Clinical trial NCT02293993
Conditions: Acute Myeloid Leukemia
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2015-01-07; Completion date: 2019-05-31
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
To evaluate the tolerability and pharmacokinetics of SGI-110 when administered subcutaneously to Japanese patients with acute myeloid leukemia (AML).

Detailed description:

Arms: arm 1: SGI-110 36mg/m2 will be administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). arm 2: SGI-110 60mg/m2 will be administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). arm 3: SGI-110 90mg/m2 will be administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). arm 4: SGI-110 60mg/m2 will be administered subcutaneously once daily for 10 days (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28).
Interventions: intervention 1: SGI-110
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
Phase 1 Study of SGI-110 in Patients With Acute Myeloid Leukemia 
(Phase 1 Trial) 
 
 
 
 
NCT Number: NCT02293993 
PRT NO.: 343-14-001 
Version Date: 13 October 2017 (Version 8) 


Protocol No. 343-14-001 
 
 
 
Phase 1 Study of SGI-110 in Patients With Acute Myeloid 
Leukemia 
(Phase 1 Trial) 
 
 
Clinical Protocol 
Protocol No.:  343-14-001 
(Translated Version) 
 
Confidential 
 
 
 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo 101-8535, Japan 
Immediately Reportable Events:  Office of Pharmacovigilance Operation, 
Pharmacovigilance Department 
E-mail:  IRE_343-14-001@otsuka.jp 
 
Version 8:  13 Oct 2017 


Protocol No. 343-14-001 
Statement of Confidentiality 
The trial protocol is to be treated as confidential information and is to be made available 
only to persons involved in the trial.  The content of the protocol is not to be disclosed to 
any third party without the prior written consent of Otsuka Pharmaceutical Co., Ltd., 
except in the case of its being explained to a candidate trial subject.  Disclosure of the 
results of the trial to academic societies or journals, etc, in part or in whole, will require 
the prior written approval of Otsuka Pharmaceutical Co., Ltd. 
 


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Trial Protocol Synopsis 
Name of Test Product 
SGI-110 
Trial Title 
Phase 1 study of SGI-110 in patients with acute myeloid leukemia. 
Trial Objectives 
Primary: 
 
To evaluate the tolerability of SGI-110 when administered subcutaneously to 
Japanese patients with acute myeloid leukemia (AML) 
Secondary: 
 
To perform pharmacokinetic (PK) evaluation of plasma SGI-110 and 
decitabine 
 
To evaluate efficacy (complete remission rate, composite complete remission 
rate, overall remission rate, overall survival, composite complete remission 
duration) 
 
To evaluate safety through observed adverse events (AEs) and examinations 
Exploratory: 
 
To perform pharmacodynamic (PD) evaluation of the extent of DNA 
hypomethylation 
Phase of Development 
Phase:  1 
Type of trial:  Exploratory trial, dose-finding trial, PK trial. 
Method 
After being reconstituted using the custom diluent provided with the 
investigational medicinal product (IMP), SGI-110 will be administered 
subcutaneously at a daily dose determined through calculation of each subject’s 
body surface area (BSA) prior to administration of the IMP in each course, 
according to each cohort. 
Each course will consist of 4 weeks (28 days).  In Cohorts 1, 2, and 4, subjects 
will receive SGI-110 once daily for 5 consecutive days (Day 1 to Day 5), 
followed by a 23-day non-dosing period (Day 6 to Day 28).  In Cohort 3, subjects 
will receive SGI-110 once daily for 10 days in total (SGI-110 will be 
administered for 5 consecutive days [Day 1 to Day 5], suspended for 2 days [Day 
6 and Day 7], then administered for another 5 consecutive days [Day 8 to Day 
12]), followed by a 16-day non-dosing period (Day 13 to Day 28). 
The sponsor will confirm the incidence of dose-limiting toxicity (DLT) during 
the DLT evaluation period in each cohort and judge the transition to the next 
cohort based on the advice of the Independent Data Monitoring Committee. 
If the number of subjects exhibiting DLT within a cohort is ≥ 2/3 or ≥ 2/6, then 
there will be no transition to the next cohort, and the maximum tolerated dose 
(MTD) will be determined as follows: 
≥ 2/3 or ≥ 2/6 subjects with DLT 
MTD 
In Cohort 1 
< 36 mg/m2 in 5-day regimen 
In Cohort 2 
36 mg/m2 in 5-day regimen 
In Cohort 4 
60 mg/m2 in 5-day regimen 
If the incidence of DLT does not reach either ≥ 2/3 or ≥ 2/6 in any of the cohorts 
in the table above, the MTD will not be determined in this study.  For Cohort 3, 
DLT will be evaluated but the MTD for 10-day regimen will not be determined 
from the incidence of DLT. 
 
[Definition of dose-limiting toxicity] 
Dose-limiting toxicity shall be defined as any of the following AEs occurring 
during Course 1 for which there is a reasonable probability or possibility of a 
causal relationship with the IMP if it cannot be reasonably explained by 
underlying disease, intercurrent illness, or concomitant medications.  The severity 
of AEs will be graded in accordance with Common Terminology Criteria for 


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Adverse Events (CTCAE) version 4.0. 
 
Non-hematologic toxicity of Grade 3 or higher, except for the following: 
 
Nausea, vomiting, or diarrhea of Grade 3 that is controllable by optimal 
therapy 
 
Grade 3 laboratory findings other than serum creatinine (Cr), bilirubin, 
aspartate aminotransferase (AST), or alanine aminotransferase (ALT), 
that are not associated with clinical manifestations 
 
Grade 4 thrombocytopenia that was not present at study entry and that is not 
resolved within 7 days 
 
Grade 4 neutropenia that was not present at study entry and that is not 
resolved within 7 days 
 
Febrile neutropenia Note 
If the febrile neutropenia is not resolved or improved during the DLT 
evaluation period, it shall be defined as DLT.  If the febrile neutropenia is 
resolved or improved during the DLT evaluation period, it shall be judged 
whether it is defined as DLT based on the background of the subject and 
through consultation with the Independent Data Monitoring Committee. 
 
Any AE that results in a delay of > 4 weeks in starting the next treatment 
course 
Note In this trial, febrile neutropenia is defined as a neutrophil count of < 500/μL 
accompanied by a fever of ≥ 38°C. 
 
The DLT evaluation period will be for the duration of Course 1.  Subjects who 
complete IMP administration and all observations during the DLT evaluation 
period, and who do not have any apparent progression of AML, will be permitted 
to continue treatment with IMP following the DLT evaluation period if they 
wish. 
The primary evaluation data for Cohorts 1, 2, and 4 will have a cutoff date of 31 
May 2016 and the data for Cohort 3 will have a cutoff date of 30 Nov 2017.  The 
period up until the data cutoff will be defined as the primary evaluation part.  
This will be followed by an extended treatment part to assess long-term safety, 
which will include those subjects on IMP treatment who have consented to 
participate in the extended treatment part.  Transition from the primary evaluation 
part to the extended treatment part will take place at the start of the next course 
after the data cutoff. 
Target Disease or 
Symptom 
AML 
Number of Patients 
Maximum:  24 subjects 
Cohort 1 (36 mg/m2, 5 days):  3 to 6 subjects 
Cohort 2 (60 mg/m2, 5 days):  3 to 6 subjects 
Cohort 3 (60 mg/m2, 10 days [ie, 5-day administration twice, with a non-dosing 
period in-between]):  6 subjects 
Cohort 4 (90 mg/m2, 5 days):  3 to 6 subjects 
Inclusion Criteria 
Patients meeting all of the following criteria at the time of screening will be 
included in this trial: 
1) Male or female patients with a diagnosis of AML (World Health 
Organization [WHO] classification 2008). 
 
Patients, 20 years of age or older, who are unresponsive to standard 
chemotherapy or have relapsed following standard chemotherapy 
 
Patients, 65 years of age or older, who are not eligible for standard 
intensive chemotherapy and who meet at least one of the following 


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criteria (applicable to Cohorts 1, 2, and 4 only): 
 
AML from myelodysplastic syndrome (MDS), or secondary 
AML 
 
Chromosomal karyotype abnormality with poor prognosis [del 
(5q), del (7q), −5, −7, abnormality of 3q (q21;q26), 
t (6;9) (p23;q34), t (9;22) (q34;q11.2), abnormality of 
11 (11q23), or complex karyotype of 3 or more unrelated 
abnormalities of any kind] 
 
Dysfunction of the heart (left ventricular ejection fraction 
[LVEF] < 50%) or lung (diffusing capacity of the lung for 
carbon monoxide [DLCO] or forced expiratory volume in the 
first second [FEV 1] < 50% of expected value) which is 
unrelated to AML 
 
Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 2 
 
75 years of age or older 
2) Patients with ECOG PS of 0 to 2. 
3) Patients with adequate vital organ function (patients whose clinical 
laboratory values meet the following conditions). 
a) Hepatic function:  total bilirubin (T-Bil) ≤ 2 × upper limit of normal 
(ULN); AST and ALT ≤ 2.5 × ULN. 
b) Renal function:  serum Cr ≤ 1.5 × ULN. 
4) Female patients of childbearing potential must not be pregnant or breast 
feeding (pregnancy test will be performed at screening).  Female 
patients of childbearing potential and all male patients must practice two 
medically acceptable methods of birth control and must not become 
pregnant or father a child while receiving treatment with SGI-110 and 
for 3 months following last dosing. 
5) Patients who have undergone prior allogeneic hematopoietic stem cell 
transplantation must have no evidence of active graft-versus host disease 
(GVHD) and must be off immunosuppressive therapy by ≥ 2 weeks 
prior to the scheduled start of IMP administration. 
6) Patients who have undergone no major surgery within 4 weeks prior to 
the scheduled start of IMP administration. 
7) Patients who have undergone no chemotherapy within 2 weeks prior to 
the scheduled start of IMP administration, nor hematopoietic stem cell 
transplantation within 8 weeks prior to the scheduled start of IMP 
administration. 
8) Patients who are able to provide written consent to participate in this 
trial by signing an informed consent form (ICF) that has been approved 
by an Institutional Review Board (IRB) (patients who are willing to 
comply with the protocol, including consent to hospitalization during 
Course 1). 
Exclusion Criteria 
Patients falling under any of the following criteria at the time of screening will be 
excluded from this trial: 
1) Patients with acute promyelocytic leukemia (APL) accompanied by 
t (15;17) (q22;q12) or (PML/RARA) karyotype abnormalities (including 
other variant types of APL). 
2) Patients with multiple cancers (except for adequately treated basal cell 
or squamous cell skin cancer, in situ cervical cancer, or other cancer 
from which the subject has been disease free for at least 3 years). 


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3) Patients with life-threatening illnesses other than AML, such as 
uncontrolled medical conditions or organ system dysfunction which, in 
the opinion of the investigator or subinvestigator, could compromise the 
subject’s safety or the study outcomes. 
4) Patients with poorly controlled arrhythmias, or any Class 3 or 4 cardiac 
disease as defined by the New York Heart Association (NYHA) 
Functional Classification. 
5) Patients with symptomatic central nervous system involvement. 
6) Patients who have received radiation therapy for extramedullary disease 
within 2 weeks prior to planned enrollment. 
7) Patients with AEs (other than alopecia) of Grade 2 or higher from prior 
therapy for AML, at the time of screening for this trial. 
8) Patients with febrile neutropenia. 
9) Patients who are human immunodeficiency virus (HIV) antibody 
positive, hepatitis B virus (HBV)-DNA positive, or with active hepatitis 
C. 
10) Patients who have taken any investigational drug or individually 
imported drug within 2 weeks prior to the scheduled start of IMP 
administration. 
11) Patients who have been treated with systemic corticosteroids as 
treatment for their AML within 2 weeks prior to the scheduled start of 
IMP administration. 
12) Patients with uncontrolled active systemic infections. 
13) Patients who have hypersensitivity to decitabine, SGI-110, or IMP 
excipients. 
14) Patients judged to be ineligible by the investigator or subinvestigator for 
any other reason. 
Discontinuation 
Criteria 
1) Apparent progression (including the relapse) of the primary disease. 
2) DLT that does not improve to the baseline level or show improvement 
by at least 1 grade within 4 weeks, or occurrence of another DLT. 
3) Delay in commencement of the next course by more than 4 weeks due to 
an AE, unless the investigator or subinvestigator judges that 
continuation of SGI-110 administration is in the patient’s best interest, 
in which case the delay may be extended by another 2 weeks. 
4) Subject becomes pregnant. 
5) Subject wishes to withdraw from the trial. 
6) The investigator or subinvestigator judges that it is difficult to continue 
IMP administration due to occurrence of an AE. 
7) The investigator or subinvestigator judges that it is necessary to 
discontinue IMP administration for any other reason. 
Investigational 
Medicinal Products, 
Dose and Regimen, 
and Treatment Period 
[Investigational medicinal product] 
SGI-110 for injection, 100 mg:  A 5-mL glass vial contains SGI-110 equivalent 
to 100 mg of free acid, as a lyophilized powder. 
SGI-110 diluent for reconstitution, 3 mL:  A 5-mL glass vial contains 3 mL of 
custom diluent for reconstitution. 
[Dose and regimen, treatment period] 
The total daily dose will be determined based on the subject’s BSA calculated 
from height and weight prior to administration in each course, according to the 
treatment cohort. 
SGI-110 will be administered subcutaneously at the determined daily dose after 
being reconstituted using the custom diluent provided. 


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In Cohorts 1, 2, and 4, subjects will receive SGI-110 once daily for 5 consecutive 
days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 
28).  One course will consist of 4 weeks (28 days).  In Cohort 3, subjects will 
receive SGI-110 once daily for 10 days in total (SGI-110 will be administered for 
5 consecutive days [Day 1 to Day 5], suspended for 2 days [Day 6 and Day 7], 
then administered for another 5 consecutive days [Day 8 to Day 12]), followed by 
a 16-day non-dosing period (Day 13 to Day 28).  One course will consist of 4 
weeks (28 days).  Refer to Section 6 Trial Design, for the detailed dose and 
regimen after the DLT evaluation period. 
The dose and regimen for each cohort is as follows: 
Cohort 1 (36 mg/m2, 5-day administration) 
Cohort 2 (60 mg/m2, 5-day administration) 
Cohort 3 (60 mg/m2, 10-day administration [ie, 5-day administration twice, 
with a non-dosing period in-between]) 
Cohort 4 (90 mg/m2, 5-day administration) 
Prohibited 
Concomitant Drugs or 
Therapies 
Only the IMP will be used for treating the primary disease, and concomitant use 
of the drugs and therapies listed below is prohibited from the time of informed 
consent to the end of the withdrawal examination. 
 
Other anti-cancer drugs, hormone therapy, antibody therapy, radiation 
therapy, thermal therapy, or other anti-cancer therapies 
 
Other investigational drugs and individually imported drugs 
 
Prophylactic therapies for the purpose of preventing AEs (except 
infection) (Prophylactic therapies to prevent recurrence of AEs observed 
after the start of the IMP administration will be allowed.) 
Endpoints 
Safety 
<Primary endpoint> 
 
DLT 
<Secondary endpoints> 
 
AEs, clinical laboratory values, vital signs (blood pressure, pulse rate, 
body temperature), body weight, ECOG PS, 12-lead electrocardiogram 
(ECG), chest X-ray 
Efficacy endpoints 
 
Complete remission rate, composite complete remission rate, overall 
remission rate, overall survival, and composite complete remission 
duration 
Pharmacokinetic endpoints 
 
SGI-110 and decitabine plasma concentrations, PK parameters 
Pharmacodynamics endpoint 
 
Extent of DNA hypomethylation in long interspersed nucleotide 
element-1 (LINE-1) 
Scheduled Trial 
Duration 
Overall trial duration:  01 Oct 2014 to 31 Dec 2019 
1) Cohorts 1, 2, and 4  
(Primary evaluation part [Cohorts 1, 2, and 4]) 
01 Oct 2014 to 31 May 2016 
(Extended treatment part [Cohorts 1, 2, and 4]) 
01 Jun 2016 to 31 Dec 2019 
2) Cohort 3 
(Primary evaluation part [Cohort 3]) 
01 Sep 2016 to 30 Nov 2017 
(Extended treatment part [Cohort 3]) 
01 Dec 2017 to 31 Dec 2019 


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Schedule of Events (Refer to 7.1 Schedule and Procedures) - Cohorts 1, 2, and 4 (5-day Regimen) 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationa
 
 
 
Course 1 (DLT Evaluation Period)b
 
Course 2 (Extended Treatment 
Period) 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D15 D22 D29c
 D1 D2-
D5 D8 D15 D22 D29c
 D1 D2-
D5 D15 D29c
 
D1-
D5 
D29 Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 
1 
2 
3 
4 
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Written Consentd
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
Patient Background Investigation 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of Concomitant Drugs and Blood 
Transfusione
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
○ 
Investigation of AEs 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
○ 
Medical Examination by Investigator or 
Subinvestigator (Subjective and Objective 
Findings) 
○ 
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Pregnancy Test (Urine or Serum Test)f
 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
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Viral Testg
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
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Verification of Eligibility, Enrollment 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsh
 
 
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□ 
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○ 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weighti
 
 
 
□ 
 
 
 
 
 
 
 
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Twelve-lead ECG 
 
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□ 
 
 
 
 
 
 
 
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Chest X-ray 
 
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Cardiac Function or Respiratory Functionj
 
 
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Hematology Testk
 
 
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Blood Biochemistry Testl
 
 
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Urinalysism
 
 
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Schedule of Events (Refer to 7.1 Schedule and Procedures) - Cohorts 1, 2, and 4 (5-day Regimen) 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationa
 
 
 
Course 1 (DLT Evaluation Period)b
 
Course 2 (Extended Treatment 
Period) 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D15 D22 D29c
 D1 D2-
D5 D8 D15 D22 D29c
 D1 D2-
D5 D15 D29c
 
D1-
D5 
D29 Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 
1 
2 
3 
4 
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
ECOG PS 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Bone Marrow Aspirationn
 
 
○ 
 
 
 
 
 
 
 
 
○ 
············································· ···························· 
 
 
○ 
Blood Sampling for PKo
 
 
 
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Blood Sampling for PDp
 
 
 
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Evaluation of Efficacyq
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
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○ 
 
 
○ 
○:  Mandatory item 
□:  If such tests or examinations have already been conducted within 4 days before Day 1, those tests/examinations may be used as the Day 1 tests/examinations. 
◊:  Optional item related to inclusion criteria 
a
If the withdrawal examination is performed within the acceptable time window for Day 8, Day 15, Day 22, or Day 29, repeated tests/examinations are not necessary for those items already 
performed for the same day.  If the discontinuation is due to a serious adverse event (SAE) or progression of disease, only those examinations that are feasible, given the subject’s state of health, 
will be performed. 
b
Hospitalization during Course 1 is mandatory.  For those subjects for whom the trial is concluded with Course 1, hospitalization until the withdrawal examination is mandatory.  For those subjects 
who continue to receive IMP administration in Course 2 and subsequent courses, hospitalization until commencement of IMP administration in Course 2 is mandatory. 
c
If IMP administration for the next course is started from Day 29, the tests designated for Day 29 should be performed between Day 26 and before IMP administration on Day 32.  (If the tests 
designated for Day 29 are performed within the acceptable time window, between Day 26 and Day 28, IMP administration for the next course will be started on or after Day 29.) 
d
Written consent at screening will be obtained prior to all observations, tests, examinations, and evaluations of this trial.  Written consent for continuation of IMP administration in Course 2 and 
subsequent courses will be obtained before the start of Course 2 (after Day 22 administration of Course 1). 
e
Details on all concomitant medications taken from 28 days before the start of IMP administration until discontinuation will be collected.  Information on any blood transfusions administered from 
28 days before the start of IMP administration until 30 days after the last administration will also be collected.  (If the subject starts another AML treatment or is transferred to another hospital, 
collection of such data will be continued up until that point.) 
f
To be performed for female subjects only.  (However, a pregnancy test is not required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who have been 
amenorrheic without a medical cause for at least 12 consecutive months.) 


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g
Human immunodeficiency virus antibody, HBV-DNA, hepatitis C virus (HCV) antibody, hepatitis B core antibody (HBcAB), and hepatitis B surface antibody (HBsAB) tests will be performed at 
screening.  For those subjects who are found to be either HBcAB or HBsAB positive at screening, a test for HBV-DNA will be done on Day 1 in Course 2 and subsequent courses. 
h
Blood pressure (systolic/diastolic), pulse rate, body temperature (measured after the subject has rested in the sitting position for at least 3 minutes) 
i
Body weight will be measured and the dose of IMP to be administered will be determined according to the calculation of BSA. 
j
Cardiac function (echocardiography or multiple-gated acquisition [MUGA] scan) or respiratory function (DLCO or FEV 1) will be measured. 
k
Hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC), white blood cell (WBC), differential WBC (visual count:  blast cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, promonocytes), platelet count, reticulocytes 
l
AST (glutamate oxaloacetate transaminase [GOT]), ALT (glutamate pyruvate transaminase [GPT]), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein (TP), albumin (ALB), 
T-Bil, blood urea nitrogen (BUN), uric acid (UA), Cr, blood glucose (fasting), Ca, Mg, Na, K, Cl 
m
Bilirubin, occult blood, protein, urobilinogen 
n
Bone marrow aspiration will be performed at screening and on Day 29 of Course 1.  In Course 2 and subsequent courses, if peripheral blood testing indicates that the subject meets criteria for 
remission, or if clear disease progression is observed, bone marrow aspiration will be performed and the following items will be examined:  percentage of bone marrow fluid (blasts, lymphoblasts, 
monoblasts, promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, pronormoblasts, erythroblasts, 
plasma cells, and megakaryocytes), myeloid/erythroid ratio (M/E ratio), cellularity. 
(If bone marrow aspiration has already been performed and any of the above items have been measured prior to acquisition of written informed consent and within the acceptable time window for 
the screening period [within 28 days before commencement of IMP administration], then those results can be used as the screening data, provided the subject’s consent is obtained.) 
o
Blood sampling for PK: 
Day 1 and Day 5:  predose, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours after dosing 
Day 2 (24 hours after Day 1 dosing), Day 3, and Day 4:  predose (predose on Day 2 is the same as 24 hours postdose on Day 1) 
[Acceptable time windows] 
Day 1 and Day 5 
predose: 
Day 1:  within 2 hours before IMP administration 
 
 
Day 5:  ± 30 minutes of 24 hours from Day 4 dosing and before the Day 5 dosing 
 
15 minutes and 30 minutes postdose: 
± 3 minutes 
 
60 minutes, 90 minutes, and 2 hours postdose: 
± 6 minutes 
 
3 hours and 4 hours postdose: 
± 12 minutes 
 
6 hours and 8 hours postdose: 
± 24 minutes 
 
24 hours postdose: 
± 30 minutes (24 hours postdose on Day 1 should be performed before Day 2 dosing) 
Day 2, Day 3, Day 4 
predose: 
± 30 minutes of 24 hours from the previous dosing and before the dosing on that day 
p
Blood sampling for PD:  blood sampling performed during screening is also acceptable for Day 1 sampling.  If the sampling is performed on Day 1, it must be performed before dosing. 
q
In Course 2 and subsequent courses, evaluation of efficacy will be performed if peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease progression is 
observed. 
 


