................................................................20 
Table 3: 
Dosing Schedule by Stage and Course ......................................................48 
Table 4: 
Schedule of Events .....................................................................................49 
Table 5: 
Clinical Laboratory Tests ...........................................................................53 
Table 6: 
Day 1 Assessments – All Stages ................................................................55 
Table 7: 
IWG 2006 MDS Response Criteria ...........................................................60 
 
LIST OF FIGURES 
Figure 1: 
LINE-1 Demethylation in Cynomolgus Monkeys – Oral Decitabine 
2 mg/kg + E7727 (1, 3, and 6 mg/kg) Daily×5 ..........................................21 
Figure 2: 
Dose Escalation Stage Algorithm ..............................................................28 
Figure 3: 
Dose Confirmation Stage Schema .............................................................30 
Figure 4: 
Fixed-Dose Combination Stage Schema ...................................................31 
 
LIST OF APPENDICES 
Appendix 1: 
Common Terminology for Adverse Events v4.0 (CTCAE v4.0) ..............81 
Appendix 2: 
Schedule of Pharmacokinetic Assessments ...............................................82 
Appendix 3: 
ECOG and Karnofsky Performance Status ................................................88 
Appendix 4: 
Summary of Changes, Amendment 1 ........................................................89 
Appendix 5: 
Summary of Changes, Amendment 2 ........................................................91 
Appendix 6: 
Summary of Changes, Amendment 3 ........................................................94 
Appendix 7: 
Summary of Changes, Amendment 4 ........................................................97 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse event 
ALT 
Alanine transaminase (serum glutamic pyruvic transaminase [SGPT]) 
AML 
Acute myelogenous leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase (serum glutamic oxaloacetic transaminase [SGOT]) 
AUC 
Area under the curve 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
BW 
Body weight 
CBC 
Complete blood count 
CDA 
Cytidine deaminase  
CDAi 
Cytidine deaminase inhibitor 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Plasma clearance 
CL/F 
Apparent plasma clearance 
Cmax 
Maximum concentration 
CMML 
Chronic myelomonocytic leukemia 
CPK 
Creatine phosphokinase  
CR 
Complete response 
CRF/eCRF 
Case report form/electronic case report form 
CRO 
Contract research organization 
CT scan 
Computed tomography scan 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DNMT 
DNA-methyltransferase 
DSRC 
Data and Safety Review Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EMEA 
Evaluation of Medicinal Products 
ESA 
Erythropoietin stimulating agents 
EU 
European Union 
FAB 
French-American-British 
FDA 
Food and Drug Administration 
FDC 
Fixed-dose combination 
FIH 
First in human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GVHD 
Graft-versus-host disease 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 


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HDPE 
High density polyethylene 
HED 
Human equivalent dose 
HI 
Hematological improvement 
HIV 
Human immunodeficiency virus 
HMA 
Hypomethylating agent 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee  
IMP 
Investigational medicinal product (the specific Astex drug product under study) 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWG 
International Working Group 
LINE-1 
Long interspersed nucleotide elements-1 
MDS 
Myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MUGA 
Multi gated acquisition (scan) 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
OTC 
Over the counter 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamic(s) 
PE 
Physical examination 
pH 
a measure of the acidity or alkalinity of an aqueous solution 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PRBCs 
Packed red blood cells 
PT 
Preferred term 
QD 
Once daily 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOC 
System organ class 
SQ 
Subcutaneous 
SUSAR 
Serious unexpected suspected adverse reaction 
T1/2 
Apparent elimination half-life 
TEAE 
Treatment emergent adverse event 
THU 
Tetrahydrouridine 
Tmax 
Time at which Cmax occurs 
ULN 
Upper limit of normal 
VD 
Volume of distribution 
VD/F 
Apparent volume of distribution 
WHO 
World Health Organization 
 


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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. 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  
(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 
Background of Treatment Options 
The standard for MDS therapy for many years has been supportive care (Heaney and Golde 1999; 
Kantarjian and Estey 2001). Intensive chemotherapy has been associated with complete response 
rates of 40% to 60%, induction mortality rates of 10% to 40% and no improvement in survival 
(Kantarjian and Estey 2001). 
Within the previous 10 years, three agents have been approved by the US FDA for the treatment 
of MDS: the immunomodulating agent lenalidomide, and the hypomethylating agents (HMAs) 
azacitidine and decitabine. These agents have dramatically changed both the course of treatment 
for MDS and have improved the outcome of patients who previously had very poor survival. 
Patients administered azacitidine at a subcutaneous dose of 75 mg/m2 daily×7 showed an overall 
response rate (CR+PR) of 15.7%, which was significantly greater than the response rate of 0% in 
the observation group (p<0.0001) (Vidaza 2016). Similarly, patients with intermediate- or high-
risk MDS who were administered IV decitabine (Dacogen®) at a dose of 20 mg/m2 daily×5 showed 
an overall response rate of 16% (Dacogen 2014). 
In summary, the increasing use of azacitidine and decitabine in the treatment of MDS has improved 
the outcome of patients who previously had very poor survival. However, current marketed HMAs 


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are subject to rapid elimination and degradation by cytidine deaminase (CDA) into inactive uridine 
counterparts (Chabot et al 1983). CDA in the gut and liver is responsible for poor bioavailability 
of these two HMAs, thus limiting their use to intravenous (IV) or subcutaneous injections 
(Karahoca and Momparler 2013). CDA inhibitors (CDAi) have been investigated for many years, 
but no drug has been approved for this use. The most widely published use has been with the CDAi 
tetrahydrouridine or THU (Beumer et al 2011; Beumer, Eiseman et al 2008; Beumer et al 2006). 
National Cancer Institute (NCI) has been investigating THU along with DNA methyltransferase 
(DNMT) inhibitor 5-fluoro-2'-deoxycytidine in clinical trials (Beumer, Parise et al 2008). 
However, THU is an unstable compound that is difficult to develop into a pharmaceutically 
acceptable drug. 
E7727 is a new potent CDAi which is pharmaceutically stable with a large safety margin. Its 
concomitant administration with oral decitabine markedly enhanced its bioavailability. This 
protocol intends to investigate the optimal dose of E7727 administered with oral decitabine that 
results in comparable AUC, Long Interspersed Nucleotide Elements-1 (LINE-1) demethylation, 
and response rate (CR+PR) to that of the approved IV decitabine 5-day regimen. The aim is to 
identify the relative doses to use as a fixed dose combination (FDC) oral product (ASTX727) of 
oral decitabine + E7727.  
Availability of an oral form of decitabine should provide significant convenience and potentially 
better treatment compliance for MDS patients. 
1.3 
Summary of Nonclinical and Clinical Data for Oral Decitabine + E7727 
Please refer to the Investigator’s Brochure (IB) for ASTX727 for detailed information on the 
Investigational Medicinal Product (IMP). Detailed information on IV decitabine 5-day regimen 
can be reviewed in the US Dacogen IV Prescribing Information (2014).  
1.3.1 
General Information 
Information on the IMP is located in Section 7.1. 
1.3.2 
Nonclinical Data 
E7727 is a 2’-fluorinated analog of tetrahydrouridine (THU) and is a novel CDAi, developed for 
oral administration. The bioavailability of decitabine and of several other therapeutic cytidine 
analogs (eg, azacitidine, cytarabine, gemcitabine) is significantly limited by a rapid metabolism 
catalyzed by CDA which is highly expressed in the gut and liver. E7727 is a potent CDAi with an 
IC50 of 0.281 μM. E7727 is also characterized by an improved stability at lower pH which has 
been a challenge with THU.  
E7727 has negligible antiproliferative activity in human cancer cell lines, did not show any 
significant inhibition in a panel of 80 physiologically important human receptors and did not 
inhibit hERG potassium channel at up to 300 μM. In vitro studies have also characterized an epimer 
of E7727 (ER-849726) that has about 1/10th the activity of E7727 as determined by an IC50 of 


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5 µM against human recombinant CDA. After oral dosing in preclinical toxicology models (mouse 
and monkey), near-equivalent levels were detected for circulating E7727 and its epimer. 
Several in vitro safety pharmacology studies were performed with various concentrations of the 
CDAi E7727 and are summarized in Table 1. 
Table 1: 
In Vitro Safety Pharmacology Studies  
Title 
System 
Key Findings for 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 
(Report NCLI-013195) 
Stability study  
Gem T½ +CDA ≤36 min 
Gem T½ +CDA +E7727 ≥66 h 
Determination of IC50 and Binding Constant 
(Ki) of MGI 25208  
(Report PHAR MGI 25208) 
Human recombinant 
CDA 
IC50 = 400 nM, Ki = 400 nM 
Determination of E7727 and ER-876437 IC50 
against human recombinant Cytidine 
Deaminase (CDA) (Report PPC-2010-04) 
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 (Report BIOL-2013-001) 
Human cell lines 
No significant inhibition of any cell line 
tested 
Several in vivo pharmacology studies were performed to determine the effect of E7727 on in vivo 
anticancer activity of oral decitabine and are summarized in Table 2. 
Table 2: 
In Vivo Pharmacology Studies 
Title 
System 
Key Findings for E7727 
Effect of E7727 on in vivo anticancer activity 
of oral decitabine against CD2-F1 mouse 
L1210 disseminated model (Report NCLI-
015044) 
L1210 mouse ALL 
disseminated model 
All 3 dose levels of E7727 (1, 10 and 
100 mg/kg) + 0.4 mg/kg oral DAC have 
significant anti-tumor activity 
Effect of E7727 on in vivo anticancer activity 
of oral decitabine against KG-1 human AML 
disseminated model (Report NCLI-014913) 
KG-1 human AML 
disseminated model 
All three doses of E7727 (1, 10 and 
100 mg/kg) + 0.3 mg/kg oral DAC have 
significant anti-tumor activity 
The pharmacodynamics (PD) of oral decitabine + E7727 were demonstrated in a one-cycle study 
in cynomolgus monkeys in which decitabine was administered at 2 mg/kg with E7727 doses of 1, 
3, or 6 mg/kg daily×5, followed by 23 days. Demethylation of LINE-1 sequences was seen for all 
three treatment groups, with the maximum demethylation effect of 17.4% to 24.5% achieved on 
Day 11 (see Figure 1). 


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Figure 1: 
LINE-1 Demethylation in Cynomolgus Monkeys – Oral Decitabine 
2 mg/kg + E7727 (1, 3, and 6 mg/kg) Daily×5 
 
Safety pharmacology studies conducted to date do not highlight an off-target concern for 
cardiovascular or other organ systems. 
1.3.3 
Clinical Data and Human Pharmacokinetics (PK) 
Preliminary data from the current study were available at the time of Amendment 3 and were used 
to inform the strength of the active drug substance included in FDC tablet. 
Previously, an open-label, Phase 1, dose-escalation trial was conducted to assess the preliminary 
oral bioavailability and safety of a single oral decitabine dose in an MDS patient population  
(Mistry et al 2011). Twelve subjects were enrolled in the study. Decitabine was administered orally 
(using the same formulation that is used for IV administration) on Day 1 of Course 1, followed by 
a 1-hour IV infusion at the recommended dose of 20 mg/m2 on Days 2–5 of Course 1. 
Biphasic elimination was observed following both IV and oral administration. Across the cohorts, 
T½ was comparable and ranged from 0.35 to 0.79 hour following oral administration and from 0.34 
to 0.61 hour following IV administration. 
Decitabine was rapidly absorbed after oral administration; the mean Tmax was 0.5 hour; however, 
oral doses from 30 mg to 120 mg did not result in increased Cmax or AUC. At the 240 mg dose, 
abrupt increases in Cmax and AUC of decitabine were observed. 


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The mean absolute bioavailability following 30, 60, 120, and 240 mg oral doses of decitabine was 
low, ranging from 3.9% to 14.1% with a very high intersubject variability. Single, oral doses of 
decitabine up to 240 mg were safe and generally well tolerated. 
1.4 
Potential Risks and Benefits to Human Subjects 
Decitabine at therapeutic exposure levels is known to result in neutropenia, thrombocytopenia, 
anemia, and pyrexia. E7727 has a wide safety margin, as preclinical toxicology studies suggest 
that transient inhibition of CDA is well tolerated and poses no known risks, with the NOAEL in 
monkeys determined to be 200 mg/kg, dosed daily×7. The starting dose of E7727 in this first-in-
human (FIH) study is 100-fold lower than the NOAEL (human equivalent dose [HED] to 2 mg/kg 
in monkeys). 
The combination of E7727 with oral decitabine may result in enhanced decitabine exposure, which 
at high doses may result in higher hematological toxicity. In addition, administration of oral 
decitabine with E7727 may result in higher GI toxicity as a result of CDA inhibition in the gut or 
higher decitabine dose used. The starting dose of oral decitabine in this study is about half the IV 
decitabine dose (20 mg fixed oral dose as opposed to the approved daily dose of 20 mg/m2 IV). It 
is also one-twelfth of the highest dose of oral decitabine (240 mg) tested in humans without E7727 
(Mistry et al 2011).  
These and other risks of oral decitabine + E7727 in humans are described further in Section 8.0, 
Risks/Precautions. For more detailed information, please refer to the IB for ASTX727 and to the 
prescribing information for decitabine (Dacogen 2014). 
The potential benefits of oral decitabine + E7727 include a significant enhancement of the oral 
bioavailability of decitabine through inhibition of CDA the enzyme responsible for metabolism of 
decitabine in the gastrointestinal (GI) tract and liver. This will provide patients with more 
convenient regimen with at least similar therapeutic benefits to the approved IV decitabine 
regimen.  
2.0 
RATIONALE 
2.1 
Rationale for the Study 
Astex Pharmaceuticals, Inc. is proposing a program to develop an oral, fixed-dose combination 
IMP, composed of oral decitabine + E7727 (ie, ASTX727) for the treatment of patients with MDS. 
Decitabine is one of 2 HMAs approved by FDA for this use. E7727 is a new chemical entity that 
is a pharmacokinetic (PK) enhancer. It increases bioavailability of decitabine through inhibition 
of CDA, an enzyme responsible for metabolism of decitabine in the GI tract and liver, thus 
enabling enhanced decitabine exposures after oral administration. E7727 is a potent and selective 
CDAi that has a wide safety margin and is pharmaceutically stable and suitable for oral use. 
This FIH trial is designed to define daily doses of the individual components so that decitabine 
exposure after oral administration is comparable to exposure after IV decitabine at the approved 


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daily dose of 20 mg/m2. The objective of the study is to establish and then confirm the doses of 
the 2 components to be used in the final fixed-drug combination product (ASTX727) using mainly 
PK (AUC) and PD (global DNA methylation in PBMCs using LINE-1) as endpoints. The doses 
that produce human exposure and/or PD comparable to that obtained after IV administration of 
decitabine at the approved daily dose using the 5-day schedule will be selected for use in 
subsequent clinical investigation. 
2.2 
Rationale for Oral Decitabine + E7727 Dose and Study Treatment Regimen 
The selection of the starting dose of E7727 is based on findings from GLP toxicology studies that 
were conducted in mice and monkeys to evaluate the non-clinical safety profile of E7727 together 
with PK data in animals regarding E7727 doses needed to enhance decitabine exposure after oral 
administration. 
E7727 appeared to be well tolerated in CD-1 mice, with no observed adverse effects seen at the 
highest dose tested (1000 mg/kg). Exposures at the no observed adverse effect level (NOAEL) of 
1000 mg/kg (highest dose tested) were similar in males and females. The Cmax after 1000 mg/kg 
was approximately 43,700 ng/mL and the AUC0-24 was ~ 125,600 ng*hour/mL.  
In rhesus monkeys, the NOAEL was 200 mg/kg/d from a 7-day repeat-dose study with a 2-week 
recovery. No accumulation or gender differences were seen in exposures. On Day 7, the Cmax at 
this dose ranged from 5,746-6,148 ng/mL, and AUC0-24 was 33,457-46,214 ng*hour/mL.  
In the Dose Escalation Stage, the starting dose for E7727 is based upon the NOAEL from monkeys 
(200 mg/kg), as well as the PK data from the oral decitabine + E7727 interaction studies in 
cynomolgus monkeys, wherein a significant effect on oral decitabine exposures was seen at E7727 
doses as low as 0.1 mg/kg when E7727 is given 1 hour before decitabine, and at 1-3 mg/kg with 
concomitant dosing. The proposed starting E7727 dose of 40 mg is approximately the HED of 
E7727 given at 2 mg/kg for monkeys (equivalent to 24 mg/m2 in humans) and offers a 100-fold 
safety margin relative to NOAEL from a GLP toxicology study in monkeys. 
As the clinical safety profile for decitabine is already well understood, the starting dose of 20 mg 
is based upon the available human experience with single dose decitabine and the experience with 
approved IV daily doses as the basis for the starting dose of decitabine in this study. The approved 
5-day daily dose is 20 mg/m2 IV or 40 mg for a BSA of 2 m2. The clinical study that assessed PK 
and safety of single oral dose decitabine (30-240 mg) showed no safety issues up to 240 mg. We 
propose a starting dose of oral decitabine of 20 mg, which is approximately one-half of the 
approved IV daily dose (for a BSA of 2 m2), and one-twelfth of the highest oral decitabine dose 
(240 mg) tested in humans (Mistry et al 2011).  
Thus, the proposed starting dose combination is 40 mg E7727 and 20 mg decitabine given 
concomitantly by mouth. 


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Preliminary PK data from both the Dose Escalation Stage and Dose Confirmation Stage informed 
selection of the strength of the FDC tablet. 
3.0 
STUDY OBJECTIVES 
3.1 
Dose Escalation Stage - Primary Objectives  
• Assess safety, tolerability, and pharmacokinetics (PK) of concomitant orally administered 
decitabine + E7727.  
• Identify a dose of oral decitabine + E7727 that together achieve a target mean decitabine AUC 
comparable to that from decitabine given by IV infusion (20 mg/m2) for 1 hour.  
3.2 
Dose Escalation Stage - Secondary Objectives 
• Determine percent change of LINE-1 demethylation in Course 1 and Course 2. 
• Assess preliminary efficacy, as determined by response rate, duration of response, 
hematological improvement, rate of transfusion independence, time to AML, and overall 
survival. 
• Evaluate other PK parameters of decitabine, E7727, and E7727-epimer. 
3.3 
Dose Escalation Stage - Exploratory Objectives 
 
 
 
 
3.4 
Dose Confirmation Stage - Primary Objectives 
• Confirm the dose of oral decitabine + E7727 identified in the Dose Escalation Stage 
administered daily×5 that achieves mean decitabine AUC (estimated from 5 days of dosing) 
and LINE-1 DNA demethylation comparable to that of IV decitabine 20 mg/m2 daily×5. 
• Assess response rate in all subjects. 
3.5 
Dose Confirmation Stage - Secondary Objectives 
• Assess safety and tolerability of oral decitabine + E7727. 
• Assess duration of response, hematological improvement, rate of transfusion independence, 
time to AML, and overall survival. 
• Evaluate other PK parameters of oral decitabine, E7727, and E7727-epimer (if needed).  
3.6 
Dose Confirmation Stage - Exploratory Objective 
 
 
3.7 
Fixed-Dose Combination Stage - Primary Objectives  
• Confirm the ASTX727 FDC tablet achieves mean decitabine AUC (estimated from 5 days of 
dosing) and LINE-1 DNA demethylation similar to that for IV decitabine 20 mg/m2 daily×5. 


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• Assess response rate in all subjects.  
3.8 
Fixed-Dose Combination Stage - Secondary Objectives 
• Assess safety and tolerability of ASTX727. 
• Assess duration of response, hematological improvement, rate of transfusion independence, 
time to AML, and overall survival. 
• Evaluate other PK parameters of ASTX727. 
3.9 
Fixed-Dose Combination Stage - Exploratory Objective 
 
 
4.0 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design  
Study ASTX727-01 will consist of three stages: Dose Escalation, Dose Confirmation, and Fixed-
Dose Combination, accordingly described below. 
4.1.1 
Dose Escalation Stage 
The Dose Escalation Stage consists of a single arm PK guided 3+3 design, the objective of which 
is to establish the target dose combination of oral decitabine + E7727 administered concomitantly 
using PK (AUC) as an endpoint. 
The starting dose for cohort 1 for E7727 is 40 mg, and the starting dose of oral decitabine is 20 mg. 
All subsequent cohort dose levels and cohort sizes will be determined by the Data and Safety 
Review Committee (DSRC) based on both safety and PK data review from at least 3 evaluable 
subjects in each cohort; see below for dose escalation guidance and Section 4.4 for description of 
DSRC functions.  
The dosing schedule for all cohorts in the Dose Escalation Stage is as follows: 
Course 1: 
• Day -3 (± 2 days): Single dose oral decitabine.  
• Day 1: IV decitabine administered at 20 mg/m2. 
• Days 2-5: Concomitant oral administration of oral decitabine + E7727.  
Course 2: 
• Day -3 (± 2 days): Single dose E7727. 
• Days 1-5: Concomitant oral administration of E7727 + decitabine. 


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The doses of single oral decitabine or oral E7727 given on Day -3 (±2 days) in Course 1 and 
Course 2 are the same doses, respectively, that are given concomitantly on Days 2-5 in Course 1 
and Days 1-5 in Course 2. 
Course ≥3: 
• Days 1-5: Concomitant oral administration of E7727 + decitabine (note, there are no Day -3 
visits beginning with Course 3). 
All subjects will continue to receive oral decitabine + E7727 daily×5 of a 28-day course in Course 
3 and thereafter until disease progression, unacceptable toxicity, subject withdrawal of consent, or 
withdrawal from the study. 
Dosing for Cohort ≥2: 
The dosing schedule for Cohort ≥2 will be the same as for Cohort 1; however, the dose levels of 
either E7727 or oral decitabine will be modified based on the decision of the DSRC guided by the 
algorithm in Figure 2. Only one of the 2 components will be escalated at any one time. If 1 DLT 
occurs in the first 3 subjects in the cohort, 3 more subjects will be added in that cohort to assess 
safety and AUC range. In the absence of Dose Limiting Toxicities (DLTs) in more than 1 of the 
first 6 subjects in any cohort, the dose of E7727 will be escalated in 20 mg increments until the 
cohort mean decitabine oral AUC/IV decitabine AUC approaches unity (within 0.90-1.10, 
inclusive). If E7727 dose adjustments fail to produce the desired oral decitabine AUC levels, or 
that smaller dose adjustment is required (5 mg instead of 20 mg), the decitabine dose (increments 
or decrements of 20 mg or 5 mg) will be adjusted until the desired AUC levels are achieved. 
• If decitabine exposures in Cohort 1 are less than 0.90 of those achieved with IV infusion from 
Day 1, increase the E7727 dose by 20 mg increments until decitabine exposures no longer 
increase; then increase the decitabine dose by 20 mg or less until the desired AUC range of 
oral decitabine (0.90-1.10 of IV decitabine) is achieved. 
• If oral decitabine AUC exposures in any cohort are more than 1.1 of the IV decitabine AUC, 
then decrease the E7727 dose by 20 mg or decrease decitabine doses by 20 mg or less until the 
desired AUC range of oral decitabine (0.90-1.10 of IV decitabine) is achieved. 
When the target level of decitabine AUC after oral administration is within 0.90-1.10 of IV 
decitabine AUC with no more than 1 DLT in 3-6 evaluable subjects, additional evaluable subjects 
may be added to the cohort to reach up to 12-18 subjects in that cohort to confirm the AUC range 
at 0.90-1.10 before opening the Dose Confirmation Stage of the trial. If the AUC range in the first 
12 subjects is out of the desired range, or more than 1 DLT occurred in 6 subjects, the DSRC can 
recommend further adjustment of the E7727 or decitabine dose in a new cohort of at least 
3 subjects until the desired AUC range (0.90-1.10) and safety (no more than 1 DLT) are achieved. 
If more than one DLT in 6 subjects is observed in any cohort, no further escalation will take place, 
and the DSRC will decide whether de-escalation of one or more components (oral decitabine 
and/or E7727) is necessary.  


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Intra-patient dose escalation will be allowed for patients who are still on treatment at lower dose 
levels in the Dose Escalation Stage once higher levels are deemed to be safe by DSRC review. 
Figure 2 provides a suggested algorithm for dose escalation; however, the DSRC may deviate from 
that algorithm based on review of emerging safety and PK data as long as there is a consensus that 
it is safe to do so. 
Up to 6 evaluable subjects may be enrolled in a cohort before PK and safety results from at least 
the first 3 subjects in that cohort become available. 


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Figure 2: 
Dose Escalation Stage Algorithm 
 
 
DOSING
Course 1:
Day -3 (±2 days)*: Single dose oral decitabine 
Day 1: decitabine IV 20 mg/m2 
Days 2-5:  oral decitabine + E7727
Course 2:
Day -3 (±2 days)*: Single dose E7727
 Days 1-5: oral decitabine + E7727
Courses ≥3:
Days 1-5: oral decitabine + E7727
DOSE ESCALATION ALGORITHM
Subjects with IPSS Intermediate-1 or -2, or High-Risk MDS, or CMML
decitabine AUC oral/IV >1.10
decitabine AUC oral/IV 0.90-1.10
De-escalate
 E7727 
Cohort ≥2
Escalate E7727 (20 mg increments) 
Stop
Escalation
Add 3-9 
Subjects
decitabine AUC oral/IV >1.10
decitabine AUC oral/IV <0.90
decitabine AUC oral/IV 0.90-1.10
De-escalate  E7727
or oral decitabine
Stop
Escalation
Add 3-9 
Subjects
Escalate E7727 to 
saturation of 
decitabine, then 
escalate decitabine
Continue oral decitabine + 
E7727 until disease 
progression or 
unacceptable toxicity 
occurs, the subject 
withdraws consent, or is 
withdrawn from study
decitabine AUC oral/IV <0.90
*The doses of oral decitabine or oral E7727 given on Day -3 (±2 days) in Course 1 and Course 
2 are the same doses, respectively, that are given on Days 2-5 in each cohort.
When the target level of decitabine AUC after oral administration is within 0.90-1.10 of IV decitabine AUC with no 
more than 1 DLT, additional subjects may be added to the cohort (to reach up to 12-18 subjects in the cohort) to 
confirm the AUC range at 0.90-1.10 before opening the Dose Confirmation Stage. If the AUC is out of the desired 
range, or more than 1 DLT occurs in the first 12 subjects, the DSRC can recommend further adjustment of the E7727 
or decitabine dose in a new cohort of 3 subjects until the desired AUC range and safety are achieved in at least 3 
subjects.


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4.1.2 
Dose Confirmation Stage 
Dose Confirmation Stage (Figure 3) will confirm the dose level of oral decitabine + E7727 
established in the Dose Escalation Stage in at least 42 evaluable subjects. Subjects will be 
randomized to the sequence of 
• Oral decitabine + E7727 daily×5 in Course 1 followed by IV decitabine daily×5 in Course 2, 
or  
• IV decitabine daily×5 in Course 1 followed by oral decitabine + E7727 daily×5 in Course 2. 
Beginning with Course 3 and all subsequent courses, subjects will receive oral decitabine + E7727 
daily×5 of a 28-day course until the subject has disease progression or unacceptable toxicity, or 
the subject withdraws consent or is withdrawn from the study. 
The DSRC will determine when sufficient data are available at the end of the Dose Escalation 
Stage to make a decision on the fixed dose levels of E7727 and oral decitabine to be further 
investigated in the Dose Confirmation Stage. 