Protocol No. 343-14-001 
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11  
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Schedule of Events (Refer to 7.1 Schedule and Procedures) - Cohort 3 (10-day Regimen):  10-day Regimen in Course 2 
(Extended Treatment Period) 
 
 
Primary Evaluation Part 
 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
Course 2 (Extended Treatment Period)b
 
Course 3 and 
Subsequent 
Courses (Extended 
Treatment Period) 
 
Extended 
Course 
 
Screening D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
11 
D 
12 
D 
15 
D 
22 D29d
 
D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
12 
D 
15 
D 
22 
D29d
 
D
1 
D2-
D5 
D 
15 D29d
 
D1-5 
D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time 
Window (Day) 
−28 
−14 1 2 3 4 
5 
8 
9-
11 12 13-
18 
19-
25 26-32 1 2 
3 4 5 8 9-12 
13-
18 
19-
25 
26-32 
1 
2-5 12-
18 26-32 
1-5 
 
Written Consente
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
Patient Background 
Investigation 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of 
Concomitant Drugs and 
Blood Transfusionf
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−−−−− 
○ 
Investigation of AEs 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−−−−− 
○ 
Medical Examination by 
Investigator or 
Subinvestigator 
(Subjective and Objective 
Findings) 
○ 
○ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
○ 
○ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy Test (Urine or 
Serum Test)g
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
Viral Testh
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
Verification of Eligibility, 
Enrollment 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
      
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
Vital Signsi
 
 
○ 
○ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
○ 
□ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
 
 
○ 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weightj
 
 
 
□  
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
□ 
 
 
 
 
 
○ 
Twelve-lead ECG 
 
○ 
□  
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Chest X-ray 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 


Protocol No. 343-14-001 
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12  
Version 8 
Schedule of Events (Refer to 7.1 Schedule and Procedures) - Cohort 3 (10-day Regimen):  10-day Regimen in Course 2 
(Extended Treatment Period) 
 
 
Primary Evaluation Part 
 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
Course 2 (Extended Treatment Period)b
 
Course 3 and 
Subsequent 
Courses (Extended 
Treatment Period) 
 
Extended 
Course 
 
Screening D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
11 
D 
12 
D 
15 
D 
22 D29d
 
D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
12 
D 
15 
D 
22 
D29d
 
D
1 
D2-
D5 
D 
15 D29d
 
D1-5 
D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time 
Window (Day) 
−28 
−14 1 2 3 4 
5 
8 
9-
11 12 13-
18 
19-
25 26-32 1 2 
3 4 5 8 9-12 
13-
18 
19-
25 
26-32 
1 
2-5 12-
18 26-32 
1-5 
 
Cardiac Function or 
Respiratory Functionk
 
 
◊ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology Testl
 
 
○ 
□  
 
 
 
○ 
 
 
○ 
○ 
○ 
□ 
 
 
 
 
○ 
 
○ 
○ 
○ 
□ 
 
○ 
○ 
□ 
 
○ 
Blood Biochemistry 
Testm
 
 
○ 
□  
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
Urinalysisn
 
 
○ 
□  
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
ECOG PS 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Bone Marrow Aspirationo
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
····································································· ························· 
 
 
○ 
Blood Sampling for PKp
 
 
 
○ ○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for PDq
 
 
 
○  
 
 
 
○ 
 
 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of Efficacyr
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
 


Protocol No. 343-14-001 
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13  
Version 8 
Schedule of Events (Refer to 7.1 Schedule and Procedures) -Cohort 3 (10-day Regimen):  5-day Regimen in Course 2 
(Extended Treatment Period) 
 
 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
 
Course 2 (Extended Treatment 
Period)b
 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D9
-11 D12 D15 D22 D29d
 D1 D2
-5 D8 D15 D22 D29d
 D1 
D2-
D5 
D15 D29d
 
D1-5 D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 1 
2 
3 
4 
5 
8 
9-
11 
12 
13-
18 
19-
25 
26-32 
1 
2-
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Written Consente
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
Patient Background Investigation 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of Concomitant Drugs 
and Blood Transfusionf
 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
 
Investigation of AEs 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
 
Medical Examination by Investigator 
or Subinvestigator (Subjective and 
Objective Findings) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy Test (Urine or Serum 
Test)g
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
Viral Testh
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
 
 
 
Verification of Eligibility, Enrollment 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsi
 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
 
 
○ 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weightj
 
 
 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
□ 
 
 
 
 
 
○ 
Twelve-lead ECG 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Chest X-ray 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Cardiac Function or Respiratory 
Functionk
 
 
◊ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
14  
Version 8 
Schedule of Events (Refer to 7.1 Schedule and Procedures) -Cohort 3 (10-day Regimen):  5-day Regimen in Course 2 
(Extended Treatment Period) 
 
 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
 
Course 2 (Extended Treatment 
Period)b
 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D9
-11 D12 D15 D22 D29d
 D1 D2
-5 D8 D15 D22 D29d
 D1 
D2-
D5 
D15 D29d
 
D1-5 D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 1 
2 
3 
4 
5 
8 
9-
11 
12 
13-
18 
19-
25 
26-32 
1 
2-
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Hematology Testl
 
 
○ 
□ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
□ 
 
○ 
○ 
○ 
○ 
□ 
 
○ 
○ 
□ 
 
○ 
Blood Biochemistry Testm
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
○ 
□ 
 
 
 
○ 
 
 
○ 
Urinalysisn
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
ECOG PS 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Bone Marrow Aspirationo
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
········································· 
······························ 
 
 
○ 
Blood Sampling for PKp
 
 
 
○ 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for PDq
 
 
 
○ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of Efficacyr
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
○:  Mandatory item 
□:  If such tests or examinations have already been conducted within 4 days before Day 1, those tests/examinations may be used as the Day 1 tests/examinations. 
◊:  Optional item related to inclusion criteria 
a
Hospitalization during Course 1 is mandatory.  For those subjects for whom the trial is concluded with Course 1, hospitalization until the withdrawal examination is mandatory.  For those subjects 
who continue to receive IMP administration in Course 2 and subsequent courses, hospitalization until commencement of IMP administration in Course 2 is mandatory. 
b
Based on the subject’s condition (the percentage of blasts in the peripheral blood and bone marrow, and peripheral blood cell counts) at the completion of Course 1, it will be determined whether or 
not the transition to Course 2 should be postponed and which regimen is used for each subject.  
c
If the withdrawal examination is performed within the acceptable time window for Day 15, Day 22, or Day 29, repeated tests/examinations are not necessary for those items already performed for 
the same day.  If the discontinuation is due to a serious adverse event (SAE) or progression of disease, only those examinations that are feasible, given the subject’s state of health, will be 
performed. 


Protocol No. 343-14-001 
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Version 8 
d
If IMP administration for the next course is started from Day 29, the tests designated for Day 29 should be performed between Day 26 and before IMP administration on Day 32.  (If the tests 
designated for Day 29 are performed within the acceptable time window, between Day 26 and Day 28, IMP administration for the next course will be started on or after Day 29.) 
e
Written consent at screening will be obtained prior to all observations, tests, examinations, and evaluations of this trial.  Written consent for continuation of IMP administration in Course 2 and 
subsequent courses will be obtained before the start of Course 2 (after Day 22 administration of Course 1). 
f
Details on all concomitant medications taken from 28 days before the start of IMP administration until discontinuation will be collected.  Information on any blood transfusions administered from 
28 days before the start of IMP administration until 30 days after the last administration will also be collected.  (If the subject starts another AML treatment or is transferred to another hospital, 
collection of such data will be continued up until that point.) 
g
To be performed for female subjects only.  (However, a pregnancy test is not required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who have been 
amenorrheic without a medical cause for at least 12 consecutive months.) 
h
Human immunodeficiency virus antibody, HBV-DNA, hepatitis C virus (HCV) antibody, hepatitis B core antibody (HBcAB), and hepatitis B surface antibody (HBsAB) tests will be performed at 
screening.  For those subjects who are found to be either HBcAB or HBsAB positive at screening, a test for HBV-DNA will be done on Day 1 in Course 2 and subsequent courses. 
i
Blood pressure (systolic/diastolic), pulse rate, body temperature (measured after the subject has rested in the sitting position for at least 3 minutes) 
j
Body weight will be measured and the dose of IMP to be administered will be determined according to the calculation of BSA. 
k
Cardiac function (echocardiography or multiple-gated acquisition [MUGA] scan) or respiratory function (DLCO or FEV 1) will be measured. 
l
Hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC), white blood cell (WBC), differential WBC (visual count:  blast cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, promonocytes), platelet count, reticulocytes 
m
AST (glutamate oxaloacetate transaminase [GOT]), ALT (glutamate pyruvate transaminase [GPT]), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein (TP), albumin (ALB), 
T-Bil, blood urea nitrogen (BUN), uric acid (UA), Cr, blood glucose (fasting), Ca, Mg, Na, K, Cl 
n
Bilirubin, occult blood, protein, urobilinogen 
o
Bone marrow aspiration will be performed at screening and on Day 29 of Course 1.  In Course 2 and subsequent courses, if peripheral blood testing indicates that the subject meets criteria for 
remission, or if clear disease progression is observed, bone marrow aspiration will be performed and the following items will be examined:  percentage of bone marrow fluid (blasts, lymphoblasts, 
monoblasts, promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, pronormoblasts, erythroblasts, 
plasma cells, and megakaryocytes), myeloid/erythroid ratio (M/E ratio), cellularity. 
(If bone marrow aspiration has already been performed and any of the above items have been measured prior to acquisition of written informed consent and within the acceptable time window for 
the screening period [within 28 days before commencement of IMP administration], then those results can be used as the screening data, provided the subject’s consent is obtained.) 
p
Blood sampling for PK: 
Day 1 and Day 12:  predose, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours after dosing 
Day 5:  90 minutes, 6 hours after dosing 
[Acceptable time windows] 
Day 1 and Day 12 
predose: 
Day 1:  within 2 hours before IMP administration 
 
 
Day 12:  ± 30 minutes of 24 hours from Day 11 dosing and before the Day 12 dosing 
 
15 minutes and 30 minutes postdose: 
± 3 minutes 
 
60 minutes, 90 minutes, and 2 hours postdose: 
± 6 minutes 
 
3 hours and 4 hours postdose: 
± 12 minutes 


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Version 8 
 
6 hours and 8 hours postdose: 
± 24 minutes 
 
24 hours postdose: 
± 30 minutes (24 hours postdose on Day 1 should be performed before Day 2 dosing) 
Day 5 
90 minutes postdose: 
± 6 minutes 
 
6 hours postdose: 
± 24 minutes 
q
Blood sampling for PD:  blood sampling performed during screening is also acceptable for Day 1 sampling.  If the sampling is performed on Day 1, it must be performed before dosing. 
r
In Course 2 and subsequent courses, evaluation of efficacy will be performed if peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease progression is 
observed. 
 


Protocol No. 343-14-001 
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Version 8 
Table of Contents 
Trial Protocol Synopsis ................................................................................. 3 
Table of Contents ......................................................................................... 17 
List of Abbreviations and Definition of Terms ......................................... 24 
1 
Introduction ........................................................................................ 28 
1.1 
Background of Trial Plan .................................................................................. 28 
1.2 
Study Results and Trial Rationale..................................................................... 29 
1.2.1 
Nonclinical Study Results .............................................................................. 29 
1.2.1.1 
Pharmacology ............................................................................................. 30 
1.2.1.2 
Safety Pharmacology .................................................................................. 30 
1.2.1.3 
Toxicity ....................................................................................................... 31 
1.2.1.4 
Genotoxicity and Mutagenicity .................................................................. 31 
1.2.1.5 
Carcinogenicity ........................................................................................... 31 
1.2.1.6 
Reproductive Toxicity ................................................................................ 31 
1.2.1.7 
Pharmacokinetics ........................................................................................ 31 
1.2.2 
Clinical Study Results .................................................................................... 32 
1.2.2.1 
Preliminary Results from Ongoing Clinical Studies .................................. 32 
1.2.2.1.1 
Phase 1/2 Study:  SGI-110-01 (AML/MDS; Monotherapy; United 
States and Canada) .................................................................................. 33 
1.2.2.1.1.1 
SGI-110-01 Phase 1 Dose Escalation Segment (AML/MDS; 
Monotherapy) ...................................................................................... 33 
1.2.2.1.1.2 
SGI-110-01 Phase 2 Dose Expansion Segment (AML/MDS; 
Monotherapy) ...................................................................................... 36 
1.2.2.1.2 
Pharmacokinetics in Study SGI-110-01 .................................................. 38 
1.2.2.1.3 
Pharmacodynamics in Study SGI-110-01 ............................................... 39 
1.2.3 
Trial Rationale ................................................................................................ 40 
2 
Trial Objectives .................................................................................. 42 
2.1 
Primary Objective ............................................................................................. 42 
3 
Trial Plan ............................................................................................. 43 
3.1 
Trial Design ...................................................................................................... 43 
3.2 
Rationale for Trial Design ................................................................................ 45 
3.3 
Endpoints .......................................................................................................... 46 


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3.3.1 
Safety .............................................................................................................. 46 
3.3.1.1 
Primary Endpoint (Primary Evaluation Part) ............................................. 46 
3.3.1.2 
Secondary Endpoints .................................................................................. 46 
3.3.2 
Efficacy Endpoints (Primary Evaluation Part) ............................................... 47 
3.3.3 
Pharmacokinetic Endpoints (Primary Evaluation Part) ................................. 47 
3.3.4 
Pharmacodynamic Endpoint (Primary Evaluation Part) ................................ 47 
3.4 
Target Number of Patients ................................................................................ 48 
3.5 
Rules to Be Observed for Enrollment and Treatment ....................................... 48 
4 
Investigational Medicinal Products .................................................. 48 
4.1 
Test Product and Comparator ........................................................................... 48 
4.1.1 
Test Product .................................................................................................... 48 
4.1.2 
Comparator ..................................................................................................... 49 
4.2 
Packaging and Labeling .................................................................................... 49 
4.2.1 
Packaging ....................................................................................................... 49 
4.2.2 
Contents of Label ........................................................................................... 49 
5 
Trial Population .................................................................................. 49 
5.1 
Target Disease ................................................................................................... 49 
5.2 
Inclusion Criteria .............................................................................................. 49 
5.3 
Exclusion Criteria ............................................................................................. 51 
6 
Trial Design ......................................................................................... 53 
6.1 
Dose, Regimen, and Treatment Period ............................................................. 53 
6.2 
Prior and Concomitant Treatment ..................................................................... 56 
6.2.1 
Prohibited Concomitant Drugs and Therapies ............................................... 56 
6.2.2 
Restricted Concomitant Drugs and Therapies ................................................ 56 
6.3 
Method of Minimizing or Avoiding Bias ......................................................... 57 
7 
Trial Procedures ................................................................................. 58 
7.1 
Schedule and Procedures .................................................................................. 58 
7.1.1 
Acquisition of Informed Consent ................................................................... 68 
7.1.2 
Screening Examination .................................................................................. 68 
7.1.3 
Subject Registration ....................................................................................... 69 
7.1.4 
Observations, Examinations, and Evaluations During the Treatment 
Period ............................................................................................................. 70 


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7.1.4.1 
Cohorts 1, 2, and 4 (5-day regimen) ........................................................... 70 
7.1.4.1.1 
Day 1 of Course 1 ................................................................................... 70 
7.1.4.1.2 
Day 2 to Day 5 of Course 1 ..................................................................... 71 
7.1.4.1.3 
Day 8, Day 15, and Day 22 of Course 1 ................................................. 71 
7.1.4.1.4 
Day 29 of Course 1 ................................................................................. 71 
7.1.4.1.5 
Day 1 of Course 2 ................................................................................... 72 
7.1.4.1.6 
Day 2 to Day 5 of Course 2 ..................................................................... 73 
7.1.4.1.7 
Day 8, Day 15, and Day 22 of Course 2 ................................................. 73 
7.1.4.1.8 
Day 29 of Course 2 ................................................................................. 73 
7.1.4.1.9 
Day 1 of Course 3 and Subsequent Courses ........................................... 74 
7.1.4.1.10 
Day 2 to Day 5 of Course 3 and Subsequent Courses ............................ 75 
7.1.4.1.11 
Day 15 of Course 3 and Subsequent Courses ......................................... 75 
7.1.4.1.12 
Day 29 of Course 3 and Subsequent Courses ......................................... 75 
7.1.4.1.13 
Day 1 to Day 29 of the Extended Course in the Extended 
Treatment Part ......................................................................................... 76 
7.1.4.2 
Cohort 3 (10-day regimen) ......................................................................... 76 
7.1.4.2.1 
Day 1 of Course 1 ................................................................................... 76 
7.1.4.2.2 
Day 2 to Day 5 and Day 9 to Day 12 of Course 1 .................................. 77 
7.1.4.2.3 
Day 8, Day 15, and Day 22 of Course 1 ................................................. 78 
7.1.4.2.4 
Day 29 of Course 1 ................................................................................. 78 
7.1.4.2.5 
Day 1 of Course 2 (10-day regimen) ...................................................... 79 
7.1.4.2.6 
Day 2 to Day 5 and Day 9 to Day 12 of Course 2 (10-day regimen) ..... 80 
7.1.4.2.7 
Day 8, Day 15, and Day 22 of Course 2 (10-day regimen) .................... 80 
7.1.4.2.8 
Day 29 of Course 2 (10-day regimen) .................................................... 80 
7.1.4.2.9 
Day 1 of Course 2 (5-day regimen) ........................................................ 81 
7.1.4.2.10 
Day 2 to Day 5 of Course 2 (5-day regimen) .......................................... 81 
7.1.4.2.11 
Day 8, Day 15, and Day 22 of Course 2 (5-day regimen) ...................... 82 
7.1.4.2.12 
Day 29 of Course 2 (5-day regimen) ...................................................... 82 
7.1.4.2.13 
Day 1 of Course 3 and Subsequent Courses (5-day regimen) ................ 82 
7.1.4.2.14 
Day 2 to Day 5 of Course 3 and Subsequent Courses (5-day 
regimen) .................................................................................................. 83 
7.1.4.2.15 
Day 15 of Course 3 and Subsequent Courses (5-day regimen) .............. 83 
7.1.4.2.16 
Day 29 of Course 3 and Subsequent Courses (5-day regimen) .............. 84 


Protocol No. 343-14-001 
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7.1.4.2.17 
Day 1 to Day 29 of the Extended Course in the Extended 
Treatment Part ......................................................................................... 84 
7.1.5 
Observations, Examinations, and Evaluations at the Time of 
Withdrawal ..................................................................................................... 84 
7.2 
Method of Evaluation ....................................................................................... 85 
7.2.1 
Safety Evaluation (Primary Evaluation Part) ................................................. 85 
7.2.1.1 
Clinical Symptoms ..................................................................................... 85 
7.2.1.2 
Dose Limiting-toxicities and Adverse Events ............................................ 86 
7.2.1.3 
Body Weight ............................................................................................... 86 
7.2.1.4 
General Condition ....................................................................................... 86 
7.2.1.5 
Vital Signs (Blood Pressure, Pulse Rate, and Body Temperature)............. 86 
7.2.1.6 
Twelve-lead Electrocardiogram .................................................................. 86 
7.2.1.7 
Chest X-ray ................................................................................................. 87 
7.2.1.8 
Hematology Test, Blood Biochemistry Test, and Urinalysis ..................... 87 
7.2.2 
Safety Evaluation (Extended Treatment Part) ................................................ 87 
7.2.2.1 
Clinical Symptoms ..................................................................................... 87 
7.2.2.2 
Adverse Events ........................................................................................... 87 
7.2.2.3 
Hematology Test ......................................................................................... 88 
7.2.3 
Efficacy Evaluation ........................................................................................ 88 
7.2.3.1 
Assessment Based on Response Criteria .................................................... 88 
7.2.3.2 
Outcome of Survival ................................................................................... 89 
7.2.3.3 
Investigations of Acute Myeloid Leukemia Treatments after Trial 
Discontinuation ........................................................................................... 89 
7.2.4 
Pharmacokinetic Evaluation ........................................................................... 89 
7.2.5 
Pharmacodynamic Evaluation ........................................................................ 91 
7.2.6 
Investigational Medicinal Product Compliance ............................................. 92 
7.3 
Measures to Be Taken for Subjects Visiting or Planning to Visit Other 
Hospitals or Departments .................................................................................. 92 
8 
Adverse Events ................................................................................... 93 
8.1 
Definitions......................................................................................................... 93 
8.1.1 
Adverse Event ................................................................................................ 93 
8.1.2 
Serious Adverse Event ................................................................................... 93 
8.2 
Response to Occurrence of Adverse Events ..................................................... 94 
8.2.1 
Actions to Be Taken for Subjects ................................................................... 94 


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8.2.2 
Expedited Reporting of Serious Adverse Events and Dose-limiting 
Toxicities ........................................................................................................ 94 
8.2.3 
Expedited Reporting of Non-serious Adverse Events Resulting in 
Discontinuation of IMP Administration ......................................................... 95 
8.3 
Assessment of Adverse Events ......................................................................... 95 
8.3.1 
Terms for Adverse Events .............................................................................. 95 
8.3.2 
Date of Onset and Recovery ........................................................................... 96 
8.3.3 
Severity (Grade) ............................................................................................. 96 
8.3.4 
Causal Relationship With Investigational Medicinal Product ....................... 96 
8.3.5 
Actions to Be Taken Regarding IMP Administration .................................... 97 
8.3.6 
Actions to Be Taken for Adverse Events ....................................................... 98 
8.3.7 
Outcome ......................................................................................................... 98 
8.4 
Follow-up Investigation of Adverse Events ..................................................... 98 
8.5 
Pregnancy .......................................................................................................... 99 
8.5.1 
Guidance to Subjects Including Contraceptive Methods ............................... 99 
8.5.2 
Actions to Be Taken by the Investigator or Subinvestigator When 
Pregnancy Is Suspected ................................................................................ 100 
8.5.3 
Actions to Be Taken by the Investigator or Subinvestigator When a 
Subject Is Discovered to Be Pregnant .......................................................... 100 
8.5.4 
Expedited Reporting of Pregnancy .............................................................. 100 
8.5.5 
Follow-up Investigation of Pregnancy ......................................................... 101 
9 
Withdrawal of Individual Subjects From the Trial ...................... 101 
9.1 
Screen Failure ................................................................................................. 101 
9.2 
Criteria and Procedures for Withdrawal of Individual Subjects ..................... 101 
9.3 
Follow-up Investigation of Subjects Who Do not Visit the Trial Site ............ 102 
10 
Collection of Case Report Form Data and Specification of 
Source Data ....................................................................................... 102 
10.1 
Collection of Case Report Form Data ............................................................. 102 
10.2 
Source Documents .......................................................................................... 103 
10.3 
Case Report Form Items to Be Treated as Source Data .................................. 104 
10.4 
Data to Be Collected by the Sponsor .............................................................. 104 
11 
Statistical Analysis ............................................................................ 104 
11.1 
Statistical Analysis Sets .................................................................................. 104 
11.1.1 
Safety Analysis Set ....................................................................................... 104 


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11.1.1.1 
Dose-limiting Toxicity Analysis Set ........................................................ 105 
11.1.2 
Efficacy Analysis Set ................................................................................... 105 
11.1.3 
Pharmacokinetic Analysis Set ...................................................................... 105 
11.1.4 
Pharmacodynamic Analysis Set ................................................................... 105 
11.2 
Handling of Data ............................................................................................. 105 
11.3 
Analysis Items and Method ............................................................................ 105 
11.3.1 
Safety Analysis ............................................................................................. 105 
11.3.1.1 
Primary Endpoint ...................................................................................... 105 
11.3.1.2 
Secondary Endpoints ................................................................................ 106 
11.3.2 
Efficacy Analysis ......................................................................................... 107 
11.3.3 
Pharmacokinetic Analysis ............................................................................ 108 
11.3.4 
Pharmacodynamic Analysis ......................................................................... 109 
11.3.5 
Demographic and Other Baseline Characteristics ........................................ 110 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan .................................................................................................. 110 
11.5 
Rationale for Target Number of Patients ........................................................ 110 
12 
Quality Control and Quality Assurance for the Trial .................. 111 
13 
General Items of Caution Pertaining to the Trial ......................... 111 
13.1 
Ethics and Good Clinical Practice Compliance .............................................. 111 
13.2 
Institutional Review Board ............................................................................. 111 
13.3 
Subject Consent .............................................................................................. 111 
13.3.1 
Procedures for Obtaining Consent ............................................................... 111 
13.3.2 
Contents of Written Information for Subjects and Informed Consent 
Form ............................................................................................................. 112 
13.3.3 
Amendments to the Written Information for Subjects or Informed 
Consent Form ............................................................................................... 113 
13.4 
Management of Investigational Medicinal Products ...................................... 113 
13.5 
Direct Access to Source Documents and Monitoring ..................................... 114 
13.5.1 
Direct Access to Source Documents ............................................................ 114 
13.5.2 
Monitoring .................................................................................................... 114 
13.5.3 
Documents to Be Retained by the Investigator ............................................ 114 
13.6 
Deviations From and Changes or Amendments to the Trial Protocol ............ 114 
13.6.1 
Deviations From the Trial Protocol .............................................................. 114 


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13.6.2 
Amendments to the Trial Protocol ............................................................... 115 
13.7 
Archiving of Records ...................................................................................... 115 
13.8 
Termination or Interruption of Part or All of the Trial ................................... 115 
13.8.1 
Termination or Interruption of the Trial at Individual Trial Sites ................ 115 
13.8.2 
Termination or Interruption of the Entire Trial ............................................ 115 
13.9 
Protection of Subjects’ Personal Information ................................................. 116 
13.10 
Compensation for Injury to Health ................................................................. 116 
13.11 
Agreement on Publication............................................................................... 116 
14 
Trial Administrative Structure ....................................................... 116 
15 
Scheduled Duration of the Trial ..................................................... 117 
16 
References ......................................................................................... 117 
 
Annex 1: 
Emergency Contact 
Annex 2: 
Trial Organization 
Annex 3: 
Lists of Trial Sites and Investigators Participating in the Trial 


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List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion 
ADL 
Activities of daily living 
AE 
Adverse event 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
APL 
Acute promyelocytic leukemia 
AST 
Aspartate aminotransferase 
BED 
Biologically effective dose 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
BW 
Body Weight 
CMML 
Chronic myelomonocytic leukemia 
Cr 
Creatinine 
CR 
Complete remission 
CRF 
Case report form 
CRi 
Complete remission with incomplete blood count recovery 
CRp 
Complete remission with incomplete platelet recovery 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DLT 
Dose-limiting toxicity 
DNMT 
DNA methyltransferase 
ECG 
Electrocardiogram, electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
FEV 1 
Forced expiratory volume in the first second 
GOT 
Glutamate oxaloacetate transaminase 
GPT 
Glutamate pyruvate transaminase 
GVHD 
Graft-versus host disease 
Hb 
Hemoglobin 
HBcAB 
Hepatitis B core antibody 
HBsAB 
Hepatitis B surface antibody 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
hERG 
Human ether-a-go-go related gene 
HI-E 
Hematological improvement of erythrocytes 
HI-P 
Hematological improvement of platelets 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 


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Abbreviation 
Expansion 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LINE-1 
Long interspersed nucleotide element-1 
LVEF 
Left ventricular ejection fraction 
M/E ratio 
Myeloid/erythroid ratio 
mCR 
Marrow complete remission 
MDS 
Myelodysplastic syndrome 
MTD 
Maximum tolerated dose 
MUGA 
Multiple-gated acquisition 
NE 
Not evaluable 
NOEL 
No observed effect level 
NYHA 
New York Heart Association 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PS 
Performance status 
PT 
Preferred term 
QTc interval 
Corrected QT interval 
QTcF interval 
QT interval as corrected by Fridericia’s formula 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SOC 
System organ class 
T-Bil 
Total bilirubin 
TP 
Total protein 
UA 
Uric acid 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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Definitions of Terms 
Term 
Definition 
Screen failure 
A screen failure is a subject from whom written informed consent is obtained, 
but to whom the investigational medicinal product (IMP) is not administered. 
Individual subject trial 
start date 
The day of obtaining the subject’s written informed consent. 
Withdrawn subject 
A subject who withdraws from the trial during Course 1 without completing 
dose-limiting toxicity (DLT) evaluation or who withdraws from the trial after 
completing DLT evaluation. 
(Subjects who withdraw during Course 1, which is the DLT evaluation period, 
and those who withdraw after the DLT evaluation will be distinguished.) 
Individual subject trial 
discontinuation date 
The day of the withdrawal examination to be performed within 5 days from the 
day when the investigator or subinvestigator determines that the subject is to be 
withdrawn from the trial. 
Completer 
A subject who receives the specified IMP during Course 1, completes 
examinations, and is evaluable for DLTs. 
Individual subject trial 
completion date 
The day when the examination scheduled for Day 29 of Course 1 is performed 
or the start day of Course 2, whichever is later. 
Individual subject trial 
period 
A period from the day of obtaining the subject’s informed consent to the day of 
trial discontinuation.  Does not include the follow-up or outcome investigation 
period. 
 


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List of Pharmacokinetic Parameters 
Abbreviation and Term (Unit) 
Expansion or Definition 
AUC∞ 
ng·h/mL 
Area under the plasma concentration-time curve from time zero 
to infinity 
AUC∞/D 
ng·h/mL/mg/m2 
AUC∞ normalized by dose 
AUC24h 
ng·h/mL 
Area under the plasma concentration-time curve from time zero 
to 24 hours 
AUC24h/D 
ng·h/mL/mg/m2 
AUC24h normalized by dose 
AUCt 
ng·h/mL 
Area under the plasma concentration-time curve calculated to 
the last observable concentration at time t 
AUCt/D 
ng·h/mL/mg/m2 
AUCt normalized by dose 
AUC_%Extrap 
% 
Percentage of AUC due to extrapolation from tlast to infinity 
([AUC∞ − AUCt] / AUC∞ × 100) 
CL/F 
L/h, 
 
L/h/m2 
Apparent clearance of drug from plasma after extravascular 
administration, 
L/h normalized by body surface area (BSA) 
CL/F/BW 
L/h/kg 
CL/F normalized in body weight 
Cmax 
ng/mL 
Maximum (peak) plasma concentration of the drug 
Cmax/D 
ng/mL/mg/m2 
Cmax normalized by dose 
λz 
h−1 
Apparent terminal-phase disposition rate constant (first-order) 
t1/2,z 
h 
Terminal-phase elimination half-life 
tlast 
h 
Time of last measurable (positive) concentration 
tmax 
h 
Time to maximum (peak) plasma concentration 
Vz/F 
L, 
 
L/m2 
Apparent volume of distribution during the terminal (λz) phase 
after extravascular administration, 
L normalized by BSA 
Vz/F/BW 
L/kg 
Vz/F normalized in body weight 
Rn,ac (AUC24h) 
 
Accumulation ratio of nth dose to first dose at regular 
administration for AUC24h 
Rn,ac (Cmax) 
 
Accumulation ratio of nth dose to first dose at regular 
administration for Cmax 
 


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1 
Introduction 
1.1 
Background of Trial Plan 
SGI-110 is a dinucleotide incorporating decitabine, an inhibitor of DNA methylation, 
with deoxyguanosine via a phosphodiester bond.  Decitabine (Dacogen®) has been 
approved and marketed in the United States (US) for the treatment of myelodysplastic 
syndrome (MDS) and in the European Union for the treatment of acute myeloid leukemia 
(AML) in elderly patients.1 
DNA methylation is a conversion to 5-methylcytosine that occurs when cytosines in the 
CpG islands located in the gene promoter region are methylated, and this methylation 
regulates gene expression.  It is believed that when DNA methylation occurs in the 
cancer suppressor gene promoter region, transcription of cancer suppressor genes is 
suppressed, which leads to cellular canceration.  Since such DNA methylation is 
mediated by DNA methyltransferase (DNMT), a drug with DNMT inhibitory effect is 
expected to be effective against reduction in transcription activity of cancer suppressor 
genes and activation of cancer genes associated with DNA methylation by DNMT. 
Decitabine is a typical drug with a DNMT inhibitory effect, and has been approved 
outside Japan as a treatment of AML and MDS owing to its DNA hypomethylation. 
Decitabine is more quickly metabolized by cytidine deaminase.  Since SGI-110 is a 
dinucleotide of decitabine and deoxyguanosine, it is cleaved into decitabine and 
deoxyguanosine.  The cleaved decitabine is gradually released into plasma.  Thus, plasma 
decitabine concentrations are maintained without acute elevation in plasma 
concentrations, resulting in prolonged exposure.  Decitabine activity is S-phase 
dependent, and prolonged exposure is believed to result in increases in S-phase leukemia 
cells exposed to decitabine.  Hence, SGI-110 is expected to be more effective than 
decitabine.  Decitabine is assumed to form a covalent complex with DNMT, thereby 
directly inhibiting DNA synthesis.  Nonclinical toxicity studies of decitabine have shown 
that increased exposure leads to cytotoxicity; therefore, the inhibition of DNA synthesis 
may be associated with an antitumor effect. 
Acute myeloid leukemia is a highly diverse blood cancer characterized by clonal 
autonomous proliferation of immature bone marrow cells with impaired differentiation 
and/or maturation capacity.  Abnormal proliferation of leukemia cells in the bone marrow 
results in marked inhibition of normal hematopoietic function, presenting various 
symptoms associated with decreased white blood cells (WBCs), anemia, and decreased 
platelets.  Acute myeloid leukemia is a serious disease and would be fatal in a short 


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period of time because of infection or bleeding if not appropriately treated.2  Among 
adult leukemias, AML is most frequent; the prevalence rate of AML in Japan is estimated 
to be approximately 2 to 4 per 100,000 population, and patients with AML account for 
approximately 55% to 65% of all patients with leukemia.3,4,5  For the treatment of AML, 
an anthracycline (standard-dose idarubicin or high-dose daunorubicin) in combination 
with a standard dose of cytarabine is recommended as remission-induction therapy in 
patients with primary untreated AML.2  This treatment achieves complete remission in 
approximately 80% of patients, but approximately 70% of these patients experience 
relapse.  Also approximately 15% of patients show resistance to the first remission-
induction therapy (poor responders to first therapy).6  Many therapies have been 
attempted for these relapsed and treatment-resistant AMLs; however, no standard therapy 
has been established yet.7 
For elderly patients with AML, a standard intensive chemotherapy, if tolerated, is 
expected to achieve a better remission rate and survival.  However, it is difficult to 
uniformly perform chemotherapy with intensity equivalent to that for treatment-naïve 
younger patients with AML because of patients’ characteristics such as decreased organ 
function.  Furthermore, the incidence of adverse drug reactions is generally high when 
chemotherapy is given to elderly patients with AML, and adverse drug reactions are 
likely to be severe.  Thus, the indication for a standard intensive chemotherapy needs to 
be carefully determined.  When standard therapy is deemed to be inappropriate based on 
the performance status (PS), complications, and/or karyotypic abnormalities before the 
start of therapy, patients are treated with low-dose cytarabine if they are treatable.  Its 
therapeutic results are however hardly adequate, and new drugs are therefore awaited.2  
Compared with intravenous decitabine, the pharmacokinetic (PK) profile of SGI-110 may 
be improved because of prolongation of exposure without acute elevation in plasma 
decitabine concentrations.  Therefore, SGI-110 is assumed to more effectively treat 
elderly patients with AML. 
As mentioned above, since SGI-110 has a better PK profile than that of intravenous 
decitabine, it may well be a novel drug for the treatment of elderly patients with AML 
and patients with relapsed or refractory AML for which no standard therapy has been 
established.  Consequently, the sponsor has decided to develop SGI-110. 
1.2 
Study Results and Trial Rationale 
1.2.1 
Nonclinical Study Results 
Results of nonclinical studies of SGI-110 are described below. 


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1.2.1.1 
Pharmacology 
Results of pharmacology studies using leukemia cell lines are described below. 
In an in vitro study of SGI-110 added to HL60 and U937, human AML cell lines, and an 
in vivo study using severe combined immunodeficiency mice having U937 xenografted, 
subcutaneous (SC) administration of SGI-110 induced overall and gene-specific 
hypomethylation. 
In a study using female nu/nu mice having HL60 cells grafted SC and receiving SGI-110 
or decitabine SC or intraperitoneally, SC administration of SGI-110 showed an inhibitory 
effect on tumor growth similarly to decitabine.  After intraperitoneal administration, the 
inhibitory effect of decitabine on tumor growth was stronger than that of SGI-110. 
1.2.1.2 
Safety Pharmacology 
Cardiovascular system 
The action of SGI-110 on the human ether-a-go-go related gene (hERG) potassium 
channel was investigated in vitro.  Whole-cell patch clamp recording was done in human 
embryonic kidney (HEK 293) cells in which hERG cDNA was stably transfected.  SGI-
110 inhibited hERG current by 1.4 ± 0.3% (mean ± standard error of the mean) at 10 μM 
and by 1.0 ± 1.3% at 300 μM.  The half maximal (50%) inhibitory concentration of SGI-
110 for hERG current was not calculated but estimated to exceed 300 μM. 
Central nervous system 
In a repeated dose toxicity study in rats, the neurobehavioral toxicity of SGI-110 
following the first SC administration (0, 5, 10, 20, or 30 mg/kg) was evaluated.  
Functional observational battery was used to observe 10 rats per dose group predose (Day 
−1) and 1 hour postdose on Day 1, and no SGI-110-related change was found in any of 
the groups.  The no observed effect level (NOEL) of SGI-110 for neurobehavioral 
function was estimated to be 30 mg/kg, the maximum dose in this study. 
Respiratory system 
A single dose (0, 15, 30, or 60 mg/kg) of SGI-110 was administered SC to rats, and the 
respiratory functions (respiratory rate, tidal volume, and minute ventilation volume) were 
continuously monitored in 8 rats per group for at least 1 hour predose and at least 4 hours 
postdose.  There was neither death attributable to SGI-110 nor effect on the general 
condition, respiratory rate, tidal volume, or minute ventilation volume.  The NOEL of 
SGI-110 was estimated to be 60 mg/kg, the maximum dose in this study. 


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1.2.1.3 
Toxicity 
Repeated-dose toxicity studies were conducted in rats and rabbits.  SGI-110 was 
administered SC once daily for 5 days with a 23-day recovery period provided.  SGI-110 
was administered at 5, 10, and 20 mg/kg/dose to rats and 1.5, 3.5, and 7.0 mg/kg/dose to 
rabbits.  In both rats and rabbits, myelosuppression, hematotoxicity (decreases in WBCs, 
red blood cell [RBC] parameters, and platelet counts), and decreased thymus weight were 
observed at all of the doses.  Toxicity findings partially or completely resolved after the 
recovery period.  The no-observable-adverse-effect level was not identified for either of 
the animal species.  The severely toxic dose in 10% in rats exceeded 20 mg/kg/dose (120 
mg/m2/dose), and the highest non-severely toxic dose (HNSTD) in rabbits was 1.5 
mg/kg/dose (18 mg/m2/dose).  In a repeated-dose toxicity study with another dosing 
schedule (twice-weekly administration), spermatocyte/spermatid degeneration in the 
testes was reported. 
In studies in cynomolgus monkeys, SGI-110 was administered SC once daily for 5 days 
(2.1 and 3 mg/kg/dose), once daily for 10 days (1.05 and 1.5 mg/kg/dose on Day 1 to Day 
5 and Day 8 to Day 12), and twice weekly for 3 weeks (1.75 and 2.5 mg/kg/dose) over 
two 30-day cycles.  Scabs were developed at the injection site.  The scabs did not resolve 
and persisted until the end of the study.  Body weight and food consumption were within 
normal limits.  Other changes observed were decreased RBCs, increased platelet count, 
and decreased neutrophil count. 
1.2.1.4 
Genotoxicity and Mutagenicity 
No study to evaluate the genotoxic or mutagenic potential of SGI-110 has been 
performed.  Decitabine is a mutagenic substance. 
1.2.1.5 
Carcinogenicity 
No study to evaluate the carcinogenic potential of SGI-110 has been performed.  No 
carcinogenicity study of decitabine has been conducted. 
1.2.1.6 
Reproductive Toxicity 
No study to evaluate the reproductive or developmental toxicity of SGI-110 has been 
conducted.  Nonclinical toxicity studies in mice and rats have demonstrated that 
decitabine is teratogenic, fetotoxic, and embryotoxic. 
1.2.1.7 
Pharmacokinetics 
There appeared to be pronounced differences among species in the PK profiles of SGI-
110 and decitabine after SC administration.  Conversion to decitabine occurred rapidly in 
rodents and rabbits but was slower in monkeys. 


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In terms of the PK of SGI-110, systemic exposure of SGI-110 decreased rapidly in rats 
and monkeys, and exposure of SGI-110 after repeated administration was dose-dependent 
in rats and rabbits. 
The relative bioavailability of decitabine following SC administration of SGI-110 to rats 
was close to 100% in contrast to that following intravenous administration. 
The concentrations of decitabine were high after SC administration of SGI-110 to mice, 
rats, and rabbits, but were much lower in monkeys.  The systemic exposure of decitabine 
decreased rapidly.  The exposure of decitabine after repeated administration of SGI-110 
was dose-dependent in rats and rabbits. 
In studies on metabolism, little metabolism was shown when SGI-110 was added to liver 
microsomes from various animals in vitro.  Studies on the induction of metabolic 
enzymes revealed that SGI-110 does not strongly induce cytochrome P-450 (CYP) 1A1/2, 
CYP2C9, or CYP3A4 in human hepatocytes.  Studies on the inhibition of metabolic 
enzymes demonstrated that SGI-110 does not have any CYP450 inhibitory effect on 
CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. 
Human plasma protein binding ratio of SGI-110 was low; in vitro unbound fraction was 
estimated to be 91%.  Decitabine, the active ingredient, showed a very low protein 
binding ratio (< 1%). 
After administration of radiolabeled decitabine, the mean cumulative urinary excretion 
rate of radioactivity was approximately 89.9% of the dose, and the mean cumulative fecal 
excretion rate of radioactivity was approximately 0.48% of the dose.  In addition, the 
mean urinary excretion rate of decitabine was approximately 4.2% of the dose. 
1.2.2 
Clinical Study Results 
Final databases for any clinical studies of SGI-110 have not been locked, and their 
clinical study reports (CSRs) have not been finalized. 
The following sections describe clinical study results, mainly interim data from Study 
SGI-110-01 involving subjects with hematopoietic tumors. 
1.2.2.1 
Preliminary Results from Ongoing Clinical Studies 
All results presented in this section are preliminary until the final study databases are 
locked and the CSRs are completed. 
The clinical program of SGI-110 includes three ongoing phase 1/2 and phase 2 studies.  
As of the cutoff date on 26 Jul 2013, a total of 225 subjects have received at least one 
dose of SGI-110, and their data have been registered in the clinical study databases. 


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 SGI-110-01 phase 1 dose escalation study (monotherapy, enrollment completed, 
treatment ongoing) involved 93 patients. 
 SGI-110-01 phase 2 extension study (monotherapy, enrollment ongoing) involved 
108 patients. 
1.2.2.1.1 
Phase 1/2 Study:  SGI-110-01 (AML/MDS; Monotherapy; 
United States and Canada) 
A phase 1/2, dose escalation, multicenter study of two subcutaneous regimens of 
SGI-110, a DNA hypomethylating agent, in subjects with intermediate- or high-risk 
myelodysplastic syndrome or acute myeloid leukemia 
Study SGI-110-01 is a first-in-human study involving subjects with MDS or AML and 
has been conducted with two regimens. 
 The dose escalation segment (phase 1) is for determination of the biologically 
effective dose (BED) and maximum tolerated dose (MTD) using long interspersed 
nucleotide element-1 (LINE-1) data. 
 The dose expansion segment (phase 2) is for evaluation of remission rates and safety 
in different subject populations (ie, MDS and AML). 
These two segments are individually described below. 
1.2.2.1.1.1 
SGI-110-01 Phase 1 Dose Escalation Segment (AML/MDS; 
Monotherapy) 
As of 26 Jul 2013, enrollment in the dose escalation segment has been completed, and 
treatment is ongoing. 
The subjects enrolled in this segment had relapsed or refractory intermediate- or high-risk 
MDS (including chronic myelomonocytic leukemia [CMML]) or AML.  The dose was 
escalated based on PK (area under the curve [AUC] for decitabine; see Section 1.2.2.1.2) 
and pharmacodynamic (PD) (hypomethylation in LINE-1; see Section 1.2.2.1.3) 
evaluations.  Each cycle consisted of 28 days.  The subjects were randomized to receive 
SGI-110 once daily for 5 days or once weekly for 3 weeks.  Randomization to these two 
regimens was completed, and the study plan was modified to enroll subjects to receive 
SGI-110 twice weekly for 3 weeks (initial dose, 60 mg/m2) because data of 
hypomethylation in LINE-1 showed that the 3-week once-weekly regimen was inferior. 
The primary endpoint in this segment was to determine the BED and MTD.  The MTD 
was decided based on the incidence of dose-limiting toxicities (DLTs) in Cycle 1.  The 
safety profiles, PK profiles, and remission rates (hematological improvement and 
response duration) for SGI-110 and decitabine, and time to progression to AML (only in 
subjects with MDS) were also evaluated. 


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In the study database as of 26 Jul 2013, data from a total of 94 subjects in the dose 
escalation segment are available for analyses.  SGI-110 was administered SC to 93 
subjects (one subject was randomized to the 90 mg/m2 once-weekly group but did not 
receive SGI-110).  Of these, SGI-110 was administered to 44 subjects once daily for 5 
days (3 to 125 mg/m2), 34 subjects once weekly for 3 weeks (6 to 125 mg/m2), and 15 
subjects twice weekly for 3 weeks (60 or 90 mg/m2). 
SGI-110 was administered SC to the majority of subjects (67%) for 2 cycles.  SGI-110 
was administered SC to 46%, 28%, 18%, and 14% of the subjects for 3, 4, 5, and 6 cycles, 
respectively.  The actual number of cycles was similar among the regimens. 
 
Activity/efficacy of SGI-110 
The following clinical effects were noted in the phase 1 dose escalation segment (63 
subjects with AML and 15 subjects with MDS): 
 AML (Kantarjian, et al8): 
 Complete remission (CR) was achieved in 5 subjects out of the subjects with 
AML who had previously received many therapies:  ie, CR in 2 subjects, 
complete remission with incomplete platelet recovery (CRp) in 1 subject, 
and complete remission with incomplete blood count recovery (CRi) in 2 
subjects were achieved with the 5-day once-daily regimen at the initial dose 
of 36 mg/m2 and the once-weekly regimen at the initial dose of 60 mg/m2. 
 No clinical remission was achieved with the twice-weekly regimen (11 
subjects received this regimen). 
 The median duration of remission or CR was 114 days (ranging from 42 to 
558 days). 
 MDS (O’Connell, et al9 and in-house document): 
 Remission was achieved in 7 subjects out of the subjects with MDS who had 
previously received many therapies:  ie, marrow complete remission (mCR) 
in 2 subjects, hematological improvement of erythrocytes (HI-E) in 2 
subjects, HI-E/hematological improvement of neutrophils in 1 subject, and 
HI-E/hematological improvement of platelets (HI-P) in 1 subject were 
achieved with the 5-day once-daily regimen at the initial dose of 18 mg/m2 
(remission achieved in 2 subjects) and the once-weekly regimen at the initial 
dose of 6 mg/m2 (remission achieved in 4 subjects).  HI-P in 1 subject with 
CMML was achieved with the twice-weekly regimen at the initial dose of 60 
mg/m2. 
 The median duration of remission or CR was 88 days (ranging from 77 to 
181 days). 


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DNA hypomethylation in LINE 1 exceeding 10% was demonstrated in all of the AML 
subjects with remission and all of the MDS subjects with mCR. 
 
Safety 
Maximum tolerated dose 
In the study, 5 DLTs (thrombocytopenia, neutropenia, febrile neutropenia, and sepsis) 
occurred in 2 subjects (both with MDS) treated with the 5-day once-daily regimen at 125 
mg/m2.  No DLT occurred in the subjects with AML. 
Therefore, the MTD for the 5-day once-daily regimen in the subjects with MDS was 90 
mg/m2.  No MTD was reached for the 5-day once-daily regimen in the subjects with 
AML, or the once-weekly regimen or the twice-weekly regimen.  The highest dose 
administered was 125 mg/m2 for the 5-day once-daily regimen and the once-weekly 
regimen, and 90 mg/m2 for the twice-weekly regimen. 
 
Serious adverse events (safety database as of 04 Sep 2013) 
Overall, serious adverse events (SAEs) occurred in 71 of the 93 subjects (76%).  The 
majority of SAEs were assessed as unrelated to the investigational medicinal product 
(IMP) by the investigator or subinvestigator. 
In addition, SAEs resulting in death occurred in 17 of the 93 subjects (18%).  In 2 
subjects, SAEs (sepsis in both) resulting in death were assessed as related to the IMP by 
the investigator or subinvestigator.  One of these subjects was treated with the 5-day 
once-daily regimen at a low dose of 18 mg/m2, and the SAE was assessed as unrelated by 
the sponsor.  The other subject was treated with the 5-day once-daily regimen at 125 
mg/m2, and the SAE was assessed as related by the sponsor. 
The system organ class (SOC) with the most frequently reported SAEs was infections 
and infestations (49%), followed by blood and lymphatic system disorders (34%). 
The most frequently reported SAEs were febrile neutropenia (34%), pneumonia (23%), 
and sepsis (11%).  Serious adverse events related to the IMP occurred in 7 of the 93 
subjects (18%), including febrile neutropenia (5%), sepsis (3%), thrombocytopenia (1%), 
atrial fibrillation (1%), dysphagia (1%), chest pain (1%), mucosal inflammation (1%), 
bacteraemia (1%), Klebsiella sepsis (1%), pneumonia (1%), pneumonia klebsiella (1%), 


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platelet count decreased (1%), pseudomonal sepsis (1%), delirium (1%), and pleural 
effusion (1%). 
 
Adverse events (clinical database as of 26 Jul 2013) 
Adverse events (AEs) occurred in 92 of the 93 subjects (99%).  The most frequently 
reported AEs were febrile neutropenia (43%), diarrhoea (37%), pneumonia (30%), 
injection site pain (29%), fatigue (28%), thrombocytopenia (26%), cough (24%), anaemia 
(23%), and dyspnoea (22%).  The SOCs with the most frequently reported Grade 3 or 
worse AEs were blood and lymphatic system disorders (69%), and infections and 
infestations (49%). 
Adverse events related to the IMP occurred in 63 of the 93 subjects (68%).  The most 
frequently reported IMP-related AEs were injection site pain (29%), thrombocytopenia 
(14%), fatigue (13%), anaemia (12%), and neutropenia (11%).  The SOC with the most 
frequently reported Grade 3 or worse IMP-related AEs was blood and lymphatic system 
disorders (30%). 
1.2.2.1.1.2 
SGI-110-01 Phase 2 Dose Expansion Segment (AML/MDS; 
Monotherapy) 
As of 26 Jul 2013, enrollment in the dose expansion segment is ongoing. 
This segment was implemented as a phase 2 randomized, extension study and evaluated 
subjects with the following four diseases: 
 Relapsed or refractory AML 
 Relapsed intermediate-2 or high-risk MDS (including CMML) previously treated 
with a hypomethylating agent 
 Treatment-naïve AML in elderly subjects (aged 65 years or older) 
 Treatment-naïve MDS (including CMML) 
In the study, the subjects were randomized to receive either 60 or 90 mg/m2 once daily 
for 5 days (one dose a day 5 times).  Thereafter, the protocol was revised to add a fifth 
treatment group, consisting of non-randomized subjects receiving 60 mg/m2 once daily 
for 10 days (subjects with relapsed or refractory AML only). 
The primary endpoint of the phase 2 study was an overall remission rate (CR, CRp, and 
CRi) assessed using criteria of an international working group.  A PD action for DNA 
methylation in LINE-1 was also evaluated. 


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In the study database as of 26 Jul 2013, data from a total of 109 subjects in the phase 2 
dose expansion segment are available for analyses.  SGI-110 was administered to 108 
subjects (one subject was randomized but did not receive SGI-110). 
Overall, SGI-110 was administered SC in the majority of subjects (78%) for 2 cycles.  
SGI-110 was administered SC to 51%, 31%, 19%, and 10% of the subjects for 3, 4, 5, 
and 6 cycles, respectively. 
 
Efficacy 
As of 26 Jul 2013, data from 50 subjects with relapsed or refractory AML and 17 elderly 
subjects with treatment-naïve AML are available.  For the overall remission rate (CR, 
CRp, or CRi) defined as the primary endpoint, remission was achieved as described 
below: 
 Of the 50 subjects with relapsed or refractory AML, complete remission (CR, CRp, or 
CRi) was achieved in 8 subjects (16%). 
 Of the 17 elderly subjects with treatment-naïve AML, complete remission (CR, CRp, 
or CRi) was achieved in 9 subjects (53%). 
 Five subjects (4 subjects with relapsed or refractory AML and 1 elderly subject with 
treatment-naïve AML) underwent stem cell transplantation after SGI-110 treatment. 
There was no difference in the complete remission rate between the 60 and 90 mg/m2 
doses (remission was achieved in 8 of 32 subjects at 60 mg/m2 and in 9 of 35 subjects at 
90 mg/m2).  Data of DNA methylation in LINE-1 before and after treatment were 
available from 50 subjects (75%).  DNA hypomethylation in LINE-1 by at least 10% was 
noted after treatment in 83% and 78% of the subjects in the 60 and 90 mg/m2 groups, 
respectively.  The median maximal hypomethylation in LINE-1 was 25% in the subjects 
with remission and 19% in the subjects without remission. 
No efficacy data have been obtained from the subjects with treatment-naïve or relapsed 
or refractory MDS or the subjects with relapsed or refractory AML treated with the 10-
day regimen at the time of data cutoff on 26 Jul 2013. 
 