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Figure 3: 
Dose Confirmation Stage Schema 
 
 
4.1.3 
Fixed-Dose Combination Stage 
This stage is a comparison between a tablet form of ASTX727 and IV decitabine 20 mg/m2. After 
enrollment in the Dose Confirmation Stage has completed, 18-24 subjects will be randomized and 
treated in a crossover study to confirm that the ASTX727 FDC yields PK exposures and DNA 
demethylation similar to those for IV decitabine. 
Subjects will be randomized in a 1:1 ratio to receive the FDC tablet daily ×5 in Course 1 followed 
by IV decitabine daily ×5 in Course 2, or the converse. In Courses ≥3, all subjects will receive the 
FDC tablet daily ×5 (in a 28-day course) until disease progression or unacceptable toxicity or 
withdrawal from the study. See Figure 4. 
DOSE CONFIRMATION
(N ≥42)
 n≈21
decitabine IV 
Course 1
Course 2
Course ≥3
Randomization
n≈42
Subjects with IPSS Intermediate-1 or -2, or 
High-Risk MDS, or CMML
 n≈21
decitabine IV 
n≈21
oral decitabine + 
E7727 
 n≈21
oral decitabine + 
E7727  
n≈42
oral decitabine + E7727
Continue E7727 + decitabine until disease progression or unacceptable toxicity occurs, 
or subject withdraws consent, or subject is withdrawn from the study


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Figure 4: 
Fixed-Dose Combination Stage Schema 
 
 
 
 
FIXED-DOSE COMBINATION STAGE SCHEMA 
(N = 18-24)
FDC tablet
daily x5
Course 1
Course 2
Course ≥3
Randomization
Subjects with IPSS Intermediate-1 or -2, or 
high-risk MDS, or CMML
 FDC tablet
daily x5
decitabine IV
1-hr infusion
daily x5 
decitabine IV
1-hr infusion
daily x5 
FDC tablet
daily x5
Continue dosing with FDC tablet 
until disease progression or 
unacceptable toxicity occurs, or 
subject withdraws consent, or 
subject is withdrawn from the 
study


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Based on (1) data from both the Dose Escalation Stage and Dose Confirmation Stage, which 
confirmed that the combination doses of 100 mg E7727 + 35 mg decitabine emulate the PK and 
PD of IV decitabine 20 mg/m2, and (2) availability of the FDC tablet combining these 2 doses, 
subjects who are still on treatment with the separate E7727 and decitabine capsules in the previous 
study stages will be allowed to transition to treatment with the more convenient FDC tablet at the 
discretion of the investigator, but no later than 23 October 2017. New clinical supplies of the E7727 
and decitabine capsules will not be supported after the expiry date (31 October 2017) of current 
supplies. 
4.2 
Discussion of Study Design 
This is a 3-stage study to investigate concomitant administration of oral decitabine + E7727. The 
Dose Escalation Stage consists of a single arm PK guided 3+3 design, the objective of which is to 
establish the target dose combination of oral decitabine + E7727 administered concomitantly using 
PK (AUC) as an endpoint. The study is not intended to identify an MTD of oral decitabine + 
E7727. Rather, dose escalation will target a dose of the two components that approximately 
achieves unity in decitabine AUC exposures compared with AUC of IV decitabine 20 mg/m2 
(AUC ratio within 0.90-1.10). Escalation will occur only after review of the PK and safety data 
from at least 3 evaluable subjects in each cohort and a recommendation from the DSRC (see 
Section 4.4).  
In the Dose Confirmation Stage, the primary objective is to confirm that the doses of oral 
decitabine + E7727 identified in the Dose Escalation Stage given as a daily×5 oral dosing regimen 
achieve a mean AUC (estimated from 5 days of dosing) and LINE-1 DNA demethylation 
comparable (as described in Sections 11.8.1 and 11.8.2) to IV decitabine given daily×5 at the 
approved dose of 20 mg/m2. The standard 2 x 2 crossover design was chosen for the first two 
courses of the Dose Confirmation Stage in order to facilitate efficient evaluation of within-subject 
comparison of AUC as well as LINE-1 demethylation between oral decitabine + E7727 and IV 
decitabine. Because of the short half-life of decitabine and the fact that in most subjects, LINE-1 
demethylation returns to baseline by Day 28 at the end of treatment course, no appreciable carry-
over effect of either AUC or LINE-1 demethylation is expected. 
In the FDC stage, the goal is to confirm that the FDC tablet formulation is similar to IV decitabine 
in an intrapatient fashion and that PK and PD results are similar to results obtained with oral 
decitabine + E7727 capsules in the Dose Confirmation Stage.  
4.3 
Study Endpoints 
4.3.1 
Dose Escalation Stage – Primary Endpoint 
• Mean decitabine AUC oral/IV: Mean AUC of oral decitabine + E7727 (Days 2 and/or 5) 
compared with IV decitabine 20 mg/m2 (Day 1). 
• Incidence and severity grades of DLTs. 


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4.3.2 
Dose Escalation Stage – Secondary Endpoints 
• AUC, Cmax, Tmax, and other PK parameters of oral decitabine, E7727, and E7727-epimer. 
• Overall incidence and severity of adverse events and clinically significant abnormal laboratory 
values. 
• Mean maximum %LINE-1 demethylation of oral decitabine + E7727 by cohort. 
• Overall response rate as measured by the IWG 2006 MDS Response Criteria, duration of 
response, hematological improvement, rate of transfusion independence, time to AML, and 
overall survival. 
4.3.3 
Dose Escalation Stage – Exploratory Endpoints 
 
 
 
 
4.3.4 
Dose Confirmation Stage – Primary Endpoints 
• Mean decitabine AUC (estimated from 5 days of dosing) and mean maximum %LINE-1 
demethylation after oral decitabine + E7727 compared with IV decitabine 20 mg/m2. 
• Response rate in all subjects. 
4.3.5 
Dose Confirmation Stage – Secondary Endpoints 
• Incidence and severity grades of adverse events and clinically significant abnormal laboratory 
values. 
• Duration of response, hematological improvement, rate of transfusion independence, time to 
AML, and overall survival. 
• Other PK parameters of oral decitabine, E7727, and E7727-epimer (if needed). 
4.3.6 
Dose Confirmation Stage – Exploratory Endpoint 
 
 
4.3.7 
Fixed-Dose Combination Stage – Primary Endpoints 
• Mean decitabine AUC and mean maximum %LINE-1 demethylation after ASTX727 
administration compared with IV decitabine 20 mg/m2.  
• Response rate in all subjects. 
4.3.8 
Fixed-Dose Combination Stage – Secondary Endpoints 
• Incidence and severity grades of AEs and clinically significant abnormal laboratory values. 
• Duration of response, hematological improvement, rate of transfusion independence, time to 
AML, and overall survival. 
• Other PK parameters of ASTX727. 


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4.3.9 
Fixed-Dose Combination Stage – Exploratory Endpoints 
 
 
4.4 
Data and Safety Review Committee (DSRC) 
A thorough review of PK and safety data by the DSRC will be regularly conducted, particularly at 
the following time points: 
• After every cohort of 3-12 evaluable subjects during the Dose Escalation Stage. 
• At the end the Dose Escalation Stage but before the Dose Confirmation Stage. 
• At least quarterly during the Dose Confirmation Stage. 
• At minimum after 18-24 subjects have received 2 courses of treatment in the FDC stage.  
The DSRC will confer when the last of at least 3 evaluable subjects in a cohort completes Course 1, 
Day 28. If warranted, the committee may meet more frequently should there be any emergent 
safety issues. This committee will comprise the principal investigators (or nominated deputies), 
medical monitor, study director, PK director, and other study team members as appropriate and 
will review available safety, PK, and PD data. The DSRC will recommend whether to continue 
dosing based on the oral decitabine + E7727 dose escalation algorithm (Figure 2) and the safety 
data (DLTs). The DSRC may decide to increase any cohort size up to a total of 12-18 subjects to 
further assess the PK and/or safety signal. No dose escalation/de-escalation will ensue until the 
DSRC meets and concurs. The DSRC will make decisions regarding continuing dose escalation 
or de-escalation, to better assess the PK and safety of oral decitabine + E7727 during the Dose 
Escalation Stage. The DSRC will decide on the exact next dose level based on the escalation 
scheme provided in Figure 2. The DSRC may also decide to investigate smaller increments or 
decrements of oral decitabine when lower strength (decitabine 5 mg) becomes available. DSRC 
may also decide to escalate/de-escalate either drug component (E7727 or oral decitabine) if AUC 
levels or safety data at any cohort warrant such escalation/de-escalation. 
The DSRC will determine when sufficient PK data are available at the end of the Dose Escalation 
Stage to make a decision on the fixed dose levels of E7727 and oral decitabine to be further 
investigated in the Dose Confirmation Stage. If population PK analyses suggest that dose levels of 
E7727 and oral decitabine are better adjusted based on body weight/body surface area (BW/BSA) 
instead of the initially recommended flat dosing in this protocol, the DSRC will determine the 
different dose strengths for subjects based on their BW or BSA. 
In addition, the DSRC will evaluate safety, PK, and PD data during the Dose Confirmation Stage 
to assess AUC and LINE-1 demethylation comparability between IV decitabine and the 
combination of E7727 + oral decitabine and to determine the final oral dose combination. This 
will be evaluated after the first subset of 6-12 subjects are randomized in the Dose Confirmation 
Stage and their PK and PD data from the first 2 completed courses become available. The DSRC 
may decide to further titrate the doses (up or down) of one or both ASTX727 drug components 


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(oral decitabine or E7727) to ensure comparability of PK and PD with decitabine IV. In that case, 
another evaluation of PK and PD data from an additional 6-12 evaluable subjects will be 
conducted. The DSRC may decide on a final dose combination that yields an AUC for oral 
decitabine marginally beyond the 0.90-1.10 window of IV decitabine AUC with supportive data. 
Approximately 42 subjects will be treated at the final recommended dose combination; therefore 
the total number of subjects in the Dose Confirmation Stage may be more than 42 if the initial dose 
combinations at the start of the Dose Confirmation Stage were not the final recommended doses. 
A formal record of each discussion will be kept and distributed to all study sites. 
4.5 
Definition of Dose-Limiting Toxicities  
While this study is not intended to define an MTD of oral decitabine + E7727, dose-limiting 
toxicities must be assessed to confirm that it is safe to escalate based on AUC data comparability 
with the approved IV decitabine dosing. 
The DLT occurring in the first course of treatment for all subjects at any cohort during dose 
escalation will guide the dose escalation decision. At subsequent courses, DLTs will guide dose 
adjustment or dose delays as discussed in Section 7.3. DLTs are defined using the Common 
Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) (Appendix 1). 
• ≥ Grade 3 non-hematologic toxicity (unless the DSRC determines that it is clearly related to 
an underlying disease or to disease progression), except the following: 
• Grade 3 nausea or vomiting that is controllable by anti-emetics. 
• Grade 3 diarrhea controllable by optimal therapy such as loperamide. 
• Grade 3 laboratory tests other than serum creatinine, bilirubin, AST, or ALT will not be 
considered a DLT unless the abnormal result(s) is/are associated with clinical manifestations. 
• Related prolonged Grade 4 thrombocytopenia that was not present prior to dosing, does not 
resolve within 14 days, and is not related to underlying disease. 
• Related febrile neutropenia or Grade 4 neutropenia that was not present prior to dosing, does 
not resolve within 14 days, and is not related to underlying disease. 
• Any toxicity (related to study treatment) that results in treatment delays of >4 weeks after Day 
28. 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects and Centers 
The Dose Escalation Stage is based on a 3+3 design, and the Dose Confirmation Stage is based on 
at least 42 evaluable subjects at the final recommended dose combination, to be enrolled at multiple 
centers. 


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5.2 
Inclusion Criteria 
To be eligible for the study, subjects must fulfill all of the following inclusion criteria: 
1) Able to understand and comply with the study procedures, understand the risks involved in the 
study, and provide written informed consent before the first study-specific procedure. 
2) Men or women ≥18 years with IPSS intermediate-1, intermediate-2, or high risk MDS with 
peripheral blasts or bone marrow blasts <20% in all study stages, including subjects with 
chronic myelomonocytic leukemia (CMML) who are candidates for treatment with a 
hypomethylating agent. 
3) Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see 
Appendix 3). 
4) Subjects with adequate organ function defined as: 
a) Hepatic: Total or direct bilirubin ≤2 X ULN; AST/SGOT and ALT/SGPT ≤2.5 X ULN. 
a) Renal: serum creatinine ≤1.5 X ULN or creatinine clearance >50 mL/min/1.73 m2 for 
subjects with creatinine levels above institutional normal. 
5) For subjects with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease 
(GVHD) and must be ≥2 weeks off systemic immunosuppressive therapy. 
6) Subjects with no major surgery within 2 weeks of first dose of study treatment. 
7) Subjects with no cytotoxic chemotherapy within 2 weeks of first dose of study treatment. 
8) 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 (FSH) 
levels in the menopausal range. 
9) 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, double-barrier method 
(use of a condom AND diaphragm, with spermicide), or abstaining from sexual intercourse. 
10) Able to swallow the number of capsules required for the treatment assignment within a 
10-minute period and tolerate 4 hours of fasting. 
5.3 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1) Previous treatment with at least 2 courses of decitabine (all stages) or azacitidine (Dose 
Confirmation Stage). 
2) Known or suspected hypersensitivity to decitabine or the components of E7727. 


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3) Treated with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-
lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing 
clinically significant adverse events from previous treatment with investigational drug or 
therapy. 
4) Poor medical risk because of other conditions such as uncontrolled systemic diseases or 
uncontrolled active infections. 
5) Diagnosis of AML with bone marrow or peripheral blast count ≥20% or other hematological 
malignancies. 
6) Life-threatening illness, medical condition or organ system dysfunction, 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 oral decitabine + E7727, or 
compromise the integrity of the study outcomes. 
7) Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ 
cervical cancer, non-metastatic prostate cancer with normal prostate-specific antigen (PSA), 
or other cancer from which the subject has been disease free for at least 3 years. 
8) Known history of human immunodeficiency virus (HIV) or if known seropositive for hepatitis 
C virus (HCV) or hepatitis B virus (HBV).  
9) Active uncontrolled gastric or duodenal ulcer. 
5.4 
Withdrawal of Subjects  
Subjects can withdraw from study treatment and continue study follow-up or withdraw from the 
study, as described below. 
5.4.1 
Withdrawal from Study Treatment 
Subjects may withdraw from study treatment but still continue study follow-up procedures. 
Investigators are encouraged to assess all subjects according to the study protocol even after 
withdrawal from study treatment.  
• Investigators can withdraw subjects from study treatment in case of unacceptable toxicity, non-
compliance, unequivocal disease progression with clinical deterioration or a need to administer 
other anticancer treatment, or if it is determined by the investigator that it is in the subject’s 
best interest.  
• Astex Pharmaceuticals may require that a subject is withdrawn from treatment for safety 
reasons or for noncompliance.  
In all cases, the reason(s) for withdrawal from study treatment must be recorded in the source 
document and on the relevant page of the subject’s case report form or electronic case report form 
(eCRF).  


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It is important to obtain follow-up information on any subject withdrawn prematurely from study 
treatment. Every effort must be made to undertake protocol-specified follow-up procedures. Refer 
to Section 5.4.3 for specific assessments. 
5.4.2 
Withdrawal from the Study 
Subjects may withdraw from the study at any time. It is important to obtain follow-up information, 
according to standard medical practice, on any subject withdrawn prematurely from the study. 
Every effort must be made to undertake at least standard assessments that are critical for efficacy 
or safety evaluation, such as Disease Progression (if the subject did not withdraw because of 
disease progression), Survival information, and Safety data. Refer to Section 5.4.3.  
5.4.3 
Follow-up Procedures after Withdrawal (from Treatment and/or the Study) 
Section 10.0 describes follow-up for AEs. At minimum, subjects should be followed up for safety 
until 30 days after the last dose of study treatment (see Section 10.2). If at all possible, for all cases, 
subjects should undergo all end-of-study assessments (Treatment Termination visit and 30-day 
Follow-up visit; see Section 9.0). 
For subjects willing to continue study follow-up procedures, the investigator should review the 
follow-up procedures with the subject, including the number of visits, the specific procedures to 
be done, and the total length of the follow-up period. The investigator must also ensure the subject 
understands that his or her medical records will continue to be available for the follow-up period 
as described in the approved ICF for the entire study period. 
5.4.4 
Replacement of Subjects 
Enrollment of subjects for each cohort and stage of the study will continue until the required 
number of evaluable subjects for that cohort and stage is reached. The evaluable subject criteria 
are described in Section 11.1. Astex Pharmaceuticals may stop the study at any time. In this event, 
the Sponsor will make reasonable efforts to ensure subjects are transitioned off study in an orderly 
manner. 
6.0 
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES 
6.1 
Enrollment 
Subjects who meet the entry criteria will be enrolled/randomized into the study. Instructions 
regarding the enrollment process will be provided to the study centers in a separate document. 
Subject identification (ID) numbers will consist of 6 digits. The first 3 digits will reflect the site 
number, followed by a 3-digit individual number within the site. The ID will be used to identify 
the subject throughout the study including the screening period and will be entered on all study 
documents. 


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6.2 
Randomization 
Randomization will occur in the Dose Confirmation Stage and the FDC Stage. In the Dose 
Confirmation Stage, subjects will be randomized in a 1:1 ratio to one of the two treatment 
sequences as described below: 
• Oral decitabine + E7727 daily×5 in Course 1 followed by IV decitabine daily×5 in Course 2, 
or  
• IV decitabine daily×5 in Course 1 followed by oral decitabine + E7727 daily×5 in Course 2. 
In the FDC Stage, subjects will be randomized in a 1:1 ratio to receive one of the following 
treatment sequences: 
• FDC tablet daily ×5 in Course 1 followed by IV decitabine daily ×5 in Course 2, or  
• IV decitabine daily ×5 in Course 1 followed by the FDC tablet daily ×5 in Course 2. 
Randomization will be stratified by the IPSS risk levels (lower risk of IPSS intermediate-1 versus 
higher risk of IPSS intermediate-2 and high-risk). Subjects with CMML will be randomized in the 
IPSS-2/high-risk 
stratum. 
Subjects 
should 
be 
treated 
as 
soon 
as 
possible 
after 
enrollment/randomization.  
Treatment assignments for the individual subjects will be determined through a computer 
generated randomization scheme and accessed through the OmniComm TrialMaster system used 
for study data management. Instructions for access and use of the OmniComm TrialMaster system 
for randomization will be provided to participating study centers in a separate document. 
6.3 
Blinding 
This is an open-label study. There will be no blinding of treatment assignment. 
7.0 
STUDY TREATMENTS 
In this FIH trial, study treatment includes the combination of oral decitabine + E7727, the two 
separate IMPs administered concomitantly and given separately at designated time points, and also 
IV decitabine. Subjects will receive study treatment at the study center in the first course of 
treatment at all stages of the study, in the first 2 courses at Dose Confirmation Stage; and whenever 
PK sampling is required. At other visits, subjects may self-administer the IMPs at home. Astex 
Pharmaceuticals, Inc. will provide each study center with guidance to be provided to subjects for 
at-home dosing and drug storage. 


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7.1 
Investigational Medicinal Products (IMPs) 
7.1.1 
Drug Form and Labeling 
E7727 20 mg, decitabine 20 mg, and if needed decitabine 5 mg will be supplied separately in 
individual unit dosage forms, each as a hard gelatin capsule of specific color. 
E7727 20 mg is available in a white opaque size 4 capsule packed in 30 count in a 30 cc white 
opaque HDPE bottle with a child resistant closure. Inactive ingredients present in the capsule are 
microcrystalline cellulose, hypromellose, and talc. 
Decitabine 20 mg is available in a Swedish orange size 4 capsule packed in 30 count in a 30 cc 
white opaque HDPE bottle with a child resistant closure. Inactive ingredients present in the capsule 
are inert sugar spheres, hypromellose, and talc. 
Decitabine 5 mg will be made available if needed in a light blue size 4 capsule packed in 30 count 
in a 30 cc white opaque HDPE bottle with a child resistant closure. Inactive ingredients present in 
the capsule are inert sugar spheres, hypromellose, and talc. 
The FDC drug form of ASTX727 is a film-coated, oval, white, immediate-release tablet containing 
the combination of E7727 (100 mg) and decitabine (35 mg) for oral administration. The tablets 
will be packed in 5 count in an opaque HDPE bottle with a child resistant closure. 
7.1.2 
Storage 
The IV decitabine drug product is sourced from commercial supplies and should be stored 
according to institutional policy and the manufacturer's label. 
E7727 20 mg, decitabine 20 mg, and decitabine 5 mg, should be stored at 2°C to 8°C in a secure, 
locked facility at the study center and accessible only to authorized study personnel. Should E7727 
and decitabine capsules be dispensed for outpatient administration, they should be dispensed by 
the study pharmacist according to institutional policy and in accordance with the Sponsor’s 
requirements. 
The FDC tablet should be stored at 2°C to 8°C (36°F to 46°F) according to institutional policy and 
the Sponsor’s requirements. 
7.1.3 
Product Reconciliation 
Records of the receipt and dispensing of IMP supplies will be kept at the study centers and 
reconciled at the end of the study to provide a complete accounting of all used and unused IMP. 
7.1.4 
Study Treatment Administration 
Subjects will be required to fast for 4 hours on days when receiving oral IMP. Fasting (no food, 
milk or alcohol) begins at least 2 hours prior to and ends 2 hours post-dose. Subjects will take oral 


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IMP(s) with 240 mL (8 fluid oz) of water. Clear liquids such as water, black coffee, tea, or fruit 
juice may be allowed as desired together with other concomitant medication that is needed to be 
given to the subject. Subjects should take the IMPs simultaneously (ie, E7727 followed 
immediately by oral decitabine). The IMPs should be taken at the same time of day (±1 hour) on 
each dosing day. If the subject vomits after oral dosing on one or more days, the dose of that day 
will not be re-administered, but vomiting should be recorded as an adverse event on the Case 
Report Form. 
7.1.5 
Missed Doses 
It is important for subjects not to miss a dose, as PK assessments will be affected. Subjects should 
take the IMPs simultaneously (ie, E7727 followed immediately by oral decitabine) and at the same 
time of day (± 1 hr) on each dosing day during courses that include PK assessments. If a subject 
takes the IMPs outside the 1-hr window during a week with PK assessments, the subject should be 
instructed to notify the investigator immediately. If a dose is missed in subsequent courses, 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 scheduled time. 
Subjects should complete all 5 daily doses; if a dose is missed, the dosing period will extend to 
6 days. 
7.2 
Active Comparator or Placebo 
IV decitabine at 20 mg/m2 will be the activate comparator as described. Decitabine is approved for 
IV infusion in the US and will be sourced locally at the US study centers. Decitabine IV will be 
provided by the sponsor as an IMP in Canada, as the product is not currently approved in Canada. 
Currently, the most commonly used regimen for treatment of MDS is 20 mg/m2, 1-hour 
intravenous infusion for 5 daily administrations (Days 1-5) in a 28-day treatment course; this will 
be the comparator regimen in this study.  
Refer to current decitabine label for storage and administration guidance. 
7.3 
Guidelines for Adjusting or Withholding Study Treatment 
The algorithm describing dose escalation guidelines between cohorts in the Dose Escalation Stage 
is presented in Section 4.1.1, Figure 2. The actual decision to escalate or de-escalate and the actual 
dose levels will be determined by the DSRC based on PK and safety data (Section 4.4). Following 
the first course of treatment, the investigator should try to the best of his/her ability to assess 
whether an adverse event is related to study treatment. If the adverse event is judged to be related 
to study treatment and if it in the opinion of the investigator it requires dose adjustment, dosing 
delay and/or dose reduction may be recommended in subsequent treatment courses according to 
the following guidelines: 
If the subject is still receiving treatment as part of the 5-day regimen, subsequent treatment days 
(Days 2-5) will be withheld if the subject develops any DLT as defined in Section 4.5, and the 
skipped doses will be missed. Dosing will also be withheld on Day 1 of any subsequent treatment 


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courses if the subject still has a DLT or other drug-related clinically significant toxicity that has 
not resolved to baseline or Grade 1 or have become ineligible by the protocol entry criteria 
(Section 5.0). Dosing may restart once the subject becomes eligible again and the DLT or other 
drug-related toxicity has resolved to either baseline or ≤Grade 1. If dosing is delayed by more than 
4 weeks beyond Day 28, then the subject will be withdrawn from treatment unless it is judged by 
the Investigator to be in the subject’s best interest to continue based on clinical benefit. If the 
subject has a DLT and it has resolved, he or she may be redosed for subsequent courses only at the 
next lower dose level of either E7727 or decitabine, if feasible. 
In the Dose Confirmation Stage and the FDC Stage, investigators should attempt to give the full 
intended dose for at least 2 courses (Course 1 and Course 2) to be able to compare PK data as long 
as it is safe to do so. In all stages of the study, it is recommended to administer at least 6 courses 
of treatment to fully assess efficacy, unless unequivocal progression necessitating intervening 
therapy or unacceptable toxicity that is not manageable by dose reduction/delay or supportive 
treatment occurs. In the FDC Stage, dose reduction should begin by reducing treatment days to 
4 days from 5. If further dose reduction is necessary, treatment days may be reduced to 3 days. It 
is recommended that dose reductions are done in consultation with the Astex medical monitor. 
For subjects transitioning from the Dose Escalation Stage or Dose Confirmation Stage to the FDC 
Stage, any ongoing or future dose reductions should follow the FDC dose reduction 
recommendations through reduction of number of dosing days per cycle (ie, 4 or 3 days of FDC 
dosing rather than 5 days) as opposed to reductions of the daily dose, based on prior tolerance and 
safety data. 
Additional delay or dose reduction may be applied based on investigator’s judgment in 
consultation with the Astex medical monitor. 
7.4 
Concomitant Treatment 
Record on the concomitant medication eCRF all treatments a subject receives, including 
supportive or palliative treatment (see below) whether prescription or over the counter (OTC), 
vitamin and mineral supplements, herbs, and medications taken for procedures (eg, biopsy). Also 
record antacids, proton pump inhibitors, H2 antagonists (these should not be taken ±4 hours of 
administration of oral decitabine + E7727). Data will be collected on the start and stop dates as 
well as the indication for use in addition to the name, start and stop dates. 
7.4.1 
Supportive or Other Treatments 
The investigator will be permitted 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. Should the subject vomit after any oral administration of study treatment, the dose(s) 
should not be re-administered on that day. 


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All supportive treatment including units of blood and platelet transfusions must be recorded on the 
eCRFs. 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, and blood culture. Subjects with 
febrile neutropenia or suspected sepsis on the basis of the physical examination are to be 
hospitalized for appropriate broad spectrum antibiotic coverage, consistent with local pathogen 
sensitivities. 
Hematopoietic growth factors will not be routinely used. However, its use is permitted in case of 
a life-threatening septic event at the discretion of the treating physician. Erythropoietin and/or 
Neupogen can be used after Course 1 in the Dose Escalation Stage, after Course 1 and 2 in the 
Dose Confirmation Stage. Use of these agents should be guided by accepted practice or 
institutional guidelines. 
7.4.2 
Prohibited Medications 
Prohibited concomitant therapies while on study are as follows: radiation therapy, chemotherapy, 
immunotherapy, or any experimental therapy. See Section 7.4 for additional information. Other 
nucleosides or drugs that are metabolized by CDA (Section 8.1) are also prohibited during the 
study when E7727 is being administered. 
7.5 
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 
the AE eCRFs. Report signs and symptoms of a potential overdose that meet SAE criteria (defined 
in Section 10.1.2) to Astex on the SAE form within 24 hours (see Section 10.3). Treat any AE 
(including SAE) based on standard care for the specific signs and symptoms. As this is the FIH 
study of oral decitabine + E7727, no data are available regarding the overdosage of oral decitabine 
+ E7727. Based on the clinical experience of decitabine, an overdosage of oral decitabine + E7727 
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 oral decitabine + E7727 or the FDC drug form. 
8.0 
RISKS/PRECAUTIONS 
Please refer to the IB for ASTX727 and the IV decitabine prescribing information. As with any 
IMP, subjects may experience reactions or complications that are unknown, and therefore 
unpredictable. 


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8.1 
Drug-Drug Interactions 
The primary PD effect of E7727 is the inhibition of CDA, which is anticipated to enhance the oral 
bioavailability of decitabine. Hence, 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). As new agents may come to market 
during the trial, confer with the sponsor’s medical monitor if questions arise. 
Neither E7727 nor decitabine are expected to produce CYP-mediated drug-drug interactions, as 
these agents have shown no potential to inhibit or induce human CYP enzymes in vitro. 
8.2 
Genotoxicity 
Decitabine is shown to be genotoxic, which could cause fetal harm. It is unknown whether E7727 
can cause fetal harm. Therefore, subjects with reproductive potential must use methods of 
contraception during the study (as described in Section 5.1) and for 60 days after the last dose of 
decitabine. 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 decitabine immediately. Pregnancy in a female subject or a male subject’s partner 
must be reported using Pregnancy Forms I and II. 
9.0 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Efficacy Assessments 
Efficacy assessments (via bone marrow aspirate or biopsy and peripheral blood count) will be 
based on the IWG 2006 MDS Response Criteria for MDS. A bone marrow aspirate/biopsy will be 
performed at Screening (within 21 days before first study treatment) and then within 7 days before 
Day 1 of every other course (Courses 3, 5, up to 7), then at the investigator’s discretion to assess 
duration of response in responding subjects. 
9.2 
Pharmacokinetic/Pharmacodynamic/Biomarker Assessments 
9.2.1 
Pharmacokinetics (PK) 
PK assessments will be based on AUC, Cmax, Cmin, and other PK parameters of decitabine, E7727, 
E7727-epimer, and cytidine levels. CDA activity will be measured at baseline from the predose 
sample in Course 1. The blood volume required per sample is 3 mL. Sampling should take place 
within ±10% of the scheduled time point, not to exceed ±1 hour at the 24-hour time point. 
Additional information regarding sample collection, processing, etc., will be provided in the 
laboratory manual. Also see Appendix 2. 
9.2.1.1 
Dose Escalation Stage, Course 1 
PK assessments will be done at the following time points in Course 1: 
• Day -3 (±2 days): 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hours after dosing. 