Safety 
Serious adverse events (safety database as of 04 Sep 2013) 
Serious adverse events occurred in 143 of the 216 subjects (66%).  The majority of SAEs 
were assessed as unrelated to the IMP by the investigator or subinvestigator. 


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In addition, SAEs resulting in death occurred in 14 of the 216 subjects (6%).  None of the 
SAEs resulting in death in the phase 2 dose expansion segment were assessed as related 
to the IMP. 
The SOC with the most frequently reported SAEs was blood and lymphatic system 
disorders (41%), followed by infections and infestations (30%). 
The most frequently reported SAEs were febrile neutropenia (37%) and pneumonia 
(13%). 
Serious adverse events related to the IMP occurred in 25 of the 216 subjects (12%), 
including febrile neutropenia (7%), pneumonia (1%), anaemia (< 1%), thrombocytopenia 
(< 1%), diarrhoea (< 1%), nausea (< 1%), oesophagitis (< 1%), small intestinal 
obstruction (< 1%), chest pain (< 1%), fatigue (< 1%), pyrexia (< 1%), 
bronchopulmonary aspergillosis (< 1%), cellulitis (< 1%), escherichia bacteraemia (< 
1%), pseudomonal bacteraemia (< 1%), sepsis (< 1%), staphylococcal sepsis (< 1%), 
upper respiratory tract infection (< 1%), hyperuricaemia (< 1%), tumour lysis syndrome 
(< 1%), and hypoxia (< 1%). 
 
Adverse events (clinical database as of 26 Jul 2013) 
Adverse events occurred in 92 of 108 subjects (85%).  The most frequently reported AEs 
were febrile neutropenia (39%), injection site pain (31%), thrombocytopenia (25%), 
diarrhoea (25%), anaemia (23%), hypokalaemia (23%), neutropenia (22%), nausea (22%), 
and fatigue (21%).  The SOCs with the most frequently reported Grade 3 or worse AEs 
were blood and lymphatic system disorders (62%), and infections and infestations (31%). 
Adverse events related to the IMP occurred in 71 of the 108 subjects (66%).  The most 
frequently reported IMP-related AEs were injection site pain (30%), neutropenia (19%), 
thrombocytopenia (19%), anaemia (17%), febrile neutropenia (13%), leukopenia (15%), 
diarrhoea (14%), nausea (14%), fatigue (12%), and constipation (11%).  The SOC with 
the most frequently reported Grade 3 or worse IMP-related AEs was blood and lymphatic 
system disorders (37%). 
1.2.2.1.2 
Pharmacokinetics in Study SGI-110-01 
Study SGI-110-01 was conducted to investigate the PK profiles of SGI-110 and 
decitabine following SC administration of SGI-110 with the 5-day once-daily regimen (3 
to 125 mg/m2), 3-week once-weekly regimen (6 to 125 mg/m2), and 3-week twice-
weekly regimen (60 or 90 mg/m2).  As a result, SGI-110 and decitabine were detected in 
the plasma of the subjects at all the dose levels of the 3 regimens.  Decitabine exposure 


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was prolonged with the dose increase, and decitabine was detected continuously for at 
least 8 hours when the dose of SGI-110 was 18 mg/m2 or higher.  SGI-110 or decitabine 
was not detectable in the plasma 24 hours after administration of SGI-110, and no 
accumulation was noted.  There was no PK difference between the 5-day once-daily 
regimen and 3-week once-weekly regimen. 
SGI-110 and decitabine exposures after SC administration of SGI-110 were evaluated 
based on the AUC.  The AUCs for both SGI-110 and decitabine increased dose 
proportionally, and the exposure increased.  The Cmax of SGI-110 or decitabine was not 
dose proportional.  The t1/2 of decitabine was prolonged after SC administration of SGI-
110 (up to 2 hours), compared with that after intravenous administration of decitabine 
(0.25 to 0.58 hours).  The mean AUCs for decitabine after SC administration of SGI-110 
at 60, 90, and 125 mg/m2 were, respectively, 0.77, 1.26, and 2.01 times the estimated 
therapeutic range (115 ng·h/mL) after 1-hour intravenous administration of decitabine 20 
mg/m2.  The mean values of Cmax were, respectively, 0.18, 0.29, and 0.44 times the 
range; therefore showing lower values than those after intravenous administration of 
decitabine. 
1.2.2.1.3 
Pharmacodynamics in Study SGI-110-01 
Overall DNA methylation in long interspersed nucleotide element-1 
DNA hypomethylation in LINE-1 was enhanced dose-dependently in subjects who 
received SGI-110 with the 5-day once-daily regimen at a dose range of 18 to 60 mg/m2; 
the BED for the 5-day once-daily regimen was deemed to be 60 mg/m2 since the 
maximum average DNA hypomethylation reached a plateau (up to 25%) at higher doses 
(90 to 125 mg/m2). 
Hypomethylation for the 3-week twice-weekly regimen reached a plateau of up to 18% at 
a dose range of 60 to 90 mg/m2. 
The extent of hypomethylation for the 3-week once-weekly regimen was lower than that 
for the 5-day once-daily regimen in all the cohorts. 
Hypomethylation at doses of 60 and 90 mg/m2 in the 3 regimens was compared.  The 
results showed that the duration of hypomethylation in LINE-1 was longer for the 3-week 
twice-weekly regimen than for the 5-day once-daily regimen, whereas the extent of 
hypomethylation was more potent for the 5-day once-daily regimen.  The extent of 
hypomethylation was weaker and the duration of hypomethylation was shorter for the 3-
week once-weekly regimen than for the other two regimens. 


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1.2.3 
Trial Rationale 
This clinical trial will be conducted to evaluate the tolerability of SGI-110 in Japanese 
patients with AML.  The target population, doses, and regimens were chosen with 
reference to a clinical trial (Study SGI-110-01) conducted outside of Japan in patients 
with AML and patients with MDS. 
The target population will be patients with AML since the patients who responded to 
treatment to a certain extent in Study SGI-110-01 were those with AML.  Also, in 
accordance with the Guidelines for Clinical Evaluation of Antimalignant Tumor Drugs 
(dated 01 Nov 2005), it was decided to select patients who are unlikely to achieve life 
prolongation or symptom relief with the generally accepted standard regimen, ie, patients 
who have relapsed after standard therapy, patients who do not respond to standard 
therapy, and elderly patients aged 65 years or older who are not eligible for standard 
chemotherapy. 
The doses selected for the trial were based on the results of a clinical trial conducted 
outside of Japan (Study SGI-110-01).  In Study SGI-110-01, the initial dose was set as 3 
mg/m2 per time (15 mg/m2 per course) with a 5-day regimen, since this is one-sixth of the 
HNSTD (18 mg/m2/time) for rabbits, the most sensitive species.  The dose was increased 
to 6 mg/m2 (30 mg/m2 per course), 18 mg/m2 (90 mg/m2 per course), 36 mg/m2 (180 
mg/m2 per course), 60 mg/m2 (300 mg/m2 per course), 90 mg/m2 (450 mg/m2 per course), 
and 125 mg/m2 (625 mg/m2 per course) with safety monitored.  As a result, no DLT was 
observed at a dose range of up to 90 mg/m2; a good tolerability profile was shown.  In 
contrast, DLTs occurred in 2 of 3 patients with MDS who received a dose increased to 
125 mg/m2 (625 mg/m2 per course).  Thus, the MTD was determined to be 90 mg/m2.  A 
3-week once-weekly regimen was also explored at an initial dose of 6 mg/m2 (18 mg/m2 
per course), which is one-sixth of the dose well tolerated in rabbits (36 mg/m2/time).  The 
dose was increased up to 125 mg/m2 (375 mg/m2 per course), but the MTD was not 
reached. 
A PD analysis to examine the BED indicated that a maximum of approximately 25% 
DNA hypomethylation in LINE-1 was achieved at doses of 60, 90, and 125 mg/m2 of the 
5-day once-daily regimen, and no great difference in the extent of hypomethylation.  
Thus, the BED was suggested to be 60 mg/m2.  In the 3-week once-weekly regimen, the 
extent of hypomethylation was low at all of the dose levels, and it was decided to 
implement the dose expansion segment for the phase 2 part with a 5-day once-daily 
regimen. 


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Efficacy was explored with the doses and regimens suggested to be the MTD and BED in 
the dose expansion segment implemented for the phase 2 part of Study SGI-110-01.  The 
results revealed that composite complete remission was achieved in 16% of subjects with 
AML receiving SGI-110 at 60 and 90 mg/m2 who had relapsed after standard therapy or 
had not responded to treatment and in 53% of elderly patients with treatment-naïve AML 
who were not eligible for standard chemotherapy, suggesting that 60 and 90 mg/m2 were 
effective doses (as of 26 Jul 2013). 
As mentioned above, the doses for the trial were chosen based on evaluations of the 
safety, efficacy, and PD of SGI-110 in a clinical trial conducted outside of Japan (Study 
SGI-110-01), and it was decided to adopt a study design to evaluate the tolerability in 
each cohort and gradually escalate the dose. 
Since the results of Study SGI-110-01 suggest that the recommended dose for non-
Japanese patients is assumed to be 60 mg/m2, the primary dose to be investigated has 
been set as 60 mg/m2.  This study is the first clinical trial of SGI-110 involving Japanese 
patients with AML and, therefore, in considering the subjects’ safety, the initial dose will 
be 36 mg/m2, which was one of the doses used in Study SGI-110-01 and is a lower dose 
than the primary dose of 60 mg/m2.  The maximum dose will be 90 mg/m2, which was 
determined to be the MTD in Study SGI-110-01 and is suggested to be effective 
according to exploratory evaluation. 
In 2014, SGI-110 at 60 mg/m2 in a 5-day regimen was chosen as a dose and regimen for 
the multi-national phase 3 trial (Study SGI-110-04) in treatment-naïve patients with AML 
who were ineligible for intensive chemotherapy.  Therefore, this protocol was amended 
to version 3 on 22 May 2015 to exclude Cohort 3 (60 mg/m2 in 10-day regimen) from the 
design.  As of Aug 2016, Study SGI-110-04 was still ongoing in Japan.  Then, another 
multi-national phase 3 trial (Study SGI-110-06) in patients with relapsed or refractory 
AML was newly planned in 2016.  Based on the results of the phase 2 segment of Study 
SGI-110-01 in patients with relapsed or refractory AML (refer to IB for the data), the 
initial dose of Study SGI-110-06 was set as 60 mg/m2 daily for 10 days.  To evaluate the 
tolerability of the dosage (60 mg/m2 in 10-day regimen) in Japanese patients before 
Study SGI-110-06 starts in Japan, this protocol was amended to version 6 on 05 Sep 2016 
to reinstate Cohort 3 into the design.  
As mentioned in Section 1.2.2 Clinical Study Results, occurrences of myelosuppression 
and decreased blood cell counts, and infections attributable to these, as well as 
occurrences of digestive symptoms are anticipated following administration of SGI-110.  


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Therefore subjects will be hospitalized during Course 1, when the IMP will be 
administered for the first time to them, so they can be carefully monitored.  Thereafter, 
the subjects are to visit the trial site at least once weekly to undergo hematological tests 
for evaluation of decreased blood cell counts and to undergo a medical examination by a 
physician to check their general condition.  In addition, a chest X-ray examination and 
blood biochemistry test are to be performed before the start of the next course in order to 
ensure the subjects’ safety. 
The subjects for the clinical trial are expected to have symptoms that may affect activities 
of daily living (ADL) such as decreased blood cell counts and infection associated with 
the progression of disease already present at study entry.  Hence, supportive care used in 
routine medical practice is to be permitted, and arrangements will be made to prevent the 
subjects’ quality of life from being undermined by participation in the trial. 
As described the above, the trial has been planned so as to adequately ensure the subjects’ 
safety.  The conduct of the trial based on this protocol is judged to be scientifically and 
ethically appropriate. 
See the investigator’s brochure for further details of data mentioned in this protocol 
and other trial results. 
 
2 
Trial Objectives 
2.1 
Primary Objective 
To evaluate the tolerability of SGI-110 when administered subcutaneously to Japanese 
patients with AML 
Secondary objectives: 
 To perform PK evaluation of plasma SGI-110 and decitabine 
 To evaluate efficacy (complete remission rate, composite complete remission rate, 
overall remission rate, overall survival, composite complete remission duration) 
 To evaluate safety through observed AEs and examinations 
Exploratory objective: 
To perform PD evaluation of the extent of DNA hypomethylation 
 


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3 
Trial Plan 
3.1 
Trial Design 
This is a phase 1, multicenter, open-label study to evaluate the tolerability of SGI-110 in 
Japanese patients with relapsed or refractory AML after undergoing standard therapy or 
Japanese patients with AML aged 65 years or older who are not eligible for standard 
chemotherapy. 
This trial consists of a screening period, DLT evaluation period, and withdrawal 
examination.  Subjects who complete IMP administration and all observations during the 
DLT evaluation period, and who do not have any apparent progression of AML, will be 
permitted to continue treatment with IMP following the DLT evaluation period if they 
wish.  The primary evaluation data for Cohorts 1, 2, and 4 will have a cutoff date of 31 
May 2016 and the data for Cohort 3 will have a cutoff date of 30 Nov 2017.  The period 
up until the data cutoff will be defined as the primary evaluation part.  This will be 
followed by an extended treatment part to assess long-term safety, which will include 
those subjects on IMP treatment who have consented to participate in the extended 
treatment part.  Transition from the primary evaluation part to the extended treatment part 
will take place at the start of the next course after the data cutoff. 
Administration of the IMP will be started in Cohort 1 (36 mg/m2 in 5-day regimen) and 3 
subjects will receive the IMP in this cohort.  If none of the 3 subjects has a DLT during 
the DLT evaluation period, the study will proceed to the next cohort.  If one of the 3 
subjects experiences a DLT, 3 additional subjects will be enrolled and DLTs will be 
evaluated in a total of 6 subjects.  The study will proceed to the next cohort only if no 
more than one of the 6 subjects has a DLT.  If the number of subjects exhibiting a DLT 
within a cohort is ≥ 2/3 or ≥ 2/6, there will be no dose escalation. 
In Cohort 2 (60 mg/m2 in 5-day regimen) and Cohort 4 (90 mg/m2 in 5-day regimen), 
DLTs will be assessed in the same manner.  However, even if none of the first 3 subjects 
enrolled has a DLT, a total of 6 subjects will be enrolled in each of Cohorts 2 and 3 of 
which the dose has been determined as the recommended dose for a next phase study. 
Based on the occurrence of DLTs, the tolerability at the recommended dose for a next 
phase study will be confirmed in Japanese subjects as well. 
The sponsor will review safety data obtained from the previous cohort(s) and judge the 
transition to the next cohort, including selection of a cohort to proceed to, based on the 
advice of the Independent Data Monitoring Committee. 


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If the number of subjects exhibiting DLT within a cohort is ≥ 2/3 or ≥ 2/6, then there will 
be no transition to the next cohort, and the MTD will be determined as follows: 
≥ 2/3 or ≥ 2/6 subjects with DLT 
MTD 
In Cohort 1 
< 36 mg/m2 in 5-day regimen 
In Cohort 2 
36 mg/m2 in 5-day regimen 
In Cohort 4 
60 mg/m2 in 5-day regimen 
If the incidence of DLT does not reach either ≥ 2/3 or ≥ 2/6 in any of the cohorts in the 
table above, the MTD will not be determined in this study.  For Cohort 3 (60 mg/m2 in 
10-day regimen), DLT will be evaluated but the MTD of 10-day regimen will not be 
determined from the incidence of DLT. 
The DLT evaluation period will be from the start of administration in Course 1 to the 
examination scheduled for Day 29 of Course 1.  However, for subjects who have 
postponed the start of IMP administration scheduled for Day 1 of Course 2 (extended 
treatment period), the DLT evaluation period will last until the start of IMP 
administration in Course 2. 
Subjects will be hospitalized for treatment during Course 1.  Subjects will be required to 
remain hospitalized until the examination scheduled for Day 29 of Course 1 if they 
complete the trial in Course 1 (until the withdrawal examination if they are withdrawn 
during Course 1) and until the start of IMP administration in Course 2 if they proceed to 
the extended treatment period of Course 2 and the subsequent courses. 
Dose-limiting toxicity shall be defined as any of the following AEs occurring during 
Course 1 for which there is a reasonable probability or possibility of a causal relationship 
with the IMP (being related to the IMP) if it cannot be reasonably explained by 
underlying disease, intercurrent illness, or concomitant medications.  The severity of AEs 
will be graded in accordance with Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
 Non-hematologic toxicity of Grade 3 or higher, except for the following: 
 Nausea, vomiting, or diarrhea of Grade 3 that is controllable by optimal 
therapy 
 Grade 3 laboratory findings other than serum creatinine (Cr), bilirubin, 
aspartate aminotransferase (AST), or alanine aminotransferase (ALT), that 
are not associated with clinical manifestations 
 Grade 4 thrombocytopenia that was not present at study entry and that is not resolved 
within 7 days 
 Grade 4 neutropenia that was not present at study entry and that is not resolved within 
7 days 


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 Febrile neutropenia Note 
If the febrile neutropenia is not resolved or improved during the DLT evaluation 
period, it shall be defined as DLT.  If the febrile neutropenia is resolved or improved 
during the DLT evaluation period, it shall be judged whether it is defined as DLT 
based on the background of the subject and through consultation with the 
Independent Data Monitoring Committee. 
 Any AE that results in a delay of > 4 weeks in starting the next treatment course 
Note In this trial, febrile neutropenia is defined as a neutrophil count of < 500/μL 
accompanied by a fever of ≥ 38°C 
 
The DLT evaluation period will be for the duration of Course 1.  Subjects who complete 
IMP administration and all observations during the DLT evaluation period, and who do 
not have any apparent progression of AML, will be permitted to continue treatment with 
IMP following the DLT evaluation period if they wish. 
3.2 
Rationale for Trial Design 
In the trial, the dose escalation was planned with consideration of the subjects’ safety and 
based on the “Guidelines for Clinical Evaluation of Antimalignant Tumor Drugs 
(Notification No. 1101001 of the Evaluation and Licensing Division, Pharmaceutical and 
Food Safety Bureau dated 01 Nov 2005).” 
As mentioned in Section 1.2.3 Trial Rationale, the doses and regimen were chosen based 
on evaluations of the safety, efficacy, and PD of SGI-110 in a clinical trial conducted 
outside of Japan (Study SGI-110-01), and it has been decided to adopt a study design to 
evaluate the tolerability in each cohort and gradually escalate the dose. 
Since results of Study SGI-110-01 suggest that the recommended dose for non-Japanese 
patients is assumed to be 60 mg/m2, the primary dose to be investigated has been set as 
60 mg/m2.  This study is the first clinical trial of SGI-110 involving Japanese patients 
with AML and, therefore, in considering the subjects’ safety, the initial dose will be 
36 mg/m2, which was one of the doses used in Study SGI-110-01 and is a lower dose 
than the primary dose of 60 mg/m2.  The maximum dose will be 90 mg/m2, which was 
determined to be the MTD in Study SGI-110-01 and is suggested to be effective 
according to exploratory evaluation.  In addition, the tolerability of SGI-110 at 60 mg/m2 
once daily for 10 days will be evaluated in Japanese patients in this study because the 
same dose and regimen is planned to be adopted in Study SGI-110-06 in patients with 
relapsed or refractory AML. 
As mentioned in Section 1.2.2 Clinical Study Results, occurrences of myelosuppression 
and decreased blood cell counts, and infections attributable to these, as well as 


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occurrences of digestive symptoms are anticipated following administration of SGI-110.  
Therefore subjects will be hospitalized during Course 1, when the IMP will be 
administered for the first time to them, so they can be carefully monitored.  Thereafter, 
the subjects are to visit the trial site at least once weekly to undergo hematological tests 
for evaluation of decreased blood cell counts and to undergo a medical examination by a 
physician to check their general condition.  In addition, a chest X-ray examination and 
blood biochemistry test are to be performed before the start of the next course in order to 
ensure the subjects’ safety. 
The subjects for the clinical trial are expected to have symptoms that may affect ADL 
such as decreased blood cell counts and infection associated with the progression of 
disease already present at study entry.  Hence, supportive care used in routine medical 
practice is to be permitted, and arrangements will be made to prevent the subjects’ quality 
of life from being undermined by participation in the trial. 
The subjects for the trial will be patients who have relapsed after existing therapy or do 
not respond to treatment, and elderly patients aged 65 years or older who are not eligible 
for standard intensive chemotherapy; therefore they have limited treatment options.  For 
ethical reasons, a subject will be allowed to continue with the IMP after the completion of 
the DLT evaluation period if they wish to do so as long as they have not experienced an 
AE during Course 1 (ie, the DLT evaluation period of the trial) that makes continuing the 
IMP difficult and have no evidence of disease progression.  Safety and efficacy will be 
continuously evaluated during the primary evaluation part.  For long-term safety 
evaluation after the end of the primary evaluation part, an extended treatment part will be 
included so that treatment can be continued for subjects who are on the IMP at that time 
if they consent to continue the treatment. 
3.3 
Endpoints 
3.3.1 
Safety 
3.3.1.1 
Primary Endpoint (Primary Evaluation Part) 
DLT 
3.3.1.2 
Secondary Endpoints 
(Primary evaluation part) 
AEs, clinical laboratory values, vital signs (blood pressure, pulse rate, body temperature), 
body weight, Eastern Cooperative Oncology Group (ECOG) PS, 12-lead 
electrocardiogram (ECG), chest X-ray 


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(Extended treatment part) 
AEs, clinical laboratory values 
3.3.2 
Efficacy Endpoints (Primary Evaluation Part) 
Complete remission rate (CR), composite complete remission rate (CR + CRi + CRp), 
overall remission rate (CR + CRi + CRp + partial response [PR]), overall survival, and 
composite complete remission duration 
3.3.3 
Pharmacokinetic Endpoints (Primary Evaluation Part) 
SGI-110 and decitabine plasma concentrations, PK parameters 
3.3.4 
Pharmacodynamic Endpoint (Primary Evaluation Part) 
Extent of DNA hypomethylation in LINE-1 
[Rationale for variable selection] 
[Safety] 
Safety in each cohort is to be evaluated in accordance with the “Guidelines for 
Clinical Evaluation of Antimalignant Tumor Drugs” (Notification No. 1101001 of 
the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau 
dated 01 Nov 2005).  DLTs and AEs are to be assessed using the criteria used for 
toxicity assessment of other anticancer drugs (CTCAE version 4.0 of the US National 
Cancer Institute). 
[Efficacy] 
Efficacy is to be evaluated in accordance with the criteria used in a phase 1/2 trial 
conducted outside of Japan (Study SGI-110-01) which was a partially modified 
version of the response criteria for AML treatment established by an international 
working group.10 
[Pharmacokinetics] 
SGI-110 and decitabine plasma concentrations in Japanese subjects are to be 
measured to evaluate PK parameters. 
[Pharmacodynamics] 
The extent of DNA hypomethylation, which is regarded as the main action of SGI-
110, is to be measured. 
 


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3.4 
Target Number of Patients 
Maximum:  24 subjects 
Cohort 1 (36 mg/m2, 5 days):  3 to 6 subjects 
Cohort 2 (60 mg/m2, 5 days):  3 to 6 subjects 
Cohort 3 (60 mg/m2, 10 days [ie, 5-day administration twice, with a non-dosing period 
in-between]):  6 subjects 
Cohort 4 (90 mg/m2, 5 days):  3 to 6 subjects 
3.5 
Rules to Be Observed for Enrollment and Treatment 
1) The dose or regimen should remain unchanged for each subject, and no subject 
should be re-enrolled. 
2) In order to avoid occurrence of unexpected serious adverse drug reactions in 
multiple subjects, the IMP should be administered to the second subject after the 
following day of Day 1 of Course 1 in the first subject at each dose level. 
3) When the administration or examination scheduled for Course 1 cannot be 
implemented for reasons other than safety, the subject should be excluded from 
the DLT evaluation, and another subject should be enrolled. 
4) Administration of SGI-110 is expected to cause myelosuppression and infection 
(eg, febrile neutropenia, pneumonia, and sepsis).  Delay or discontinuation of 
administration should be determined for subjects who have experienced or are 
suspected to have experienced pyrexia or infection based on data from laboratory 
tests, physical examination (body temperature), and imaging tests before the start 
of the next course and continuing the treatment. 
5) In and after Course 2 (extended treatment period), IMP administration may be 
suspended (skipped) from Day 2 and onwards at the discretion of the investigator 
or subinvestigator, depending on the subject’s condition.  Subjects who fall under 
any of the discontinuation criteria should be withdrawn from the trial. 
 
4 
Investigational Medicinal Products 
4.1 
Test Product and Comparator 
4.1.1 
Test Product 
Code Name 
SGI-110 
Generic Name 
Undecided 
Chemical Name 
Sodium (2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1 (2H)-yl)-2-
(hydroxymethyl) tetrahydrofuran-3-yl ((2R,3S,5R)-5-(2-amino-6-oxo-1H-
purin-9 (6H)-yl)-3-hydroxytetrahydrofuran-2-yl) methyl phosphate 
Content and Formulation 
SGI-110 for injection, 100 mg contains SGI-110 equivalent to 100 mg of 
free acid, as a lyophilized powder in a 5-mL glass vial.  SGI-110 diluent 


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Code Name 
SGI-110 
for reconstitution, 3 mL contains 3 mL of custom diluent for reconstitution 
in a 5-mL glass vial. 
Storage Conditions 
SGI-110 for injection, 100 mg:  2°C to 8°C 
SGI-110 diluent for reconstitution, 3 mL:  2°C to 30°C 
 
4.1.2 
Comparator 
Not applicable 
4.2 
Packaging and Labeling 
4.2.1 
Packaging 
Investigational medicinal products supplied will be SGI-110 for injection, 100 mg and 
SGI-110 diluent for reconstitution, 3 mL in 2 separate vials.  Each vial is closed with a 
fluororesin laminated rubber stopper and a blue flip-off cap for SGI-110 for injection, 
100 mg or a white flip-off cap for SGI-110 diluent for reconstitution, 3 mL. 
4.2.2 
Contents of Label 
The information written on the label includes specification that the drug is for use in a 
clinical trial, the code name, lot number, expiration date, and storage conditions of the 
IMP, and the name and address of the sponsor. 
 
5 
Trial Population 
5.1 
Target Disease 
AML 
5.2 
Inclusion Criteria 
Patients meeting all of the following criteria at the time of screening will be included in 
this trial: 
1) Male or female patients with a diagnosis of AML (World Health Organization 
[WHO] classification 2008). 
 Patients, 20 years of age or older, who are unresponsive to standard 
chemotherapy or have relapsed following standard chemotherapy 
 Patients, 65 years of age or older, who are not eligible for standard intensive 
chemotherapy and who meet at least one of the following criteria (applicable 
to Cohorts 1, 2, and 4 only): 
 AML from MDS, or secondary AML 


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 Chromosomal karyotype abnormality with poor prognosis [del (5q), del 
(7q), −5, −7, abnormality of 3q (q21;q26), t (6;9) (p23;q34), t (9;22) 
(q34;q11.2), abnormality of 11 (11q23), or complex karyotype of 3 or 
more unrelated abnormalities of any kind] 
 Dysfunction of the heart (left ventricular ejection fraction [LVEF] < 50%) 
or lung (diffusing capacity of the lung for carbon monoxide [DLCO] or 
forced expiratory volume in the first second [FEV 1] < 50% of expected 
value) which is unrelated to AML 
 ECOG PS of 2 
 75 years of age or older 
2) Patients with ECOG PS of 0 to 2. 
3) Patients with adequate vital organ function (patients whose clinical laboratory 
values meet the following conditions). 
a) Hepatic function:  total bilirubin (T-Bil) ≤ 2 × upper limit of normal (ULN); 
AST and ALT ≤ 2.5 × ULN. 
b) Renal function:  serum Cr ≤ 1.5 × ULN. 
4) Female patients of childbearing potential must not be pregnant or breast feeding 
(pregnancy test will be performed at screening).  Female patients of childbearing 
potential and all male patients must practice two medically acceptable methods of 
birth control and must not become pregnant or father a child while receiving 
treatment with SGI-110 and for 3 months following last dosing.  If male patients 
have female partners of childbearing potential, those partners must also practice 
medically acceptable methods of birth control for the same period. 
5) Patients who have undergone prior allogeneic hematopoietic stem cell 
transplantation must have no evidence of active graft-versus host disease (GVHD) 
and must be off immunosuppressive therapy by ≥ 2 weeks prior to the scheduled 
start of IMP administration. 
6) Patients who have undergone no major surgery within 4 weeks prior to the 
scheduled start of IMP administration. 
7) Patients who have undergone no chemotherapy within 2 weeks prior to the 
scheduled start of IMP administration, nor hematopoietic stem cell transplantation 
within 8 weeks prior to the scheduled start of IMP administration. 
8) Patients who are able to provide written consent to participate in this trial by 
signing an informed consent form (ICF) that has been approved by an Institutional 
Review Board (IRB) (patients who are willing to comply with the protocol, 
including consent to hospitalization during Course 1). 
 
[Rationale for inclusion criteria] 
1) The target population of the trial will be patients with AML who are expected to 
respond to SGI-110 in reference to a preceding clinical trial conducted outside of 
Japan (Study SGI-110-01).  It has been decided to select patients who do not respond 


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to conventional therapy or for whom generally accepted standard therapy are not 
available in accordance with the “Guidelines for Clinical Evaluation of 
Antimalignant Tumor Drugs.”  The lower limit of age is set as 20 years for patients 
who are unresponsive to standard therapy or have relapsed after treatment since 
informed consent can be obtained from subjects aged 20 years or older.  The lower 
limit of age is set as 65 years for patients who are not eligible for standard intensive 
chemotherapy in reference to studies conducted outside of Japan. 
As mentioned in Section 1.2.3 Trial Rationale, a regimen of SGI-110 at 60 mg/m2 
once daily for 10 days is planned to be adopted in Study SGI-110-06 in patients with 
relapsed or refractory AML.  Therefore, the tolerability of SGI-110 at 60 mg/m2 once 
daily for 10 days will be evaluated in patients with relapsed or refractory AML in 
Cohort 3 (60 mg/m2 in 10-day regimen), which is consistent with the target 
population in Study SGI-110-06. 
2), 3) These criteria have been provided to ensure the subjects’ safety in reference to 
the “Guidelines for Clinical Evaluation of Antimalignant Tumor Drugs.” 
4) The criterion has been provided in consideration of the safety of fetuses and 
infants because SGI-110 has shown genotoxicity, teratogenicity, fetotoxicity, and 
embryotoxicity and it is unknown whether or not SGI-110 is transferred into breast 
milk. 
5) to 7) The criteria have been provided to select patients having no effect of previous 
treatment in reference to the “Guidelines for Clinical Evaluation of Antimalignant 
Tumor Drugs” and a study conducted outside of Japan (Study SGI-110-01). 
8) The criterion has been provided for ethical reasons based on Good Clinical 
Practice.  Hospitalization during Course 1, which is the DLT evaluation period, is to 
be mandatory in reference to the “Guidelines for Clinical Evaluation of 
Antimalignant Tumor Drugs.” 
 
5.3 
Exclusion Criteria 
Patients falling under any of the following criteria at the time of screening will be 
excluded from this trial: 
1) Patients with acute promyelocytic leukemia (APL) accompanied by 
t (15;17) (q22;q12) or (PML/RARA) karyotype abnormalities (including other 
variant types of APL). 


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2) Patients with multiple cancers (except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other cancer from which the 
subject has been disease free for at least 3 years). 
3) Patients with life-threatening illnesses other than AML, such as uncontrolled 
medical conditions or organ system dysfunction which, in the opinion of the 
investigator or subinvestigator, could compromise the subject’s safety or the study 
outcomes. 
4) Patients with poorly controlled arrhythmias, or any Class 3 or 4 cardiac disease as 
defined by the New York Heart Association (NYHA) Functional Classification. 
5) Patients with symptomatic central nervous system involvement. 
6) Patients who have received radiation therapy for extramedullary disease within 2 
weeks prior to planned enrollment. 
7) Patients with AEs (other than alopecia) of Grade 2 or higher from prior therapy 
for AML, at the time of screening for this trial. 
8) Patients with febrile neutropenia. 
9) Patients who are human immunodeficiency virus (HIV) antibody positive, 
hepatitis B virus (HBV)-DNA positive, or with active hepatitis C. 
10) Patients who have taken any investigational drug or individually imported drug 
within 2 weeks prior to the scheduled start of IMP administration. 
11) Patients who have been treated with systemic corticosteroids as treatment for their 
AML within 2 weeks prior to the scheduled start of IMP administration. 
12) Patients with uncontrolled active systemic infections. 
13) Patients who have hypersensitivity to decitabine, SGI-110, or IMP excipients. 
14) Patients judged to be ineligible by the investigator or subinvestigator for any other 
reason. 
[Rationale for exclusion criteria] 
1) Patients with APL will be excluded because it is reported that the remission rate is 
high in patients treated with all-trans retinoic acid, arsenic trioxide, etc. 
2), 5), 6), 10), 11) These criteria have been provided for reasons of subject safety and 
because the conditions mentioned in these criteria may affect efficacy evaluation. 
3), 4), 7) to 9), 12), 13) These criteria have been provided for reasons of subject safety. 
14) The criterion has been provided so that the investigator or subinvestigator can 
consider factors other than those mentioned above when selecting subjects. 
 
Reference:  NYHA Functional Classification 
I 
Presence of heart disease, but no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea 
(shortness of breath), or anginal pain. 
II 
Slight limitation of physical activity.  Comfortable at rest. 


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Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath), or anginal pain. 
III 
Marked limitation of physical activity.  Comfortable at rest. 
Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Unable to carry on any physical activity without discomfort because of heart disease. 
Symptoms of heart failure or anginal pain at rest.  If any physical activity is 
undertaken, discomfort increases. 
(Additional) 
IIs:  Slight limitation of physical activity 
IIm:  Moderate limitation of physical activity 
Source:  Guidelines for Diagnosis and Treatment of Cardiovascular Diseases (2004-2005 Joint Working 
Group report) 
Guidelines for Treatment of Acute Heart Failure (2006 revision) - Digest Version 
Societies participating in the Joint Working Group:  Japanese Circulation Society, Japanese 
Association for Thoracic Surgery, Japanese Society for Cardiovascular Surgery, Japanese College of 
Cardiology, and Japanese Heart Failure Society 
http://www.j-circ.or.jp/guideline/pdf/JCS2006_maruyama_d.pdf 
 
6 
Trial Design 
6.1 
Dose, Regimen, and Treatment Period 
The total daily dose will be determined based on the subject’s body surface area (BSA) 
calculated from height and weight prior to administration in each course, according to the 
treatment cohort. 
SGI-110 will be administered SC at the determined daily dose after being reconstituted 
using the custom diluent provided. 
In Cohorts 1, 2, and 4, subjects will receive SGI-110 once daily for 5 consecutive days 
(Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28).  One 
course will consist of 4 weeks (28 days).  In Cohort 3, subjects will receive SGI-110 once 
daily for 10 days in total (SGI-110 will be administered for 5 consecutive days [Day 1 to 
Day 5], suspended for 2 days [Day 6 and Day 7], then administered for another 5 
consecutive days [Day 8 to Day 12]), and the dosing will be suspended for 16 days (Day 
13 to Day 28).  One course will consist of 4 weeks (28 days). 
The dose and regimen for each cohort is as follows: 
Cohort 1 (36 mg/m2, 5-day administration) 
Cohort 2 (60 mg/m2, 5-day administration) 
Cohort 3 (60 mg/m2, 10-day administration [ie, 5-day administration twice, with a non-
dosing period in-between]) 
Cohort 4 (90 mg/m2, 5-day administration) 


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SGI-110 for injection, 100 mg contains SGI-110 equivalent to 100 mg of free acid, as a 
lyophilized powder in a 5-mL glass vial.  Subjects who complete IMP administration and 
all observations during the DLT evaluation period, and who do not have any apparent 
progression of AML, will be permitted to continue treatment with IMP following the 
DLT evaluation period if they wish, and will receive treatment according to the same 
dosing schedule as Course 1 (Cohorts 1, 2, and 4). 
In Cohort 3, subjects will receive SGI-110 for 10 days in Course 1 (DLT evaluation 
period), for 10 or 5 days in Course 2 (Extended treatment period), for 5 days in Course 3 
and subsequent courses.  The investigator will determine whether or not the transition to 
Course 2 should be postponed and which regimen is used for each subject, as described 
below, based on the subject’s condition (the percentage of blasts in the peripheral blood 
and bone marrow, and peripheral blood cell counts) at the completion of Course 1.  
1) Has blasts in the peripheral blood:  Subject will proceed to Course 2 without delay 
and receive SGI-110 for 10 days. 
2) No blasts in the peripheral blood:  The percentage of blasts in the bone marrow 
will be assessed. 
a) The percentage of blasts in the bone marrow is ≥5%:  Subject will proceed to 
Course 2 without delay and receive SGI-110 for 10 days. 
b) The percentage of blasts in the bone marrow is <5%:  The neutrophil and 
platelet counts in the peripheral blood will be assessed. 
i) The neutrophil count is ≥ 500/μL and platelet count is ≥ 50000/μL:  
Subject will proceed to Course 2 without delay and receive SGI-110 for 5 
days. 
ii) The neutrophil count is < 500/μL or platelet count is < 50000/μL:  
Transition to Course 2 will be postponed, and the subject’s peripheral 
blood will be assessed at least once a week.  After that, if the subject has 
no blasts in the peripheral blood but the neutrophil and platelet counts are 
recovered to ≥ 500/μL and ≥ 50000/μL, respectively, he/she will proceed 
to Course 2 and receive SGI-110 for 5 days.  If blasts are found in the 
subject’s peripheral blood while his/her transition to Course 2 is on hold, 
he/she will proceed to Course 2 and receive SGI-110 for 10 days.  For 
subjects whose transition to Course 2 is on hold because blasts are not 
found in his/her peripheral blood and the neutrophil and platelet counts are 
< 500/μL and < 50000/μL, respectively, it is possible to proceed to Course 
2 and receive SGI-110 for either 5 or 10 days at the discretion of the 
investigator or subinvestigator based on the benefit-risk balance for the 
subject. 
 
SGI-110 diluent for reconstitution, 3 mL contains 3 mL of custom diluent for 
reconstitution in a 5-mL glass vial. 


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SGI-110 for injection, 100 mg vial and SGI-110 diluent for reconstitution, 3 mL should 
be stored at 2°C to 8°C and 2°C to 30°C, respectively, until use.  Both vials are for single 
use only as they are free of preservatives. 
[Rationale for dose, regimen, and treatment period] 
[Dose] 
In the phase 1 part (ie, dose escalation segment) of a phase 1/2 trial conducted outside 
of Japan (Study SGI-110-01), no DLT occurred when SGI-110 was administered at a 
dose range of up to 90 mg/m2 for 5 days to patients with MDS and patients with 
AML who had relapsed after standard therapy or had not responded to treatment, and 
2 of 3 patients with MDS experienced DLTs (thrombocytopenia, neutropenia, febrile 
neutropenia, and sepsis) after administration at 125 mg/m2.  Hence, the MTD was 
estimated to be 90 mg/m2 (no DLT occurred in patients with AML who had received 
SGI-110 at a dose range of up to 125 mg/m2).  The BED was determined to be 
60mg/m2 based on the evaluation of DNA hypomethylation in LINE-1.  In the dose 
expansion segment implemented as the phase 2 part, two dose levels of 60 and 
90mg/m2 were compared in patients with AML who had relapsed after standard 
therapy or had not responded to treatment and treatment-naïve patients with AML 
who were not eligible for standard chemotherapy; the composite remission rates were 
very similar (25% and 26%, respectively).11 
Based on these, the trial is designed to administer SGI-110 at an initial dose of 36 
mg/m2 (one level lower than 60 mg/m2) for 5 days and then increase the dose to up to 
90 mg/m2 (one level higher than 60 mg/m2) so as to evaluate the safety of 60 mg/m2, 
the recommended dose for non-Japanese patients, in Japanese subjects. 
[Regimen and treatment period] 
In the dose escalation segment of Study SGI-110-01, 3 regimens were adopted for 
evaluation:  ie, a 5-day regimen (Day 1 to Day 5), a once-weekly regimen (Day 1, 
Day 8, and Day 15), and a twice-weekly regimen (Day 1, Day 4, Day 8, Day 11, Day 
15, and Day 18).  At the end of the dose escalation segment, the Independent Data 
Monitoring Committee recommended transition to the dose expansion segment (ie, 
the phase 2 part) and adoption of a 5-day once-daily regimen in the dose expansion 
segment because the extent of hypomethylation was lower for the once-weekly 
regimen than for the 5-day once-daily regimen.  Likewise, it was decided to adopt a 
5-day once-daily regimen for the trial. 


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[Rationale for dose, regimen, and treatment period:  Cohort 3] 
A phase 1/2 trial was conducted outside of Japan (Study SGI-110-01) in patients with 
AML who had relapsed after standard chemotherapy or had not responded to 
treatment.  Based on the results obtained in the dose expansion segment conducted as 
phase 2 segment in the Study SGI-110-01, which is shown below, 60 mg/m2 once 
daily for 10 days has been chosen as a dose and treatment period for Cohort 3. 
 When comparing 60 mg/m2 in 5-day regimen with 90 mg/m2 in 5-day regimen, 
there were no differences in remission rate and overall survival. 
 When comparing 60 mg/m2 in 5-day regimen with 60 mg/m2 in 10-day regimen, 
the time to achieve complete remission was shorter and the extent of 
hypomethylation was more potent in 10-day regimen. 
A phase 3 trial (Study SGI-110-06) in patients with relapsed or refractory AML is 
newly planned.  Since the dose and treatment period of Study SGI-110-06 has been 
set as 60 mg/m2 once daily for 10 days, the tolerability of the same regimen 
(60 mg/m2 once daily for 10 days) in Japanese patients was decided to be evaluated 
in this study. 
 
6.2 
Prior and Concomitant Treatment 
6.2.1 
Prohibited Concomitant Drugs and Therapies 
Only the IMP will be used for treating the primary disease, and concomitant use of the 
drugs and therapies listed below is prohibited from the time of informed consent to the 
withdrawal examination. 
 Other anti-cancer drugs, hormone therapy, antibody therapy, radiation therapy, 
thermal therapy, or other anti-cancer therapies 
 Other investigational drugs and individually imported drugs 
 Prophylactic therapies for the purpose of preventing AEs (except infection) 
(Prophylactic therapies to prevent recurrence of AEs observed after the start of the 
IMP administration will be allowed.) 
6.2.2 
Restricted Concomitant Drugs and Therapies 
Any drug or therapy that is not prohibited, as specified above, can be administered during 
the trial. 
The investigator or subinvestigator should administer blood transfusions for supportive 
care as appropriate.  Prophylactic medications should be provided if necessary in order to 
prevent bacterial, fungal, viral, and opportunistic infections and deaths from these 


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infections.  Antibiotics and other drugs can be given to prevent and control febrile 
neutropenia.  In the trial, febrile neutropenia is defined as a neutrophil count below 
500/μL and body temperature of 38°C or higher. 
Subjects with fever will undergo physical examination and peripheral blood tests 
(including differential leukocyte count and blood culture).  Subjects who have been 
confirmed to have febrile neutropenia or sepsis (including suspected cases) by physical 
examination will be hospitalized and properly treated with a broad-spectrum antibiotic 
and other medication.  The package insert should be observed for use of hematopoietic 
growth factors such as a granulocyte-colony stimulating factor. 
When any drugs other than the IMP (excluding physiological saline and dextrose solution 
used for reconstitution) have been used from 28 days before the start of IMP 
administration until the date of withdrawal from the trial, the name of the drug, purpose 
of use, regimen, daily dose, route of administration, and start and end dates of treatment 
will be recorded in the case report form (CRF) (or in the medical records during the 
extended treatment part).  If blood transfusion has been performed, the type, purpose, 
volume, and date of blood transfusion will be recorded in the CRF (or in the medical 
records during the extended treatment part).  For treatments other than medication and 
blood transfusion, the name, purpose, and start and end dates of the therapy will be 
recorded in the CRF (or in the medical records during the extended treatment part). 
[Rationales for prohibited concomitant drugs and therapies] 
The prohibited concomitant drugs and therapies are specified because they may affect 
safety and efficacy evaluations.  Supportive care used in routine medical practice, and 
medications to prevent infection, are allowed because patients in the trial are anticipated 
to have symptoms that may affect ADL such as decreased blood cell counts and infection 
associated with progression of the underlying disease, AML.  In addition decreased blood 
cell counts are anticipated after IMP administration. 
 
6.3 
Method of Minimizing or Avoiding Bias 
Not applicable 
 


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7 
Trial Procedures 
7.1 
Schedule and Procedures 
The investigator or subinvestigator will perform investigations, observations, 
examinations, and evaluations during the trial period in accordance with the “Schedule of 
Events” shown in Table 7.1-1.  Items that trial associates are capable of performing, such 
as the patient background survey, may be performed by trial associates under the 
supervision of the investigator or subinvestigator. 
Evaluation of DLTs, the primary objective of the trial, will take place from the first 
dosing in Course 1 to the examination scheduled for Day 29 of Course 1.  However, the 
DLT evaluation period will last up until the first dosing in Course 2 for subjects who 
have postponed the start of IMP administration scheduled for Day 1 of Course 2 
(extended treatment period). 
The trial period for each subject will be from the day of informed consent to the day of 
withdrawal from the trial.  However, if AEs (including abnormal changes in laboratory 
values) that occur during the trial period have not resolved by the date of withdrawal 
from the trial, they will be followed up in accordance with Section 8.4 Follow-up 
Investigation of Adverse Events. 


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Table 7.1-1 
Schedule of Events 
Cohorts 1, 2, and 4 (5-day Regimen) 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationa
 
 
 
 
Course 1 (DLT Evaluation Period)b
 
Course 2 (Extended Treatment 
Period) 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D15 D22 D29c
 D1 D2-
D5 D8 D15 D22 D29c
 D1 D2-
D5 D15 D29c
 
D1-
D5 
D29 Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 
1 
2 
3 
4 
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Written Consentd
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
Patient Background Investigation 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of Concomitant Drugs and Blood 
Transfusione
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
○ 
Investigation of AEs 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
○ 
Medical Examination by Investigator or 
Subinvestigator (Subjective and Objective 
Findings) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy Test (Urine or Serum Test) f
 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
Viral Testg
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
 
 
 
Verification of Eligibility, Enrollment 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsh
 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
 
 
○ 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weighti
 
 
 
□ 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
□ 
 
 
 
 
 
○ 
Twelve-lead ECG 
 
○ 
□ 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Chest X-ray 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Cardiac Function or Respiratory Functionj
 
 
◊ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology Testk
 
 
○ 
□ 
 
 
 
 
○ 
○ 
○ 
○ 
□ 
 
○ 
○ 
○ 
○ 
□ 
 
○ 
○ 
□ 
 
○ 
Blood Biochemistry Testl
 
 
○ 
□ 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
60  
Version 8 
Table 7.1-1 
Schedule of Events 
Cohorts 1, 2, and 4 (5-day Regimen) 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationa
 
 
 
 
Course 1 (DLT Evaluation Period)b
 
Course 2 (Extended Treatment 
Period) 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D15 D22 D29c
 D1 D2-
D5 D8 D15 D22 D29c
 D1 D2-
D5 D15 D29c
 
D1-
D5 
D29 Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 
1 
2 
3 
4 
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Urinalysism
 
 
○ 
□ 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
ECOG PS 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Bone Marrow Aspirationn
 
 
○ 
 
 
 
 
 
 
 
 
○ 
············································· ···························· 
 
 
○ 
Blood Sampling for PKo
 
 
 
○ 
○ 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for PDp
 
 
 
○ 
 
 
 
 
○ 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of Efficacyq
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
○:  Mandatory item 
□:  If such tests or examinations have already been conducted within 4 days before Day 1, those tests/examinations may be used as the Day 1 tests/examinations. 
◊:  Optional item related to inclusion criteria 
a
If the withdrawal examination is performed within the acceptable time window for Day 8, Day 15, Day 22, or Day 29, repeated tests/examinations are not necessary for those items already 
performed for the same day.  If the discontinuation is due to an SAE or progression of disease, only those examinations that are feasible, given the subject’s state of health, will be performed. 
b
Hospitalization during Course 1 is mandatory.  For those subjects for whom the trial is concluded with Course 1, hospitalization until the withdrawal examination is mandatory.  For those subjects 
who continue to receive IMP administration in Course 2 and subsequent courses, hospitalization until commencement of IMP administration in Course 2 is mandatory. 
c
If IMP administration for the next course is started from Day 29, the tests designated for Day 29 should be performed between Day 26 and before IMP administration on Day 32.  (If the tests 
designated for Day 29 are performed within the acceptable time window, between Day 26 and Day 28, IMP administration for the next course will be started on or after Day 29.) 
d
Written consent at screening will be obtained prior to all observations, tests, examinations, and evaluations of this trial.  Written consent for continuation of IMP administration in Course 2 and 
subsequent courses will be obtained before the start of Course 2 (after Day 22 administration of Course 1). 
e
Details on all concomitant medications taken from 28 days before the start of IMP administration until discontinuation will be collected.  Information on any blood transfusions administered from 
28 days before the start of IMP administration until 30 days after the last administration will also be collected.  (If the subject starts another AML treatment or is transferred to another hospital, 
collection of such data will be continued up until that point.) 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
61  
Version 8 
f
To be performed for female subjects only.  (However, a pregnancy test is not required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who have been 
amenorrheic without a medical cause for at least 12 consecutive months.) 
g
Human immunodeficiency virus antibody, HBV-DNA, hepatitis C Virus (HCV) antibody, hepatitis B core antibody (HBcAB), and hepatitis B surface antibody (HBsAB) tests will be performed at 
screening.  For those subjects who are found to be either HBcAB or HBsAB positive at screening, a test for HBV-DNA will be done on Day 1 in Course 2 and subsequent courses. 
h
Blood pressure (systolic/diastolic), pulse rate, body temperature (measured after the subject has rested in the sitting position for at least 3 minutes) 
i
Body weight will be measured and the dose of IMP to be administered will be determined according to the calculation of BSA. 
j
Cardiac function (echocardiography or multiple-gated acquisition [MUGA] scan) or respiratory function (DLCO or FEV 1) will be measured. 
k
Hemoglobin (Hb), hematocrit (Hct), RBC, WBC, differential WBC (visual count:  blast cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, myelocytes, metamyelocytes, 
segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, promonocytes), platelet count, reticulocytes 
l
AST (glutamate oxaloacetate transaminase [GOT]), ALT (glutamate pyruvate transaminase [GPT]), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein (TP), albumin (ALB), 
T-Bil, blood urea nitrogen (BUN), uric acid (UA), Cr, blood glucose (fasting), Ca, Mg, Na, K, Cl 
m
Bilirubin, occult blood, protein, urobilinogen 
n
Bone marrow aspiration will be performed at screening and on Day 29 of Course 1.  In Course 2 and subsequent courses, if peripheral blood testing indicates that the subject meets criteria for 
remission, or if clear disease progression is observed, bone marrow aspiration will be performed and the following items will be examined:  percentage of bone marrow fluid (blasts, lymphoblasts, 
monoblasts, promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, pronormoblasts, erythroblasts, 
plasma cells, and megakaryocytes), myeloid/erythroid ratio (M/E ratio), cellularity. 
(If bone marrow aspiration has already been performed and any of the above items have been measured prior to acquisition of written informed consent and within the acceptable time window for 
the screening period [within 28 days before commencement of IMP administration], then those results can be used as the screening data, provided the subject’s consent is obtained.) 
o
Blood sampling for PK: 
Day 1 and Day 5:  predose, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours after dosing 
Day 2 (24 hours after Day 1 dosing), Day 3, and Day 4:  predose (predose on Day 2 is the same as 24 hours postdose on Day 1) 
[Acceptable time windows] 
Day 1 and Day 5 
predose: 
Day 1:  within 2 hours before IMP administration 
 