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• Day 1: 0 (pre-dose), 0.25, 0.5, 1 (immediately before end of infusion), 1.083 (1 hour 5 min; 
5 min after end of infusion), then 1.5, 2, 3, 4 and 6 hours from start of infusion. 
• Day 2: 0 (predose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing (Day 2, 24-hour 
sample is the pre-dose sample of Day 3). 
• Day 3: pre-dose only (this is Day 2, 24-hour sample). 
• Day 4: pre-dose only. 
• Day 5: 0 (predose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours. 
9.2.1.2 
Dose Escalation Stage, Course 2 
• Day -3 (±2 days): 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing (if 
24-hour sample is on Day 1 then obtain sample before the E7727 dose if E7727 dose 
administered one day before Day 1). 
9.2.1.3 
Dose Confirmation Stage 
PK assessments from the Dose Escalation Stage showed that decitabine blood levels on the first 
day of oral dosing (Day 2) were lower than on Day 5. This necessitates additional assessments of 
decitabine levels over the 5 days of oral dosing to estimate the AUC over the entire 5-day cycle. 
PK assessments will be done at the following time points according to the randomization 
assignment in Courses 1 and 2. 
When receiving IV decitabine: 
• Day 1: 0 (pre-dose), 0.25, 0.5, 1 (immediately before end of infusion), then 1.083 (1 hour 
5 min; 5 min after end of infusion), 1.5, 2, 3, 4 and 6 hours from the start of infusion. 
When receiving oral decitabine + E7727: 
• Day 1: 0 (pre-dose), and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing (Day 1, 24-hour 
sample is the pre-dose sample of Day 2). 
• Day 2: 0 (pre-dose), and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing (Day 2, 24-hour 
sample is the pre-dose sample of Day 3). 
• Day 3: 0 (pre-dose), 0.5, 1, and 2 hours after dosing. 
• Day 4: 0 (pre-dose), 0.5, 1, and 3 hours after dosing. 
• Day 5: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours after dosing. 
After complete PK data from the first 12-24 subjects in the Dose Confirmation Stage are evaluated, 
PK assessments may be further modified to reduce the number of required collections. 
9.2.1.4 
Fixed-Dose Combination Stage 
When receiving the FDC tablet: 


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• Day 1: 0 (pre-dose), and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing (Day 1, 24-hour 
sample is the pre-dose sample of Day 2). 
• Day 2: 0 (pre-dose). 
• Day 3: 0 (pre-dose). 
• Day 4: 0 (pre-dose). 
• Day 5: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours after dosing. 
When receiving IV decitabine: 
• Day 1: 0 (pre-dose), 0.25, 0.5, 1 (immediately before end of infusion), then 1.083 (1 hour 
5 min; 5 min after end of infusion), 1.5, 2, 3, 4 and 6 hours from the start of infusion. 
9.2.2 
Pharmacodynamics 
PD assessments will be based on cytidine levels and LINE-1 DNA methylation. 
9.2.2.1 
Dose Escalation Stage 
LINE-1 DNA methylation will be assessed at Screening and at the following time points in 
Course 1: 
• Day 1 (pre-dose), and at Days 8, 15, 22. 
LINE-1 DNA methylation will be assessed at the following time points in Course 2: 
• Day 1 (pre-dose), Days 8, 15, 22, and 29 (ie, before Course 3). 
9.2.2.2 
Dose Confirmation Stage 
LINE-1 DNA methylation will be assessed at Screening and at the following time points in 
Courses 1 and 2 only in Dose Confirmation Stage: 
• Day 1 (pre-dose), and at Days 8, 15, 22, and 29 (ie, before the subsequent course). 
9.2.2.3 
Fixed-Dose Combination Stage 
LINE-1 DNA methylation will be assessed at Screening and at the following time points in 
Courses 1 and 2 in the FDC stage: 
• Day 1 (pre-dose), and at Days 8, 15, 22, and 29 (ie, before Course 3, Day 1). 


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9.3 
Safety Assessments 
Safety will be assessed by subject reported and investigator observed AEs, along with physical 
examination, ECGs and clinical laboratory tests (hematology, chemistries, and urinalysis). AEs 
will be monitored through the 30-Day (+5 day) Follow-up Visit. 
9.4 
Study Procedures 
9.4.1 
Schedule of Events  
Table 3 shows the dosing schedule by Stage and Course. Table 4 presents the complete schedule 
of events for all study stages, with details following in text. Additional information on the study 
procedures is provided in the study procedures manual. A detailed dosing schedule by stage and 
course is in Table 3. Time points for PK assessments are in Appendix 2. At any time in the study, 
one or more assessments may be eliminated at the recommendation of the DSRC if no longer 
needed to assess safety, PK, or PD of the study treatment. 
Clinical and diagnostic laboratory evaluations are detailed before study entry, throughout the 
study, and at the follow-up evaluation. The purpose of obtaining these detailed measurements is 
to ensure adequate assessments of efficacy, PK, PD, safety, and tolerability. Repeat clinical 
evaluations and laboratory studies more frequently if clinically indicated. 
Note any deviation from protocol procedures. Investigators are responsible for implementing 
appropriate measures to prevent the recurrence of violations and deviations and to report to their 
IRB/IEC according to policy. 
 
 


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Table 3: 
Dosing Schedule by Stage and Course 
Course (28 Days) 
1 
2 
≥3 
Course Day 
-3 (±2) 
1 
2-5 
-3 (±2) 
1-5 
1-5 
Dose Escalation Stage 
 
 
 
 
 
 
Single dose decitabine (oral) 
x 
 
 
 
 
 
Single dose E7727  
 
 
 
x 
 
 
IV decitabine (20 mg/m2)  
 
x 
 
 
 
 
Oral decitabine + E7727  
 
 
x 
 
x 
x 
Dose Confirmation Stage 
 
 
 
 
 
 
If randomized to IV decitabine in Course 1, then: 
 
 
 
 
 
 
     IV decitabine (20 mg/m2) 
 
x 
x 
 
 
 
     Oral decitabine + E7727  
 
 
 
 
x 
x 
If randomized to oral decitabine + E7727 in Course 1, then: 
 
 
 
 
 
 
     Oral decitabine + E7727  
 
x 
x 
 
 
x 
     IV decitabine (20 mg/m2) 
 
 
 
 
x 
 
Fixed-Dose Combination Stage 
 
 
 
 
 
 
If randomized to IV decitabine in Course 1, then: 
 
 
 
 
 
 
     IV decitabine (20 mg/m2) 
 
x 
x 
 
 
 
     FDC tablet  
 
 
 
 
x 
x 
If randomized to the FDC tablet in Course 1, then: 
 
 
 
 
 
 
     FDC tablet 
 
x 
x 
 
 
x 
     IV decitabine (20 mg/m2) 
 
 
 
 
x 
 
Transition to FDC Tablet 
 
x 
x 
 
x 
x 
NOTE: On days when subjects are administered E7727 + oral decitabine, subjects should take the IMPs simultaneously (ie, E7727 followed immediately by oral 
decitabine). The IMPs should be taken at the same time of day (±1 hour) on each dosing day, in at least the first 2 courses of treatment. 


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Table 4: 
Schedule of Events  
Course (28 Days) 
1 
2 
≥3a 
Tx 
Termb 
30-
Day 
FUc Survival 
Course Day 
-3d 
(±2) 
1 2-5 
8 
(±1) 
15 
(±2) 
22 
(±2) 
-3d 
(±2) 
1 
2-5 
8 
(±1) 
15 
(±2) 
22 
(±2) 
1 
2-5 
8 
(±2) 
15 
(±2) 
22 
(±2) 
 
 
 
Study Treatment Administration   
(see Table 3) 
 
x 
x 
x 
 
 
 
x 
x 
x 
 
 
 
x 
x 
 
 
 
 
PROCEDURESa 
Screeninge 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyf 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s confirmation of eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam or (symptom-directed PE)g 
x 
x 
x (x) (x) 
(x) 
(x) 
x 
x 
(x) 
(x) 
(x) 
(x) 
x 
 
 
 
 
x 
(x) 
 
Height  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/BSA calculationh 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
Vital signsi 
x 
x 
x (x) 
 
 
 
x 
x 
(x) 
 
 
 
x 
 
 
 
 
x 
 
 
ECOG statusj 
x 
x 
x 
 
 
 
 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
 
12-lead ECGk 
x 
x 
x 
  
 
 
 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
ECHO or MUGAl 
x 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications/AEsm 
x 
x 
x (x) 
x 
x 
x 
x 
x 
(x) 
x 
x 
x 
x 
 
 
 
 
x 
x 
 
Transfusion requirementsn 
x 
x 
x (x) 
x 
x 
x 
x 
x 
(x) 
x 
x 
x 
x 
 
 
 
 
x 
 
 
LABORATORY ASSESSMENTSa 
 
 
Hematologyo 
x 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
 
 
 
x 
 
 
Chemistryp 
x 
x 
x 
 
 
 
 
x 
x 
 
 
 
 
x 
 
 
 
 
x 
 
 
Urinalysisq 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Serum or urine pregnancy testr 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
IPSS Risk Categorys 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LINE-1 DNA methylation; 
 
 
x 
 
x 
 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
 
 
 
 
 
 
 


Astex Pharmaceuticals, Inc. 
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Table 4: 
Schedule of Events (Cont’d) 
Course (28 Days) 
1 
2 
≥3a 
Tx 
Termb 
30-
Day 
FUc Survival 
Course Day  
-3d 
(±2) 
1 2-5 
8 
(±1) 
15 
(±2) 
22 
(±2) 
-3d 
(±2) 
1 
2-5 
8 
(±1) 
15 
(±2) 
22 
(±2) 
1 
2-5 
8 
(±2) 
15 
(±2) 
22 
(±2) 
 
 
 
PK – Dose Escalation Stageu 
 
x 
x 
x 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
PK – Dose Confirmation Stageu 
 
 
x 
x 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
PK – FDC Stageu 
 
 
x 
x 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Response assessmentv 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Bone marrow aspirate/biopsyw 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Conversion to AMLx 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
a. 
The visit schedule and assessments are at the investigator’s discretion after Course 6, with the exception of adverse event and dosing information, which will still be collected. Continue to collect 
efficacy assessments, response assessment and survival data according to the protocol until disease progression (for response assessment) or death (for survival assessment). 
b. 
Perform Treatment Termination Visit procedures when a subject withdraws from further study treatment regardless of whether the subject withdrew from the whole study or not. The visit may 
occur at any time after the last study treatment and before the 30-day Follow-up visit. If the Treatment Termination Visit occurs close to the 30-day Follow-up visit, the 2 visits may be combined.  
c. 
30-Day Follow-up Visit must occur 30 (+5) days after the last dose of study treatment or within 3 days before starting new treatment. For 30-Day Follow-up via telephone, assess as much as 
possible but at a minimum assess AEs. 
d. 
Day -3 (±2 days): Applies only to Dose Escalation Stage Course 1 and Course 2. 
e. 
Screening: Must occur within 14 days before the first dose of decitabine, except for bone marrow biopsy/aspirate (may occur within 21 days before first dose of study treatment), and ECHO/MUGA 
(may occur within 28 days before first dose of study treatment). 
f. 
Medical history: Includes demographics and disease history at Screening. 
g. 
Physical Exam (PE): A complete PE performed at Screening per the institutional standard practice includes examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, nervous system and genitourinary system (if applicable). After Screening, symptom-directed PE (indicated by (x)) will be done pre-dose on Days 2-5 only if the subject is 
visiting the clinic for study purposes, and at all subsequent visits at the investigator’s discretion. For Dose Escalation Stage subjects who had full PE performed at Screening within 4 days of Course 
1 Day -3, it is not necessary to repeat the full PE on Day 1 during Course 1; a symptom-directed PE on Day 1 can be done instead. For Dose Escalation Stage subjects who had a full PE at Day -3 
(±2) in Course 1 and Course 2, it is not necessary to repeat the full PE on Day 1 during these courses; a symptom-directed PE on Day 1 can be done instead. For Dose Confirmation Stage or Fixed-
Dose Combination Stage, subjects who had full PE performed at Screening within 4 days of Course 1 Day 1, it is not necessary to repeat the full PE on Day 1 during Course 1; a symptom-directed 
PE on Day 1 can be done instead. 
h. 
BSA calculation applies only to the Screening and the first visit of the course in which the subject is receiving IV decitabine (20 mg/m2) or whenever dosing is given per surface area. Day 1, Dose 
Escalation Stage; Day 1, Dose Confirmation Stage (Course 1 or 2 according to randomization). Use actual body weights only for BSA calculations. BSA does not need to be performed at the 
Termination visit. 
i. 
Vital signs: Include resting systolic/diastolic blood pressure, resting respiration rate, resting heart rate, and body temperature. Assess after the subject has rested in the sitting position for at least 3 
minutes. On Days 2-5 in Course 1 and Course 2, perform vital signs only if the subject is visiting the clinic for study procedures (eg, administration of IV decitabine). 
j. 
ECOG status: Complete at Screening and predose as indicated in above table.  In Course 1, if assessed on Day -3 (±2) in Dose Escalation Stage or Screening (± 4 days) in the Dose Confirmation 
Stage or Fixed-Dose Combination Stage, it is not necessary to repeat on Day 1. 


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k. 
12-Lead ECG (single tracing only, unless clinically significant abnormality for which triplicate ECG is preferred for confirmation, eg, QTc >500 msec): Obtain predose as indicated in above table.  
In Course 1, if assessed on Day -3 (±2) in Dose Escalation Stage or Screening (± 4 days) in the Dose Confirmation Stage or Fixed-Dose Confirmation Stage, it is not necessary to repeat on Day 1. 
Either the Bazett’s or Fridericia’s formula may be used to calculate the QTc interval but must be consistently used throughout the study. Course ≥3: Day 1 only. 
l. 
ECHO/MUGA: May be done within 28 days of first dose of study treatment. 
m. 
Concomitant medications/Adverse events: Collect all AEs on indicated study days through the 30-Day Follow-up Visit. Collect all concomitant treatments through the termination visit and then 
only those used to treat AEs through the 30-Day Follow-up Visit. After 30-day follow up, collect only SAEs that are considered related to the study treatment. 
n. 
Transfusion requirements: Assess PRBC and platelet transfusions 8 weeks prior to study entry and then at on indicated study days.  
o. 
Hematology: Must include complete blood count with manual differential and platelet counts. In Course 1, Day -3 (±2) in Dose Escalation Stage and Course 1, Day 1 in the Dose Confirmation 
Stage or Fixed-Dose Combination Stage, hematology evaluations do not need to be repeated if Screening tests are within 4 days of first dose of study treatment. In Course 2, Day 1 in the Dose 
Escalation Stage, hematology evaluations do not need to be repeated if Course 2 Day -3 (±2) is performed within 4 days of Course 2, Day 1 dose. Additional laboratory assessments may be done 
at the investigator’s discretion for clinical interventions. 
p. 
Chemistry: 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 (Section 5.2). Course 1, Day -3 (±2) in the Dose Escalation Stage and Course 1, Day 1 in the Dose 
Confirmation Stage or Fixed-Dose Combination Stage, chemistry evaluations do not need to be repeated if screening tests are within 4 days of first dose of study treatment. In Course 2, Day 1 in 
the Dose Escalation Stage, chemistry evaluations do not need to be repeated if Course 2 Day -3 (±2) is performed within 4 days of Course 2, Day 1 dose. For Course 1, Day -3 (±2) in Dose 
Escalation Stage and Course 1, Day 1 in the Dose Confirmation Stage or Fixed-Dose Confirmation Stage, all chemistry evaluations must meet study entry criteria before dosing.  Additional 
laboratory assessments may be done at the investigator’s discretion for clinical interventions.   
q. 
Urinalysis: Dipstick only (microscopic analysis required only to follow up abnormal findings or if dipstick not performed). (See Table 5.) Includes microscopic examination. Course 1, Day -3 (±2), 
Dose Escalation Stage only. Course 1, Day 1 – Dose Confirmation Stage or Fixed-Dose Combination Stage. Urinalysis evaluations do not need to be repeated if screening tests are within 4 days 
before first dose of study treatment.  
r. 
Pregnancy test: Serum or urine; only for women of child-bearing potential. 
s. 
IPSS Risk Category: Int-1: 0.5–1; - Int-2: 1.5-2; High risk: ≥2.5. 
t. 
LINE-1 DNA methylation: LINE-1 DNA at Screening and pre-dose in Courses 1, 2,  and 3 only, and on designated days of Course 1 and 2 only (see Sections 9.2.2, 9.4.3.2, 9.4.3.4, 9.4.4, 9.4.5, 
9.4.5.1). Information regarding sample collection storage is provided in the Study Laboratory Manual.  
u. 
PK: see Appendix 2. 
v. 
Response assessment: Refer to Table 7 for the appropriate disease assessment.  
w. 
Bone marrow aspirate or biopsy: The screening bone marrow aspirate or biopsy must occur within 21 days of the first dose of study treatment. Bone marrow aspirate must be done to verify first 
CR, PR, mCR immediately when peripheral blood counts suggest a response, and within 7 days before the start of each odd course (Courses 3, 5, up to 7), as long as the subject continues to be 
responding, then according to local standard practice. Otherwise, this may be done at the investigator’s discretion. 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. 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, Other. An anonymized report of all bone marrow testing results will be recorded 
on the Case Report Form. A portion of bone marrow aspirates will be used for assessing 
. 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. 
x. 
Conversion to AML: Follow all subjects for survival who have stopped study treatment. Contact each subject at least every 3 months until death or withdrawal of consent. This assessment may be 
conducted by telephone. 
 


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9.4.2 
Screening and Baseline Procedures 
After the investigator or sub-investigator confirms that a subject is eligible and willing to 
participate in the study, study center personnel will forward the appropriate documentation to the 
attention of the sponsor according to the study manual. 
Within 14 days before treatment administration (unless otherwise specified), perform the 
following study procedures and tests: 
• Written informed consent. The ICF must be signed and dated by the subjects before any 
study-specific samples are collected or study-specific procedures are initiated. 
• Complete medical history, including demographics (date of birth, sex, race). Record disease 
history, including the date of initial diagnosis. Document concurrent medical signs and 
symptoms to establish baseline conditions. 
• Investigator’s confirmation of eligibility. Perform all necessary procedures and evaluations to 
document that the subject meets each eligibility criterion. 
• Complete physical exam as per the institution standard practice including examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, 
nervous system, and genitourinary system (if applicable). 
• Obtain height and weight/BSA calculation. 
• Vital signs include resting (assessed after the subject has rested in a sitting position for at least 
3 minutes) systolic/diastolic blood pressure, resting respiration rate, resting heart rate, and body 
temperature (vital signs). 
• ECOG performance status (Appendix 3).  
• 12-lead ECG – single tracing only (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, one formula but must be consistently used 
throughout the study. Course ≥3: Day 1 only. 
• ECHO or MUGA; may be performed up to 28 days before study treatment. 
• Record concomitant medications. 
• Assess transfusion dependency status. See Section 9.6 for definitions of transfusion 
dependence and independence.  
• Collect blood samples for hematology and serum chemistry, and urine sample for 
urinalysis (Table 5). 
• 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. 
• Assess IPSS, number of prior cancer treatments. 
• Obtain whole blood sample for LINE-1 DNA methylation (all groups). 


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• Collect bone marrow aspirate or biopsy including bone marrow cytogenetics of 20 clones (may 
be performed up to 21 days before administration of study treatment). A portion of Screening 
bone marrow aspirates will be used for assessing 
. 
Table 5: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Pregnancy Test 
-Complete blood count 
(CBC) 
-Manual differential 
-Platelet count 
-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 described in Table 4. 
 
9.4.3 
Treatment and Follow-up Procedures 
9.4.3.1 
Course 1, Day -3 (±2) – Dose Escalation Stage Only 
Complete the following assessments before dosing: 
• Complete physical examination (PE) including weight/BSA (may be a symptom-directed PE 
if a full PE was completed within 4 days of this visit). 
• Vital signs. 
• ECOG performance status (Appendix 3; may be waived if completed within 4 days prior to 
visit). 
• 12-lead ECG – single tracing only. 
• Record concomitant medications /adverse events. 
• Verify transfusion dependency status.  
• Collect blood samples for hematology and serum chemistry, and urine sample for urinalysis 
(Table 5). (May be waived if completed within 4 days prior to the visit.) 
• Obtain PK sample per Appendix 2. 


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• Administer oral decitabine at assigned cohort dose level after a fast of at least 2 hours; 
administer with 240 mL (8 fluid ounces) of water. No food, milk or alcohol should be allowed 
for at least 2 hours post-dose. Clear liquids such as water, black coffee, tea, or fruit juice may 
be allowed as desired. Ensure subject is clinically stable prior to discharging home after all PK 
samples have been obtained. 
9.4.3.2 
Course 1, Day 1 – All Stages 
Complete the following assessments before dosing (see Table 6): 
• Physical examination: see Table 6. 
• Weight/BSA calculation: see Table 6. 
• Vital signs. 
• ECOG Performance Status (Appendix 3; may be waived if completed within 4 days prior to 
visit). 
• 12-lead ECG – single tracing only (may be waived if completed within 4 days prior to visit). 
• Record concomitant medications and adverse events. 
• Record any transfusion requirements since last visit (for the Dose Confirmation Stage, assess 
transfusion dependency status). 
• Collect blood samples for hematology and serum chemistry, and urine sample for 
urinalysis (Table 5). (May be waived if completed within 4 days prior to the visit.) 
• Obtain whole blood sample for LINE-1 DNA methylation. 
• Obtain PK samples per Appendix 2. 
• Assess response. 
 


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Table 6: 
Day 1 Assessments – All Stages 
Assessment 
Dose Escalation  
Stage 
Dose Confirmation 
Stage 
Fixed-Dose 
Combination Stage 
Physical Examinationa 
Symptom-directed Exam 
Complete Exam 
Complete Exam 
Weight/BSA calculation 
x/x 
x/xb 
x/xb 
LINE-1 demethylation 
x 
x 
x 
Predose PK sample 
x 
x 
x 
a Symptom-directed PE for subjects in the Dose Escalation Stage if completed at Day -3(± 2) visit or for subjects in 
Dose Confirmation Stage or FDC Stage if full PE completed at Screening visit within 4 days of this visit. 
b When receiving IV decitabine (unless oral decitabine + E7727 requires Weight/BSA dose adjustment after PK 
review by DSRC). 
Dosing and post-dosing procedures: 
• Administer the study treatment: 
• Dose Escalation Stage: IV decitabine (20 mg/m2) as a 1-hour infusion. 
• Dose Confirmation Stage: Either IV decitabine (20 mg/m2) or oral decitabine + E7727 at 
assigned dose (based on randomization assignment). 
• FDC Stage: Either FDC tablet administered orally, or IV decitabine (20 mg/m2) as a 1-hour 
infusion. 
If administering oral decitabine + E7727, or the FDC tablet, administer after a fast of at least 
2 hours, with 240 mL (8 fluid ounces) of water. No food, milk or alcohol should be allowed for at 
least 2 hours post-dose. Clear liquids such as water, black coffee, tea, or fruit juice may be allowed 
as desired.  
• Obtain PK samples per Appendix 2. 
• Record any new concomitant medications and adverse events. 
9.4.3.3 
Course 1, Days 2-5 – All Stages  
On days the subject comes to the clinic for IV decitabine or PK assessments complete the following 
assessments before dosing:  
• Symptom-directed physical examination. 
• Vital signs. 
• Record concomitant medications and adverse events (pre- and post-dosing). 
• Record any transfusion requirements since last visit. 
• Collect PK samples per Appendix 2 (pre- and post-dosing). 
Dosing and post-dosing procedures: 
• Administer the study treatment: 
• Dose Escalation Stage: oral decitabine + E7727 at assigned dose for cohort. 


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• Dose Confirmation Stage: Either IV decitabine (20 mg/m2) or oral decitabine + E7727 at 
assigned dose (based on randomization assignment). 
• FDC Stage: Either FDC tablet administered orally, or IV decitabine (20 mg/m2) as a 1-hour 
infusion. 
If administering oral decitabine + E7727, or the FDC tablet, administer after a fast of at least 
2 hours, administer with 240 mL (8 fluid ounces) of water. No food, milk or alcohol should be 
allowed for at least 2 hours post-dose. Clear liquids such as water, black coffee, tea, or fruit juice 
may be allowed as desired. 
• Record any new concomitant medications and adverse events. 
9.4.3.4 
Course 1, Days 8, 15, 22 – All Stages  
Complete the following for all stages unless otherwise indicated: 
• Symptom-directed physical examination. 
• Record concomitant medications and adverse events. 
• Record any transfusion requirements since last visit. 
• Collect hematology samples (Table 5). 
• Collect whole blood sample for LINE-1 DNA methylation. 
9.4.3.5 
Course 2, Day -3 (±2) – Dose Escalation Stage only 
Complete the following predose: 
• Complete physical examination (symptom directed only if subject is visiting the clinic for 
study procedures). 
• Vital signs only if subject is visiting the clinic for study procedures. 
• ECOG performance status (Appendix 3). 
• 12-lead ECG – single tracing only. 
• Record concomitant medications and adverse events (pre- and post-dosing). 
• Record any transfusion requirements since last visit. 
• Collect blood samples for hematology and chemistry samples (Table 6). 
• Collect PK sample (see Appendix 2) (pre- and post-dosing). 


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Dosing and post-dosing procedures: 
• Administer single oral dose of E7727 at assigned cohort dose level after a 2-hour fast with 
240 mL (8 fluid ounces) of water. No food, milk or alcohol should be allowed for at least 
2 hours post-dose. Liquids such as water, black coffee, tea, or fruit juice may be allowed as 
desired. 
• Record any new concomitant medications and adverse events. 
9.4.4 
Course 2, Days 1-5 – All Stages  
Complete the following predose: 
• Complete physical examination on Day 1 (may be symptom-directed for Dose Escalation Stage 
subjects if completed at Day -3 [±2] visit) and symptom-directed physical examination on Days 
2-5 only if subject is visiting the clinic for study procedures. 
• Weight and BSA calculation (BSA calculation required on Day 1 in Dose Escalation Stage and 
for those receiving IV decitabine in Dose Confirmation Stage, Day 1 only). 
• Vital signs: Days 2-5 only if subject is visiting the clinic for study procedures. 
• EGOG performance status (Day 1 only). 
• 12-lead ECG – single tracing only (Day 1 only). 
• Record concomitant medications and adverse events (pre- and post-dosing). 
• Record any transfusion requirements since last visit. 
• Collect blood samples for hematology and serum chemistry on Day 1 only (Table 5). 
• Obtain sample for LINE-1 DNA methylation (Day 1 only). 
• Collect samples for PK assessment (see Appendix 2) (pre- and post-dosing). 
Dosing and post-dosing procedures: 
• Administer the study treatment: 
• Dose Escalation Stage: oral decitabine + E7727 at assigned dose. 
• Dose Confirmation Stage: Either IV decitabine (20 mg/m2) or oral decitabine + E7727 at 
assigned dose (based on randomization assignment). 
• FDC Stage: Either FDC tablet administered orally, or IV decitabine (20 mg/m2) as a 1-hour 
infusion. 
If administering oral decitabine + E7727, or the FDC tablet, administer after a fast of at least 
2 hours, administer with 240 mL (8 fluid ounces) of water. No food, milk or alcohol should be 
allowed for at least 2 hours post-dose. Clear liquids such as water, black coffee, tea, or fruit juice 
may be allowed as desired.  


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• Record any new concomitant medications and adverse events. 
9.4.5 
Course 2, Days 8, 15, and 22 – All Stages  
Complete the following for all stages unless otherwise indicated: 
• Symptom-directed physical examination. 
• Record concomitant medications and adverse events. 
• Record any transfusion requirements since last visit. 
• Collect hematology samples (Table 5). 
• Collect whole blood sample for LINE-1 DNA methylation. 
9.4.5.1 
Course ≥3, Days 1-5 – All Stages  
All procedures are to be completed at all visits through Course 6. Beginning with Course 7 and 
later courses, all procedures are at the discretion of the investigator except for Adverse Event, 
dosing information, and response assessment. Data will be collected on all procedures completed. 
Complete the following predose: 
• Complete physical examination (Day 1 only). 
• Vital signs (Day 1 only). 
• EGOG performance status (Day 1 only). 
• 12-lead ECG – single tracing only (Day 1 only). 
• Record concomitant medications and adverse events (Day 1 only). 
• Record any transfusion requirements since last visit (Day 1 only). 
• Collect blood samples for hematology and chemistry (Day 1 only) (Table 5). 
• Collect whole blood sample for LINE-1 DNA methylation (only Course 3 Day 1 predose) 
• Assess response (obtain predose on Day 1 in every odd numbered course). 
• Bone marrow aspirate or biopsy within 7 days before the start of Course 3, Course 5, and 
Course 7, as long as the subject continues to be responding; thereafter, according to a schedule 
that is standard practice at the study center. A portion of bone marrow aspirates will be used 
for assessing 
. 
Dosing and post-dosing procedures: 
• Administer oral decitabine + E7727 at assigned dose, or the FDC tablet, after a fast of at least 
2 hours, administer with 240 mL (8 fluid ounces) of water. No food or milk should be allowed 


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for at least 2 hours post-dose. Clear liquids such as water, black coffee, tea, or fruit juice may 
be allowed as desired. No alcohol should be ingested throughout an entire treatment day. 
• Record any new concomitant medications and adverse events. 
9.4.5.2 
Treatment Termination 
Perform Treatment Termination Visit procedures when a subject withdraws from further study 
treatment regardless of whether the subject withdrew from the whole study or not. The visit may 
occur at any time after the last study treatment and before the 30-Day Follow-up Visit. If the 
Treatment Termination Visit occurs close to the 30-Day Follow-up Visit, the 2 visits may be 
combined. Complete the following upon subject termination: 
• Complete physical examination, weight, vital signs, ECOG performance status, 12-lead ECG 
(single tracing only). 
• Record concomitant medications and adverse events. 
• Record any transfusion requirements since last visit. 
• Collect blood samples for hematology and serum chemistry and urine sample for 
urinalysis (Table 5). 
• Serum or urine pregnancy test: for women of child-bearing potential only. 
9.4.5.3 
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 treatment. The 30-day Follow-up Visit may be completed in 
person or by telephone. For 30-Day Follow-up via telephone, assess as much as possible but at a 
minimum assess AEs. If the 30-day Follow-up Visit occurs close to the Treatment Termination 
Visit, the 2 visits may be combined. 
• Symptom-directed physical examination. 
• ECOG performance status (Appendix 3). 
• Assess concomitant medications and adverse events. 
• Assess response (see Table 7). 
• Perform bone marrow aspirate or biopsy. 
9.4.5.4 
Survival/Conversion to AML 
Follow all subjects for survival who have stopped study treatment. Contact each subject every 
3 months until death or withdrawal of consent. This assessment may be conducted by telephone. 