 
Day 5:  ± 30 minutes of 24 hours from Day 4 dosing and before the Day 5 dosing 
 
15 minutes and 30 minutes postdose: 
± 3 minutes 
 
60 minutes, 90 minutes, and 2 hours postdose: 
± 6 minutes 
 
3 hours and 4 hours postdose: 
± 12 minutes 
 
6 hours and 8 hours postdose: 
± 24 minutes 
 
24 hours postdose: 
± 30 minutes (24 hours postdose on Day 1 should be performed before Day 2 dosing) 
Day 2, Day 3, Day 4 
predose: 
± 30 minutes of 24 hours from the previous dosing and before the dosing on that day 
p
Blood sampling for PD:  blood sampling performed during screening is also acceptable for Day 1 sampling.  If the sampling is performed on Day 1, it must be performed before dosing. 
q
In Course 2 and subsequent courses, evaluation of efficacy will be performed if peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease progression is 
observed. 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
62  
Version 8 
Table 7.1-1 
Schedule of Events 
Cohort 3 (10-day Regimen):  10-day Regimen in Course 2 (Extended Treatment Period) 
 
 
Primary Evaluation Part 
 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
Course 2 (Extended Treatment Period)b
 
Course 3 and 
Subsequent 
Courses (Extended 
Treatment Period) 
 
Extended 
Course 
 
Screening D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
11 
D 
12 
D 
15 
D 
22 D29d
 
D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
12 
D 
15 
D 
22 
D29d
 
D
1 
D2-
D5 
D 
15 
D29
d
 
D1-5 
D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time 
Window (Day) 
−28 −14 1 
2 
3 4 5 8 9-11 12 13-
18 
19-
25 26-32 1 
2 
3 4 
5 8 9-12 13-18 19-
25 
26-32 
1 2-5 12-
18 
26-
32 
1-5 
 
Written Consente
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
Patient Background 
Investigation 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of 
Concomitant Drugs and 
Blood Transfusionf
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−−−−− 
○ 
Investigation of AEs 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−−−−− 
○ 
Medical Examination by 
Investigator or 
Subinvestigator 
(Subjective and Objective 
Findings) 
○ 
○ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
○ 
○ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy Test (Urine or 
Serum Test)g
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
Viral Testh
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
Verification of Eligibility, 
Enrollment 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
      
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
Vital Signsi
 
 
○ 
○ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
○ 
□ ○ ○ ○ ○ ○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
 
 
○ 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weightj
 
 
 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
□ 
 
 
 
 
 
○ 
Twelve-lead ECG 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
63  
Version 8 
Table 7.1-1 
Schedule of Events 
Cohort 3 (10-day Regimen):  10-day Regimen in Course 2 (Extended Treatment Period) 
 
 
Primary Evaluation Part 
 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
Course 2 (Extended Treatment Period)b
 
Course 3 and 
Subsequent 
Courses (Extended 
Treatment Period) 
 
Extended 
Course 
 
Screening D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
11 
D 
12 
D 
15 
D 
22 D29d
 
D
1 
D
2 
D
3 
D
4 
D
5 
D
8 
D9-
12 
D 
15 
D 
22 
D29d
 
D
1 
D2-
D5 
D 
15 
D29
d
 
D1-5 
D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time 
Window (Day) 
−28 −14 1 
2 
3 4 5 8 9-11 12 13-
18 
19-
25 26-32 1 
2 
3 4 
5 8 9-12 13-18 19-
25 
26-32 
1 2-5 12-
18 
26-
32 
1-5 
 
Chest X-ray 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Cardiac Function or 
Respiratory Functionk
 
 
◊ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology Testl
 
 
○ 
□ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
□ 
 
 
 
 
○ 
 
○ 
○ 
○ 
□ 
 
○ 
○ 
□ 
 
○ 
Blood Biochemistry 
Testm
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
Urinalysisn
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
ECOG PS 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Bone Marrow Aspirationo
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
····································································· 
························· 
 
 
○ 
Blood Sampling for PKp
 
 
 
○ ○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for PDq
 
 
 
○ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of Efficacyr
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
64  
Version 8 
Table 7.1-1 
Schedule of Events 
Cohort 3 (10-day Regimen):  5-day Regimen in Course 2 (Extended Treatment Period) 
 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
 
Course 2 (Extended Treatment 
Period)b
 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D9
-11 D12 D15 D22 D29d
 D1 D2
-5 D8 D15 D22 D29d
 
D1 
D2-
D5 
D15 D29d
 
D1-5 D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 1 
2 
3 
4 
5 
8 
9-
11 
12 
13-
18 
19-
25 
26-32 
1 
2-
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Written Consente
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
 
 
Patient Background Investigation 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigation of Concomitant Drugs 
and Blood Transfusionf
 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
 
Investigation of AEs 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
−−−−−− 
 
Medical Examination by Investigator 
or Subinvestigator (Subjective and 
Objective Findings) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy Test (Urine or Serum 
Test)g
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
Viral Testh
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
 
 
 
Verification of Eligibility, 
Enrollment 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsi
 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
○ 
○ 
□ 
○ 
○ 
○ 
 
 
○ 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weightj
 
 
 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
 
□ 
 
 
 
 
 
○ 
Twelve-lead ECG 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Chest X-ray 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Cardiac Function or Respiratory 
Functionk
 
 
◊ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
65  
Version 8 
Table 7.1-1 
Schedule of Events 
Cohort 3 (10-day Regimen):  5-day Regimen in Course 2 (Extended Treatment Period) 
 
 
 
Primary Evaluation Part 
Extended 
Treatment 
Part 
Withdrawal 
Examinationc
 
Course 1 (DLT Evaluation Period)a
 
 
Course 2 (Extended Treatment 
Period)b
 
Course 3 and 
Subsequent Courses 
(Extended Treatment 
Period) 
Extended 
Course 
 
Screening D1 D2 D3 D4 D5 D8 D9
-11 D12 D15 D22 D29d
 D1 D2
-5 D8 D15 D22 D29d
 
D1 
D2-
D5 
D15 D29d
 
D1-5 D29 
Within 5 days 
after 
Withdrawal 
Acceptable Time Window (Day) 
−28 −14 1 
2 
3 
4 
5 
8 
9-
11 
12 
13-
18 
19-
25 
26-32 
1 
2-
5 
6-
10 
12-
18 
19-
25 
26-32 
1 
2-5 
12-
18 
26-32 
1-5 
 
Hematology Testl
 
 
○ 
□ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
□ 
 
○ 
○ 
○ 
○ 
□ 
 
○ 
○ 
□ 
 
○ 
Blood Biochemistry Testm
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
Urinalysisn
 
 
○ 
□ 
 
 
 
 
 
 
 
 
 
○ 
□ 
 
 
 
 
○ 
□ 
 
 
○ 
 
 
○ 
ECOG PS 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
Bone Marrow Aspirationo
 
 
○ 
 
 
 
 
 
 
 
 
 
 
○ 
········································· 
······························ 
 
 
○ 
Blood Sampling for PKp
 
 
 
○ 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for PDq
 
 
 
○ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of Efficacyr
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
○ 
 
 
 
○ 
 
 
○ 
○:  Mandatory item 
□:  If such tests or examinations have already been conducted within 4 days before Day 1, those tests/examinations may be used as the Day 1 tests/examinations. 
◊:  Optional item related to inclusion criteria 
a
Hospitalization during Course 1 is mandatory.  For those subjects for whom the trial is concluded with Course 1, hospitalization until the withdrawal examination is mandatory.  For those subjects 
who continue to receive IMP administration in Course 2 and subsequent courses, hospitalization until commencement of IMP administration in Course 2 is mandatory. 
 
b
Based on the subject’s condition (the percentage of blasts in the peripheral blood and bone marrow, and peripheral blood cell counts) at the completion of Course 1, it will be determined whether or 
not the transition to Course 2 should be postponed and which regimen is used for each subject.  
c
If the withdrawal examination is performed within the acceptable time window for  Day 15, Day 22, or Day 29, repeated tests/examinations are not necessary for those items already performed for 
the same day.  If the discontinuation is due to a serious adverse event (SAE) or progression of disease, only those examinations that are feasible, given the subject’s state of health, will be 
performed. 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
66  
Version 8 
d
If IMP administration for the next course is started from Day 29, the tests designated for Day 29 should be performed between Day 26 and before IMP administration on Day 32.  (If the tests 
designated for Day 29 are performed within the acceptable time window, between Day 26 and Day 28, IMP administration for the next course will be started on or after Day 29.) 
e
Written consent at screening will be obtained prior to all observations, tests, examinations, and evaluations of this trial.  Written consent for continuation of IMP administration in Course 2 and 
subsequent courses will be obtained before the start of Course 2 (after Day 22 administration of Course 1). 
f
Details on all concomitant medications taken from 28 days before the start of IMP administration until discontinuation will be collected.  Information on any blood transfusions administered from 
28 days before the start of IMP administration until 30 days after the last administration will also be collected.  (If the subject starts another AML treatment or is transferred to another hospital, 
collection of such data will be continued up until that point.) 
g
To be performed for female subjects only.  (However, a pregnancy test is not required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who have been 
amenorrheic without a medical cause for at least 12 consecutive months.) 
h
Human immunodeficiency virus antibody, HBV-DNA, hepatitis C virus (HCV) antibody, hepatitis B core antibody (HBcAB), and hepatitis B surface antibody (HBsAB) tests will be performed at 
screening.  For those subjects who are found to be either HBcAB or HBsAB positive at screening, a test for HBV-DNA will be done on Day 1 in Course 2 and subsequent courses. 
i
Blood pressure (systolic/diastolic), pulse rate, body temperature (measured after the subject has rested in the sitting position for at least 3 minutes) 
j
Body weight will be measured and the dose of IMP to be administered will be determined according to the calculation of BSA. 
k
Cardiac function (echocardiography or multiple-gated acquisition [MUGA] scan) or respiratory function (DLCO or FEV 1) will be measured. 
l
Hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC), white blood cell (WBC), differential WBC (visual count:  blast cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, promonocytes), platelet count, reticulocytes 
m
AST (glutamate oxaloacetate transaminase [GOT]), ALT (glutamate pyruvate transaminase [GPT]), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein (TP), albumin (ALB), 
T-Bil, blood urea nitrogen (BUN), uric acid (UA), Cr, blood glucose (fasting), Ca, Mg, Na, K, Cl 
n
Bilirubin, occult blood, protein, urobilinogen 
o
Bone marrow aspiration will be performed at screening and on Day 29 of Course 1.  In Course 2 and subsequent courses, if peripheral blood testing indicates that the subject meets criteria for 
remission, or if clear disease progression is observed, bone marrow aspiration will be performed and the following items will be examined:  percentage of bone marrow fluid (blasts, lymphoblasts, 
monoblasts, promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, pronormoblasts, erythroblasts, 
plasma cells, and megakaryocytes), myeloid/erythroid ratio (M/E ratio), cellularity. 
(If bone marrow aspiration has already been performed and any of the above items have been measured prior to acquisition of written informed consent and within the acceptable time window for 
the screening period [within 28 days before commencement of IMP administration], then those results can be used as the screening data, provided the subject’s consent is obtained.) 
p
Blood sampling for PK: 
Day 1 and Day 12:  predose, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours after dosing 
Day 5:  90 minutes, 6 hours after dosing 
[Acceptable time windows] 
Day 1 and Day 12 
predose: 
Day 1:  within 2 hours before IMP administration 
 
 
Day 12:  ± 30 minutes of 24 hours from Day 11 dosing and before the Day 12 dosing 
 
15 minutes and 30 minutes postdose: 
± 3 minutes 
 
60 minutes, 90 minutes, and 2 hours postdose: 
± 6 minutes 
 
3 hours and 4 hours postdose: 
± 12 minutes 


Protocol No. 343-14-001 
Confidential - Otsuka Proprietary Information 
67  
Version 8 
 
6 hours and 8 hours postdose: 
± 24 minutes 
 
24 hours postdose: 
± 30 minutes (24 hours postdose on Day 1 should be performed before Day 2 dosing) 
Day 5 
90 minutes postdose: 
± 6 minutes 
 
6 hours postdose: 
± 24 minutes 
q
Blood sampling for PD:  blood sampling performed during screening is also acceptable for Day 1 sampling.  If the sampling is performed on Day 1, it must be performed before dosing. 
r
In Course 2 and subsequent courses, evaluation of efficacy will be performed if peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease progression is observed.


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7.1.1 
Acquisition of Informed Consent 
Prior to any medical procedures for the trial, including the screening examination, the 
investigator or subinvestigator will obtain written consent from subjects. 
The investigator or subinvestigator will record the following subject information 
collected during the informed consent process in subject registration documents (list of 
screened subjects and list of enrolled subjects) and the CRF. 
 Date of informed consent acquisition 
 Subject number (3-digit trial site number + 4-digit in-site serial number) 
 Subject identification code 
Note For site numbers, see Annex 3, Lists of Trial Sites and Investigators Participating in 
the Trial. 
7.1.2 
Screening Examination 
Examination items at screening are listed below.  The investigator or subinvestigator will 
screen subjects who have provided consent based on data collected within 14 days before 
the start of treatment in Course 1.  The use of data collected before informed consent will 
require the subject’s consent for the use. 
The following information collected from the screening examination and the date of 
examination and measurement will be documented in the medical records and CRF: 
Examination items at screeninga 
Subject Background 
Sex, date of birth, height, diagnosis of AML (WHO classification) and date of 
the diagnosis, prior treatment for AML (whether or not the subject has 
undergone hematopoietic stem cell transplantation [if yes, date of 
transplantation, type of transplantation, ie, bone marrow transplantation, 
peripheral blood stem cell transplantation, or cord blood transplantation; in 
case of bone marrow transplantation or peripheral blood stem cell 
transplantation, type of graft, ie, autograft or allograft] and response to the 
treatment; whether or not the subject has undergone radiation therapy [if yes, 
the start and end dates of therapy]; whether or not the subject has received 
other prior treatment for AML [if yes, type of treatment, the start and end dates 
of treatment, and regimen]) and response to the treatment, karyotype at 
screening, cytogenetic abnormalities, extramedullary lesions found after the 
diagnosis of AML and their sites, (maximum) proportion of blast cells 
(leukemia cells) in the bone marrow after the diagnosis of AML, diagnosis of 
malignancies other than AML, date of the diagnosis, treatment provided and 
date of healing, diagnosis of medically important past illness and date of the 
diagnosis, and diagnosis of complications found at the time of informed 
consent and date of the diagnosis 
Clinical Symptoms 
Subjective symptoms and objective findings 
Pregnancy Testb 
Urinary or serum HCG 
Viral Test 
HIV antibody, HBV-DNA, HCV antibody, HBcAB, and HBsAB 


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Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Twelve-lead ECG and 
Chest X-ray 
Twelve-lead ECG and chest X-ray 
Cardiac Function or 
Respiratory Functionc 
For cardiac function, LVEF will be measured by echocardiography or MUGA 
scan.  For respiratory function, DLCO or FEV 1 will be measured. 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
Bone Marrow 
Aspirationd 
Percentage of bone marrow fluid (blasts, lymphoblasts, monoblasts, 
promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab 
leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, 
pronormoblasts, erythroblasts, plasma cells, and megakaryocytes), M/E ratio, 
and cellularity 
HCG = Human chorionic gonadotropin 
aFor PD evaluation on Day 1, blood samples can be collected at the time of the screening examination.  
bA pregnancy test will be performed in female subjects at the trial site.  However, a pregnancy test is not 
required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who 
have been amenorrheic without a medical cause for at least 12 consecutive months. 
cFor cardiac function, LVEF will be measured by either echocardiography or MUGA scan according to 
the procedures specified by the trial site, and the date and results of measurement will be documented 
in the medical records and CRF.  For respiratory function, DLCO or FEV 1 will be measured, and the 
date and results of measurement will be documented in the medical records and CRF. 
dIf bone marrow aspiration has already been performed and any of the above items have been measured 
prior to acquisition of written informed consent and within the acceptable time window for the 
screening period (within 28 days before commencement of IMP administration), then those results 
can be used as the screening data. 
 
7.1.3 
Subject Registration 
The investigator or subinvestigator will record subjects who have provided consent, meet 
all the inclusion criteria, and do not fall under any of the exclusion criteria in a 
“registration request form,” and send the form to the registration center.  The registration 
center will send a “registration verification form” which provides the cohort number for 
the registered subject to the investigator or subinvestigator. 
When an examination has been performed more than once during the screening period 
and on Day 1 of Course 1, the data closest to the registration date should be used to 
decide the eligibility. 


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7.1.4 
Observations, Examinations, and Evaluations During the 
Treatment Period 
7.1.4.1 
Cohorts 1, 2, and 4 (5-day regimen) 
7.1.4.1.1 
Day 1 of Course 1 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration on Day 1 of Course 1, and the dates of the conduct and 
data obtained will be documented in the medical records and CRF.  If measurement of 
body weight, 12-lead ECG, hematology test, blood biochemistry test, and urinalysis have 
been completed within 4 days before Day 1, the available data can be used instead. 
If results of the examination conducted after registration or the subject’s condition do not 
meet the inclusion criteria or fall under any of the exclusion criteria, IMP administration 
scheduled for Day 1 should not be started until the subject meets the inclusion criteria 
without falling under any of the exclusion criteria. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weighta 
Body weight 
Twelve-lead ECG 
Twelve-lead ECG 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
aBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 
For PK and PD evaluations, blood samples will be collected at the following timepoints: 
PK Evaluation 
Predose, and 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 
hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing 
PD Evaluation 
Predose (blood can be collected at the time of the screening examination 
instead) 
 
Hospitalization during Course 1 is mandatory.  For those subjects for whom the trial is 
concluded with Course 1, hospitalization until the examination scheduled for Day 29 of 
Course 1 (until the withdrawal examination for those who are withdrawn from the trial in 
Course 1) is mandatory.  For those subjects who continue to receive IMP administration 
in Course 2 and subsequent courses, hospitalization until commencement of IMP 
administration on Day 1 of Course 2 is mandatory. 


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7.1.4.1.2 
Day 2 to Day 5 of Course 1 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
 
For PK evaluation, blood samples will be collected at the following timepoints: 
PK Evaluation 
Day 2, Day 3, and Day 4:  predose (predose blood sampling on Day 2 is the 
same as that at 24 hours postdose on Day 1) 
Day 5:  predose, and 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 
3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing 
 
7.1.4.1.3 
Day 8, Day 15, and Day 22 of Course 1 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
PD evaluation 
Blood sampling 
 
7.1.4.1.4 
Day 29 of Course 1 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Pregnancy Testa 
Urinary or serum HCG 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weight 
Body weight 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 


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Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
Bone Marrow Aspiration 
Percentage of bone marrow fluid (blasts, lymphoblasts, monoblasts, 
promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab 
leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, 
pronormoblasts, erythroblasts, plasma cells, and megakaryocytes), M/E ratio, 
and cellularity 
PD Evaluation 
Blood sampling 
HCG = Human chorionic gonadotropin 
aA pregnancy test will be performed in female subjects at the trial site.  However, a pregnancy test is not 
required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who 
have been amenorrheic without a medical cause for at least 12 consecutive months. 
 
Prior to transition to Course 2 and subsequent courses, written informed consent (using 
written information for subjects) to extended treatment in Course 2 and subsequent 
courses will be obtained from subjects who wish to continue to receive the treatment and 
are eligible for extended treatment in the opinion of the investigator or subinvestigator 
(between Day 22 of Course 1 and the start of Course 2).  In principle, each course should 
consist of 28 days, and if the examination scheduled for Day 29 is performed between 
Day 26 and Day 28 for example, which is within the acceptable window, IMP 
administration for the next course should be started on or after Day 29 of the current 
course. 
7.1.4.1.5 
Day 1 of Course 2 
If written informed consent is obtained for extended treatment, the observations, 
examinations, and evaluations listed below will be conducted before the start of IMP 
administration on Day 1 of Course 2, and the dates of the conduct and data obtained will 
be documented in the medical records and CRF.  If measurement of vital signs and body 
weight, hematology test, blood biochemistry test, and urinalysis have been completed 
within 4 days before Day 1, the available data can be used instead. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Viral Testa 
HBV-DNA 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weightb 
Body weight 


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Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
aA viral test will be performed only in subjects who are found to be either HBcAB or HBsAB positive at 
screening. 
bBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 
7.1.4.1.6 
Day 2 to Day 5 of Course 2 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.1.7 
Day 8, Day 15, and Day 22 of Course 2 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.1.8 
Day 29 of Course 2 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 


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Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
In principle, each course should consist of 28 days, and if the examination scheduled for 
Day 29 is performed between Day 26 and Day 28 for example, which is within the 
acceptable window, IMP administration for the next course should be started on or after 
Day 29 of the current course. 
7.1.4.1.9 
Day 1 of Course 3 and Subsequent Courses 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration on Day 1 of Course 3, and the dates of the conduct and 
data obtained will be documented in the medical records and CRF.  If measurement of 
vital signs and body weight, hematology test, blood biochemistry test, and urinalysis have 
been completed within 4 days before Day 1, the available data can be used instead. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Viral Testa 
HBV-DNA 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weightb 
Body weight 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
aA viral test will be performed only in subjects who are found to be either HBcAB or HBsAB positive at 
screening. 
bBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 


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7.1.4.1.10 
Day 2 to Day 5 of Course 3 and Subsequent Courses 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.1.11 
Day 15 of Course 3 and Subsequent Courses 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.1.12 
Day 29 of Course 3 and Subsequent Courses 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 


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In principle, each course should consist of 28 days, and if the examination scheduled for 
Day 29 is performed between Day 26 and Day 28 for example, which is within the 
acceptable window, IMP administration for the next course should be started on or after 
Day 29 of the current course.  Written informed consent (using written information for 
subjects) will be obtained from subjects who wish to continue to receive the treatment in 
the extended treatment part and are eligible for extended treatment in the opinion of the 
investigator or subinvestigator (before the start of a new course in the extended treatment 
part). 
7.1.4.1.13 
Day 1 to Day 29 of the Extended Course in the Extended 
Treatment Part 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration on Day 1 of each course and during each course, and the 
dates of the conduct and data obtained will be documented in the medical records.  In 
addition, examinations related to safety will be performed as necessary, and the dates of 
the conduct and data obtained will be documented in the medical records. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
 
7.1.4.2 
Cohort 3 (10-day regimen) 
7.1.4.2.1 
Day 1 of Course 1 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration on Day 1 of Course 1, and the dates of the conduct and 
data obtained will be documented in the medical records and CRF.  If measurement of 
body weight, 12-lead ECG, hematology test, blood biochemistry test, and urinalysis have 
been completed within 4 days before Day 1, the available data can be used instead. 
If results of the examination conducted after registration or the subject’s condition do not 
meet the inclusion criteria or fall under any of the exclusion criteria, IMP administration 
scheduled for Day 1 should not be started until the subject meets the inclusion criteria 
without falling under any of the exclusion criteria. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weighta 
Body weight 
Twelve-lead ECG 
Twelve-lead ECG 


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Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
aBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 
For PK and PD evaluations, blood samples will be collected at the following timepoints: 
PK Evaluation 
Predose, and 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 
hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing 
PD Evaluation 
Predose (blood can be collected at the time of the screening examination 
instead) 
 
Hospitalization during Course 1 is mandatory.  For those subjects for whom the trial is 
concluded with Course 1, hospitalization until the examination scheduled for Day 29 of 
Course 1 (until the withdrawal examination for those who are withdrawn from the trial in 
Course 1) is mandatory.  For those subjects who continue to receive IMP administration 
in Course 2 and subsequent courses, hospitalization until commencement of IMP 
administration on Day 1 of Course 2 is mandatory. 
7.1.4.2.2 
Day 2 to Day 5 and Day 9 to Day 12 of Course 1 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
 
For PK and PD evaluation, blood samples will be collected at the following timepoints: 
PK Evaluation 
Day 2:  predose (predose blood sampling on Day 2 is the same as that at 24 
hours postdose on Day 1) 
Day 5:  90 minutes and 6 hours after dosing 
Day 12:  predose, and 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 
hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing 
PD Evaluation 
Day 8:  predose 
 


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7.1.4.2.3 
Day 8, Day 15, and Day 22 of Course 1 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
PD evaluation 
Blood sampling 
 
7.1.4.2.4 
Day 29 of Course 1 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Pregnancy Testa 
Urinary or serum HCG 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weight 
Body weight 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
Bone Marrow Aspiration 
Percentage of bone marrow fluid (blasts, lymphoblasts, monoblasts, 
promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab 
leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, 
pronormoblasts, erythroblasts, plasma cells, and megakaryocytes), M/E ratio, 
and cellularity 
PD Evaluation 
Blood sampling 
HCG = Human chorionic gonadotropin 
aA pregnancy test will be performed in female subjects at the trial site.  However, a pregnancy test is not 
required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who 
have been amenorrheic without a medical cause for at least 12 consecutive months. 
 