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9.5 
Missed Evaluations 
Evaluations should occur within the visit window specified by the protocol. If an evaluation is 
missed, reschedule and perform it as close as possible to the original date. If rescheduling becomes, 
in the investigator’s opinion, medically unnecessary because the evaluation would occur too close 
to the next scheduled evaluation, it may be omitted. 
9.6 
Response Criteria 
The response criteria for evaluation of MDS are based on the International Working Group criteria 
published by Cheson et al. (2006) and are shown in Table 7. 
Table 7: 
IWG 2006 MDS Response Criteria 
Complete Response (CR): the following for 4 weeks 
Peripheral: normal peripheral counts with persistent granulocyte count ≥ 1.0 x 109/L, platelet ≥ 100 x 109/L 
Marrow: normal bone marrow with persistent marrow blasts ≤ 5%; peripheral dysplasia will be noted 
Partial Response (PR): the following for 4 weeks 
Peripheral: normal peripheral counts with granulocyte count ≥ 1.0 x 109/L and platelet count ≥ 100 x 109/L 
Marrow: normal bone marrow and marrow blasts > 5% but were reduced by 50% or more 
Marrow Complete Response (mCR): the following 4 weeks 
Reduction of bone marrow blasts to ≤ 5% without normalization of peripheral counts 
Hematological Improvement (HI): lasts at least 8 weeksa 
Erythroid Response (HI-E): Major Response: hemoglobin increase ≥ 1.5 g/dL or RBC transfusion dependence 
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 
Neutrophil Response (HI-N): Major Response: granulocyte increase ≥ 100%, and by an absolute increase ≥0.5 X 
109/L 
a  Abnormal baseline counts were the averages of at least two measurements over at least one week prior to therapy, 
not influenced by transfusions. 
Transfusion dependence and independence will be defined by the transfusion requirements during 
the 8 weeks before study treatment start (Steensma et al 2009):  
• Transfusion dependent anemia at baseline: documentation of 2 units or more PRBCs within 56 
days of the first day of study treatment 
• Post-treatment Transfusion independence : no blood transfusion of 2 or more units of PRBCs 
for 56 days or more after treatment 


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10.0 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Adverse Event (AE) 
Adverse Event (AE): Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including a clinically significant abnormal finding in laboratory tests or other 
diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without 
any judgment about causality. An AE can arise from any use of the drug and from any route of 
administration, formulation, or dose, including an overdose.  
Disease progression is not considered to be an AE or 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 serious adverse events (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 
(e.g., invasive procedures such as biopsies). 
10.1.2 
Serious Adverse Events (SAEs) 
An AE is considered serious, if in the view of either the investigator or sponsor, it results in any 
of the following outcomes: 
• Death. 
• A life-threatening AE. 
• An AE is considered “life-threatening” if in the view of either the investigator, or sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of an existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• A congenital anomaly or birth defect. 
Important medical events that may not result in death, be life-threatening or require hospitalization 
may be considered serious when, based on the appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in the definition of SAE. Examples of such medical events are intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or 
development of drug dependency or drug abuse. 


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10.2 
Adverse Event Reporting and Descriptions 
Record new AEs from the start of study treatment until 30 days after the last dose of study 
treatment. Also record screening procedure-related AEs that occur before the start of study 
treatment. 
Record all treatment-emergent AEs (AEs occurring after the start of study treatment) either 
observed by the investigator or one of his or her medical collaborators, or reported by the subject 
spontaneously, or in response to the direct question below, in the AEs section of the subject’s 
CRF/eCRF, in the source document, and if applicable, record on the SAE form. Whenever 
possible, the investigator should group signs and symptoms (including laboratory tests or other 
results of diagnostic procedures) into a single diagnosis under a single term. For example, cough, 
rhinitis, and sneezing might be reported as “upper respiratory infection” or a pulmonary infiltrate, 
positive sputum culture and fever might be reported as “pneumonia.” 
To optimize consistency of AE reporting across centers, ask the subject a standard, general, non-
leading question to elicit any AEs (such as “Have you had any new symptoms, injuries, illnesses 
since your last visit?”).  
For any change in laboratory results, vital signs, physical examination, radiologic exam or ECG 
measurements that arises after treatment, the investigator will decide if the finding or result is 
clinically significant and will determine if it is necessary to repeat the evaluation. If the investigator 
judges the finding or result as clinically significant, it must be recorded as an AE, and if applicable, 
reported as an SAE. Clinically significant laboratory findings include any laboratory result for 
which a therapeutic intervention is initiated to correct the abnormality; this excludes intervention 
to correct the abnormality as part of the disease state or disease progression. 
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 v4.0 for grading the severity (intensity) of AEs. The 
CTCAE v4.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each 
referenced AE. Should a subject experience any AE not listed in the CTCAE v4.0, use the 
following grading system to assess severity: 
• Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 – Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL), such as preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc. 


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


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


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Report all deaths with the primary cause of death as the SAE term, as death is the outcome of the 
event, not the event itself. If an autopsy was performed, report the primary cause of death on the 
autopsy report as the SAE term. Forward autopsy and postmortem reports to Astex 
Pharmaceuticals Drug Safety, or designee, as outlined above. 
If study treatment is discontinued, temporarily suspended or dose reduced because of an SAE, 
include this information in the SAE report. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that qualify for mandatory 
expedited reporting to regulatory authorities where the SAE is suspected to be caused by the study 
treatment and is considered unexpected (i.e., not defined as expected in the current IB clinical 
study protocol, or approved labeling for marketed drugs). In this case, Astex Pharmaceuticals Drug 
Safety or designee will report to the relevant regulatory authorities and forward a formal 
notification describing the SUSAR to investigators, according to regulatory requirements. Each 
investigator must then notify his or her IRB/IEC of the SUSAR as required by local regulatory 
authorities and in accordance with IRB/IEC policy. 
10.4 
Follow-up for Adverse Events 
Follow all AEs and SAEs assessed as related to study treatment or study procedures that are 
encountered during the protocol-specified AE reporting period (1) to resolution, (2) until the 
investigator assesses the subject as stable and the event is following a clinically expected outcome, 
or (3) until the subject is lost to follow-up or withdraws consent. 
11.0 
STATISTICS 
Statistical analyses will be performed by Astex Pharmaceuticals, Inc. or its designee. 
Data summaries and listings will be generated using SAS version 9.3 or higher (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 and spurious data. The 
clinical study report will describe deviations from the statistical analysis plan, if any. 
11.1 
Sample Size  
11.1.1 
Dose Escalation Stage 
For this stage, no formal statistical tests of hypotheses are performed to calculate sample size. The 
Dose Escalation Stage follows a standard 3+3 design, with a cohort size of 3-12 evaluable subjects 
(and may be extended to 18 subjects to confirm the AUC range, if recommended by the DSRC). 
The enrollment of subjects in the Dose Escalation Stage will continue until the desired decitabine 
AUC level (AUC ratio of 0.90 to 1.10 of oral decitabine to IV decitabine) and safety are achieved, 
as described in Section 4.1.1. A subject is considered evaluable for the Dose Escalation Stage if 
all the criteria below are met: 


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• Complete Course 1 dosing regimen with sufficient PK data available. 
• Safety assessment for the 28 days of Course 1. 
11.1.2 
Dose Confirmation Stage 
At least 42 evaluable subjects are planned for enrollment into the Dose Confirmation Stage. 
Forty-two evaluable subjects with an IPSS risk level of intermediate-1, intermediate-2, or high risk 
are needed to assess decitabine AUC (estimated from 5 days of dosing) and LINE-1 demethylation, 
using a standard 2 x 2 cross-over design, between IV decitabine 20 mg/m2 daily×5 and the 
recommended doses of oral decitabine + E7727 as determined in the Dose Escalation Stage. 
Evaluable subjects for this assessment of decitabine and LINE-1 DNA demethylation are those 
who meet all the following criteria: 
• Complete the dosing regimens in Courses 1 and 2 with sufficient PK data available. 
• Have at least one bone marrow aspirate/biopsy after Course 2. 
In an equivalence test of the mean decitabine AUCs of oral decitabine + E7727 (estimated from 
5 days of dosing) compared with IV decitabine using two one-sided tests on data from a 2 x 2 
cross-over design, a sample size of 42 achieves 86% power at a 10% significance level when the 
true ratio of the means is 1.0, the coefficient of variation on the original, unlogged scale is 0.50 
which was estimated from a previous study described in the Dacogen Prescribing Information 
(2014), and the equivalence limits of the mean ratio are 0.75 and 1.33. 
This same sample size of 42 in the same 2 x 2 cross-over design achieves 80% power to detect the 
non-inferiority, with respect to the mean maximum %LINE-1 demethylation from baseline, of oral 
decitabine + E7727 compared with IV decitabine using a one-sided t-test when the margin of non-
inferiority is -0.05, the true mean difference is 0, the standard deviation (SD) is 0.15 and the 
significance level is 0.10. The SD of the paired differences of 0.15 was estimated from a previous 
study. 
11.1.3 
Fixed-Dose Combination Stage 
Subjects in a standard 2 x 2 crossover design are considered evaluable for equivalence analysis if 
those subjects complete treatment in Courses 1 and 2 with sufficient PK data. A total of 
18-24 evaluable subjects included in the 2 one-sided equivalence tests for mean oral decitabine 
AUC compared with mean IV decitabine AUC will provide 75%-88% power at a 10% significance 
level when the true ratio of means is 1.0, the coefficient of variation under an unlogged scale is 
0.55, and the equivalence limits for the ratio of means are 0.65 and 1.539. 
The 18-24 subjects who complete Courses 1 and 2 with sufficient LINE-1 data in the same 2 x 2 
crossover design will provide 78%-86% power to detect non-inferiority, with respect to the mean 
maximum %LINE-1 demethylation from baseline, of the ASTX727 FDC tablet compared with IV 


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decitabine using a one-sided t-test when the margin of non-inferiority is 0.075, the true mean 
difference is 0, the standard deviation (SD) is 0.15 and the significance level is 0.10. 
11.2 
Data Sets to be Analyzed 
11.2.1 
All Enrolled Subjects 
This data set will contain available data from all enrolled subjects, including those who did not 
receive any study treatment. This data set will be used for analysis of subject disposition. 
11.2.2 
Efficacy 
The efficacy data set will include data from all enrolled subjects who receive any amount of study 
treatment. 
11.2.3 
Safety 
The safety data set will be the same as the efficacy data set, which includes data from all enrolled 
subjects who receive any amount of study treatment. In the safety analysis, no data exclusion is 
allowed because of protocol deviations. 
11.2.4 
Pharmacokinetics 
The PK data set will include all available plasma concentrations for decitabine, E7727, and E7727-
epimer for subjects who have received study treatment. PK parameters will be derived for all PK-
evaluable subjects, provided sufficient data points are available.  
11.2.5 
Pharmacodynamics and Biomarker Analyses 
Subjects will be included in the PD and biomarker analyses if their DNA global methylation  
(LINE-1) data or biomarker data are successfully collected and tested. 
11.3 
Schedule of Analyses 
Analyses of safety, efficacy, PD, and PK data will be regularly performed for review by the DSRC 
for the purpose of guiding decisions such as dose escalation, de-escalation, and change in cohort 
size, determination of subsequent dose level during the Dose Escalation Stage. Final and complete 
analyses of all data, however, will be performed at the end of the Dose Confirmation Stage after 
all subjects have completed at least two courses of therapy (as planned). Additional survival 
analysis based on long-term follow-up may be conducted as needed. 
In the Dose Confirmation Stage, the DSRC will review data from the first 6-12 subjects with 
complete PK and PD data from the first 2 courses to confirm the doses used for ASTX727 
components. If a dose change is required, another assessment of PK and PD data will be done after 
6-12 subjects have received the new doses. 


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In the FDC Stage, data from subjects who have complete PK and PD data from Courses 1 and 2 
of the FDC Stage will be reviewed to confirm that data with the FDC tablet are similar to data with 
IV decitabine. 
No formal interim analyses are planned for this study. 
11.4 
Analysis of Subject Disposition 
The number and percentage (n, %) of subjects enrolled, treated, lost to follow up, and withdrawn 
(with reason) will be summarized by study stage. The All Enrolled Subject Data Set will be used 
for disposition analysis. The number screened and reasons for screen fails will be noted if the 
information is available. 
The number of subjects transitioned from E7727 + decitabine capsules to the ASTX727 FDC tablet 
will be summarized by subjects’ original study stage and treatment cohorts. 
11.5 
Analysis of Demographic and Baseline Data 
Subject demographic and baseline characteristics will be summarized using mean, standard 
deviation, median, minimum, and maximum for continuous variables, and by counts and 
percentages for categorical variables based on all treated subjects (safety and efficacy dataset). 
Summaries will be provided separately by stage of study and, if deemed necessary, by dose cohort 
or treatment sequence. 
11.6 
Efficacy Analyses 
Efficacy analyses will be conducted based on all treated subjects (efficacy dataset) by stage of the 
study, and if deemed necessary, by dose cohort (Dose Escalation Stage). 
Response rates and rates of hematologic improvement will be calculated as defined by the IWG 
2006 MDS Response Criteria. The 95% CIs will be estimated for the response rate calculated. 
Duration of response (in number of days) will be calculated from the first time the response is 
observed to time of relapse or last time point in the study. Rate of transfusion independence will 
be calculated based on the number of transfusion-dependent subjects who had no transfusion for 
at least 56 days during treatment. 
Overall survival will be defined as the number of days from the day the subject received the first 
dose of IV decitabine, oral decitabine + E7727, or the FDC tablet, to the date of death (regardless 
of cause). Time to AML  will be the number of days from the day the subject received the first 
dose of IV decitabine, oral decitabine + E7727, or the FDC tablet, to the date of death or the date 
of MDS progression to AML as defined by ≥20% blasts in bone marrow or peripheral blood using 
the WHO classification. Both of these time-to-event endpoints will be evaluated using the Kaplan-
Meier method. Survival time and time to AML will be censored on the last date of contact if a 
subject is lost to follow up prior to reaching a time-to-event endpoint.  


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11.7 
Safety Analyses 
Safety analyses include the analyses of AEs, DLTs, concomitant medications, laboratory values, 
vital signs and ECG assessments. Safety analyses will be conducted on all treated subjects (safety 
dataset), by stage of study and dose cohort as appropriate. 
AE terms reported by study subjects or observed by investigators will be mapped to the appropriate 
system organ class (SOC) and preferred term (PT) according to the MedDRA version 16.0. 
Severity of AE will be graded using NCI CTCAE version 4.0. All adverse events will be listed. 
Treatment-emergent adverse events (TEAEs) will be summarized using counts and percentages 
by MedDRA SOC and PT and by CTC AE grades. TEAEs are defined as events that occurred or 
worsened after the first dose of study treatment. Summaries of all TEAEs, all related TEAEs, all 
serious TEAEs and all serious related TEAEs will be provided. 
DLTs are defined in Section 4.5. Instances of DLTs will be identified in each dose cohort and 
listed separately to assist in determining the desired dose level for the combination of oral 
decitabine + E7727 in the Dose Escalation Stage. DLTs will be summarized by severity and 
seriousness (Y/N), as well as relationship to the study treatment.  
Concomitant medications will be coded according to the WHO DRUG Dictionary (December 
2012 version) and summarized by Therapeutic subgroup (ATC level 2) and generic name. 
Concomitant medications are the medications taken with a start date on or after the start of the 
administration of the study treatment. 
Laboratory values will be listed. Laboratory values will also be graded, if possible and deemed 
necessary, by CTCAE in conjunction with the Harrison (18th edition) lab book normals. Shift 
tables will display (1) shift from baseline to worst laboratory value grade during the study, and 
(2) shift from baseline to last lab value grade at the end of the study. 
Vital Signs will be summarized by visit using proportion of subjects with each vital sign being too 
high or too low according to the conventionally accepted vital sign normal ranges. 
For analysis of ECGs, QTc will be coded using CTCAE 4.0, and shift tables will be used to show 
the shift from baseline grade to worst grade and from baseline to the last visit QTc grade. 
11.8 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
11.8.1 
Pharmacokinetic Analyses 
The PK data set will be used for analysis of all PK parameters. PK parameters of decitabine, E7727, 
and E7727-epimer will be derived for each subject using a non-compartmental approach. 
PK parameters will be summarized descriptively using mean, standard deviation, median and 
range by dose cohort and course/days, and by stage of the study if deemed necessary. In particular, 
PK values obtained after oral decitabine + E7727 or the FDC tablet will be compared descriptively 
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In addition, the decitabine AUC values obtained from the 2 x 2 crossover design part of the study 
(Dose Confirmation and FDC Stages) will be analyzed for equivalence of means using the 
confidence interval (CI) method. The AUC values from the two treatments are considered 
comparable for the purpose of this phase 1-2 study, if the two-sided 80% CI of the mean AUC 
ratio lies entirely within the range of 0.75 – 1.33 in the Dose Confirmation Stage or 0.65-1.539 in 
the FDC Stage. 
PK dose proportionality will be tested using linear regression between dose and dose-adjusted 
parameter estimates; correlation of PK to PD will be assessed. 
11.8.2 
Pharmacodynamic/Biomarker Analyses 
Subjects will be included in the PD and biomarker analyses if their DNA global methylation 
(LINE-1) data or biomarker data are successfully collected and tested. PD and biomarkers will be 
summarized descriptively (using mean, standard deviation, median and range for continuous 
variables and counts and percentages for categorical variables) by dose cohort and course/days, 
and by stage of the study if deemed necessary.  
In addition, the mean maximum %LINE-1 demethylation from baseline obtained from the 2 x 2 
crossover design part of the study will be analyzed for non-inferiority of means (oral decitabine + 
E7727 compared with IV decitabine in the Dose Confirmation Stage, and the FDC tablet compared 
with IV decitabine in the FDC Stage) using the confidence interval (CI) method. Oral decitabine 
+ E7727 is considered non-inferior to IV decitabine with respect to LINE-1 demethylation, for the 
purpose of this phase 1-2 study, if the upper bound of the two-sided 80% CI of the difference in 
mean maximum %LINE-1 demethylation between oral decitabine + E7727 and IV decitabine is 
below 0.05 in the Dose Confirmation Stage. In the FDC Stage, the upper bound of the two-sided 
80% CI for the difference of mean maximum %LINE-1 demethylation between the FDC tablet 
and IV decitabine must be <0.075 to achieve non-inferiority. The details of this analysis will be 
defined in the statistical analysis plan. 
Additional biomarker analysis will include assessment of baseline CDA activity and changes in 
circulating 
 levels post-treatment. 
11.9 
Interim Analysis 
No formal interim analysis is planned for this study. However, safety data will be routinely 
reviewed, and a thorough review of safety data will be conducted after every cohort of at least 
3 subjects during the Dose Escalation Stage, at the end the Dose Escalation Stage, and at least 
quarterly during the Dose Confirmation Stage. In addition, during the Dose Confirmation Stage 
and FDC Stage, data assessments will be conducted by the DSRC as described above in 
Section 11.3. 


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11.10 Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed, unless otherwise specified. Data from 
subjects lost to follow up will be included in statistical analyses up to the time of last evaluation. 
Data from all enrolled subjects will be included in the data listings, and summary tables (with the 
exception of the subject disposition table) will be based on data from all treated subjects. Actions 
on spurious data, if any, will be described fully in the clinical study report. 
12.0 
STUDY DURATION AND TERMINATION 
The study is expected to start in Q2 2014. The Dose Escalation Stage is expected to take 12 months, 
and the Dose Confirmation Stage is expected to take approximately 12 months. The FDC Stage is 
expected to take approximately 12 months. 
13.0 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
13.1 
Compliance Statement 
The study will be conducted in accordance with the ICH GCP guidelines; US Title 21 CFR Parts 
11, 50, 54, 56, and 312; and the principles enunciated in the Declaration of Helsinki and all human 
clinical research regulations in the countries where the study is to be conducted. 
13.2 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, federal regulations US 
21 CFR Part 50, and ICH GCP guidelines and any other local regulations. The investigator, or a 
person delegated by the investigator, must explain the medical aspects of the study, including the 
nature of the study and the treatment, orally and in writing, in such a manner that the subject is 
aware of potential benefits and risks. Subjects must be informed that participation is voluntary and 
that they may withdraw from the study at any time, without prejudice. Subjects, or a legal guardian 
if the subject is unable to, must give informed consent in writing. 
The informed consent process must be conducted, documented in the source document  
(including the date), and the form must be signed, before the subject undergoes any study-specific 
procedures. 
13.3 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) 
The investigator must submit the protocol, protocol amendments, and the ICF for the proposed 
study, along with any other documents required by the center’s IRB/IEC to the center’s duly 
constituted IRB/IEC for review and approval. The investigator must also ensure that the IRB/IEC 
reviews the progress of the study on a regular basis and, if necessary, renews its approval of the 
study on an annual basis. A copy of each IRB/IEC approval letter must be forwarded to the sponsor 
before the study is implemented. Documentation of subsequent reviews of the study must also be 
forwarded to the sponsor. 


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14.0 
ADMINISTRATIVE PROCEDURES 
14.1 
Sponsor’s Responsibilities 
Astex Pharmaceuticals reserves the right to terminate the study at any time. Astex Pharmaceuticals 
and the investigators will assure that adequate consideration is given to the protection of the 
subjects’ interests. Astex Pharmaceuticals retains the right to terminate the study and remove all 
study materials from a study center at any time. Specific circumstances that may precipitate such 
termination are: 
• Request by Health Authority to terminate the study. 
• Unsatisfactory subject enrollment with regard to quality or quantity. 
• Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects, maintain adequate study records or inaccurate, 
incomplete or late data recording on a recurrent basis. 
• The incidence or severity of AEs in this or other studies indicating a potential health hazard 
caused by the study treatment. 
14.1.1 
Study Supplies 
The sponsor will supply sufficient quantities of the following materials to each clinical center: 
• Oral decitabine + E7727 as described in Section 7.0. 
• Decitabine IV to Canadian study centers (see Section 14.2.2). 
• FDC tablet as described in Section 7.0. 
• Case Report Forms or data collection tools. 
14.1.2 
Investigator Training 
All study centers will have a center-specific study initiation meeting to ensure the center staff 
understand the protocol, study requirements, and data capture processes. This training will take 
place before the first subject is enrolled. Each study center will be provided with information 
regarding GCP and regulations specific to the conduct of clinical studies. Each center is 
responsible for ensuring that new team members are adequately trained and the training is 
documented. 
14.1.3 
Ongoing Communication of Safety Information during the Study 
The sponsor will provide the investigator with documentation of SAEs, from this study and other 
studies, that are related to Astex IMP and unexpected (see Section 10.3.1), as appropriate. The 
investigator must forward this documentation to the IRB/IEC, as described in Section 10.3.1. 


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The sponsor will also notify the investigator about any other significant safety findings that could 
alter the safety profile of the IMP from what is described in the protocol and significantly affect 
the safety of subjects, affect the conduct of the study, or alter the IRB/IEC’s opinion about 
continuation of the study. This does not include safety issues that could be mitigated by simple 
changes in the protocol decided by the DSRC (Section 4.4) such as limiting some of the eligibility 
criteria or reducing the IMP dose or dosing schedule. 
14.1.4 
Study Monitoring 
Representatives of Astex Pharmaceuticals will monitor the study. Routine monitoring visits will 
be conducted to: 
• Assure compliance with the study protocol and appropriate regulations. 
• Verify that (1) the informed consent process was conducted before initiation of any study-
specific procedures (i.e., 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 treatments are stored properly and under the proper conditions, that they are 
in sufficient supply, and that receipt, use, and return of oral decitabine + E7727 at the study 
centers are controlled and documented adequately. 
• Verify that the investigator and study center personnel remain adequately qualified throughout 
the study. 
• Verify that the research facilities, including laboratories and equipment, are maintained 
adequately to safely and properly conduct the study. 
14.1.5 
Study Auditing and Inspecting 
The sponsor may audit the study conduct, compliance with the protocol and accuracy of the data 
in one or more centers.  
The investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections by 
the sponsor, IRB/IEC, government regulatory bodies and Astex Pharmaceuticals Quality 
Assurance personnel or its designees by providing direct access to source data/documents after 
appropriate notification from sponsor. 


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14.2 
Investigator’s 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 
Decitabine, E7727, and FDC Tablet Accountability 
Initial supply of E7727 and decitabine capsules (ie, not decitabine IV) will be provided to US sites, 
as decitabine IV is commercially available in the US. However, E7727 and decitabine  
(capsules and IV) will be provided by Astex to Canadian sites, as decitabine IV is not approved in 
Canada. Thereafter, the study pharmacist is responsible for ordering resupplies. 
The FDC tablet will be supplied by Astex to all study centers. 
Keep E7727 and decitabine in a locked, limited-access room. The study treatment must not be 
used outside the context of the protocol. Under no circumstances should the investigator or other 
study center personnel supply E7727 or decitabine to other investigators, subjects, or clinics or 
allow supplies to be used other than as directed by this protocol without prior authorization from 
Astex Pharmaceuticals. 
The monitor will regularly review and verify all E7727 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 E7727 and/or decitabine and other 
study material is destroyed or returned to the sponsor on completion of the study. If E7727 and/or 
decitabine is destroyed at the study center, there should be documentation of destruction at the 
study center. The sponsor and/or their representatives will verify final drug accountability. Drug 
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 


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investigator should maintain documents not for submission to Astex Pharmaceuticals, (e.g., 
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. 
• 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 components samples which are collected as part of routine medical care or as 
part of protocol procedures may be stored and analyzed for PK or PD analyses.  
After the study, samples may be used for additional investigation to help identify factors that may 
influence response to therapy. Such samples will be used in compliance with guidelines defined 
by FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover 
Human Specimens that are Not Individually Identifiable (issued 25 April 2006) and European 
Agency for the Evaluation of Medicinal Products (EMEA)’s Reflection Paper on 
Pharmacogenomic Samples, Testing and Data Handling (EMEA 2007). Astex Pharmaceuticals, 
Inc. will not store study samples in a biobank. 
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 


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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. 
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 DSRC safety decisions for immediate implementation for safety reasons 
(Section 4.4).  
For all other changes, Astex Pharmaceuticals will initiate any change to the protocol in a protocol 
amendment document. The study center will submit the amendment to the IRB/IEC together with, 
if applicable, a revised model ICF. If the change in any way increases the risk to the subject, 
information on the increased risk must be provided to subjects already actively participating in the 
study, and they must read, understand and sign any revised ICF confirming willingness to remain 
in the study. 
The investigator must obtain IRB/IEC approval before any protocol amendment can be 
implemented, except for administrative changes or changes necessary to eliminate an immediate 
risk to study subjects, as outlined above. 
15.0 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The sponsor encourages the scientific publication of data from clinical research studies. However, 
investigators may not present or publish partial or complete study results individually without 


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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. Therapeutic advances in 
hematology. 2011;2(1):33-43. 
Bennett JM. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 
1982;51(2):189-99. 
Beumer J, Eiseman J, Gilbert J, Holleran J, Yellow-Duke A, Clausen D, et al. Plasma 
pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, 
triacetyl-THU (taTHU), in mice. Cancer Chemotherapy and Pharmacology. 2011;67(2):421-30. 
Beumer JH, Eiseman JL, Parise RA, Joseph E, Covey JM, Egorin MJ. Modulation of gemcitabine 
(2',2'-difluoro-2'-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 
3,4,5,6-tetrahydrouridine. Clin Cancer Res. 2008;14(11):3529-35. 
Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, et al. Pharmacokinetics, 
metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2'-
deoxycytidine in mice. Clin Cancer Res. 2006;12(24):7483-91. 
Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, et al. Concentrations 
of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) and its cytotoxic 
metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer 
Chemother Pharmacol. 2008;62(2):363-8. 
Chabot GG, Bouchard J, Momparler RL. Kinetics of deamination of 5-aza-2'-deoxycytidine and 
cytosine arabinoside by human liver cytidine deaminase and its inhibition by 3-deazauridine, 
thymidine or uracil arabinoside. Biochem Pharmacol. 1983;32(7):1327-8. 
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):3671-4. 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood. 2006;108(2):419-25. 
Dacogen. Dacogen (decitabine for injection) Prescribing Information. 2014. 
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):2079-88. 
Heaney ML, Golde DW. Myelodysplasia. N Engl J Med. 1999;340(21):1649-60. 