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Prior to transition to Course 2, it will be assessed when to start Course 2 and which 
regimen (10-day regimen or 5-day regimen) to use in reference to Section 6.1 Dose, 
Regimen, and Treatment Period. 
Written informed consent (using written information for subjects) to extended treatment 
in Course 2 and subsequent courses will be obtained from subjects who wish to continue 
to receive the treatment and are eligible for extended treatment in the opinion of the 
investigator or subinvestigator (between Day 22 of Course 1 and the start of Course 2).  
In principle, each course should consist of 28 days, and if the examination scheduled for 
Day 29 is performed between Day 26 and Day 28 for example, which is within the 
acceptable window, IMP administration for the next course should be started on or after 
Day 29 of the current course. 
7.1.4.2.5 
Day 1 of Course 2 (10-day regimen) 
If written informed consent is obtained for extended treatment, the observations, 
examinations, and evaluations listed below will be conducted before the start of IMP 
administration on Day 1 of Course 2, and the dates of the conduct and data obtained will 
be documented in the medical records and CRF.  If measurement of vital signs and body 
weight, hematology test, blood biochemistry test, and urinalysis have been completed 
within 4 days before Day 1, the available data can be used instead. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Viral Testa 
HBV-DNA 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weightb 
Body weight 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
aA viral test will be performed only in subjects who are found to be either HBcAB or HBsAB positive at 
screening. 
bBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 


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7.1.4.2.6 
Day 2 to Day 5 and Day 9 to Day 12 of Course 2 (10-day 
regimen) 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.2.7 
Day 8, Day 15, and Day 22 of Course 2 (10-day regimen) 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.2.8 
Day 29 of Course 2 (10-day regimen) 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 


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In principle, each course should consist of 28 days, and if the examination scheduled for 
Day 29 is performed between Day 26 and Day 28 for example, which is within the 
acceptable window, IMP administration for the next course should be started on or after 
Day 29 of the current course. 
7.1.4.2.9 
Day 1 of Course 2 (5-day regimen) 
If written informed consent is obtained for extended treatment, the observations, 
examinations, and evaluations listed below will be conducted before the start of IMP 
administration on Day 1 of Course 2, and the dates of the conduct and data obtained will 
be documented in the medical records and CRF.  If measurement of vital signs and body 
weight, hematology test, blood biochemistry test, and urinalysis have been completed 
within 4 days before Day 1, the available data can be used instead. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Viral Testa 
HBV-DNA 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weightb 
Body weight 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
aA viral test will be performed only in subjects who are found to be either HBcAB or HBsAB positive at 
screening. 
bBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 
7.1.4.2.10 
Day 2 to Day 5 of Course 2 (5-day regimen) 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 


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7.1.4.2.11 
Day 8, Day 15, and Day 22 of Course 2 (5-day regimen) 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.2.12 
Day 29 of Course 2 (5-day regimen) 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
In principle, each course should consist of 28 days, and if the examination scheduled for 
Day 29 is performed between Day 26 and Day 28 for example, which is within the 
acceptable window, IMP administration for the next course should be started on or after 
Day 29 of the current course. 
7.1.4.2.13 
Day 1 of Course 3 and Subsequent Courses (5-day regimen) 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration on Day 1 of Course 3, and the dates of the conduct and 
data obtained will be documented in the medical records and CRF.  If measurement of 


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vital signs and body weight, hematology test, blood biochemistry test, and urinalysis have 
been completed within 4 days before Day 1, the available data can be used instead. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Viral Testa 
HBV-DNA 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weightb 
Body weight 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
aA viral test will be performed only in subjects who are found to be either HBcAB or HBsAB positive at 
screening. 
bBody weight will be measured and the dose of IMP to be administered will be determined according to 
the calculation of BSA. 
 
7.1.4.2.14 
Day 2 to Day 5 of Course 3 and Subsequent Courses (5-day 
regimen) 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration, and the dates of the conduct and data obtained will be 
documented in the medical records and CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.1.4.2.15 
Day 15 of Course 3 and Subsequent Courses (5-day regimen) 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 


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7.1.4.2.16 
Day 29 of Course 3 and Subsequent Courses (5-day regimen) 
The observations, examinations, and evaluations listed below will be conducted, and the 
dates of the conduct and data obtained will be documented in the medical records and 
CRF. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
If peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
In principle, each course should consist of 28 days, and if the examination scheduled for 
Day 29 is performed between Day 26 and Day 28 for example, which is within the 
acceptable window, IMP administration for the next course should be started on or after 
Day 29 of the current course.   
7.1.4.2.17 
Day 1 to Day 29 of the Extended Course in the Extended 
Treatment Part 
The observations, examinations, and evaluations listed below will be conducted before 
the start of IMP administration on Day 1 of each course and during each course, and the 
dates of the conduct and data obtained will be documented in the medical records.  In 
addition, examinations related to safety will be performed as necessary, and the dates of 
the conduct and data obtained will be documented in the medical records. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
 
7.1.5 
Observations, Examinations, and Evaluations at the Time of 
Withdrawal 
The observations, examinations, and evaluations listed below will be conducted within 5 
days after withdrawal from the trial has been decided, and the dates of the conduct and 


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data obtained will be documented in the medical records and CRF.  If the withdrawal 
examination takes place within the acceptable time window for Day 8, Day 15, Day 22, 
or Day 29, it is not necessary to repeat items that have been performed in the 
examinations for Day 8, Day 15, Day 22, or Day 29 for the withdrawal examination.  If 
the withdrawal is due to an SAE or progression of the primary disease, only those 
examinations that are feasible, given the subject’s state of health, will be performed in 
consideration of the subject’s conditions. 
Clinical Symptoms 
Subjective symptoms and objective findings 
Pregnancy Testa 
Urinary or serum HCG 
Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature 
Body Weight 
Body weight 
Twelve-lead ECG and 
chest X-ray 
Twelve-lead ECG and chest X-ray 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
General Condition 
ECOG PS 
Bone Marrow Aspirationb 
Percentage of bone marrow fluid (blasts, lymphoblasts, monoblasts, 
promyelocytes, myelocytes, metamyelocytes, segmented neutrophils, stab 
leucocytes, lymphocytes, eosinophils, monocytes, basophils, normoblasts, 
pronormoblasts, erythroblasts, plasma cells, and megakaryocytes), M/E ratio, 
and cellularity 
HCG = Human chorionic gonadotropin 
aA pregnancy test will be performed in female subjects at the trial site.  However, a pregnancy test is not 
required for subjects who have undergone bilateral oophorectomy or hysterectomy, or subjects who 
have been amenorrheic without a medical cause for at least 12 consecutive months. 
bIf peripheral blood testing indicates that the subject meets criteria for remission, or if clear disease 
progression is observed, bone marrow aspiration will be performed. 
 
7.2 
Method of Evaluation 
7.2.1 
Safety Evaluation (Primary Evaluation Part) 
7.2.1.1 
Clinical Symptoms 
The investigator or subinvestigator will examine subjects at the timepoints stipulated in 
the protocol, and record subjective symptoms and objective findings that are deemed to 
be AEs in the CRF. 


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7.2.1.2 
Dose Limiting-toxicities and Adverse Events 
Dose limiting-toxicities and AEs will be assessed in accordance with the CTCAE version 
4.0.  See the sections on AEs for details. 
Occurrence of DLTs will be recorded in the CRF in a timely manner after the end of the 
DLT evaluation period, and if any DLT occurs, detailed information of the DLT (date of 
onset, severity, seriousness, outcome, and relationship with the IMP) as well as the status 
of IMP administration in Course 1 will be also recorded in the CRF.  In Course 2 and 
subsequent courses as well, detailed information of any DLTs will be recorded in the 
CRF. 
7.2.1.3 
Body Weight 
Body weight will be measured in accordance with the procedures specified at the trial site, 
and the date of measurement and data obtained will be documented in the medical 
records and CRF. 
7.2.1.4 
General Condition 
Each subject’s general condition will be assessed by reference to the Japanese version of 
the ECOG PS, and the date of assessment and assessment results will be documented in 
the medical records and CRF.  Death will be scored as 5. 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
These criteria are indices for general condition.  Activity restricted because of local symptoms should be 
based on clinical judgment. 
Source:  Common Toxicity Criteria Version 2.0 published on 30 April 1999 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf); 
website of Japan Clinical Oncology Group (http://www.jcog.jp/) 
 
7.2.1.5 
Vital Signs (Blood Pressure, Pulse Rate, and Body 
Temperature) 
Blood pressure (systolic/diastolic), pulse rate, and body temperature will be measured (in 
the sitting position after 3-minute rest), and the date of measurement and data obtained 
will be documented in the medical records and CRF. 
7.2.1.6 
Twelve-lead Electrocardiogram 
Twelve-lead ECG will be performed in accordance with the procedures specified at the 
trial site.  A central ECG reading facility will analyze heart rate, PR interval, RR interval, 


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QRS interval, QT interval, and corrected QT interval (QTc interval).  The QT interval 
(QT interval as corrected by Fridericia’s formula [QTcF interval]) will be calculated 
using the following formula:  QTcF = (QT interval/RR interval)1/3.  The central ECG 
reading facility will report analysis results to the investigator or subinvestigator.  Then, 
the investigator or subinvestigator will check the results, and sign the analysis report and 
enter the date of confirmation.  The investigator or subinvestigator will decide whether 
the ECG is normal or abnormal based on the analysis results submitted by the central 
ECG reading facility, and will document the decision and the date and time of the 
examination in the medical records and CRF.  Clinically significant findings will be 
assessed as AEs. 
7.2.1.7 
Chest X-ray 
A chest X-ray will be taken in accordance with the procedures specified at the trial site, 
and the date of examination and findings obtained will be documented in the medical 
records and CRF.  Clinically significant findings will be assessed as AEs. 
7.2.1.8 
Hematology Test, Blood Biochemistry Test, and Urinalysis 
Blood and urine samples will be collected for determination of the parameters listed 
below in accordance with the procedures specified by the trial site.  The dates of blood 
sampling and urine collection, and measurement results will be documented in the 
medical records and CRF. 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
Blood Biochemistry Test 
AST (GOT), ALT (GPT), ALP, LDH, TP, ALB, T-Bil, BUN, UA, Cr, blood 
glucose (fasting), Ca, Mg, Na, K, and Cl 
Urinalysis 
Bilirubin, occult blood, protein, and urobilinogen 
 
7.2.2 
Safety Evaluation (Extended Treatment Part) 
7.2.2.1 
Clinical Symptoms 
The investigator or subinvestigator will examine subjects at the timepoints stipulated in 
the protocol, and document subjective symptoms and objective findings that are deemed 
to be AEs in the medical records. 
7.2.2.2 
Adverse Events 
Adverse events will be assessed in accordance with the CTCAE version 4.0, and their 
details will be documented in the medical records.  See the sections on AEs for details. 


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7.2.2.3 
Hematology Test 
Blood samples will be collected for determination of the parameters listed below in 
accordance with the procedures specified by the trial site.  The date of blood sampling 
and measurement results will be documented in the medical records. 
Hematology Test 
Hb, Hct, RBC count, WBC count, differential WBC count (visual count:  blast 
cells [leukemia cells], lymphoblastoid cells, monoblasts, promyelocytes, 
myelocytes, metamyelocytes, segmented neutrophils, stab leucocytes, 
lymphocytes, eosinophils, monocytes, basophils, prolymphocytes, and 
promonocytes), platelet count, and reticulocytes 
7.2.3 
Efficacy Evaluation 
7.2.3.1 
Assessment Based on Response Criteria 
The investigator or subinvestigator will evaluate response in each course in accordance 
with the response criteria in Table 7.2-1, which is based on the response criteria for AML 
treatment established by an international working group,10 and will document evaluation 
results in the medical records and CRF.  The evaluation results to be documented in the 
medical records and CRF will be “not evaluable (NE)” when no bone marrow 
examination has been performed, “progressive disease” when disease clearly progressed 
without CR, CRi, or CRp achieved after the start of IMP administration, or “no response” 
when no remission or relapse has been confirmed in the course. 
The best overall response for each subject and the date of the first response (CR, CRi, or 
CRp) will be documented in the medical records and CRF at the time of trial completion 
or withdrawal from the trial.  Also recorded will be the date of the first relapse, if relapse 
occurred thereafter, and the date of the last evaluation, if no relapse occurred. 


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Table 7.2-1 
Response Criteria 
 
Bone Marrow 
Peripheral Blood 
CR 
 
Blast cells < 5% 
 
Neutrophil count > 1,000/μL 
 
Platelet count ≥ 100,000/μL 
 
No blast cell 
 
Transfusion independence 
CRp 
 
Blast cells < 5% 
 
Neutrophil count > 1,000/μL 
 
Platelet count < 100,000/μL 
 
No blast cell 
 
RBC transfusion independence 
Morphologic CRi 
 
Blast cells < 5 % 
 
Neutrophil count < 1,000/μL 
 
No blast cell 
PR 
 
Rate of decrease in blast 
cells in the bone marrow 
≥ 50% and ratio of blast 
cells of 5% to 25% 
 
Neutrophil count > 1,000/μL 
 
Platelet count ≥ 100,000/μL 
 
No blast cell 
Relapse 
 
Leukemia cells (blast cells) ≥ 5% in the bone marrow or presence 
of leukemia cells (blast cells) in the peripheral blood are 
manifested again after CR, CRi, or CRp has been achieved. 
 
Leukemia cells with abnormal chromosomes are revealed again in 
chromosomal testing. 
 
7.2.3.2 
Outcome of Survival 
The survival of each subject will be investigated at the end of the primary evaluation part 
of the trial (see Section 15 Scheduled Duration of the Trial) and recorded in the CRF.  
The date of survival confirmation will be recorded in the CRF if the subject is alive, the 
date of death and its reason if the subject has died, and the date of final survival 
confirmation if it is unknown whether the subject is alive. 
7.2.3.3 
Investigations of Acute Myeloid Leukemia Treatments after 
Trial Discontinuation 
Treatment for AML given on or after the date of withdrawal from the trial will be 
investigated from the date of withdrawal from the trial until the end of the primary 
evaluation part in the trial (see Section 15 Scheduled Duration of the Trial), and detailed 
information and the start date of the subsequent AML treatment will be documented in 
the medical records and CRF. 
7.2.4 
Pharmacokinetic Evaluation 
Blood will be sampled and processed in accordance with the following procedures, and 
the plasma samples will be cryopreserved at ≤ −70°C (preset temperature) until collection 


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by the sample collecting facility.  The sample collecting facility will transport the 
samples packed in dry ice to the laboratory performing drug concentration measurements. 
1) Blood sampling 
At each blood sampling timepoint, 6 mL of blood will be drawn into a tube 
containing tetrahydrouridine and di-potassium ethylenediaminetetraacetic acid 
(EDTA).  The tube will be slowly inverted 8 to 10 times to mix the blood with 
these agents and kept in an ice bath until centrifugation.  The sample tubes will be 
centrifuged within 2 hours after sampling at 1800 g and approximately 4°C for 10 
minutes or at 1500 g and approximately 4°C for 15 minutes.  The separated 
plasma will be transferred into two labelled polypropylene tubes (primary sample 
and backup sample).  The date and time of blood sampling will be documented in 
the medical records and CRF. 
2) Blood sampling timepoints 
[Cohorts 1, 2, and 4] 
Day 1 and Day 5:  predose, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 
hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours (Day 5) after dosing 
Day 2, Day 3, and Day 4:  predose (predose on Day 2 is the same as 24 hours 
postdose on Day 1.) 
[Acceptable time windows] 
Day 1 and Day 5 
Predose on Day 1:  within 2 hours before IMP administration 
Predose on Day 5:  ± 30 minutes of 24 hours from Day 4 dosing 
and before the Day 5 dosing 
 
15 minutes and 30 minutes postdose:  ± 3 minutes 
 
60 minutes, 90 minutes, and 2 hours postdose:  ± 6 minutes 
 
3 hours and 4 hours postdose:  ± 12 minutes 
 
6 hours and 8 hours postdose:  ± 24 minutes 
 
24 hours postdose:  ± 30 minutes (24 hours postdose on Day 1 
should be performed before Day 2 dosing) 
Day 2, Day 3, and 
Day 4 
Predose:  ± 30 minutes of 24 hours from the previous dosing and 
before the dosing on that day 
[Cohort 3] 
Day 1 and Day 12:  predose, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 
hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing 
Day 5:  90 minutes and 6 hours after dosing 
[Acceptable time windows] 
Day 1 and Day 12 
Predose on Day 1:  within 2 hours before IMP administration 
Predose on Day 12:  ± 30 minutes of 24 hours from Day 11 dosing 
and before the Day 12 dosing 
 
15 minutes and 30 minutes postdose:  ± 3 minutes 
 
60 minutes, 90 minutes, and 2 hours postdose:  ± 6 minutes 
 
3 hours and 4 hours postdose:  ± 12 minutes 
 
6 hours and 8 hours postdose:  ± 24 minutes 
 
24 hours postdose:  ± 30 minutes (24 hours postdose on Day 1 
should be performed before Day 2 dosing) 


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Day 5 
90 minutes postdose:  ± 6 minutes 
 
6 hours postdose:  ± 24 minutes 
 
3) Plasma drug concentration measurement 
Plasma concentrations (of SGI-110 and its active metabolite [decitabine]) will be 
measured using the liquid chromatography-tandem mass spectrometry method 
validated by Frontage Laboratories Inc.  Remaining samples after the plasma drug 
concentration measurement will be stored at Frontage Laboratories Inc. until after 
the CSR is prepared and the sponsor instructs them to be discarded. 
Measurement results will be reported electronically by Frontage Laboratories Inc. 
to an organization designated by the sponsor.  Frontage Laboratories Inc. will 
separately prepare a final report (one original copy), retain it, and submit its 
duplicate copy electronically to the sponsor.  The sponsor will treat this final 
report as a source document.  The investigator or subinvestigator will not be 
required to record it in the CRF. 
7.2.5 
Pharmacodynamic Evaluation 
Blood will be sampled and processed in accordance with the following procedures, and 
the blood samples will be kept frozen until collection by the sample collecting facility.  
The sample collecting facility will extract DNA from the samples and transport the DNA 
packed in dry ice to the PD measurement laboratory. 
1) Blood sampling 
At each blood sampling timepoint, 10 mL of blood will be drawn into a tube 
containing EDTA.  The tube will be slowly inverted 8 to 10 times to mix the 
blood with EDTA, and then kept frozen.  The date of blood sampling will be 
documented in the medical records and CRF. 
2) Blood sampling timepoints 
At screening (the same schedule for all of the cohorts):  any timepoint between 
the acquisition of informed consent and IMP administration on Day 1 
Day 1, Day 8, Day 15, Day 22, and Day 29 of Course 1:  predose.  (Blood 
sampling scheduled for Day 1 can be performed during the screening examination 
period.  On the day of IMP administration, blood should be collected before IMP 
administration.) 
3) DNA extraction 
The sample collecting facility will extract DNA after cryopreserving the sample. 
4) Analysis of DNA methylation in LINE-1 
DNA methylation in LINE-1 will be measured using the pyrosequencing assay 
validated by the PD measurement laboratory.  Remaining samples after the 
measurement will be stored at the PD measurement laboratory until the sponsor 
instructs to discard them after the CSR is prepared. 
Measurement results will be reported electronically by the PD measurement 
laboratory to an organization designated by the sponsor.  The PD measurement 
laboratory will separately prepare a final report (one original copy), retain it, and 


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submit its duplicate copy electronically to the sponsor.  This final report will be 
treated as a source document, and recording in the CRF is not required. 
7.2.6 
Investigational Medicinal Product Compliance 
The investigator or subinvestigator will document the date and time of IMP 
administration, cohort, dose, and administration site in the medical records and CRF (or 
in the medical records during the extended treatment part).  When the IMP is not 
administered at the timepoints stipulated in the protocol, the reason should be recorded in 
the CRF (or in the medical records during the extended treatment part). 
7.3 
Measures to Be Taken for Subjects Visiting or Planning to Visit 
Other Hospitals or Departments 
At the time of obtaining informed consent, the investigator or subinvestigator will 
confirm whether or not the subject is receiving treatment at another hospital or 
department.  If the subject is receiving treatment at another hospital or department, the 
investigator or subinvestigator will inform, with the subject’s consent, the attending 
physician of that hospital or department about the subject’s participation in the clinical 
trial and the IMP being used.  The investigator or subinvestigator will also obtain and 
record in the CRF (or in the medical records during the extended treatment part) 
information on the treatment that the subject is receiving at the other hospital or 
department (name of disease being treated and information on the type of treatment or 
measures being implemented) and judge whether or not the subject should participate in 
the trial. 
If a subject visits another hospital or department during the trial period, the investigator 
or subinvestigator will inform the attending physician of that hospital or department 
about the subject’s participation in the clinical trial and the IMP being used.  The 
investigator or subinvestigator will also obtain and record in the CRF (or in the medical 
records during the extended treatment part) information on the treatment that the subject 
receives at the other hospital or department (name of disease treated and information on 
the type of treatment or measures implemented) and judge whether or not the subject 
should continue to participate in the trial. 
 


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8 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event 
(International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use [ICH] E2A guideline:  Definition) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.a 
For this trial, the term “medical product” is regarded as “IMP,” and to secure the safety of 
subjects, AEs occurring from consent to the start of IMP administration are included in 
the definition of AEs in addition to the definition given by ICH. 
If a disease, symptom, or sign existing at the time of acquisition of informed consent 
worsens after acquisition of informed consent, or if an AE occurring between the 
acquisition of informed consent and start of IMP administration worsens after 
administration of the IMP, the exacerbation will be treated as a new AE. 
In this trial, however, progression (including relapse) of an underlying disease will not be 
treated as an AE.  (If a symptom associated with progression [relapse] of an underlying 
disease corresponds to an “AE,” the symptom will be evaluated as an AE.) 
8.1.2 
Serious Adverse Event 
An SAE is defined as an AE corresponding to one of the events listed in 1) to 6) below.a 
The seriousness of AEs occurring during the period from consent to the start of IMP 
administration will also be judged. 
1) An event resulting in death 
2) A life-threatening event 
The term “life-threatening” refers to an event in which the patient was at a risk of 
death at the time of the event.  It does not refer to an event which hypothetically 
might have caused death, had it been more severe. 
                                                 
a“Clinical Safety Data Management”, Notification No. 227 of the Examination Division, 
Pharmaceutical Affairs Bureau dated 20 Mar 1995 (ICH E2A). 


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3) An event requiring in-patient hospitalization or prolongation of existing 
hospitalization for treatment 
4) An event resulting in persistent or significant disability/incapacity 
5) An event causing a congenital anomaly/birth defect 
6) A major event resulting in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization, but 
which may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed in 1) to 5) above.  Examples of such events are intensive 
treatment in an emergency room for bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
Explanation of hospitalization for treatment of an SAE: 
Hospitalization for treatment means that the subject must be hospitalized at a medical 
institution for treatment of an AE, typically for at least one night.  This includes 
hospitalization for treatment of the AE in which no particular medical procedures are 
carried out (rest therapy).  However, it does not include hospitalization for undergoing 
tests or treatment for an underlying disease or complication that has not worsened since 
the subject’s entry into the trial, hospitalization for social reasons or convenience not 
intended for treatment of the AE, or hospitalization for treatment or tests scheduled prior 
to participation in the trial. 
8.2 
Response to Occurrence of Adverse Events 
8.2.1 
Actions to Be Taken for Subjects 
The investigator or subinvestigator will provide adequate medical care for all clinically 
significant, trial-related AEs throughout the period of subject participation in the trial as 
well as thereafter.  If treatment for an AE is necessary, the subject will be informed of 
this. 
8.2.2 
Expedited Reporting of Serious Adverse Events and Dose-
limiting Toxicities 
1) Serious Adverse Events 
a) Any SAEs occurring during the trial period regardless of causal relationship 
with the IMP 
b) Serious adverse events occurring during the follow-up period (see Section 8.4 
Follow-up Investigation of Adverse Events), if a follow-up investigation is 
performed, for which a causal relationship with the IMP cannot be ruled 
out,Note or AEs that become serious during the follow-up period for which a 
causal relationship with the IMP cannot be ruled out Note 


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c) Among SAEs occurring after completion of the trial (after the follow-up 
investigation, if a follow-up investigation is performed) and reported by 
subjects to the investigator or subinvestigator, those for which the investigator 
or subinvestigator cannot rule out a causal relationship with the IMP Note 
Note Including those for which a causal relationship is not determined. 
 
2) Dose-limiting Toxicities 
Any toxicity specified in Section 3.13.1 Trial Plan occurring during the DLT 
evaluation period (Course 1) will be reported. 
 
3) Procedures for Expedited Reporting 
a) When an AE falling under any of the above items (1) or (2) occurs, the 
investigator or subinvestigator will notify the sponsor promptly after 
becoming aware of the event (within 24 hours, in principle) in person, by 
telephone, or by e-mail (refer to Annex 1 Emergency Contact). 
b) The investigator will then promptly submit a detailed report on any SAEs 
occurring after the start of IMP administration to the head of the trial site and 
the sponsor within 10 days after becoming aware of them using the report 
form of the trial site or sponsor.  Any additional information will also be 
promptly relayed to the sponsor (within 24 hours, in principle) in person, by 
telephone, or by e-mail, and additional reporting will be performed if 
necessary. 
c) When the investigator or subinvestigator is requested by the sponsor, the head 
of the trial site, or the IRB to prepare additional information (autopsy report, 
terminal care report, or other required information) on a reported SAE, the 
investigator or subinvestigator will respond to the request. 
8.2.3 
Expedited Reporting of Non-serious Adverse Events Resulting in 
Discontinuation of IMP Administration 
When a non-serious AE occurs for which the investigator or subinvestigator judges that 
IMP administration should be discontinued (but not when IMP administration is merely 
temporarily interrupted), the investigator or subinvestigator will notify the sponsor within 
3 working days in principle after their judgment in person, by telephone, or by e-mail 
(refer to Annex 1 Emergency Contact). 
8.3 
Assessment of Adverse Events 
The investigator or subinvestigator will assess AEs for the following items. 
8.3.1 
Terms for Adverse Events 
If the disease responsible for an AE can be specified, the name of the diagnosed disease 
will be recorded in the CRF (or in the medical records during the extended treatment 
part) and not the individual symptoms. 