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Kantarjian H, Estey E. Myelodysplastic syndromes. 6th ed. DeVita VT, Hellman S, Rosenberg 
SA, editors: Lippincott Williams & Wilkins; 2001. 
Karahoca M, Momparler RL. Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-
deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clinical 
epigenetics. 2013;5(1):3. 
Mistry B, Jones M, Kubiak P. A phase 1 study to assess the absolute bioavailability and safety of 
an oral solution of decitabine in subjects with Myelodysplastic Syndromes (MDS). Blood. 
2011;118:ABstract 3801. 
Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA, Garcia-Manero G, et al. Multicenter 
study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic 
syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 
2009;27(23):3842-8. 
Vidaza. Vidaza (azacitidine for injection) for SC or IV use. Prescribing information. 2016. 
 


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17.0 
APPENDICES 


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APPENDIX 1: 
COMMON TERMINOLOGY FOR ADVERSE EVENTS V4.0 
(CTCAE V4.0) 
For links to the NCI-CTCAE version 4, refer to 
HTTP://CTEP.CANCER.GOV/PROTOCOLDEVELOPMENT/CODES_VALUES.HTM#CTC 


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APPENDIX 2: 
SCHEDULE OF PHARMACOKINETIC ASSESSMENTS 
The schedule for PK assessments is shown in the tables on the following pages. 
 


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Pharmacokinetics Sampling Schedule for the Dose Escalation Stage 
Course 1 
Course 2 
Day -3 (±2) 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day 5 Day -3 (±2) 
Day  
1 
Day  
2 
Day  
3 
Day 4 
Day 5 
Study Treatment 
oral decitabine 
IV decitabine 
Oral decitabine + E7727 
E7727 
Oral decitabine + E7727 
Pre-dose (Time 0) 
x 
x 
x 
xa 
x  
x  
x 
 
 
 
 
 
Time point after dosing or start of 
infusion (hour): 
 
0.25 
x 
x 
x 
 
 
x 
x 
 
 
 
 
 
0.5 
x 
x 
x  
 
 
x  
x 
 
 
 
 
 
1 
x 
xb 
x 
 
 
x 
x 
 
 
 
 
 
1.083 (1 hour 5 min) 
 
xc 
 
 
 
 
 
 
 
 
 
 
1.5 
x 
x 
x 
 
 
x 
x 
 
 
 
 
 
2 
x 
x 
x 
 
 
x 
x 
 
 
 
 
 
3 
x 
x 
x 
 
 
x 
x 
 
 
 
 
 
4 
x 
x 
x 
 
 
x 
x 
 
 
 
 
 
6 
x 
x 
x 
 
 
x 
x 
 
 
 
 
 
8 
 
 
x 
 
 
x 
x 
 
 
 
 
 
24a 
 
 
xa 
 
 
 
xa 
 
 
 
 
 
a The pre-dose time point is same as 24-hour time point on previous day; the 24-hour time point is the same as the pre-dose time point on the following day. 
b The 1-hour sample should be taken immediately prior to the end of the decitabine infusion. 
c The 1-hour, 5-min sample should be taken 5 minutes after completion of the decitabine infusion. 
NOTE: PK evaluation includes decitabine, E7727, E7727-epimer, 
. 
NOTE: Volume per blood draw = 3 mL. Total blood draw for Course 1 + Course 2 = 156 mL. No more than 33 mL of blood will be drawn in any 24-hour period. Additional 
information regarding sample collection, processing, etc., will be provided in the laboratory manual. 
NOTE: PK sampling should take place within ±10% of the scheduled time point, not to exceed 1 hour at the 24-hour time point. 
 
 
 


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Pharmacokinetics Sampling Schedule for Dose Confirmation Stage 
Study Treatment 
IV decitabine in Course 1 
Oral Decitabine + E7727 in Course 2 
If randomized to  
sequence of 
Course 1: IV decitabine  
Course 2: oral decitabine + 
E7727 
 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Pre-dose  
(Time 0) 
x 
 
 
 
 
x 
xa 
x 
x 
x 
Time point after oral dose or  
start of infusion (hour): 
 
0.25 
x 
 
 
 
 
x 
x 
 
 
x 
0.5 
x 
 
 
 
 
x 
x 
x 
x 
x 
1 
xb 
 
 
 
 
x 
x 
x 
x 
x 
1.083  
(1 hour 5 min) 
xc 
 
 
 
 
 
 
 
 
 
1.5 
x 
 
 
 
 
x 
x 
 
 
x 
2 
x 
 
 
 
 
x 
x 
x 
 
x 
3 
x 
 
 
 
 
x 
x 
 
x 
x 
4 
x 
 
 
 
 
x 
x 
 
 
x 
6 
x 
 
 
 
 
x 
x 
 
 
x 
8 
 
 
 
 
 
x 
x 
 
 
x 
24a 
 
 
 
 
 
xa 
xa 
 
 
 
a The pre-dose time point is same as 24-hour time point on previous day; the 24-hour time point is the same as the pre-dose time point on the following day. 
b The 1-hour sample should be taken immediately prior to the end of the decitabine infusion. 
c The 1-hour, 5-min sample should be taken 5 minutes after completion of the decitabine infusion. 
NOTE: PK evaluation includes decitabine and E7727 (required) and E7727-epimer and cytidine (if needed) - in Dose-Confirmation Stage when receiving the oral combination. 
NOTE: Volume per blood draw = 3 mL. The total blood volume planned for Course 1 + Course 2 = ~150 mL. The blood draw schedule may be modified during Dose 
Confirmation to eliminate certain days and/or time points. The total number of blood draws in Dose Confirmation will not increase from the above schedule but may decrease 
after assessment of PK data from the first 12-24 subjects. Additional information regarding sample collection, processing, etc., will be provided in the laboratory manual. 
NOTE: PK sampling should take place within ±10% of the scheduled time point, not to exceed 1 hour at the 24-hour time point. 


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Pharmacokinetics Sampling Schedule for Dose Confirmation Stage 
Study Treatment 
Oral Decitabine + E7727 in Course 1 
IV decitabine in Course 2 
If randomized to  
sequence of 
Course 1: Oral decitabine + 
E7727  
Course 2: IV decitabine 
 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Pre-dose 
(Time 0) 
x 
xa 
x 
x 
x 
x 
 
 
 
 
Time point after oral dose or start of 
infusion (hour): 
 
0.25 
x 
x 
 
 
x 
x 
 
 
 
 
0.5 
x 
x 
x 
x 
x 
x 
 
 
 
 
1 
x 
x 
x 
x 
x 
xb 
 
 
 
 
1.083  
(1 hour 5 min) 
 
 
 
 
 
xc 
 
 
 
 
1.5 
x 
x 
 
 
x 
x 
 
 
 
 
2 
x 
x 
x 
 
x 
x 
 
 
 
 
3 
x 
x 
 
x 
x 
x 
 
 
 
 
4 
x 
x 
 
 
x 
x 
 
 
 
 
6 
x 
x 
 
 
x 
x 
 
 
 
 
8 
x 
x 
 
 
x 
 
 
 
 
 
24a 
xa 
xa 
 
 
 
 
 
 
 
 
a The pre-dose time point is same as 24-hour time point on previous day; the 24-hour time point is the same as the pre-dose time point on the following day. 
b The 1-hour sample should be taken immediately prior to the end of the decitabine infusion. 
c The 1-hour, 5-min sample should be taken 5 minutes after completion of the decitabine infusion. 
NOTE: PK evaluation includes decitabine and E7727 (required) and E7727-epimer and cytidine (if needed) - in Dose-Confirmation Stage when receiving the oral combination. 
NOTE: Volume per blood draw = 3 mL. Total blood volume planned for Course 1 + Course 2 = ~150 mL. The blood draw schedule may be modified during Dose Confirmation to 
eliminate certain days and/or time points. The total number of blood draws in Dose Confirmation will not increase from the above schedule but may decrease after assessment 
of PK data from the first 12-24 subjects. Additional information regarding sample collection, processing, etc., will be provided in the laboratory manual. 
NOTE: PK sampling should take place within ±10% of the scheduled time point, not to exceed 1 hour at the 24-hour time point. 
 
 


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Pharmacokinetics Sampling Schedule for FDC Stage 
Study Treatment 
IV decitabine in Course 1 
FDC in Course 2 
If randomized to  
sequence of 
Course 1: IV decitabine  
Course 2: FDC tablet 
 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Pre-dose  
(Time 0; within 1 hour pre-dose) 
x 
 
 
 
 
x 
xa 
x 
x 
x 
Time point after oral dose or start  
of infusion (hour) and window: 
 
0.25 (15 ± 1.5 min) 
x 
 
 
 
 
x 
 
 
 
x 
0.5 (30 ± 3 min) 
x 
 
 
 
 
x 
 
 
 
x 
1 (within 5 min before completion  
of IV infusion - see Tasks below) 
xb 
 
 
 
 
x 
 
 
 
x 
1.083  
(5 min + 0.5 min)  
xc 
 
 
 
 
 
 
 
 
 
1.5 (30 min ± 3 min) 
x 
 
 
 
 
x 
 
 
 
x 
2 (± 12 min) 
x 
 
 
 
 
x 
 
 
 
x 
3 (± 18 min) 
x 
 
 
 
 
x 
 
 
 
x 
4 (± 24 min) 
x 
 
 
 
 
x 
 
 
 
x 
6 (± 36 min) 
x 
 
 
 
 
x 
 
 
 
x 
8 (± 48 min) 
 
 
 
 
 
x 
 
 
 
x 
24a  
 
 
 
 
 
xa 
 
 
 
 
a The pre-dose time point is same as 24-hour time point on previous day; the 24-hour time point is the same as the pre-dose time point on the following day. 
b Obtain the 1-hour sample at the end of infusion: the sample should be collected during the final 5 minutes of infusion while drug is being administered. Do not obtain after the 
infusion has stopped. (2) Conclude the infusion as soon as practically possible after the sample has been obtained; disconnect the drug infusion bag, bolus flush drug out of the 
line with IV fluid, and start a drug-free drip. (3) Start the clock for post infusion immediately after the flush. 
c The 1-hour, 5-min sample should be taken 5 minutes after completion of the decitabine infusion. 
NOTE: Volume per blood draw = 3 mL. The total blood volume planned for Course 1 + Course 2 = ~105 mL. The blood draw schedule may be modified during this stage to 
eliminate certain days and/or time points. The total number of blood draws will not increase from the above schedule but may decrease after assessment of PK data from the 
first 12-18 subjects. Additional information regarding sample collection, processing, etc., will be provided in the laboratory manual. 
NOTE: PK sampling should take place within ±10% of the scheduled time point, not to exceed 1 hour at the 24-hour time point. 
 


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Pharmacokinetics Sampling Schedule for FDC Stage 
Study Treatment 
FDC in Course 1 
IV decitabine in Course 2 
If randomized to  
sequence of 
Course 1: FDC tablet  
Course 2: IV decitabine 
 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day  
5 
Pre-dose  
(Time 0; within 1 hour pre-dose) 
x 
xa 
x 
x 
x 
x 
 
 
 
 
Time point after oral dose or start  
of infusion (hour) and window: 
 
0.25  (15 ± 1.5 min) 
x 
 
 
 
x 
x 
 
 
 
 
0.5 (30 ± 3 min) 
x 
 
 
 
x 
x 
 
 
 
 
1 (within 5 min before completion of  
IV infusion - see Tasks below) 
x 
 
 
 
x 
xb 
 
 
 
 
1.083  
(5 min + 0.5 min)  
 
 
 
 
 
xc 
 
 
 
 
1.5 (30 min ± 3 min) 
x 
 
 
 
x 
x 
 
 
 
 
2 (± 12 min) 
x 
 
 
 
x 
x 
 
 
 
 
3 (± 18 min) 
x 
 
 
 
x 
x 
 
 
 
 
4 (± 24 min) 
x 
 
 
 
x 
x 
 
 
 
 
6 (± 36 min) 
x 
 
 
 
x 
x 
 
 
 
 
8 (± 48 min) 
x 
 
 
 
x 
 
 
 
 
 
24a  
xa 
 
 
 
 
 
 
 
 
 
a The pre-dose time point is same as 24-hour time point on previous day; the 24-hour time point is the same as the pre-dose time point on the following day. 
b Obtain the 1-hour sample at the end of infusion: the sample should be collected during the final 5 minutes of infusion while drug is being administered. Do not obtain after the 
infusion has stopped. (2) Conclude the infusion as soon as practically possible after the sample has been obtained; disconnect the drug infusion bag, bolus flush drug out of the 
line with IV fluid, and start a drug-free drip. (3) Start the clock for post infusion immediately after the flush. 
c The 1-hour, 5-min sample should be taken 5 minutes after completion of the decitabine infusion. 
NOTE: Volume per blood draw = 3 mL. The total blood volume planned for Course 1 + Course 2 = ~105 mL. The blood draw schedule may be modified during this stage to 
eliminate certain days and/or time points. The total number of blood draws will not increase from the above schedule but may decrease after assessment of PK data from the 
first 12-18 subjects. Additional information regarding sample collection, processing, etc., will be provided in the laboratory manual. 
NOTE: PK sampling should take place within ±10% of the scheduled time point, not to exceed 1 hour at the 24-hour time point. 
 
 


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APPENDIX 3: 
ECOG AND KARNOFSKY PERFORMANCE STATUS 
Score 
ECOG Description 
Score 
Karnofsky Description 
0 
Fully active, able to carry on all predisease 
performance without restriction 
100 
Normal: no complaints, no evidence of 
disease 
90 
Able to carry on normal activity; minor 
symptoms 
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; some 
symptoms 
70 
Cares for self; unable to carry on normal 
activities 
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 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: hospitalized but death 
not imminent 
4 
Completely disabled. Cannot carry on any 
self-care. Totally confined to bed or chair 
20 
Very sick: active supportive care needed 
10 
Moribund: fatal processes are progressing 
rapidly 
5 
Dead 
0 
Dead 
Sources: 
ECOG Performance Status — http://www.ecog.org/general/perf_stat.html (accessed August 30, 2007). 
Karnofsky Performance Status — http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/ 
neurology/braintumor/table3.htm (accessed February 11, 2008). 
 


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APPENDIX 4: 
SUMMARY OF CHANGES, AMENDMENT 1 
Rationale for Amendment 1: 
The following main changes have been made in Amendment 1 to facilitate arrival at an optimal 
dose earlier during the course of the trial, to reduce subject exposure to subtherapeutic doses, and 
to reduce the burden of assessments: 
• The study design has been modified from a 6+6 design to a 3+3 design to allow dose escalation 
if the PK data are consistent across the first 3 subjects in a given cohort and no DLTs are 
observed. At least another 3 subjects are to be enrolled in that cohort if the PK data are variable 
across the first 3 subjects or if 1 DLT occurs. The Data and Safety Review Committee will 
continue to conduct routine review of safety and PK data. 
• The requirement for hematology assessments has been eliminated on Days 2-5 in Course 1 and 
Course 2, as weekly hematology assessments are sufficient with decitabine therapy. 
Hematology will continue to be assessed on Days 1, 8, 15, and 22 of the first 2 courses. 
Summary of Changes: 
Typographical errors have been corrected and minor changes to the text that have been made for 
clarity are not summarized below. 
1) Header: IND number removed, as some study centers are ex-US. 
2) PROTOCOL TITLE PAGE: EudraCT Number added. 
3) PROTOCOL SYNOPSIS:  
a) Study Centers Planned/Country: Canada added. 
b) Study Design and Investigational Plan: Dose Escalation Stage: changed from 6+6 to 3+3. 
c) Sample Size and Statistical Analyses: Clarification made that when the AUC range for a 
3-subject cohort is between 0.90-1.10 of IV decitabine, and no more than 1 DLT has 
occurred, additional evaluable subjects may be added (for up to 12-18 in that cohort). 
d) Study Duration and Termination: duration of the Dose Escalation Stage revised to 
12 months. 
4) Section 4.1.1: changed to 3+3 design; modified to reflect the change from 6+6 to 3+3. 
Additional subjects may be added to reach a total of up to 12-18 subjects in a cohort for robust 
assessment of AUC range and safety before moving to the Dose Confirmation Stage. 
5) Figure 2: revised in accordance with changes to study design. 
6) Section 4.2: changed to 3+3 design. 
7) Section 4.4: change made to allow DSRC to increase a cohort size to a total of up to 12-18 
additional subjects.  


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8) Section 5.1: changed to 3+3 design. 
9) Section 5.2: Inclusion criterion 4a clarified to indicate omission of AST assessment will not be 
considered a protocol deviation. 
10) Table 4: Schedule of Events:  
a) Physical exam: required on Days 2-5 only if subject is visiting the clinic for study purposes. 
b) Vital signs: required on Days 2-5 only if subject is visiting the clinic for study procedures. 
c) Concomitant medications and transfusion requirements: may be assessed on Days 2-5 if 
subject is visiting the clinic for study procedures. 
d) Hematology: assessments on Days 2-5 in Course 1 and Course 2 removed. 
11) Section 9.4.3.3: Clarification made that the indicated assessments are to be done on days the 
subject comes to the clinic for IV decitabine or PK assessments. Collection of hematology 
samples has been removed. 
12) Section 9.4.3.5: Clarification made that symptom-directed physical exam and vital signs may 
be completed if subject is visiting the clinic for study procedures. 
13) Section 9.4.4: Clarification made that symptom-directed physical exam and vital signs (Days 
2-5) may be completed if subject is visiting the clinic for study procedures. Collection of 
hematology samples on Days 2-5 has been removed. 
14) Section 11.1.1: Changed from 6+6 to 3+3 design. 
15) Section 11.9: Review of safety data changed from after every cohort of 6 to after every cohort 
of at least 3 subjects (during Dose Escalation). 
16) Section 12.0: Duration of Dose Escalation Stage revised to 12 months.  


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APPENDIX 5: 
SUMMARY OF CHANGES, AMENDMENT 2 
Rationale for Amendment 2: 
The following main changes have been made in Amendment 2: 
• Eliminate the Dose Confirmation – Open Label Expansion portion of the study. This portion 
may not add significant value, as PK, PD, efficacy, and safety will be adequately assessed in 
the randomized part of the Dose Confirmation Stage.  
• Obtain additional PK assessments on Days 2, 3, and 4 during the oral course of the Dose 
Confirmation Stage to enable estimation of PK over 5 dosing days. This is prompted by the 
expected variation in decitabine PK levels after Day 1 of oral dosing compared with Days 2-
5, based on data from the Dose Escalation Stage. 
• Clarify that PK and PD data reviews by the DSRC will take place during the Dose 
Confirmation Stage to ensure that the doses of the 2 components of ASTX727 result in the 
desired PK and PD comparability with IV decitabine.  
• Incorporate items from Administrative Letters 2, 3, and 4: 
o Administrative Letter #2: Clarification that initial supplies of E7727 and decitabine 
(capsules and IV) will be provided to Canadian study centers, as decitabine IV is not 
approved in Canada. Clarification that subjects should take the IMPs simultaneously and 
at the same time of day (± 1 hour) on each dosing day. 
o Administrative Letter #3: Clarification to allow intra-patient dose escalation to a higher 
dose established as safe in a subsequent cohort. Instructions added for situations in which 
a dose is missed. 
o Administrative Letter #4: Clarification that study centers may follow a schedule according 
to local standard practice after Course 7 for bone marrow aspirate or biopsy to verify 
continuous response. 
Summary of Changes: 
Typographical errors have been corrected and minor changes to the text that have been made for 
clarity are not summarized below. 
1) PROTOCOL TITLE PAGE and SPONSOR AND INVESTIGATOR SIGNATURE 
PAGE: Address for Astex Pharmaceuticals, Inc. updated. Medical Monitor information 
updated. 
2) PROTOCOL SYNOPSIS: 
• Dose Confirmation Stage – Open-Label Expansion eliminated. 
• Dose Confirmation Stage Primary Objectives: Clarification that mean oral decitabine AUC 
will be estimated from 5 days of dosing. 


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• Inclusion Criterion #2: a, b, and c removed. 
• Dose Confirmation Stage Primary Endpoint – Clarification that mean decitabine AUC will 
be an estimate over 5 dosing days. 
• Sample size for Dose Escalation Stage: Revised from 1 DLT in 12 subjects to 1 DLT in 6 
subjects. 
• Sample Size for Dose Confirmation Stage – Changed to at least 42 subjects at the final 
recommended dose combination. 
• Interim Analysis: Text added to indicate that ongoing data review will be performed by the 
Data and Safety Review Committee (DSRC). 
3) Section 3.4, Dose Confirmation Stage – Primary Objectives: Clarification that the mean 
oral decitabine AUC will be estimated from 5 days of dosing. 
4) Section 4.1.1, Dose Escalation Stage, Dosing for Cohort ≥2: Modified to allow intra-patient 
dose escalation for subjects who are still on treatment at lower dose levels in the Dose 
Escalation Stage once higher levels are deemed to be safe by DSRC review. 
5) Figure 2, Dose Escalation Stage Algorithm: Updated to align with amendment. 
6) Figure 3, Dose Confirmation Stage Schema: Updated to align with amendment (Open-label 
expansion removed). 
7) Section 4.2, Discussion of Study Design: Clarification that estimated PK over 5 days of 
dosing will be used to compare oral combination and IV decitabine. Open-label expansion text 
removed. 
8) Section 4.3.4, Dose Confirmation Stage – Primary Endpoints: Clarification that mean 
decitabine AUC will be an estimate over 5 dosing days.  
9) Section 4.4, Data Safety and Review Committee (DSRC): New text added (last paragraph) 
to indicate the DSRC will review safety, PK, and PD data during the Dose Confirmation Stage 
and determine a final dose combination. 
10) Section 5.1, Number of Subjects and Centers: Text modified to at least 42 subjects at the 
final recommended dose combination. 
11) Section 5.2, Inclusion Criteria, #2: a, b, and c removed. 
12) Section 5.2, Inclusion Criteria, #4a: “Omission of AST assessment at screening or during the 
study is not considered a protocol deviation” removed. 
13) Section 7.1.2, Storage: New statement added as 1st paragraph for clarification: “The IV 
decitabine drug product is sourced from commercial supplies and should be stored according 
to institutional policy and the manufacturer's label.” 
14) Section 7.1.5, Missed Doses: New section added to describe the procedure in the event a dose 
is missed. 


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15) Section 7.2, Active Comparator or Placebo: Statement added to indicate that decitabine IV 
will be provided by Astex as an IMP in Canada (as decitabine is not currently approved in 
Canada). 
16) Section 9.1, Efficacy Assessments: Clarified to indicate that after Course 7, bone marrow 
aspirates may be performed according to a schedule that is standard practice at the study center. 
17) Section 9.2.1.3, Dose Confirmation Stage: PK assessments have been added to Day 2, Day 
3, and Day 4, with additional explanatory text. 
18) Table 3, Dosing Schedule by Stage and Course: Dose Confirmation Stage – Open Label 
Expansion information has been removed. 
19) Table 4, Schedule of Events: Footnote ‘w’: wording modified to align with Administrative 
Letter #4. 
20) Table 6, Day 1 Assessments: Dose Confirmation Stage – Open Label Expansion column 
removed. 
21) Section 9.4.5.1, Course ≥3, Days 1-5 – Dose Escalation Stage and Dose Confirmation 
Stage: Bone marrow aspirate or biopsy: Revised to indicate that after Course 7, study centers 
may assess according to a schedule that is standard of care at the center (this aligns with 
Administrative Letter #4). 
22) Section 11.1.2, Dose Confirmation Stage: revised from 84 to at least 42 subjects. 
23) Section 11.3, Schedule of Analysis: 2nd paragraph added to indicate that the DSRC will review 
data from the first 6-12 subjects with complete PK and PD data from Courses 1 and 2 to 
confirm the dose combination. 
24) Section 11.8.1, Pharmacokinetic Analyses: Statement added to 3rd paragraph to clarify that 
AUC will be estimated over 5 days of dosing. 
25) Section 11.9, Interim Analysis: Statement added to emphasize DSRC review during the Dose 
Confirmation Stage. 
26) Section 14.1.1, Study Supplies: Bullet added to indicate that IV decitabine will be provided 
by Astex to Canadian sites. 
27) Section 14.2.2, Decitabine and E7727 Accountability: Text added to clarify provision of 
IMPs. 
28) Section 14.2.5, Tissue and Blood Sample Collection/Storage: 2nd paragraph, last sentence 
added to clarify that Astex does not intend to store samples at a biobank. 
29) Appendix 2, Schedule of Pharmacokinetic Assessments: sampling schedule for Dose 
Confirmation Stage has been modified to include sampling on Days 2, 3, and 4. Total blood 
volume revised from 99 mL to ~150 mL for Courses 1 and 2. 


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APPENDIX 6: 
SUMMARY OF CHANGES, AMENDMENT 3 
Rationale for Amendment 3: 
The main changes described below have been made in Amendment 3 to add a third stage to the 
study to confirm the FDC tablet formulation yields PK and PD data similar to data for IV 
decitabine and to gather additional efficacy and safety data with the FDC in 18-24 subjects. 
In addition, the clarification made in Administrative Letter #5 has been incorporated: Inclusion 
Criterion #2 applies to subjects enrolled in all stages of the study, including the FDC Stage. 
The main changes in this amendment are listed below. Minor changes to the text that have been 
made for clarity are not listed. 
1) PROTOCOL SYNOPSIS:  
a. Investigational Medicinal Product: A description of the FDC tablet has been added. 
b. Dose Confirmation Stage – Exploratory Objective and Endpoint changed to: 
 
 
c. FDC Stage: Study Objectives added. 
d. Study Design and Investigational Plan: a description of the FDC Stage has been added. 
e. Study Treatment: Statement added that the FDC tablet is to be administered at the same 
time of day, with water, with the subject in a fasted state. 
f. Study Endpoints for the FDC Stage have been added. 
g. Sample Size and Statistical Analysis: Sample size justification for the FDC Stage has 
been added. 
h. Study Duration and Termination: Estimated duration (12 months) for the FDC Stage has 
been added. 
2) Abbreviations and Definitions: FDC has been added and defined. 
3) Section 1.3.3: Opening statement added to indicate that preliminary data from the study were 
used to inform the strength of the FDC tablet. 
4) Section 2.2: Statement added at end of section to indicate that preliminary data from the study 
were used to inform the strength of the FDC tablet. 
5) Sections 3.7, 3.8, 3.9: Primary, secondary, and exploratory objectives added, respectively, for 
the FDC Stage. 
6) Section 4.1: FDC Stage added to the opening sentence. 
7) Figure 2: CMML has been added to the ‘Dose Escalation Algorithm’ box. 
8) Figure 3: CMML has been added to the description of subjects. 
9) Section 4.1.3: A description of the FDC study design and investigational plan has been added. 
10) Figure 4: New figure added showing the study schema for the FDC Stage. 


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11) Section 4.2: A brief description of the goal of the FDC Stage has been added as the 4th 
paragraph. 
12) Section 4.3.6: Dose Confirmation Stage Exploratory Endpoint changed to: 
 
 
13) Sections 4.3.7, 4.3.8, 4.3.9: Study endpoints for the FDC Stage have been added. 
14) Section 4.4: Bullet statement added regarding the frequency with which the DSRC will meet 
to review data from the FDC Stage. 
15) Section 6.2: Explanation of randomization and the treatment groups for the FDC Stage, and 
statement added that subjects with CMML will be randomized in the IPSS-2/high-risk stratum 
(as IPSS risk level is not applicable to subjects with CMML). 
16) Section 7.1.1: A description of the FDC tablet has been added. 
17) Section 7.1.2: Storage instructions for the FDC tablet have been added. 
18) Section 7.3: Instructions for dose reduction have been added. 
19) Section 9.2.1.4: PK sampling schedule for the FDC Stage has been added. 
20) Section 9.2.2.3: LINE-1 DNA methylation assessment schedule for the FDC Stage added. 
21) Table 3: Dosing schedule for the FDC Stage has been added. 
22) Table 4: Title modified and PK sampling schedule for the FDC Stage added. Footnotes edited 
for clarification. 
23) Section 9.4.2: Bullet added to indicate that a portion of Screening bone marrow aspirates will 
be used for assessing 
. 
24) Table 6: Day 1 assessments for the FDC Stage have been added. 
25) Section 9.4.3.2: Study treatment administration instructions for the FDC Stage have been 
added. 
26) Section 9.4.3.3: Study treatment administration instructions for the FDC Stage have been 
added. 
27) Section 9.4.4: Study treatment administration instructions for the FDC Stage have been added. 
28) Section 9.4.5.1: Statement added to indicate that a portion of bone marrow aspirates will be 
used for assessing 
. 
29) Section 11.1.3: Sample size justification for the FDC Stage has been added. 
30) Section 11.3: Paragraph added to explain timing of data review in the FDC Stage. 
31) Section 11.6: ‘FDC tablet’ added where indicated. 
32) Section 11.8.1: ‘FDC tablet’ added where indicated, and range of the two-sided 80% CI of the 
mean AUC ratio in FDC Stage added. 


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33) Section 11.8.2: Statement added regarding upper bound of the two-sided 80% CI for the 
difference of mean maximum %LINE-1 demethylation between the FDC tablet and IV 
decitabine. 
34) Section 12.0: Estimated duration (12 months) for the FDC Stage has been added. 
35) Section 14.1.1: Bullet statement added to indicate information for FDC tablet is provided in 
Section 7.0. 
36) Section 14.2.2: Statement added after first paragraph to indicate FDC tablet will be supplied 
by Astex. 
37) Appendix 2: PK sampling schedules for the FDC Stage have been added. 


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APPENDIX 7: 
SUMMARY OF CHANGES, AMENDMENT 4 
Rationale for Amendment 4: 
Subjects ongoing in either the Dose Escalation Stage or Dose Confirmation Stage are allowed to 
transition from E7727 and oral decitabine capsules to the more convenient FDC tablet, which has 
the optimal dose combination of E7727 and decitabine that emulates the PK and PD of decitabine 
IV 20 mg/m2. The specified date of transition is based on the supply expiry date of the capsules. 
Clarification made in Administrative Letter #6 (dated 03 October 2016) has been incorporated: the 
8-hour time point for PK measurement on Day 1 of the IV decitabine course that erroneously 
appeared in the tables for “Pharmacokinetic Sampling Schedule for FDC Stage” in Appendix 2 
(Protocol Amendment 3) has been removed. 
The main changes in this amendment are listed below. (Typographical errors have been corrected.) 
PROTOCOL SYNOPSIS: 
Study Design and Investigational Plan: Information regarding transition from E7727 + 
decitabine capsules to the ASTX727 FDC tablet added for subjects ongoing in the Dose Escalation 
and Dose Confirmation Stages. 
Study Assessments and Procedures: Last paragraph: Language added for subjects transitioning 
from capsules to the FDC tablet. 
SECTION 4.0, INVESTIGATIONAL PLAN: 
Section 4.1.3: Explanation of transition from capsules to the FDC tablet given for subjects ongoing 
in the Dose Escalation Stage or Dose Confirmation Stage. 
SECTION 7.0, STUDY TREATMENTS: 
Section 7.3: 3rd paragraph: Clarification made that dose reductions are recommended to be done 
in consultation with the Astex medical monitor. 
Section 7.3: 4th paragraph: language added to indicate that dose reductions for subjects who 
transition from capsules to the ASTX727 tablet should follow the FDC dose reduction 
recommendations (ie, reducing the number of dosing days). 
SECTION 9.0, STUDY ASSESSMENTS AND PROCEDURES: 
Table 3: Dosing schedule added for transition from capsules to FDC tablet. 
SECTION 11.0, STATISTICS: 
Section 11.4: Statement added to describe disposition analysis for subjects who transition from 
capsules to the FDC tablet. 

SAP_001.pdf: 
CONFIDENTIAL
This document is a confidential communication of Astex Pharmaceuticals, Inc. Acceptance of the document 
constitutes agreement by the recipient that the contents will not be disclosed to any unauthorized personnel without 
the prior written authorization of Astex Pharmaceuticals, Inc.
ASTX727-01
Statistical Analysis Plan
(Phase 2 Dose Confirmation Stage and Fixed-Dose Combination Stage)
A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of 
ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with 
Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS)
Date: 08 August 2018
Based on: Protocol Version 5.0
NCT02103478


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AUTHORED BY:
APPROVED BY:


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TABLE OF CONTENTS
ABBREVIATIONS AND DEFINITIONS...................................................................................5 
1.0 
INTRODUCTION..............................................................................................................6 
1.1 
Myelodysplastic syndromes.....................................................................................6 
1.2 
Treatment Options ...................................................................................................6 
1.2.1 
Oral Decitabine and Cedazuridine (E7727)............................................7 
1.2.2 
ASTX727 Fixed-Dose Combination.......................................................7 
1.2.3 
Administration of ASTX727...................................................................7 
2.0 
STUDY OBJECTIVES......................................................................................................8 
2.1 
Dose Confirmation Stage – Primary Objectives......................................................8 
2.2 
Dose Confirmation Stage – Secondary Objectives..................................................8 
2.3 
Dose Confirmation Stage – Exploratory Objective .................................................8 
2.4 
Fixed-Dose Combination Stage – Primary Objectives............................................8 
2.5 
Fixed-Dose Combination Stage – Secondary Objectives........................................8 
2.6 
Fixed-Dose Combination Stage – Exploratory Objective .......................................8 
3.0 
STUDY DESIGN................................................................................................................8 
3.1 
Dose Confirmation Stage.........................................................................................8 
3.2 
Fixed-Dose Combination Stage...............................................................................9 
3.3 
Discussion of Study Design...................................................................................12 
3.4 
Study Endpoints.....................................................................................................12 
3.4.1 
Dose Confirmation Stage – Primary Endpoints....................................12 
3.4.2 
Dose Confirmation Stage – Secondary Endpoints................................12 
3.4.3 
Dose Confirmation Stage – Exploratory Endpoint ...............................12 
3.4.4 
Fixed-Dose Combination Stage – Primary Endpoints ..........................12 
3.4.5 
Fixed-Dose Combination Stage – Secondary Endpoints ......................12 
3.4.6 
Fixed-Dose Combination Stage – Exploratory Endpoints....................13 
3.5 
Data and Safety Review Committee......................................................................13 
4.0 
SAMPLE SIZE.................................................................................................................13 
4.1 
Dose Confirmation Stage.......................................................................................13 
4.2 
Fixed-Dose Combination Stage.............................................................................13 
5.0 
ANALYSIS SETS.............................................................................................................14 
5.1 
All Subject Analysis Set ........................................................................................14 
5.2 
Efficacy Analysis Set.............................................................................................14 
5.3 
Safety Analysis Set ................................................................................................14 
5.4 
Pharmacokinetics Analysis Set..............................................................................14 
5.5 
Pharmacodynamics and Biomarker Analysis Set ..................................................14 


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6.0 
SCHEDULE OF ANALYSES.........................................................................................14 
7.0 
STATISTICAL ANALYSIS ...........................................................................................15 
7.1 
Subject Disposition................................................................................................15 
7.2 
Demographic and Other Baseline Characteristics .................................................15 
7.3 
Efficacy Variables and Analyses ...........................................................................16 
7.3.1 
Response Rate.......................................................................................16 
7.3.2 
Overall Survival ....................................................................................17 
7.3.3 
Time to AML ........................................................................................17 
7.3.4 
Duration of Response............................................................................18 
7.3.5 
Transfusion Independence ....................................................................18 
7.4 
Safety Variables and Analyses...............................................................................19 
7.4.1 
Study Treatment and Exposure.............................................................19 
7.4.2 
Adverse Events......................................................................................19 
7.4.3 
Concomitant Medications .....................................................................20 
7.4.4 
Laboratory Tests....................................................................................20 
7.4.5 
Vital Signs.............................................................................................21 
7.4.6 
Electrocardiogram (ECG) .....................................................................21 
7.4.7 
ECOG Performance Status....................................................................21 
7.4.8 
Physical Examination............................................................................21 
7.5 
Pharmacokinetics Analysis....................................................................................21 
7.5.1 
AUC Equivalence Analysis ..................................................................22 
7.6 
Pharmacodynamic/Biomarker Analyses................................................................22 
7.7 
Handling of Missing Data and Other Data Anomalies..........................................22 
7.8 
Handling of Protocol Deviations ...........................................................................22 
8.0 
REFERENCES.................................................................................................................23 
 
LIST OF TABLES
Table 1: 
Modified IWG 2006 MDS Response Criteria ...........................................16 
 
LIST OF FIGURES
Figure 1: 
Dose Confirmation Stage Schema .............................................................10 
Figure 2: 
Fixed-Dose Combination Stage Schema ...................................................11 
 
LIST OF APPENDICES
Appendix 1: 
Implementation Guide For Response Assessment.....................................25
 


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ABBREVIATIONS AND DEFINITIONS
AE
adverse event
AML
acute myeloid leukemia
ANC
absolute neutrophil count
AUC
area under the curve
BQL
below the limit of quantification
BSA
body surface area
CDA
cytidine deaminase 
CDAi
cytidine deaminase inhibitor
CI
confidence interval
Cmax
maximum concentration
CMML
chronic myelomonocytic leukemia
CR
complete response
CRF/eCRF
case report form/electronic case report form
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DSRC
Data and Safety Review Committee
ECG
electrocardiogram
GI
gastrointestinal
HI
hematological improvement
HI-E
erythroid response 
HI-N
neutrophil response
HI-P
platelet response
HMA
hypomethylating agent
IPD
important protocol deviations
IPSS
International Prognostic Scoring System
IV
intravenous
IWG
International Working Group
LINE-1
long interspersed nucleotide elements-1
LVEF
left ventricular ejection fraction
mCR
marrow complete response
MDS
myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
OR
overall response
PD
pharmacodynamic(s)
pH
a measure of the acidity or alkalinity of an aqueous solution
PK
pharmacokinetic(s)
PR
partial response
PT
preferred term
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SDTM
Standard Data Tabulation Model
SOC
system organ class
TEAE
treatment emergent adverse event
THU
tetrahydrouridine
Tmax
time at which Cmax occurs
WHO
World Health Organization


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1.0
INTRODUCTION
This Statistical Analysis Plan (SAP) is based on ASTX727-01 protocol version 5 (dated 06 April 
2017). Analyses and statistical reporting for ASTX727-01 will be conducted by Astex 
Pharmaceuticals, Inc. (Astex) Biometrics department using SAS version 9.4 or higher. The study 
consists of 3 stages: Phase 1 Dose Escalation Stage, Phase 2 Dose Confirmation Stage, and Fixed-
Dose Combination Stage. This analysis plan describes the analyses only for Phase 2 Dose 
Confirmation Stage and Fixed-Dose Combination Stage.
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). Consecutive daily dosing for a minimum of 5 or 7 days in 
28-day cycles is the labelled administration schedule and is necessary to achieve the desired 
effects. Relapse rapidly occurs in responders whose HMA treatment is suspended (Cabrero et al 
2015). Treatment can therefore continue for several months or even years—a significant hardship 
for patients undergoing treatment because of the 5 to 7 clinic visits required each month, and the 
1-hour IV infusion or large volume of subcutaneous injection. A possible consequence is non-
compliance or early discontinuation of a beneficial treatment. More convenient oral administration 
of HMAs has historically proven difficult due to rapid metabolism by cytidine deaminase (CDA)


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during passage through the gastrointestinal (GI) mucosa and liver. To achieve even modest 
exposures of azacitidine requires administration of large doses, which are associated with Grades 
3 and 4 gastrointestinal 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 benefit the 
most.
1.2.1
Oral Decitabine and Cedazuridine (E7727)
Cedazuridine is a 2’-fluorinated analog of tetrahydrouridine (THU) and is a novel cytidine 
deaminase inhibitor (CDAi), developed for oral administration. The bioavailability of decitabine 
and of several other therapeutic cytidine analogs (eg, azacitidine, cytarabine, gemcitabine) is 
significantly limited by a rapid metabolism catalyzed by cytidine deaminase (CDA) which is highly 
expressed in the gut and liver. Cedazuridine is a potent CDAi with an IC50 of 0.281 ȝ0
Cedazurdine is also characterized by an improved stability at lower pH which has been a challenge 
with THU. 
Cedazuridine has negligible antiproliferative activity in human cancer cell lines, did not show any 
significant inhibition in a panel of 80 physiologically important human receptors and did not 
inhibit hERG potassium channel at up to 300 ȝ0 In vitro studies have also characterized an 
epimer of cedazuridine (ER-849726) that has about 1/10th the activity of cedazuridine as 
determined by an IC50 of 5 μM against human recombinant CDA. After oral dosing in preclinical 
toxicology models (mouse and monkey), near-equivalent levels were detected for circulating 
cedazuridine and its epimer.
1.2.2
ASTX727 Fixed-Dose Combination 
The fixed-dose combination (FDC) drug form of ASTX727 used in study ASTX727-01 is film-
coated, oval, white, immediate-release, fixed-dose combination of 100 mg cedazuridine and 35 mg 
decitabine for oral administration. 
1.2.3
Administration of ASTX727
ASTX727 was administered to subjects in the Dose Confirmation Stage initially as separate 
capsules of cedazuridine and decitabine. Subjects still on treatment with capsules as of 23 October 
2017 were permitted to transition to treatment with the ASTX727 FDC tablet at that time (at the 
discretion of the investigator), as new supplies of cedazuridine and decitabine capsules were not 
supported after the supply expiry date (31 October 2017). In the FDC Stage, ASTX727 was 
administered to subjects as FDC tablets.


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2.0
STUDY OBJECTIVES
2.1
Dose Confirmation Stage – Primary Objectives
x
Confirm the dose of oral decitabine + cedazuridine identified in the Dose Escalation Stage 
administered daily×5 that achieves mean decitabine AUC (estimated from 5 days of dosing) 
and LINE-1 DNA demethylation comparable to that of IV decitabine 20 mg/m2 daily×5.
x
Assess response rate in all subjects.
2.2
Dose Confirmation Stage – Secondary Objectives
x
Assess safety and tolerability of oral decitabine + cedazuridine.
x
Assess duration of response, hematological improvement, rate of transfusion independence, 
time to AML, and overall survival.
x
Evaluate other PK parameters of oral decitabine, cedazuridine, and cedazuridine-epimer (if 
needed).
2.3
Dose Confirmation Stage – Exploratory Objective
2.4
Fixed-Dose Combination Stage – Primary Objectives
x
Confirm the ASTX727 FDC tablet achieves mean decitabine AUC (estimated from 5 days of 
dosing) and LINE-1 DNA demethylation similar to that for IV decitabine 20 mg/m2 daily×5.
x
Assess response rate in all subjects. 
2.5
Fixed-Dose Combination Stage – Secondary Objectives
x
Assess safety and tolerability of ASTX727 FDC.
x
Assess duration of response, hematological improvement, rate of transfusion independence, 
time to AML, and overall survival.
x
Evaluate other PK parameters of ASTX727 FDC.
2.6
Fixed-Dose Combination Stage – Exploratory Objective
3.0
STUDY DESIGN
3.1
Dose Confirmation Stage
The Dose Confirmation Stage (Figure 1) involving at least 42 evaluable subjects was conducted 
to confirm the dose level of oral decitabine + cedazuridine established in the Dose Escalation 
Stage. Subjects were randomized to the sequence of:


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x
Oral decitabine + cedazuridine daily×5 in Course 1 followed by IV decitabine daily×5 in 
Course 2, or 
x
IV decitabine daily×5 in Course 1 followed by ASTX727 daily×5 in Course 2.
Beginning with Course 3 and all subsequent courses, subjects continued to receive ASTX727
daily×5 of a 28-day course until disease progression or unacceptable toxicity, or the subject 
withdrew consent or was withdrawn from the study.
At the conclusion of the Dose Escalation Stage, the Data and Safety Review Committee (DSRC)
made a decision on the fixed dose levels of cedazuridine (100 mg) and oral decitabine (35 mg) to 
be further investigated in the Dose Confirmation Stage.
Subjects ongoing in the Dose Confirmation Stage as of 23 October 2017 were transitioned from 
ASTX727 capsules to the ASTX727 FDC tablet.
3.2
Fixed-Dose Combination Stage
This stage is a comparison between a tablet form of ASTX727 and IV decitabine 20 mg/m2. After 
enrollment in the Dose Confirmation Stage had completed, 18-24 subjects were planned to be 
randomized and treated in a crossover study to confirm that the ASTX727 FDC yields PK 
exposures and DNA demethylation similar to those for IV decitabine.
Subjects were randomized in a 1:1 ratio to receive the FDC tablet daily×5 in Course 1 followed by 
,9GHFLWDELQHGDLO\îLQ&RXUVHRUWKHFRQYHUVH,Q&RXUVHVDOOVXEMHFWVUHFHLYHd the FDC 
tablet daily×5 (in a 28-day course) until disease progression or unacceptable toxicity or withdrawal 
from the study. See Figure 2.


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Figure 1:
Dose Confirmation Stage Schema
 
DOSE CONFIRMATION
(N ш42)
 Ŷу21
decitabine IV 
Course 1
Course 2
Course ш3
Randomization
nу42
Subjects with IPSS Intermediate-1 or -2, or 
High-Risk MDS, or CMML
 Ŷу21
decitabine IV 
Ŷу21
oral decitabine + 
E7727 
 Ŷу21
oral decitabine + 
E7727  
Ŷу42
oral decitabine + E7727
Continue E7727 + decitabine until disease progression or unacceptable toxicity occurs, 
or subject withdraws consent, or subject is withdrawn from the study


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Figure 2:
Fixed-Dose Combination Stage Schema
 
FIXED-DOSE COMBINATION STAGE SCHEMA 
(N = 18-24)
FDC tablet
daily x5
Course 1
Course 2
Course ш3
Randomization
Subjects with IPSS Intermediate-1 or -2, or 
high-risk MDS, or CMML
 FDC tablet
daily x5
decitabine IV
1-hr infusion
daily x5 
decitabine IV
1-hr infusion
daily x5 
FDC tablet
daily x5
Continue dosing with FDC tablet 
until disease progression or 
unacceptable toxicity occurs, or 
subject withdraws consent, or 
subject is withdrawn from the 
study


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3.3
Discussion of Study Design
In the Dose Confirmation Stage, the primary objective was to confirm that the doses of oral 
decitabine + cedazurdine identified in the Dose Escalation Stage given as a daily×5 oral dosing 
regimen achieve a mean AUC (estimated from 5 days of dosing) comparable to that of IV 
decitabine given daily×5 at the approved dose of 20 mg/m2. The standard 2×2 crossover design 
was chosen for the first two courses of the Dose Confirmation Stage in order to facilitate efficient 
evaluation of within-subject comparison of AUC between ASTX727 and IV decitabine. Because 
of the short half-life of decitabine, no appreciable carry-over effect of AUC is expected.
In the FDC stage, the goal was to confirm that the FDC tablet formulation is similar to IV 
decitabine in an intrapatient fashion and that PK and PD results are similar to results obtained with 
ASTX727 capsules in the Dose Confirmation Stage.
3.4
Study Endpoints
3.4.1
Dose Confirmation Stage – Primary Endpoints
x
Mean decitabine AUC (estimated from 5 days of dosing) and mean maximum %LINE-1
demethylation after oral decitabine + cedazuridine compared with IV decitabine 20 mg/m2.
x
Response rate in all subjects.
3.4.2
Dose Confirmation Stage – Secondary Endpoints
x
Incidence and severity grades of adverse events and clinically significant abnormal laboratory 
values.
x
Duration of response, hematological improvement, rate of transfusion independence, time to 
AML, and overall survival.
x
Other PK parameters of oral decitabine, cedazuridine, and cedazuridine-epimer (if needed).
3.4.3
Dose Confirmation Stage – Exploratory Endpoint
x
3.4.4
Fixed-Dose Combination Stage – Primary Endpoints
x
Mean decitabine AUC and mean maximum %LINE-1 demethylation after administration of 
ASTX727 FDC compared with IV decitabine 20 mg/m2.
x
Response rate in all subjects.
3.4.5
Fixed-Dose Combination Stage – Secondary Endpoints
x
Incidence and severity grades of AEs and clinically significant abnormal laboratory values.
x
Duration of response, hematological improvement, rate of transfusion independence, time to 
AML, and overall survival.
x
Other PK parameters of ASTX727 FDC.


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3.4.6
Fixed-Dose Combination Stage – Exploratory Endpoints
.
3.5
Data and Safety Review Committee 
The Data and Safety Review Committee (DSRC) comprised the principal investigators (or 
nominated deputies), medical monitor, study director, PK director, and other study team members 
as appropriate. In the Dose Confirmation Stage, the DSRC evaluated safety, PK, and PD data (1) to 
assess PK AUC and LINE-1 demethylation comparability between IV decitabine and the 
combination of cedazuridine + oral decitabine and (2) to determine the final oral dose combination. 
4.0
SAMPLE SIZE
4.1
Dose Confirmation Stage
At least 42 evaluable subjects were planned for enrollment into the Dose Confirmation Stage.
Forty-two evaluable subjects were needed to assess decitabine AUC (estimated from 5 days of 
dosing) and LINE-1 demethylation, using a standard 2×2 crossover design, between IV decitabine 
20 mg/m2 daily×5 and the recommended doses of oral decitabine + cedazuridine as determined in 
the Dose Escalation Stage. Evaluable subjects for this assessment of decitabine AUC and LINE-1
DNA demethylation were those who meet all the following criteria:
x
Complete the dosing regimens in Courses 1 and 2 with sufficient PK data available.
x
Have at least one bone marrow aspirate/biopsy after Course 2.
In an equivalence test of the mean decitabine AUCs of ASTX727 (estimated from 5 days of 
dosing) compared with IV decitabine using two one-sided tests on data from a 2×2 cross-over 
design, a sample size of 42 achieves 86% power at a 10% significance level when the true ratio of 
the means is 1.0, the coefficient of variation on the original, unlogged scale is 0.50 which was 
estimated from a previous study described in the Dacogen Prescribing Information (2014), and the 
equivalence limits of the mean ratio are 0.75 and 1.33.
This same sample size of 42 in the same 2×2 cross-over design achieves 80% power to detect the 
non-inferiority, with respect to the mean maximum %LINE-1 demethylation from baseline, of 
ASTX727 compared with IV decitabine using a one-sided t-test when the margin of non-inferiority 
is -0.05, the true mean difference is 0, the standard deviation (SD) is 0.15 and the significance 
level is 0.10. The SD of the paired differences of 0.15 was estimated from a previous Astex study.
4.2
Fixed-Dose Combination Stage
Subjects in a standard 2×2 crossover design were considered evaluable for equivalence analysis if 
those subjects complete treatment in Courses 1 and 2 with sufficient PK data. A total of 18-24 
evaluable subjects included in the 2 one-sided equivalence tests for mean oral decitabine AUC 
compared with mean IV decitabine AUC will provide 75%-88% power at a 10% significance level 


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when the true ratio of means is 1.0, the coefficient of variation under an unlogged scale is 0.55, 
and the equivalence limits for the ratio of means are 0.65 and 1.539.
The 18-24 subjects who completed Courses 1 and 2 with sufficient LINE-1 data in the same 
2×2 crossover design will provide 78%-86% power to detect non-inferiority, with respect to the 
mean maximum %LINE-1 demethylation from baseline, of the ASTX727 FDC tablet compared 
with IV decitabine using a one-sided t-test when the margin of non-inferiority is -0.075, the true 
mean difference is 0, the standard deviation (SD) is 0.15 and the significance level is 0.10.
5.0
ANALYSIS SETS
5.1
All Subject Analysis Set
This analysis set contains available data from all enrolled subjects, including those who did not 
receive any study treatment. This analysis set will be used for analysis of subject disposition. 
5.2
Efficacy Analysis Set
The Efficacy Analysis Set includes data from all enrolled subjects who received any amount of 
study treatment. 
5.3
Safety Analysis Set
The safety analysis set is the same as the Efficacy Analysis Set, which includes data from all 
enrolled subjects who received any amount of study treatment. In the safety analysis, no data 
exclusion will be allowed because of protocol deviations.
5.4
Pharmacokinetics Analysis Set
The PK Analysis Set will include data from all treated subjects for whom sufficient PK samples 
were collected to enable calculation of full AUCs on PK assessment days.
5.5
Pharmacodynamics and Biomarker Analysis Set
PD Analysis Set for LINE-1 methylation will be all subjects who received at least one course 
(Days 1-5) study treatment and had baseline and Day 8 or Day 15 LINE-1 methylation data. PD 
Analysis Set for other biomarkers will be based on those subjects who had biomarker data collected 
and analyzed.
6.0
SCHEDULE OF ANALYSES
In the Dose Confirmation Stage, the DSRC will review data from the first 6-12 subjects with 
complete PK and PD data from the first 2 courses to confirm the doses used for ASTX727 
components. 


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In the FDC Stage, data from subjects who have completed PK and PD data from Courses 1 and 2 
of the FDC Stage will be reviewed to confirm that data with the FDC tablet are similar to data with 
IV decitabine.
Formal analyses including all data to the data cutoff date June 05, 2018, in the Dose Confirmation 
Stage and the FDC Stage will be conducted for preparation of the clinical study report.
No formal interim analyses are planned for this study.
7.0
STATISTICAL ANALYSIS
Unless otherwise specified, all statistical tests and confidence intervals created will be two-sided 
with alpha = .05. The SAS® statistical package (version 9.4 or a later version) will be used for the 
analyses.
In general, the first dosing date is defined as the first date the subject received any study treatment.
Within each stage, subject disposition, demographics and baseline characteristics will be 
summarized by treatment sequence and both sequences combined. Adverse events will be 
summarized by actual treatment received (Section 7.4.2). Efficacy analyses, laboratory tests, vital 
signs, ECG, and ECOG performance status will be summarized with both treatment sequences 
combined. 
7.1
Subject Disposition
Subject disposition including numbers screened, treated, and treatment discontinuation by reason,
as well as the reasons for study exit (ie, death or reasons that subjects were not followed for 
survival status) will be summarized using frequencies and percentages according to study visit,
treatment discontinuation, and withdrawal from study case report form pages. Sample size for the 
Efficacy, Safety, PK, and PD Analysis sets will be clearly identified. Subjects in the All Subject 
Analysis Set will be included in the disposition analysis.
7.2
Demographic and Other Baseline Characteristics
The Efficacy Analysis Set, which is the same as the Safety Analysis Set (Section 5.1.2), will be 
used to summary demographic and baseline characteristics. The demographic variables consist of 
age, age category, sex, ethnicity, race, and geographical region. Baseline characteristics include 
height, weight, BSA, ECOG performance status, IPSS risk category, time since prior diagnosis,
cytogenetic risk levels, peripheral blood (including blasts) counts, and BM blasts.
Baseline values are generally the last value pre-dose collected on or before the first dosing date
unless otherwise specified.
Age at baseline, if not already provided through data collection, will be calculated as the integer 
part of (date of enrollment minus date of birth)/365.25. 


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Time since Diagnosis will be calculated as the (date of 1st dosing – date of diagnosis). If the day 
is missing for date of diagnosis, the 15th of the month will be used. If the month is missing, July 1st 
will be used. If the year is missing, the date will remain as missing. 
Subject demographic and baseline characteristics will be summarized by mean, standard deviation, 
median, minimum, and maximum for continuous variables; and by counts and percentages for 
categorical variables.
7.3
Efficacy Variables and Analyses
Efficacy analyses will be based on the Efficacy Analysis Set (Section 5.1.2).
7.3.1
Response Rate
The evaluation of response (Table 1) is based on IWG 2006 MDS Response Criteria (Cheson et al 
2006). Details of response assessments are described in Appendix 1.
Table 1:
Modified IWG 2006 MDS Response Criteria
Complete Response (CR): the following for 4 weeks
Peripheral: 1RUPDOSHULSKHUDOFRXQWVZLWKSHUVLVWHQWJUDQXORF\WHFRXQWî9/SODWHOHWî9/L and 
+JE g/dL.
Marrow: 1RUPDOERQHPDUURZZLWKSHUVLVWHQWPDUURZEODVWV3HUVLVWHQWG\VSODVLDZLOOEHQRWHG
Partial Response (PR): the following for 4 weeks
Peripheral: 1RUPDOSHULSKHUDOFRXQWVZLWKJUDQXORF\WHFRXQWî9/SODWHOHWFRXQWî9/L, and 
Hgb  g/dL.
Marrow: Normal bone marrow and marrow blasts >5%, but were reduced by 50% or more.
Marrow Complete Response (mCR): the following 4 weeks
5HGXFWLRQRIERQHPDUURZEODVWVWRDQGGHFUHDVHE\RUPRUHZLWKRXWQRUPDOL]DWLRQRISHULSKHUDO
counts.
Hematological Improvement (HI): lasts at least 8 weeks
Erythroid Response (HI-E):
Major 
Response:
HemRJORELQLQFUHDVHJG/or RBC transfusion 
independence 
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.
Neutrophil Response (HI-N):
Major 
Response:
*UDQXORF\WHLQFUHDVHDQGE\DQDEVROXWHLQFUHDVH
î9/L.
Baseline value is defined as the average of any values obtained before and on the first dosing date. 
If there is only one value before treatment then it will be used as the baseline value.
The following rates will be estimated using sample proportions and 95% Clopper-Pearson 
confidence interval based on the number of subjects in the Efficacy Analysis Set:
x
CR.


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x
PR.
x
mCR.
x
CR+PR+mCR.
x
CR+PR+mCR+HI.
x
HI (HI-E, HI-P or HI-N).
o
HI-E.
o
HI-P.
o
HI-N.
If adequate baseline 
 is available, responses will also be 
summarized by selected baseline 
. 
7.3.2
Overall Survival
Overall survival is defined as the number of days from the day the subject received the first dose 
of study treatment 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 in 
the Study Discontinuation CRF page, whichever is later.
The Kaplan-Meier plot will be provided based on the Efficacy Analysis Set. Estimated median 
survival and 95% confidence intervals will also be provided if available.
7.3.3
Time to AML
Time to AML is defined as the number of days from the day the subject received the first dose of 
study treatment WRWKHGDWHRI0'6SURJUHVVLRQWR$0/DVGHILQHGE\EODVWVLQERQHPDUURZ
or peripheral blood or death of any cause. The event date of time to AML will be based on the 
earliest date of following:
x
Death date.
x
AML conversion date defined as the earliest date of the following:
o
AML conversion date on the Conversion to AML CRF page.
o
AML conversion date on the Subject Information CRF page.
o
The first date when a record of EODVWV in bone marrow was reported or 2 consecutive 
records of EODVWV peripheral blood were reported.
Subjects without a time to AML event as described above will be censored on the date of last 
contact.


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The Kaplan-Meier plot for time to AML will be provided based on the Efficacy Analysis Set.
Estimated median survival and 95% confidence intervals will also be provided if available.
7.3.4
Duration of Response
Duration of response will be using Kaplan-Meir method only for responders separately for CR, 
PR, mCR, and CR+PR+mCR from the first time a response category (CR, PR, and mCR) is 
initiated, as addressed in the Implementation Guide of Response Assessment in Appendix 1, to the 
earliest date of disease progression defined as below:
x
Death date.
x
AML conversion as described in Section 7.3.3.
x
Disease progression date on the Subject Information CRF page.
x
Last treatment date if the reason for treatment discontinuation is Progressive Disease.
x
Study exit date on the Study Discontinuation CRF page if the reason for study discontinuation 
is Progressive Disease.
x
Date of disease progression on the Survival Follow-up CRF page.
In the absence of progressive disease, subjects will be censored on the last date of disease 
assessment including Survival Follow-up on which clearly shows progressive disease have not 
occurred. Subjects who receive alternative anti-cancer therapy for MDS/CMML or subsequent 
AML (except for bone marrow transplant) will also be censored on the last date of disease 
assessment as described above before receiving the alternative therapy or progressive disease,
whichever occurs earlier.
7.3.5
Transfusion Independence 
Transfusion dependence and independence is defined as follows:
x
Transfusion dependence at baseline: documentation of 2 units or more of transfusion within 
56 days of the first day of study treatment.
x
Post-treatment transfusion independence: no transfusion for 56 consecutive days or more after 
the first dose of study treatment.
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) divided by the number of subjects who were transfusion dependent 
at baseline (N). The 95% Clopper-Pearson confidence interval 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. 


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7.4
Safety Variables and Analyses
Safety Analysis will be performed using the Safety Analysis Set (Section 5.1.3). Safety will be 
assessed by subject-reported and investigator-observed AEs, along with physical examination, 
clinical laboratory tests (hematology, chemistries), vital signs, concomitant medications, and 
ECGs. Exposure to study treatment, reasons for discontinuation, deaths, and causes of deaths will
be tabulated.
7.4.1
Study Treatment and Exposure
The number of courses completed or partially completed per subject will be summarized using 
descriptive statistics. Frequency count and percentage of dose delayed courses reported by 
investigator will be calculated based on the total number of treatment courses all subjects received. 
Dose reduced courses, defined as the courses in which any investigator-assigned dose is lower than 
the dose level determined in the Dose Escalation Stage (100 mg for cedazuridine and 35 mg for 
decitabine), will be summarized using frequency count and percentage based on the total number 
of courses all subjects received. Subject follow-up time will also be summarized using mean, 
standard deviation, median, and range.
7.4.2
Adverse Events
Adverse event (AE) terms reported by study subjects or observed by investigators will be mapped 
to the appropriate System Organ Class (SOC) and Preferred Term (PT) according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Severity of AE will be graded using Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Treatment-emergent AEs (TEAEs) are defined as events that first occurred or worsened, after the 
first dose of study treatment until 30 days after the last dose of study treatment or the start of a 
post-treatment alternative anti-cancer treatment for MDS/chronic myelomonocytic leukemia
(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 Astex 
Data Programming Conventions.
All AE data collected in the study database will be listed, 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  $( OHDGLQJ WR WUHDWPHQWGLVFRQWLQXDWLRQDQ\6$( and subcategories of SAEs
(death vs not death) will be produced. 


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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 for each stage:
x
IV decitabine.
x
ASTX727 (ie, oral decitabine + cedazuridine for Dose Confirmation Stage or ASTX727 FDC 
for Fixed-dose Combination Stage) in Cycle 1 or Cycle 2.
x
ASTX727 in Cycle 3 or later.
x
Total for ASTX727.
x
Total for the Stage.
The number and percentage of subjects experiencing AEs will be summarized by MedDRA SOCs 
(sorted alphabetically) with PTs sorted alphabetically within each SOC, and by CTCAE grade. 
The number and percentage of subjects experiencing AEs will also be summarized by PT and 
sorted by event frequency. Related AEs, serious AEs (SAEs), and related SAEs will be 
summarized similarly. In summarizing AEs, 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.
7.4.3
Concomitant Medications
Concomitant medications are the medications taken with a start date on or after the start of the 
administration 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.
7.4.4
Laboratory Tests 
Laboratory values will also be graded, if possible, by CTCAE v4.0 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.
/DERUDWRU\YDOXHVUHFRUGHGDVDQLQWHUYDOVXFKDV[[RUZLOOEHKDQGOHGLIQHFHVVDU\
for calculation purposes, following the data programming standards as detailed in the Astex Data 
Programming Conventions.


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7.4.5
Vital Signs
Vital Signs will be summarized by visit and treatment sequence using proportion of subjects with 
each vital sign being too high or too low according to conventionally accepted vital sign normal 
ranges as following:
x
Pulse rate 110 bpm or greater.
x
Pulse rate 50 bpm or less.
x
Diastolic blood pressure 110 mmHg or greater.
x
Diastolic blood pressure 55 mmHg or less.
x
Systolic blood pressure 180 mmHg or greater.
x
Systolic blood pressure 80 mmHg or less.
x
Respiration rate 20 breaths/min or greater.
x
Body temperature 39°C or greater.
7.4.6
Electrocardiogram (ECG)
QTc values will be graded (grade 1, 2, DQGbased on CTCAE 4.0, and the shift table showing 
the shift from baseline grade to the worst grade, and from baseline grade to the last available grade 
will be provided.
7.4.7
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.
7.4.8
Physical Examination
Physical examination data will be preserved in a Study Data Tabulation Model (SDTM) dataset.
No particular analysis will be conducted.
7.5
Pharmacokinetics Analysis
The PK Analysis Set (Section 5.1.4) will be used for analysis of all PK parameters. PK parameters 
of decitabine, cedazuridine, and cedazuridine-epimer will be derived for each subject using a non-
compartmental approach. The details of PK analysis plan will be covered under a separate PK 
Analysis Plan document.


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7.5.1
AUC Equivalence Analysis
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. 
This analysis will be based on actual treatment. Subjects without 5-day AUC0-t data in both of 
ASTX727 and IV decitabine will not be included.
7.6
Pharmacodynamic/Biomarker Analyses
The PD and Biomarker Analysis Set (Section 5.1.5) will be used for analyses of LINE-1
methylation and other biomarkers. All data will be summarized descriptively (using mean, 
standard deviation, median, and range for continuous variables and counts and percentages for 
categorical variables) by treatment sequence and visit for each biomarker. 
Maximum %LINE-1 demethylation (defined as the largest percent decrease from baseline in 
methylation values within a subject between Day 8 and Day 22 of each treatment course) will be 
analyzed separately for Course 1 and Course 2 with baseline methylation defined as below:
x
For Course 1, baseline is defined as last value obtained before or on Day 1 pre-dose.
x
For Course 2, baseline is defined as the value obtained on Day 1.
Within each course, subjects to be included for analysis need to complete whole course of 
treatment. The 95% CIs for the difference of mean maximum %LINE-1 demethylation between 
ASTX727 and IV decitabine will be generated using an analysis of variance (ANOVA) model 
separately for Course 1 and Course 2.
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 last evaluation.
7.8
Handling of Protocol Deviations
Important Protocol Deviations (IPDs) categories will be defined by the study team during the IPD 
reviews throughout the study prior to the data lock date. IPD will be tabulated by IPD category 
and listed.


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8.0
REFERENCES
Bejanyan N, Sekeres MA. The revolution of myelodysplastic syndromes. Therapeutic advances in 
hematology. 2011;2(1):33–43.
Bennett JM. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 
1982;51(2):189–199.
Beumer J, Eiseman J, Gilbert J, Holleran J, Yellow-Duke A, Clausen D, et al. Plasma 
pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, 
triacetyl-THU (taTHU), in mice. Cancer Chemother Pharmacol. 2011;67(2):421–430.
Beumer JH, Eiseman JL, Parise RA, Joseph E, Covey JM, Egorin MJ. Modulation of gemcitabine 
(2',2'-difluoro-2'-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 
3,4,5,6-tetrahydrouridine. Clin Cancer Res. 2008;14(11):3529–3535.
Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, et al. Pharmacokinetics, 
metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2'-
deoxycytidine in mice. Clin Cancer Res. 2006;12(24):7483–7491.
Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, et al. Concentrations 
of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) and its cytotoxic 
metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer 
Chemother Pharmacol. 2008;62(2):363–368.
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.
Chabot GG, Bouchard J, Momparler RL. Kinetics of deamination of 5-aza-2'-deoxycytidine and 
cytosine arabinoside by human liver cytidine deaminase and its inhibition by 3-deazauridine, 
thymidine or uracil arabinoside. Biochem Pharmacol. 1983;32(7):1327–1328.
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(2):419–425.
Dacogen. Dacogen (decitabine for injection) Prescribing Information. 2014.


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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.
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.
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.
Kantarjian H, Estey E. Myelodysplastic syndromes. 6th ed. DeVita VT, Hellman S, Rosenberg 
SA, editors: Lippincott Williams & Wilkins; 2001.
Karahoca M, Momparler RL. Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-
deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin Epigenetics. 
2013;5(1):3. 
Longo DL et al. 2011. Harrison's principles of internal medicine (18th edition). New York: 
McGraw-Hill Medical Publishing Division.
Mistry B, Jones M, Kubiak P. A phase 1 study to assess the absolute bioavailability and safety of 
an oral solution of decitabine in subjects with Myelodysplastic Syndromes (MDS). Blood. 
2011;118:Abstract 3801. 
Shukron O, Vainstein V, Kündgen A, Germing U, Agur Z. Analyzing transformation of 
myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database.
Am J Hematol. 2012;87:853–860.
Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA, Garcia-Manero G, et al. Multicenter 
study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic 
syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 
2009;27(23):3842–3848.
Vidaza. Vidaza (azacitidine for injection) for SC or IV use. Prescribing information. 2012. 


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APPENDIX 1:
Implementation Guide For Response Assessment
The rules for determination of MDS responses and the corresponding durations of responses are 
described in the following sections. These rules are based on the “best” same-day blood counts 
(PB blasts, neutrophils, platelets, and Hgb) measured within a treatment course and the 
transfusion-free period requirement. The “best” was defined in the sense that blood count criteria 
were met for a particular response status. For BM blasts, if the current course did not have a BM 
evaluation, the immediately preceding BM evaluation was used.
Rules for CR
The subject must have one of the following baseline values to be eligible for a CR.
Hgb <11 g/dL
Platelets <100 × 109/L
Neutrophils <1.0 × 109/L
BM Blasts >5% 
PB Blasts >5%
To be a CR, the subject must have fulfilled all of the following blood count criteria (the same-day 
counts for PB blasts, neutrophils, platelets, and Hgb were required) and have been transfusion free,
with confirmation period 28 days:
+JE11 g/dL
3ODWHOHWV100 × 109/L
Neutrophils 1.0 × 109/L
%0%ODVWV
PB Blasts absent (no value of PB blasts in the database is interpreted as absent)
The start date of CR must have been >7 days after any RBC transfusion and >3 days after any 
platelet transfusion.
The duration of confirmation period for CR was calculated from the first time a subject fulfilled 
these criteria to the earliest time point when BM blasts became >5%, PB blasts > 0%, or when any 
of the blood counts no longer met the above criteria, the subject received an RBC or platelet 
transfusion, or the subject showed a clinical progression as determined by the investigator. 


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In determining duration of CR, if one measurement of BM blasts increased above the 5% level and 
then decreased to this level or lower without receiving an alternative treatment, the subject was
considered to have maintained WKHOHYHO
Rules for PR
To be a PR, subjects must have demonstrated all CR criteria with a relaxed requirement for BM 
blasts level. The BM blasts must have decreased by 50% or more compared with the pretreatment 
level but were still above 5%. The duration of confirmation period for PR is calculated from the 
first time a subject fulfilled these criteria to the earliest time point when BM blasts, peripheral 
blasts or any of the blood counts no longer met the above criteria, the subject received an RBC or 
platelet transfusion, or the subject showed a clinical progression as determined by the investigator.
Rules for mCR
To be eligible for mCR, subjects must have had a baseline BM blast >5%. An mCR could be 
GHFODUHGLISRVWWUHDWPHQW%0EODVWVEHFRPHand decreased by 50% over the pretreatment 
level with confirmation period 28 days until disease progression.
End of confirmation period for mCR was considered the earliest time point when BM blasts 
become >5% or a clinical progression was determined by the investigator. In determining duration 
of mCR, if one measurement of BM blasts were above the 5% level and then decreased to this 
level or lower without receiving an alternative treatment, the subject was considered to have 
maintained the 5% level.
Rules for CR+PR+mCR
Subjects who have CR, PR, or mCR will be considered a responder for CR+PR+mCR. The 
duration of CR+PR+mCR is measured from the initiation of CR, PR, or mCR, to the day that the 
subject do not meet criteria for CR, PR, and mCR.
Rules for HI-E
HI-E status was determined based on RBC transfusion and Hgb level at baseline and during the 
posttreatment period. To be eligible for HI-E, the subject must have had a baseline RBC 
transfusion dependence (any RBC transfusion within 4 weeks prior to C1D1) or had a baseline 
Hgb <11.0 g/L.  
For subjects with RBC transfusion dependence at baseline, an HI-E was declared if the subjects 
did not receive any RBC transfusion for a 56-day period of confirmation posttreatment, 
regardless of Hgb level.
For subjects without RBC transfusion dependence at baseline but with a baseline Hgb <11.0 g/L,
an HI-E was declared if subjects had an Hgb increase by 1.5 g/L for 56 days (at least one count 


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per course above threshold) and did not receive any RBC transfusions for 56 days. The start date 
of Hgb increase must have been >7 days after any RBC transfusion.
Duration of confirmation period for HI-E was calculated from the first time the HI-E criteria was
fulfilled until the subject no longer met the HI-E criteria or disease progression.
Rules for HI-P
To be eligible for HI-P, a subject had to have a baseline platelet count <100 × 109/L.  
To be considered an HI-P a subject had to remain independent of platelet transfusions, and have 
platelet counts meet the criteria as described below, for a 56-day period of confirmation 
posttreatment. The start date of response must have been >3 days after any platelet transfusion.
x
If the baseline platelet count was <20 × 109/L, the count must have increased to 20 × 109/L 
and by at least 100%.
x
If the baseline count was 20 × 109/L, the count must have increased by 30 × 109/L.
The duration of confirmation period for HI-P was calculated from the first time the HI-P criteria 
was fulfilled until the subject no longer met the HI-P criteria or disease progression.
Rules for HI-N
G-CSF or GM-CSF was not to be administered. Clinical review of concomitant medication data 
listings was conducted to confirm that there were no such instances of subject use.
The subject must have had a baseline ANC of <1.0 × 109/L to be eligible for an HI-N response.  
To have a response, ANC must have increased by ZLWKDQDEVROXWHLQFUHDVHRI × 109/L 
and been maintained for a 56-day period of confirmation (at least one count per course above 
threshold).
The duration of confirmation period for HI-N was calculated from the first time the HI-N criteria 
was fulfilled until the subject no longer met the HI-N criteria or disease progression.


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. 
ASTX727-01 
Statistical Analysis Plan  
(Phase 1 Dose Escalation Stage) 
A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of 
ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with 
Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS) 
Date: 12 July 2017 
Based on: Protocol Version 5.0 
NCT02103478


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AUTHORED BY: 
APPROVED BY: 
DocuSign Envelope ID: A7C2E440-57AA-4486-9F44-FAB9F8FEF59E


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................4 
LIST OF FIGURES .......................................................................................................................4 
ABBREVIATIONS AND DEFINITIONS ...................................................................................5 
1.0 
INTRODUCTION..............................................................................................................6 
1.1 
Myelodysplastic syndromes .....................................................................................6 
1.2 
Treatment Options ...................................................................................................6 
1.2.1 
Oral Decitabine and E7727 .....................................................................7 
2.0 
STUDY OBJECTIVES ......................................................................................................7 
2.1 
Primary Objective ....................................................................................................7 
2.2 
Secondary Objectives...............................................................................................7 
2.3 
Exploratory Objectives ............................................................................................7 
3.0 
STUDY DESIGN ................................................................................................................7 
3.1 
Overall Study Design ...............................................................................................7 
3.2 
Discussion of Study Design ...................................................................................10 
3.3 
Study Endpoints .....................................................................................................11 
3.3.1 
Primary Endpoint ..................................................................................11 
3.3.2 
Secondary Endpoints .............................................................................11 
3.3.3 
Exploratory Endpoints ..........................................................................11 
3.4 
Data and Safety Review Committee ......................................................................11 
3.5 
Definition of Dose-Limiting Toxicities .................................................................12 
4.0 
SAMPLE SIZE .................................................................................................................12 
5.0 
ANALYSIS SETS.............................................................................................................12 
5.1.1 
All Subject Analysis Set .......................................................................12 
5.1.2 
Efficacy Analysis Set ............................................................................13 
5.1.3 
Safety Analysis Set ...............................................................................13 
5.1.4 
Pharmacokinetics Analysis Set .............................................................13 
5.1.5 
Pharmacodynamics and Biomarker 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 
Efficacy Variables and Analyses ...........................................................................14 
7.3.1 
Response Rate .......................................................................................14 
7.3.2 
Overall Survival ....................................................................................16 


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7.3.3 
Time to AML ........................................................................................16 
7.3.4 
Duration of Response ............................................................................16 
7.3.5 
Transfusion Independence ....................................................................17 
7.4 
Safety Variables and Analyses ...............................................................................17 
7.4.1 
Study Treatment and Exposure .............................................................17 
7.4.2 
Adverse Events......................................................................................18 
7.4.3 
Dose-Limiting Toxicity .........................................................................18 
7.4.4 
Concomitant Medications .....................................................................18 
7.4.5 
Laboratory Tests....................................................................................19 
7.4.6 
Vital Signs .............................................................................................19 
7.4.7 
Electrocardiogram (ECG) .....................................................................19 
7.4.8 
ECOG Performance Status ....................................................................20 
7.4.9 
Echocardiogram / Multigated Acquisition (ECHO/MUGA) ................20 
7.4.10 
Physical Examination ............................................................................20 
7.5 
Pharmacokinetics Analysis ....................................................................................20 
7.5.1 
Calculation of Decitabine AUC ............................................................20 
7.5.2 
Calculation of the Ratio for Decitabine 5-day AUC0-t for Oral:IV .......21 
7.5.3 
Dose Proportionality .............................................................................21 
7.5.4 
PK Summary .........................................................................................21 
7.6 
Pharmacodynamic/Biomarker Analyses ................................................................21 
7.7 
Handling of Missing Data and Other Data Anomalies ..........................................22 
7.8 
Handling of Protocol Deviations ...........................................................................22 
8.0 
REFERENCES .................................................................................................................23 
APPENDIX 1:  IMPLEMENTATION GUIDE FOR RESPONSE ASSESSMENT .............25 
 
LIST OF TABLES 
Table 1: 
Modified IWG 2006 MDS Response Criteria ...........................................15 
 
LIST OF FIGURES 
Figure 1: 
Dose Escalation Stage Algorithm ..............................................................10 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AUC 
area under the curve 
BQL 
below the limit of quantification 
BSA 
body surface area 
CDA 
cytidine deaminase  
CDAi 
cytidine deaminase inhibitor 
CI 
confidence interval 
Cmax 
maximum concentration 
CMML 
chronic myelomonocytic leukemia 
CR 
complete response 
CRF/eCRF 
case report form/electronic case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSRC 
Data and Safety Review Committee 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
HI 
hematological improvement 
HI-E 
erythroid response  
HI-N 
neutrophil response 
HI-P 
platelet response 
HMA 
hypomethylating agent 
IPD 
important protocol deviations 
IPSS 
International Prognostic Scoring System 
IV 
intravenous 
IWG 
International Working Group 
LINE-1 
long interspersed nucleotide elements-1 
LVEF 
left ventricular ejection fraction 
mCR 
marrow complete response 
MDS 
myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
OR 
overall response 
PD 
pharmacodynamic(s) 
pH 
a measure of the acidity or alkalinity of an aqueous solution 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
THU 
tetrahydrouridine 
Tmax 
time at which Cmax occurs 
WHO 
World Health Organization 
 


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1.0 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on ASTX727-01 protocol version 5. Analyses and 
statistical reporting for ASTX727-01 will be conducted by Astex Pharmaceuticals Biometrics 
department using SAS version 9.4 or higher. This analysis plan describes the analyses only for the 
Dose Escalation Stage.   
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 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 
(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  
The standard for MDS therapy for many years has been supportive care (Heaney and Golde 1999; 
Kantarjian and Estey 2001). Intensive chemotherapy has been associated with complete response 
rates of 40% to 60%, induction mortality rates of 10% to 40%, and no improvement in survival 
(Kantarjian and Estey 2001).  
Within the previous 10 years, three agents have been approved by the US FDA for the treatment 
of MDS: the immunomodulating agent lenalidomide, and the hypomethylating agents (HMAs) 
azacitidine and decitabine. Patients administered azacitidine at a subcutaneous dose of 75 mg/m2 
daily×7 showed an overall response rate (CR+PR) of 15.7%, which was significantly greater than 
the response rate of 0% in the observation group (p<0.0001) (Vidaza 2012). Similarly, patients 
with intermediate- or high-risk MDS who were administered IV decitabine (Dacogen®) at a dose 
of 20 mg/m2 daily×5 showed an overall response rate of 16% (Dacogen 2014). 


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1.2.1 
Oral Decitabine and E7727 
E7727 is a 2’-fluorinated analog of tetrahydrouridine (THU) and is a novel cytidine deaminase 
inhibitor (CDAi), developed for oral administration. The bioavailability of decitabine and of several 
other therapeutic cytidine analogs (eg, azacitidine, cytarabine, gemcitabine) is significantly limited 
by a rapid metabolism catalyzed by cytidine deaminase (CDA) which is highly expressed in the gut 
and liver. E7727 is a potent CDAi with an IC50 of 0.281 μM. E7727 is also characterized by an 
improved stability at lower pH which has been a challenge with THU.  
E7727 has negligible antiproliferative activity in human cancer cell lines, did not show any 
significant inhibition in a panel of 80 physiologically important human receptors and did not 
inhibit hERG potassium channel at up to 300 μM. In vitro studies have also characterized an 
epimer of E7727 (ER-849726) that has about 1/10th the activity of E7727 as determined by an 
IC50 of 5 µM against human recombinant CDA. After oral dosing in preclinical toxicology models 
(mouse and monkey), near-equivalent levels were detected for circulating E7727 and its epimer. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
x Assess safety, tolerability, and pharmacokinetics (PK) of concomitant orally administered 
decitabine + E7727.  
x Identify a dose of oral decitabine + E7727 that together achieve a target mean decitabine AUC 
comparable to that from decitabine given by IV infusion (20 mg/m2) for 1 hour.  
2.2 
Secondary Objectives  
x Determine percent change of long interspersed nucleotide elements-1 (LINE-1) demethylation in 
Course 1 and Course 2. 
x Assess preliminary efficacy, as determined by response rate, duration of response, 
hematological improvement, rate of transfusion independence, time to AML, and overall 
survival. 
x Evaluate other PK parameters of decitabine, E7727, and E7727-epimer. 
2.3 
Exploratory Objectives 
 
 
 
 
3.0 
STUDY DESIGN 
3.1 
Overall Study Design 
Stage 1 of ASTX727-01 was a phase 1 pharmacokinetic guided dose-escalation study of a 
combination of E7727 with oral decitabine in subjects with myelodysplastic syndromes (MDS). 
The starting dose for cohort 1 for E7727 was 40 mg, and the starting dose of oral decitabine was 


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20 mg. All subsequent cohort dose levels and cohort sizes were determined by the Data and Safety 
Review Committee (DSRC) based on both safety and PK data review from at least 3 evaluable 
subjects in each cohort; see below for dose escalation guidance and Section 3.4 for description of 
DSRC functions.  
The dosing schedule for all cohorts in the Dose Escalation Stage is as follows: 
Course 1: 
x Day -3 (± 2 days): Single dose oral decitabine.  
x Day 1: IV decitabine administered at 20 mg/m2. 
x Days 2-5: Concomitant oral administration of oral decitabine + E7727.  
Course 2: 
x Day -3 (± 2 days): Single dose E7727. 
x Days 1-5: Concomitant oral administration of E7727 + decitabine. 
The doses of single oral decitabine or oral E7727 given on Day -3 (±2 days) in Course 1 and 
Course 2 were the same doses, respectively, that were given concomitantly on Days 2-5 in Course 
1 and Days 1-5 in Course 2. 
Course ≥3: 
x Days 1-5: Concomitant oral administration of E7727 + decitabine (note, there are no Day -3 
visits beginning with Course 3). 
All subjects continued to receive oral decitabine + E7727 daily×5 of a 28-day course in Course 3 
and thereafter until disease progression, unacceptable toxicity, subject withdrawal of consent, or 
withdrawal from the study. 
Dosing for Cohort ≥2: The dosing schedule for Cohort ≥2 was the same as for Cohort 1; however, 
the dose levels of either E7727 or oral decitabine could have been modified based on the decision 
of the DSRC guided by the algorithm in Figure 1. Only one of the 2 components could have been 
escalated at any one time. If 1 dose limiting toxicity (DLT) occurred in the first 3 subjects in the 
cohort, 3 more subjects could have been added in that cohort to assess safety and AUC range. In 
the absence of DLTs in more than 1 of the first 6 subjects in any cohort, the dose of E7727 was to 
be escalated in 20 mg increments until the cohort mean decitabine oral AUC/IV decitabine AUC 
approached unity (within 0.90-1.10, inclusive). If E7727 dose adjustments failed to produce the 
desired oral decitabine AUC levels, or a smaller dose adjustment was required (5 mg instead of 
20 mg), the decitabine dose (increments or decrements of 20 mg or 5 mg) was to be adjusted until 
the desired AUC levels were achieved. More details of dose adjustment are described in protocol 
section 4.4.1.  


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When the target level of decitabine AUC after oral administration was within 0.90-1.10 of IV 
decitabine AUC with no more than 1 DLT in 3-6 evaluable subjects, additional evaluable subjects 
were added to the cohort to reach up to 12-18 subjects in that cohort to confirm the AUC range at 
0.90-1.10 before opening the Dose Confirmation Stage of the trial. If the AUC range in the first 
12 subjects was out of the desired range, or more than 1 DLT occurred in 6 subjects, the DSRC 
could recommend further adjustment of the E7727 or decitabine dose in a new cohort of at least 3 
subjects until the desired AUC range (0.90-1.10) and safety (no more than 1 DLT) were achieved. 
If more than one DLT in 6 subjects was observed in any cohort, no further escalation would take 
place, and the DSRC would decide whether de-escalation of one or more components (oral 
decitabine and/or E7727) was necessary.  


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Figure 1: 
Dose Escalation Stage Algorithm 
 
 
3.2 
Discussion of Study Design 
The study was not intended to identify a maximum tolerated dose of oral decitabine + E7727. 
Rather, dose escalation targeted a dose of the 2 components that approximately achieved unity in 
decitabine AUC exposures compared with AUC of IV decitabine 20 mg/m2 (AUC ratio within 
DOSING
Course 1:
Day -3 (±2 days)*: Single dose oral decitabine 
Day 1: decitabine IV 20 mg/m2 
Days 2-5:  oral decitabine + E7727
Course 2:
Day -3 (±2 days)*: Single dose E7727
 Days 1-5: oral decitabine + E7727
Courses ≥3:
Days 1-5: oral decitabine + E7727
DOSE ESCALATION ALGORITHM
Subjects with IPSS Intermediate-1 or -2, or High-Risk MDS
decitabine AUC oral/IV 
> approx 1.10
decitabine AUC oral/IV 
approx 0.90-1.10
De-escalate
 E7727 
Cohort ≥2
Escalate E7727 (20 mg increments)
Stop
Escalation
decitabine AUC oral/IV 
> approx 1.10
decitabine AUC oral/IV 
< approx 0.90
decitabine AUC oral/IV 
approx 0.90-1.10
De-escalate  E7727
or oral decitabine
Stop
Escalation
Escalate E7727 to 
saturation of 
decitabine, then 
escalate decitabine
Continue oral decitabine + 
E7727 until disease 
progression or 
unacceptable toxicity 
occurs, the subject 
withdraws consent, or is 
withdrawn from study
decitabine AUC oral/IV 
< approx 0.90
*The doses of oral decitabine or oral E7727 given on Day -3 (±2 days) in Course 1 and Course 
2 are the same doses, respectively, that are given on Days 2-5 in each cohort.
When the target level of decitabine AUC after oral administration is within approximately 0.90-1.10 of IV 
decitabine AUC with no more than 1 DLT per 6 subjects, expand the cohort to reach up to 12-18 total subjects in 
the cohort to confirm the AUC range before opening the Dose Confirmation Stage. If the AUC is out of the desired 
range, or more than 1 DLT occurs per 6 subjects, the DSRC can recommend further adjustment of the E7727 or 
decitabine dose in a new cohort of 3 subjects until the desired AUC range and safety are achieved in at least 3 
subjects.


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0.90-1.10). Escalation occurred only after review of the PK and safety data from at least 
3 evaluable subjects in each cohort and a recommendation from the DSRC (see Section 3.4).  
3.3 
Study Endpoints  
3.3.1 
Primary Endpoint  
x Mean decitabine AUC oral/IV: Mean AUC of oral decitabine + E7727 (Days 2 and/or 5) 
compared with IV decitabine 20 mg/m2 (Day 1).  
x Incidence and severity grades of DLTs. 
3.3.2 
Secondary Endpoints 
x AUC, Cmax, Tmax, and other PK parameters of oral decitabine, E7727, and E7727-epimer. 
x Overall incidence and severity of adverse events and clinically significant abnormal laboratory 
values. 
x Mean maximum %LINE-1 demethylation of oral decitabine + E7727 by cohort. 
x Overall response rate as measured by the International Working Group (IWG) 2006 MDS 
Response Criteria, duration of response, hematological improvement, rate of transfusion 
independence, time to AML, and overall survival. 
3.3.3 
Exploratory Endpoints 
 
 
 
 
3.4 
Data and Safety Review Committee  
A thorough review of PK and safety data by the DSRC was regularly conducted, particularly after 
every cohort of 3-12 evaluable subjects during the Dose Escalation Stage. 
The DSRC conferred when the last of at least 3 evaluable subjects in a cohort completed Course 1, 
Day 28. This committee comprised the principal investigators (or nominated deputies), medical 
monitor, study director, PK director, and other study team members as appropriate and reviewed 
available safety, PK, and PD data. The DSRC recommended whether to continue dosing based on 
the oral decitabine + E7727 dose escalation algorithm (Figure 1) and the safety data (DLTs). The 
DSRC made decisions regarding continuing dose escalation or de-escalation, to better assess the 
PK and safety of oral decitabine + E7727 during the Dose Escalation Stage. The DSRC decided 
on the exact next dose level based on the escalation scheme provided in Figure 1. DSRC could 
have also decided to escalate/de-escalate either drug component (E7727 or oral decitabine) if AUC 
levels or safety data at any cohort warranted such escalation/de-escalation.  


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3.5 
Definition of Dose-Limiting Toxicities  
A DLT occurring in the first course of treatment for all subjects at any cohort during dose 
escalation guided the dose escalation decision. At subsequent courses, DLTs guided dose 
adjustment or dose delays as discussed in protocol Section 7.3. DLTs were defined using the 
Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03).  
x ≥ Grade 3 non-hematologic toxicity (unless the DSRC determines that it is clearly related to 
an underlying disease or to disease progression), except the following: 
o Grade 3 nausea or vomiting that is controllable by anti-emetics. 
o Grade 3 diarrhea controllable by optimal therapy such as loperamide. 
x Grade 3 laboratory tests other than serum creatinine, bilirubin, AST, or ALT will not be 
considered a DLT unless the abnormal result(s) is/are associated with clinical manifestations. 
x Related prolonged Grade 4 thrombocytopenia that was not present prior to dosing, does not 
resolve within 14 days, and is not related to underlying disease. 
x Related febrile neutropenia or Grade 4 neutropenia that was not present prior to dosing, does 
not resolve within 14 days, and is not related to underlying disease. 
x Any toxicity (related to study treatment) that results in treatment delays of >4 weeks after Day 
28. 
4.0 
SAMPLE SIZE 
For this stage, no formal statistical tests of hypotheses were performed to calculate sample size. 
The Dose Escalation Stage contained multiple cohorts with a cohort size of 3-12 evaluable subjects 
(and could have been extended to 18 subjects to confirm the AUC range if recommended by the 
DSRC) for each cohort. The enrollment of subjects in the Dose Escalation Stage continued until 
the desired decitabine AUC level (AUC ratio of 0.90 to 1.10 of oral decitabine to IV decitabine) 
and safety were achieved, as described in Section 3.1. A subject was considered evaluable for dose 
escalation if all the criteria below were met: 
x Completed Course 1 dosing regimen with sufficient PK data available. 
x Had safety assessment for the 28 days of Course 1. 
5.0 
ANALYSIS SETS 
5.1.1 
All Subject Analysis Set 
This analysis set contains available data from all enrolled subjects, including those who did not 
receive any study treatment. This analysis set will be used for analysis of subject disposition.  


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5.1.2 
Efficacy Analysis Set 
The Efficacy Analysis Set includes data from all enrolled subjects who receive any amount of 
study treatment.  
5.1.3 
Safety Analysis Set 
The safety analysis set is the same as the Efficacy Analysis Set, which includes data from all 
enrolled subjects who received any amount of study treatment. In the safety analysis, no data 
exclusion will be allowed because of protocol deviations. 
5.1.4 
Pharmacokinetics Analysis Set 
The PK Analysis Set will include data from all treated subjects for whom sufficient PK samples 
were collected to enable calculation of full AUCs on PK assessment days. 
5.1.5 
Pharmacodynamics and Biomarker Analysis Set 
PD Analysis Set for LINE-1 methylation will be all subjects who received at least one course 
(Days 1-5) study treatment and had baseline and Day 8 or Day 15 LINE-1 methylation data. PD 
Analysis Set for other biomarkers will be based on those subjects who had biomarker data collected 
and analyzed. 
6.0 
SCHEDULE OF ANALYSES 
Analyses of safety, efficacy, PD, and PK data will be regularly performed for review by the DSRC 
for the purpose of guiding decisions such as dose escalation, de-escalation, and change in cohort 
size, determination of subsequent dose level during the Dose Escalation Stage. Formal analyses 
including all data collected up to June 1, 2017, will be performed for preparation of the clinical 
study report for the dose escalation stage of ASTX727-01. Additional analyses will be conducted 
when all subjects are out of study. 
No formal interim analyses are planned for this study. 
7.0 
STATISTICAL ANALYSIS 
Unless otherwise specified, all statistical tests and confidence intervals created will be two-sided 
with alpha = .05. The SAS® statistical package (version 9.4 or a later version) will be used for the 
analyses. 
In general, the first dosing date is defined as the first date the subject received decitabine IV, oral 
decitabine, or E7727. All analyses will be conducted by cohort and all cohorts combined unless 
otherwise specified. 


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7.1 
Subject Disposition 
Subject disposition including numbers screened, treated, and treatment discontinuation by reason, 
as well as the reasons for study exit (ie, death or reasons that subject were not followed up for 
survival status) will be summarized using frequencies and percentages according to the study visit, 
treatment discontinuation, and withdrawal from study case report form pages. Sample size for the 
Efficacy, Safety, PK, and PD Analysis sets will be clearly identified. Subjects in the All Subject 
Analysis Set will be included in the disposition analysis. 
7.2 
Demographic and Other Baseline Characteristics 
The Efficacy Analysis Set (Section 5.1.2) will be used to summary demographic and baseline 
characteristics. The demographic variables consist of age, age category, sex, ethnicity, race, and 
geographical region. Baseline characteristics include height, weight, BSA, ECOG performance 
status, IPSS risk category, time since prior diagnosis, cytogenetic risk levels, peripheral blood 
(including blasts) counts, and BM blasts. 
Baseline values are generally the last value collected on or before the 1st dosing date unless 
otherwise specified. 
Age at baseline, if not already provided through data collection, will be calculated as the integer 
part of (date of enrollment- date of birth)/365.25.  
Time since Diagnosis will be calculated as the (date of 1st dosing  – date of diagnosis). If the day 
is missing for date of diagnosis, the 15th of the month is used. If the month is missing, July 1st is 
used. If the year is missing, the date is left as missing.  
Subject demographic and baseline characteristics will be summarized by mean, standard deviation, 
median, minimum, and maximum for continuous variables; and by counts and percentages for 
categorical variables.  
7.3 
Efficacy Variables and Analyses 
Efficacy analyses will be based on the Efficacy Analysis Set (Section 5.1.2).  
7.3.1 
Response Rate 
The evaluation of response (Table 1) is based on IWG 2006 MDS Response Criteria (Cheson et al 
2006). Details of response assessments are described in Appendix 1. 


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Table 1: 
Modified 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. 
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. 
Marrow: Normal bone marrow and marrow blasts >5%, but were reduced by 50% or more. 
Marrow Complete Response (mCR): the following 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 or RBC transfusion dependence 
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. 
Neutrophil Response (HI-N): 
Major 
Response: 
Granulocyte increase ≥100%, and by an absolute increase 
≥0.5×109/L. 
Baseline value is defined as the average of any values obtained before and on the first dosing date. 
If there is only one value before treatment then it will be used as the baseline value. 
The following rates will be estimated using sample proportions and 95% Clopper-Pearson 
confidence interval based on the number of subjects in the Efficacy Analysis Set: 
x Overall response (OR [CR+PR+mCR+HI]). 
x CR+PR+mCR. 
x CR. 
x PR. 
x mCR. 
x HI (HI-E, HI-P or HI-N). 
o HI-E. 
o HI-P. 
o HI-N. 
If adequate baseline 
 is available responses will also be 
summarized by selected baseline 
.  


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7.3.2 
Overall Survival 
Overall survival is defined as the number of days from the day the subject received the first dose 
of study treatment 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 in 
the Study Discontinuation CRF page, whichever is later. 
The Kaplan-Meier plot will be provided based on the Efficacy Analysis Set. Estimated median 
survival and 95% confidence intervals will also be provided if available. 
7.3.3 
Time to AML  
Time to AML is defined as the number of days from the day the subject received the first dose of 
study treatment to the date of MDS progression to AML as defined by ≥20% blasts in bone marrow 
or peripheral blood or death of any cause. The event date of time to AML will be based on the 
earliest date of following: 
x Death date. 
x AML conversion date defined as the earliest date of the following: 
o AML conversion date on the Conversion to AML CRF page. 
o AML conversion date on the Subject Information CRF page. 
o The first date when a record of ≥20% blasts in bone marrow was reported or 2 consecutive 
records of ≥20% blasts peripheral blood were reported. 
Subjects without a time to AML event as described above will be censored on the date of last 
contact.  
The Kaplan-Meier plot for time to AML will be provided based on the Efficacy Analysis Set. 
Estimated median survival and 95% confidence intervals will also be provided if available. 
7.3.4 
Duration of Response 
Duration of response will be calculated separately for CR, PR, mCR, and CR+PR+mCR from the 
first time a response category (CR, PR, and mCR) is initiated, as addressed in the Implementation 
Guide of Response Assessment in Appendix 1, to the earliest of the following dates: 
x Death date. 
x End of response as addressed in Appendix 1, where date of disease progression is defined as 
the earliest date of: 
o AML conversion as described in Section 7.3.3. 
o disease progression date on the Subject Information CRF page. 
o last treatment date if the reason for treatment discontinuation is Progressive Disease. 


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o study exit date on the Study Discontinuation CRF page if the reason for study 
discontinuation is Progressive Disease. 
o date of disease progression on the Survival Follow-up CRF page. 
Duration of response will be summarized using mean, standard deviation, standard error, 
minimum, median, and maximum for subjects who achieved a corresponding response during the 
study. The longest duration will be selected within a subject for summary if multiple responses 
occurred in a subject. 
7.3.5 
Transfusion Independence  
Transfusion dependence and independence is defined as follows:  
x Transfusion dependence at baseline: documentation of 2 units or more of transfusion within 
56 days of the first day of study treatment. 
x Post-treatment transfusion independence: no transfusion for 56 consecutive days or more after 
treatment. 
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) divided by the number of subjects who were transfusion dependent 
at baseline (N). The 95% Clopper-Pearson confidence interval for transfusion independence rates 
will be provided. Analyses will also be provided by duration of transfusion follow-up (≥56 days, 
≥84 days and more). 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.  
7.4 
Safety Variables and Analyses 
Safety Analysis will be performed using the Safety Analysis Set (Section 5.1.3). Safety will be 
assessed by subject-reported and investigator-observed AEs, along with physical examination, 
clinical laboratory tests (hematology, chemistries), vital signs, concomitant medications, and 
ECGs. Exposure to study treatment, reasons for discontinuation, deaths, and causes of deaths will 
be tabulated.  
7.4.1 
Study Treatment and Exposure  
The number of courses received per subject will be summarized using descriptive statistics. 
Frequency count and percentage of dose delayed courses reported by investigator will be 
calculated based on the total number of treatment courses all subjects received. Dose reduced 
courses, defined as the courses in which the dose is reduced by 20% or more relative to the planned 
dose within the course, will be summarized using frequency count and percentage for oral 
decitabine, E7727, and IV decitabine separately based on the total number of courses all subjects 
received for each study medication. 


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7.4.2 
Adverse Events  
Adverse event (AE) terms reported by study subjects or observed by investigators will be mapped 
to the appropriate System Organ Class (SOC) and Preferred Term (PT) according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Severity of AE will be graded using Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
Treatment-emergent AEs (TEAEs) are defined as events that first occurred or worsened, after the 
first dose of study treatment until 30 days after the last dose of study treatment or the start of an 
alternative anti-cancer treatment for MDS/chronic myelomonocytic leukemia (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 an 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 Astex Data Programming 
Conventions.  
All AE data collected in the study database will be listed, 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. A similar table with related AE counts will also be produced. 
Related events are those that the Investigator considered to be suspected to be related to study 
treatment as described in the study protocol. 
The number and percentage of subjects experiencing AEs will be summarized by MedDRA SOCs 
(sorted alphabetically) with PTs sorted alphabetically within each SOC, and by CTCAE grade. 
The number and percentage of subjects experiencing AEs will also be summarized by PT and 
sorted by event frequency. Related AEs, serious AEs, and related serious AEs will be summarized 
similarly. In summarizing AEs, if 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. 
7.4.3 
Dose-Limiting Toxicity 
Protocol specified DLTs were identified based on CTCAE v4.03 (Section 3.5). Frequency count 
and percentage of DLTs will be summarized by cohort. DLTs will also be identified in the listing 
of AEs.  
7.4.4 
Concomitant Medications 
Concomitant medications are the medications taken with a start date on or after the start of the 
administration 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. 


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Medications taken beyond 30 days from the last dose of study treatment or after the start of an 
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. 
7.4.5 
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 Astex Data 
Programming Conventions. 
7.4.6 
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 following:  
x Pulse rate 110 bpm or greater. 
x Pulse rate 50 bpm or less. 
x Diastolic blood pressure 110 mmHg or greater. 
x Diastolic blood pressure 55 mmHg or less. 
x Systolic blood pressure 180 mmHg or greater. 
x Systolic blood pressure 80 mmHg or less. 
x Respiration rate 20 breaths/min or greater. 
x Body temperature 39°C or greater. 
7.4.7 
Electrocardiogram (ECG) 
Abnormal ECG findings will be summarized by visit. Subjects with any post-baseline abnormal 
ECG findings will also be tabulated. 


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QTc values will be graded based on CTCAE 4.0.3, and the shift table showing the shift from 
baseline grade to the worst grade, and from baseline grade to the last available grade will be 
provided. 
7.4.8 
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. 
7.4.9 
Echocardiogram / Multigated Acquisition (ECHO/MUGA) 
Summary statistics for left ventricular ejection fraction (LVEF, %) and abnormality (normal or 
abnormal) will be presented at baseline and last visit. Summary statistics for change from baseline 
of LVEF (%) will also be presented for subjects with valid baseline and any post-baseline LVEF 
data. 
7.4.10 
Physical Examination 
Physical examination data will be presented in a data listing. 
7.5 
Pharmacokinetics Analysis  
The PK Analysis Set (Section 5.1.4) will be used for analysis of all PK parameters. PK parameters 
of decitabine, E7727, and E7727-epimer will be derived for each subject using a non-
compartmental approach.  
7.5.1 
Calculation of Decitabine AUC 
7.5.1.1 
Calculation of Decitabine Daily AUCs 
AUCs (the area under the concentration-time curve) will be calculated by the linear up/log down 
method using the measured concentration-time values above the BQL (below the limit of 
quantification). In particular, AUC0-t (the area under the concentration-time curve from time zero 
to the time of the last (tlast) quantifiable concentration (Ct)) by dose/cohort and course/days will be 
used for estimating decitabine cumulative 5-day AUC0-t exposures. 
7.5.1.2 
Decitabine 5-day AUC0-t 
For estimating decitabine 5-day cumulative AUC0-t exposures in the Dose Escalation stage after 
oral ASTX727 combination, the following assumptions were used: 
x Steady state is reached on the 2nd day of dosing with oral E7727+decitabine combination.  
x Based on steady state achievement on Day 2, decitabine AUC0-t from Day 5 in Dose Escalation 
(4th dosing day with combination) would be representative of daily AUC0-t on Days 2 through 
5 in a putative 5-day dosing with ASTX727.   


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Thus, to estimate total 5-day oral decitabine AUC0-t exposures using PK data from Dose 
Escalation, Day 2 AUC (first oral combination dose) was added to Day 5 AUC0-t × 4.  
For estimating decitabine 5-day AUC0-t exposures after IV infusion, Day 1 (IV-infusion) AUC0-t 
was multiplied by 5 based on information from Dacogen prescribing information that there was no 
accumulation on Day 5 vs Day1 for 5-day IV infusion.   
7.5.2 
Calculation of the Ratio for Decitabine 5-day AUC0-t for Oral:IV 
To compare decitabine cumulative 5-day systemic exposures between Oral E7727+decitabine 
combination and IV infusion, the ratio of 5-day AUC0-t exposure estimates for Oral and IV 
administration was derived (Oral:IV) for each dose cohort. This ratio was used to assess the 
progress in dose escalation for achieving targeted IV AUC0-t using oral ASTX7272.  
7.5.3 
Dose Proportionality 
PK dose proportionality will be tested using linear regression between dose and dose-adjusted 
parameter estimates. A “Power model” will be applied to each of the PK parameters including 
AUC0-inf, AUC0-t and Cmax for decitabine and E7727, when applicable. 
7.5.4 
PK Summary 
Daily decitabine AUC will be summarized descriptively using mean, standard deviation, median, 
and range by dose cohort and course/days if deemed necessary. Decitabine 5-day AUC0-t will be 
summarized separately for ASTX727+E7727 and IV decitabine using descriptive statistics by 
cohort. 
7.6 
Pharmacodynamic/Biomarker Analyses 
The PD and Biomarker Analysis Set (Section 5.1.5) will be used for analyses of LINE-1 
methylation and other biomarkers. All data will be summarized descriptively (using mean, 
standard deviation, median, and range for continuous variables and counts and percentages for 
categorical variables) by dose cohort and visit for each biomarker.  
Maximum %LINE-1 demethylation (defined as the largest percent decrease from baseline in 
methylation values within a subject between Day 8 and Day 22 of the first treatment course) will be 
summarized using mean, standard deviation, standard error, minimum, median, and maximum.  
Additional biomarker analysis will include assessment of baseline CDA activity and changes in 
circulating 
 levels post-treatment. Changes in 
 after treatment with 
E7727 will be analyzed by comparing post-dose 
 levels to pre-dose values at each 
dosing day of E7727 per subject. Mean change of 
 will be presented by E7727 
dosing day. 


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7.7 
Handling of Missing Data and Other Data Anomalies 
No missing data imputations are planned for the study, except as specified. Subjects lost to follow-
up will be included in statistical analyses to the point of the data cut-off date. 
7.8 
Handling of Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before the first 
subject visit and updated during the IPD reviews throughout the study prior to data cut-off date. 
IPDs will include violation of major inclusion or exclusion criteria. IPD will be tabulated by cohort 
and listed by cohort and subject. 


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8.0 
REFERENCES 
Bejanyan N, Sekeres MA. The revolution of myelodysplastic syndromes. Therapeutic advances in 
hematology. 2011;2(1):33-43.  
Bennett JM. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 
1982;51(2):189-199.  
Beumer J, Eiseman J, Gilbert J, Holleran J, Yellow-Duke A, Clausen D, et al. Plasma 
pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, 
triacetyl-THU (taTHU), in mice. Cancer Chemotherapy and Pharmacology. 2011;67(2):421-430.  
Beumer JH, Eiseman JL, Parise RA, Joseph E, Covey JM, Egorin MJ. Modulation of gemcitabine 
(2',2'-difluoro-2'-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 
3,4,5,6-tetrahydrouridine. Clin Cancer Res. 2008;14(11):3529-3535.  
Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, et al. Pharmacokinetics, 
metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2'-
deoxycytidine in mice. Clin Cancer Res. 2006;12(24):7483-7491.  
Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, et al. Concentrations 
of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) and its cytotoxic 
metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer 
Chemother Pharmacol. 2008;62(2):363-368.  
Chabot GG, Bouchard J, Momparler RL. Kinetics of deamination of 5-aza-2'-deoxycytidine and 
cytosine arabinoside by human liver cytidine deaminase and its inhibition by 3-deazauridine, 
thymidine or uracil arabinoside. Biochem Pharmacol. 1983;32(7):1327-1328.  
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(2):419-425.  
Dacogen. Dacogen (decitabine for injection) Prescribing Information. 2014.  
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.  


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Kantarjian H, Estey E. Myelodysplastic syndromes. 6th ed. DeVita VT, Hellman S, Rosenberg 
SA, editors: Lippincott Williams & Wilkins; 2001. 
Karahoca M, Momparler RL. Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-
deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin Epigenetics. 
2013;5(1):3.  
Longo DL et al. 2011. Harrison's principles of internal medicine (18th edition). New York: 
McGraw-Hill Medical Publishing Division.  
Mistry B, Jones M, Kubiak P. A phase 1 study to assess the absolute bioavailability and safety of 
an oral solution of decitabine in subjects with Myelodysplastic Syndromes (MDS). Blood. 
2011;118:Abstract 3801.  
Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA, Garcia-Manero G, et al. Multicenter 
study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic 
syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 
2009;27(23):3842-3848.  
Vidaza. Vidaza (azacitidine for injection) for SC or IV use. Prescribing information. 2012.  


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APPENDIX 1:  Implementation Guide For Response Assessment 
The rules for determination of MDS responses and the corresponding durations of responses are 
described in the following sections. These rules are based on the “best” same-day blood counts 
(PB blasts, neutrophils, platelets, and Hgb) measured within a treatment course and the 
transfusion-free period requirement. The “best” was defined in the sense that blood count criteria 
were met for a particular response status. For BM blasts, if the current course did not have a BM 
evaluation, the immediately preceding BM evaluation was used.  
Rules for CR 
The subject must have one of the following baseline values to be eligible for a CR. 
Hgb <11 g/dL 
Platelets <100 × 109/L 
Neutrophils <1.0 × 109/L 
BM Blasts >5%  
PB Blasts >5% 
To be a CR, the subject must have fulfilled all of the following blood count criteria (the same-day 
counts for PB blasts, neutrophils, platelets, and Hgb were required) and have been transfusion free, 
for ≥28 days: 
Hgb ≥11 g/dL  
Platelets ≥100 × 109/L  
Neutrophils ≥1.0 × 109/L 
BM Blasts ≤5%  
PB Blasts absent (no value of PB blasts in the database is interpreted as absent) 
The start date of CR must have been >7 days after any RBC transfusion and >3 days after any 
platelet transfusion. 
The duration of CR was calculated from the first time a subject fulfilled these criteria to the earliest 
time point when BM blasts became >5%, PB blasts > 0%, or when any of the blood counts no 
longer met the above criteria, the subject received an RBC or platelet transfusion, or the subject 
showed a clinical progression as determined by the investigator.  


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In determining duration of CR, if one measurement of BM blasts increased above the 5% level and 
then decreased to this level or lower without receiving an alternative treatment, the subject was 
considered to have maintained the ≤5% level.  
Rules for PR 
To be a PR, subjects must have demonstrated all CR criteria with a relaxed requirement for BM 
blasts level. The BM blasts must have decreased by 50% or more compared with the pretreatment 
level but were still above 5%. The duration of PR is calculated from the first time a subject fulfilled 
these criteria to the earliest time point when BM blasts, peripheral blasts or any of the blood counts 
no longer met the above criteria, the subject received an RBC or platelet transfusion, or the subject 
showed a clinical progression as determined by the investigator.  
Rules for mCR 
To be eligible for mCR, subjects must have had a baseline BM blast >5%. An mCR could be 
declared if post treatment BM blasts become ≤5% and decreased by ≥50% over the pretreatment 
level for ≥28 days until disease progression. 
End of mCR was considered the earliest time point when BM blasts become >5% or a clinical 
progression was determined by the investigator. In determining duration of mCR, if one 
measurement of BM blasts were above the 5% level and then decreased to this level or lower 
without receiving an alternative treatment, the subject was considered to have maintained the ≤5% 
level. 
Rules for CR+PR+mCR 
Subjects who have CR, PR, or mCR will be considered a responder for CR+PR+mCR. The 
duration of CR+PR+mCR is measured from the initiation of CR, PR, or mCR, to the day that the 
subject do not meet criteria for CR, PR, and mCR.  
Rules for HI-E 
HI-E status was determined based on RBC transfusion and Hgb level at baseline and during the 
posttreatment period. To be eligible for HI-E, the subject must have had a baseline RBC 
transfusion dependence (any RBC transfusion within 4 weeks prior to C1D1) or had a baseline 
Hgb <11.0 g/L.   
For subjects with RBC transfusion dependence at baseline, an HI-E was declared if the subjects 
did not receive any RBC transfusion for a ≥56-day period posttreatment, regardless of Hgb level. 
For subjects without RBC transfusion dependence at baseline but with a baseline Hgb <11.0 g/L, 
an HI-E was declared if subjects had an Hgb increase by ≥1.5 g/L for ≥56 days (at least one count 
per course above threshold) and did not receive any RBC transfusions for ≥56 days. The start date 
of Hgb increase must have been >7 days after any RBC transfusion. 


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Duration of HI-E was calculated from the first time the HI-E criteria was fulfilled until the subject 
no longer met the HI-E criteria or disease progression.   
Rules for HI-P 
To be eligible for HI-P, a subject had to have a baseline platelet count <100 × 109/L.   
To be considered an HI-P a subject had to remain independent of platelet transfusions, and have 
platelet counts meet the criteria as described below, for a ≥56-day period posttreatment. The start 
date of response must have been >3 days after any platelet transfusion. 
x If the baseline platelet count was <20 × 109/L, the count must have increased to ≥20 × 109/L 
and by at least 100%. 
x If the baseline count was ≥20 × 109/L, the count must have increased by 30 × 109/L. 
The duration of HI-P was calculated from the first time the HI-P criteria was fulfilled until the 
subject no longer met the HI-P criteria or disease progression. 
Rules for HI-N 
G-CSF or GM-CSF was not to be administered. Clinical review of concomitant medication data 
listings was conducted to confirm that there were no such instances of subject use.   
The subject must have had a baseline ANC of <1.0 × 109/L to be eligible for an HI-N response.   
To have a response, ANC must have increased by ≥100% with an absolute increase of ≥0.5 × 109/L 
and been maintained for a 56-day period (at least one count per course above threshold). 
The duration of HI-N was calculated from the first time the HI-N criteria was fulfilled until the 
subject no longer met the HI-N criteria or disease progression.