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8.3.2 
Date of Onset and Recovery 
 Date of onset: 
The date of onset of an AE or date of confirmation of an AE will be recorded in the 
CRF (or in the medical records during the extended treatment part).  If a disease, 
symptom, or sign existing at the time of acquisition of informed consent worsens, the 
date of exacerbation will be recorded in the CRF (or in the medical records during the 
extended treatment part) as “date of onset of AE.”  Also, if an AE occurring between 
the acquisition of informed consent and start of IMP administration worsens after 
administration of the IMP, the exacerbation will be recorded in the CRF (or in the 
medical records during the extended treatment part) as a new AE with the date of 
exacerbation recorded as “date of onset of exacerbated AE.” 
 Date of recovery: 
The date of recovery of an AE or date of confirmation of recovery of an AE will be 
recorded in the CRF (or in the medical records during the extended treatment part). 
8.3.3 
Severity (Grade) 
Severity (grade) of AEs will be classified using the following five categories of Grades 1 
to 5 in accordance with the CTCAE version 4.0. 
In this trial, febrile neutropenia is defined as a neutrophil count below 500/μL 
accompanied by a fever of 38°C or higher. 
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 ADL.a 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates “or” within the description of the grade. 
aInstrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
bSelf care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
8.3.4 
Causal Relationship With Investigational Medicinal Product 
The causal relationship between the IMP and AEs occurring after the start of IMP 
administration will be judged according to the following two categories. 
1) Not related 
For reasons such as the following, the possibility of a relationship between 
occurrence of an AE and the IMP is not reasonably conceivable. 


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a) The event can be assumed to be caused by an underlying disease, 
complication(s), or previous disease(s). 
b) The event can be assumed to be associated with age, sex, or some other 
demographic factor. 
c) A temporal relationship between IMP administration and occurrence of the 
AE is unlikely. 
Example:  An AE that occurs after a considerable lapse of time from the 
conclusion of IMP administration. 
d) Considering the time course of the AE and IMP administration, a relationship 
with the IMP is unlikely. 
Example:  Despite continuous administration of the IMP, the AE disappeared 
spontaneously without any treatment (except cases in which it is judged that 
the subject became habituated to the IMP during continued administration). 
e) The event can be assumed to be caused by concomitant drug(s). 
f) The event can be assumed to be incidental (such as an accident or incidental 
disease). 
Example:  “femoral bone fracture” occurring in a traffic accident. 
g) A relationship with the IMP can be ruled out for other reasons based on 
medical consideration. 
2) Related 
For reasons such as the following, the possibility of a relationship between 
occurrence of an AE and the IMP is reasonably conceivable. 
a) A relationship is predictable from the pharmacological and toxicological 
effects of the IMP. 
Examples:  Occurrence of “pancytopenia” when effects on the hematopoietic 
system have been observed in non-clinical studies, or the occurrence of 
“dehydration” when the drug has a diuretic effect. 
b) The event has been observed in previous non-clinical studies and/or clinical 
studies. 
Example:  An AE with high incidences in phase 1 studies. 
c) A temporal relationship is suspected between IMP administration and onset of 
the AE. 
Example:  “Allergic dermatitis” occurring several days after the start of IMP 
administration. 
d) A relationship is suspected based on the outcome of an AE after 
discontinuation or dose reduction of the IMP. 
Example:  Prompt disappearance of “nausea” after discontinuation of the IMP. 
e) A relationship with the IMP cannot be ruled out for other reasons based on 
medical consideration. 
8.3.5 
Actions to Be Taken Regarding IMP Administration 
Actions to be taken regarding IMP administration following the occurrence of an AE 
after initiation of IMP administration will be selected from among the following. 


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 No change 
 Discontinuation of IMP administration 
 Interruption of IMP administration 
 Unknown 
 Not applicable 
8.3.6 
Actions to Be Taken for Adverse Events 
The performance of medical treatments (medications and/or other treatments) for AEs 
and details of the treatments will be described in the CRF (or in the medical records 
during the extended treatment part). 
8.3.7 
Outcome 
The outcome of an AE will be selected from the following six categories (one only). 
If the subject died, the date of death will be recorded in the CRF (or in the medical 
records during the extended treatment part); if the subject’s condition was 
recovering/resolving, not recovered/not resolved, or unknown, the date of outcome 
confirmation will be recorded in the CRF (or in the medical records during the extended 
treatment part [Cohorts 1, 2, and 4]). 
 Recovered/resolved 
 Recovering/resolving 
 Not recovered/not resolved 
 Recovered/resolved with sequelae 
 Fatal 
 Unknown (for some reason, a follow-up investigation could not be performed even 
once) 
8.4 
Follow-up Investigation of Adverse Events 
The term “recovered” used below means that a subject who had an AE prior to the start 
of IMP administration returned to his or her original condition, or a subject who had an 
AE after the start of IMP administration returned to his or her condition before the start of 
IMP administration. 
1) If an AE has not resolved by the end of the withdrawal examination, the 
investigator or subinvestigator will explain to the subject the need for post-trial 
follow-up investigation and request the subject’s cooperation.  The investigator or 
subinvestigator will conduct a follow-up investigation within 4 weeks after the 
end of the trial and record information regarding the AE in the subject’s medical 
records.  If an AE has not resolved by the end of the withdrawal examination, the 
investigator or subinvestigator will record the outcome in the CRF as 
“recovering/resolving,” “not recovered/not resolved,” or as otherwise appropriate. 


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2) If an AE has not resolved by the day of the follow-up investigation and a causal 
relationship with the IMP cannot be ruled out, Note follow-up investigation will be 
continued until the event resolves or becomes stable and information regarding 
the AE will be recorded in the subject’s medical records.  If a causal relationship 
between the AE and the IMP can be ruled out, no further follow-up will be made 
beyond the day of the initial follow-up investigation. 
3) If, between the end of the withdrawal examination and the day of the follow-up 
investigation, a new SAE for which a causal relationship with the IMP cannot be 
ruled out Note occurs, or if an AE that has not resolved by the end of the 
withdrawal examination and for which a causal relationship with the IMP cannot 
be ruled out Note becomes serious, follow-up investigation will be conducted until 
the AE resolves or becomes stable and information regarding the AE will be 
recorded in the subject’s medical records. 
4) If an SAE for which a relationship with the IMP cannot be ruled out Note is 
discovered after the end of the withdrawal examination, or after the day of the 
initial follow-up investigation (if performed), follow-up investigation will be 
conducted until the AE resolves or becomes stable or until follow-up of the 
subject becomes impossible and information regarding the AE will be recorded in 
the subject’s medical records. 
5) If the treatment for AML is initiated after the end of the withdrawal examination, 
and it is difficult to confirm the subject’s outcome under the influence of the 
treatment in the opinion of the investigator or subinvestigator, no follow-up 
investigation of the AE will be performed even if the subject has not recovered 
from the AE by the end of the withdrawal examination. 
Note Including those for which a causal relationship is not determined. 
8.5 
Pregnancy 
If women of childbearing potential or male subjects whose partners are capable of 
becoming pregnant participate in the trial, the investigator or subinvestigator will attend 
to the following. 
 Information on pregnancy in the written information for subjects and ICF 
 Explanation of contraceptive methods 
 Reporting and follow-up of cases of pregnancy 
8.5.1 
Guidance to Subjects Including Contraceptive Methods 
1) Before the start of the trial, the investigator or subinvestigator will explain to the 
subjects the importance of using contraception and the risks associated with 
pregnancy of a female subject or partner of a male subject and, after subjects have 
read the written information for subjects and understood it, the investigator or 
subinvestigator will have subjects sign the ICF. 
2) If women of childbearing potential or male subjects whose partners are capable of 
becoming pregnant wish to participate in the trial, the investigator or 


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subinvestigator will instruct them to practice contraception during the period 
specified in the trial protocol. 
3) Contraceptive methods include condoms, pills, pessaries, intrauterine device, 
implantable contraceptive devices Note, spermicide Note, vasectomy, and tubal 
ligation.  However, if a female subject or male subject’s partner is without 
question unable to become pregnant (ie, has undergone bilateral ovariectomy or 
hysterectomy or has not experienced menses for at least 12 consecutive months 
without an alternative medical cause, or the male subject/partner has undergone 
bilateral orchidectomy), use of contraception is unnecessary.  
Note Methods not approved or authorized in Japan. 
4) The investigator or subinvestigator will instruct the subjects that if the 
contraceptive measures fail and evidence of pregnancy of the female subject or 
male subject’s partner such as delay in menstruation is observed during the trial, 
this should be promptly reported to the investigator or subinvestigator. 
8.5.2 
Actions to Be Taken by the Investigator or Subinvestigator When 
Pregnancy Is Suspected 
If the investigator or subinvestigator or a subject suspects that the subject has become 
pregnant before initiation of IMP administration, initiation of IMP administration will be 
withheld and a pregnancy test will be performed.  If the test result is positive, the trial 
subject will be withdrawn without receiving IMP administration.  If a pregnancy is 
suspected after initiation of IMP administration, IMP administration will be discontinued 
(refer to Section 9.2 Criteria and Procedures for Withdrawal of Individual Subjects). 
8.5.3 
Actions to Be Taken by the Investigator or Subinvestigator When 
a Subject Is Discovered to Be Pregnant 
When a female subject is found to be pregnant, the investigator or subinvestigator will 
withdraw the subject from the trial and perform follow-up investigation until delivery or 
end of pregnancy, and report this in writing to the sponsor. 
After discontinuation of IMP administration, the investigator or subinvestigator will 
perform the withdrawal examinations and follow-up observation stipulated in the 
protocol, in so far as they do not affect the pregnancy.  For example, examinations such 
as radiography should not be performed even if they are stipulated in the protocol. 
8.5.4 
Expedited Reporting of Pregnancy 
When a female subject or a partner of a male subject is found to be pregnant during the 
trial, the investigator or subinvestigator will promptly report this to the sponsor in person, 
by telephone, or by e-mail (refer to Annex 1 Emergency Contact).  The investigator or 
subinvestigator will then provide any additional information requested by the sponsor. 


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8.5.5 
Follow-up Investigation of Pregnancy 
If a female subject becomes pregnant, the investigator or subinvestigator will perform 
follow-up investigation of the pregnancy up to delivery or the end of pregnancy and 
report the results of follow-up in writing to the sponsor.  When a subject or subject’s 
partner has delivered, it is best that the neonate be observed for at least 6 months after 
delivery. 
 
9 
Withdrawal of Individual Subjects From the Trial 
Any subject may discontinue participation in the trial at any time without medical 
disadvantage.  The investigator or subinvestigator may withdraw a subject from the trial 
at any time if it is considered necessary for medical treatment of that subject. 
9.1 
Screen Failure 
If a subject is a screen failure, the following information should be recorded in the CRF 
for screen failure subjects. 
Date of investigation (the start date of the screening examination), date of informed 
consent acquisition, date of birth, sex, reason for screen failure. 
9.2 
Criteria and Procedures for Withdrawal of Individual Subjects 
In any of the events listed below, the investigator or subinvestigator will withdraw the 
subject from the trial, perform the tests such as the withdrawal examination stipulated in 
Section 7.1 Schedule and Procedures, and promptly inform the sponsor of the withdrawal 
(Annex 1 Emergency Contact).  The investigator or subinvestigator will record the date 
and reason for withdrawal in the CRF. 
For subjects who do not undergo the withdrawal examination, the date of withdrawal will 
be the day when the investigator or subinvestigator deems withdrawal is necessary. 
If withdrawal is necessitated by problems with safety, such as the occurrence of an AE or 
aggravation of the underlying disease, the investigator or subinvestigator will promptly 
take appropriate measures and perform follow-up if necessary (refer to Section 8.4 
Follow-up Investigation of Adverse Events). 
1) Apparent progression (including the relapse) of the primary disease. 
2) Dose-limiting toxicity that does not improve to the baseline level or show 
improvement by at least 1 grade within 4 weeks, or occurrence of another DLT. 
3) Delay in commencement of the next course by more than 4 weeks due to an AE, 
unless the investigator or subinvestigator judges that continuation of SGI-110 


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administration is in the patient’s best interest, in which case the delay may be 
extended by another 2 weeks. 
4) Subject becomes pregnant. 
5) Subject wishes to withdraw from the trial. 
6) The investigator or subinvestigator judges that it is difficult to continue IMP 
administration due to occurrence of an AE. 
7) The investigator or subinvestigator judges that it is necessary to discontinue IMP 
administration for any other reason. 
9.3 
Follow-up Investigation of Subjects Who Do not Visit the Trial Site 
When a subject fails to visit the trial site and the reason is unknown, the investigator or 
subinvestigator will immediately contact the subject or their family by telephone or other 
means to confirm whether or not AEs have occurred and encourage the subject to return.  
If again the subject fails to visit the site after being contacted, the following information 
should be obtained and recorded in the CRF (or in the medical records during the 
extended treatment part). 
1) The date of investigation 
2) The method of investigation 
3) Whether or not the subject was contacted 
4) Reason why the subject does not (or cannot) visit the trial site 
5) Occurrence or non-occurrence of AEs.  If an AE has occurred:  name of the event, 
date of onset and date of recovery, seriousness, severity, relationship to the IMP, 
measures taken regarding IMP administration, outcome. 
6) If follow-up investigation is impossible:  the reason why 
 
10 
Collection of Case Report Form Data and Specification of 
Source Data 
10.1 
Collection of Case Report Form Data 
1) Electronic Data Capture (EDC) will be used in the primary evaluation part of the 
trial, and the paper CRF will be used in the extended treatment part for data 
collection. 
2) Subject data will be entered directly into the database from the trial site via a Web 
browser.  These data collected by EDC will constitute the CRF.  The 12-lead ECG 
analysis results obtained from the ECG reading facility (central ECG reading 
facility) will be transferred from the ECG measurement facilities directly to the 
sponsor. 
3) Regarding quality assurance of CRFs, the guidelines specified in “Use of 
Electromagnetic Records and Electronic Signatures in Applications for Approval 
or Licensing of Drugs” (PFSB Notification No. 0401022, dated 01 Apr 2005) and 


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“Guidance on Electronic Capture of Clinical Study Data” (Drug Evaluation 
Committee, Japan Pharmaceutical Manufacturers Association, dated 01 Nov 
2007) will be observed 
4) For every subject who provides consent to participate in the trial, a CRF will be 
created on an EDC data entry screen that conforms to the items of CRF data 
collection described in the trial protocol. 
5) The investigator, subinvestigator, or trial associate will create CRFs according to 
the manual provided by the sponsor.  If source documents are available and the 
objectivity of the data can be ensured, then the data may be recorded in a CRF by 
a trial associate. 
6) When entering data into CRFs from the trial site, a predetermined check will be 
automatically performed.  The investigator, subinvestigator, or a trial associate 
will make corrections as necessary. 
7) The sponsor will verify CRFs in comparison to source documents and conduct 
data reviews.  If additional query is necessary, the sponsor will issue an intra-
system query and the investigator, subinvestigator, or a trial associate will 
perform data correction or provide a response to the sponsor’s query as necessary. 
8) A history of all revisions made after the initial data entry is saved on the server 
will be automatically recorded within the system (date and time of revision, name 
of person making revision, pre- and post-revision data, reason for revision, date 
and time of query, name of person issuing query, details of query, etc). 
9) After completion of all CRF data entry and confirmation that the content is 
correct and complete, including confirmation of the audit trail, the investigator 
will attach an electronic signature. 
10) Details concerning data collection will be specified in a separate manual prepared 
in advance. 
10.2 
Source Documents 
1) Source documents are defined as those documents that are the source of data 
transcribed into CRFs as trial results. 
Medical records and other records (medical records, nursing records, prescription 
records), registration verification forms, subject screening list, ICFs, clinical 
laboratory test and other measurement reports, ECG charts, IMP management 
records, and other documents 
2) The investigator or the trial site will retain all trial-related documents and records 
except CRFs in such a manner that enables the sponsor or the regulatory authority 
to have direct access to the documents and records. 
3) The original ICFs will be retained according to the method specified by each trial 
site. 
4) After completion of the trial, the sponsor will retain the original CRFs on CD-
ROM or some other appropriate electronic medium and the investigator or the 
trial site will retain copies. 
5) The original report on results of drug concentration measurement will be kept by 
the laboratory performing drug concentration measurements, and the original 


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report on results of PD measurements will be kept by the PD measurement 
laboratory; copies will be kept by the sponsor. 
10.3 
Case Report Form Items to Be Treated as Source Data 
Of the data recorded in the CRF, the following items will be treated as CRF-based source 
data. 
 Investigator’s signature, date of the investigator’s confirmation 
 Comments presented for each item 
 Occurrence or non-occurrence of AEs.  If an AE has occurred:  name of the event, 
severity, seriousness, measures taken regarding IMP administration, treatment of AE, 
outcome, (causal) relationship to the IMP 
 Reason for withdrawal 
 Response to previous treatment 
 Presence or absence, dose and regimen, and reason for use of concomitant drugs 
 Presence or absence, details, and reason for implementation of concomitant therapies 
 Cause of death found in an investigation on the outcome of survival 
10.4 
Data to Be Collected by the Sponsor 
1) CRFs (data following acquisition of informed consent) 
2) Clinical laboratory results and reference values 
3) Copies of results of drug concentration measurement 
4) Copies of results of PD measurement 
5) Copies of ECG charts 
6) 12-lead ECG analysis report 
 
11 
Statistical Analysis 
The analysis sets, endpoints, analysis subjects, analysis methods, and other relevant 
matters in the primary evaluation part are defined in this section.  Planned statistical 
analyses are detailed in the statistical analysis plan and PK analysis plan prepared 
separately.  The statistical analysis plan and PK analysis plan will be finalized before 
database lock. 
11.1 
Statistical Analysis Sets 
11.1.1 
Safety Analysis Set 
The safety analysis set will include subjects who have received at least one dose of the 
IMP. 


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11.1.1.1 
Dose-limiting Toxicity Analysis Set 
The DLT analysis set will include subjects in whom tolerability has been assessed in 
Cohorts 1 to 4 (subjects who have received all doses and completed all assessments 
scheduled for the DLT evaluation period). 
11.1.2 
Efficacy Analysis Set 
The efficacy analysis set will include subjects who have received at least one dose of the 
IMP and have data of the efficacy endpoints after the start of IMP administration. 
11.1.3 
Pharmacokinetic Analysis Set 
The PK analysis set will include subjects whose plasma drug concentrations have been 
measured. 
11.1.4 
Pharmacodynamic Analysis Set 
The PD analysis set will include subjects in whom the extent of DNA hypomethylation in 
LINE-1 has been measured. 
11.2 
Handling of Data 
1) Acceptable time windows of timepoints for examinations 
The acceptable time windows of timepoints for examinations to be used in 
tabulation are detailed in the statistical analysis plan. 
2) Handling of missing data 
How to handle missing data is described in the statistical analysis plan. 
3) Handling of events and censoring 
In the analysis of overall survival, all deaths (regardless of cause) will be defined 
as events, and time to death from the start date of IMP administration will be 
analyzed.  If subjects are alive at the end of the primary evaluation part, they will 
be censored (the day of survival confirmation will be the day of censoring). 
11.3 
Analysis Items and Method 
11.3.1 
Safety Analysis 
11.3.1.1 
Primary Endpoint 
1) Definition 
DLT 
 
2) Analysis set 
DLT analysis set 
 


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3) Analysis method 
Dose-limiting toxicities (by preferred term [PT]) occurring during Course 1 in 
each cohort will be tabulated (number and percentage of subjects with DLTs). 
11.3.1.2 
Secondary Endpoints 
1) Definitions 
a) AEs 
b) Clinical laboratory values 
c) Vital signs (blood pressure, pulse rate, and body temperature) and body 
weight 
d) ECOG PS 
e) Twelve-lead ECG 
f) Chest X-ray 
 
2) Analysis set 
Safety analysis set 
 
3) Analysis method 
a) Adverse events 
The following tabulations will be performed for each cohort: 
 All AEs occurring after the start of IMP administration (treatment-
emergent adverse events) (all events, SOCs, and PTs) will be 
summarized using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
 Adverse events will be summarized (number and percentage of subjects 
with AEs) by CTCAE grade. 
However, if an event occurs more than once in the same subject, the most 
severe episode will be included in the tabulation. 
 Adverse events in treated subjects in each course will be summarized 
(number and percentage of subjects with AEs) by timing of occurrence. 
 Deaths, other SAEs, and AEs leading to discontinuation will be 
summarized. 
 Adverse drug reactions (AEs assessed as related to the IMP) will be 
summarized in the same manner as AEs. 
 Dose-limiting toxicities (including events occurring after the start of 
Course 2) will be summarized (number and percentage of subjects with 
DLTs). 
b) Clinical laboratory values 
Hematological and blood biochemistry data at each timepoint will be 
summarized by cohort as follows: 
 Descriptive statistics of measurements 
 Descriptive statistics of change from baseline 


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 A shift table of the value at the last evaluation and the worst value after 
the treatment relative to the baseline value by CTCAE grade 
Urinalysis data at each timepoint will be summarized by cohort as follows: 
 A shift table of the value at the last evaluation and the worst value after 
the treatment relative to the baseline value by CTCAE grade 
c) Vital signs (blood pressure, pulse rate, and body temperature) and body 
weight 
Vital signs (blood pressure, pulse rate, and body temperature) and body 
weight at each timepoint will be summarized by cohort as follows: 
 Descriptive statistics of measurements 
 Descriptive statistics of change from baseline 
d) Eastern Cooperative Oncology Group performance status 
Eastern Cooperative Oncology Group PS at each timepoint will be 
summarized by cohort (the number and percentage of subjects for each score). 
e) Twelve-lead electrocardiogram 
Heart rate, PR interval, RR interval, QRS interval, QT interval, and QTcF 
interval, at each timepoint will be summarized by cohort as follows: 
 Descriptive statistics of measurements 
 Descriptive statistics of change from baseline 
QTcF interval at the last evaluation and the worst value (maximum value after 
the start of treatment) will be summarized by cohort. 
 The number and percentage of subjects with a measured value > 450 ms, 
> 480 ms, or > 500 ms will be calculated. 
 The number and percentage of subjects with change > 30 ms or > 60 ms 
will be calculated. 
Assessment of ECG abnormalities (normal or abnormal) at each timepoint 
will be summarized by cohort as follows: 
 A shift table of data from baseline 
f) Chest X-ray 
Assessment of chest X-ray abnormalities (normal or abnormal) at each 
timepoint will be summarized by cohort as follows: 
 A shift table of data from baseline 
11.3.2 
Efficacy Analysis 
1) Definitions 
a) Evaluation of the complete remission rate (CR), composite complete 
remission rate (CR + CRi + CRp), and overall remission rate (CR + CRi + 
CRp + PR) based on the response criteria for AML treatment established by 
an international working group (with partial modifications) 
b) Composite complete remission duration 
c) Overall survival 


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2) Analysis set 
Efficacy analysis set 
 
3) Analysis methods 
a) Remission 
Data will be summarized by cohort as follows: 
 Assessment in each course (CR, CRp, CRi, PR, no response, progressive 
disease, or NE) 
 Distribution of the best overall response:  complete remission rate (CR), 
composite complete remission rate (CR + CRi + CRp), and overall 
remission rate (CR + CRi + CRp + PR) 
b) Composite complete remission duration 
Descriptive statistics of time from the first composite complete remission to 
relapse will be calculated for subjects who have achieved composite complete 
remission. 
c) Overall survival 
A Kaplan-Meier plot will be generated for each cohort that includes at least 6 
treated subjects. 
11.3.3 
Pharmacokinetic Analysis 
1) Analysis items 
a) SGI-110 and decitabine plasma concentrations 
b) Pharmacokinetic parameters for SGI-110 and decitabine in plasma 
Day 1:  Cmax, Cmax/D, AUC24h, AUC24h/D, AUCt, AUCt/D, AUC∞, AUC∞/D, 
tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, Vz/F, Vz/F/BW, and tlast 
Day 5 (Cohorts 1, 2, and 4) or Day 12 (Cohort 3):  Cmax, Cmax/D, AUC24h, 
AUC24h/D, tmax, λz, t1/2,z, CL/F, CL/F/BW, Vz/F, Vz/F/BW, and tlast 
c) AUC ratio of decitabine to SGI-110 
 Day 1:  AUC∞ and AUCt 
 Day 5 (Cohorts 1, 2, and 4):  AUC24h 
 Day 12 (Cohort 3):  AUC24h 
d) Accumulation of SGI-110 and decitabine 
 R5,ac (AUC24h) and R5,ac (Cmax) (Cohorts 1, 2, and 4) 
 R10,ac (AUC24h) and R10,ac (Cmax) (Cohort 3) 
e) Non-linearity after multiple dosing of SGI-110 and decitabine 
 Ratio of AUC24h on Day 5 (Cohorts 1, 2, and 4) or Day 12 (Cohort 3) to 
AUC∞ on Day 1 
 
2) Analysis set 
PK analysis set 


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3) Calculation methods 
 Cmax, AUC24h, AUCt, AUC∞, tmax, λz, AUC_%Extrap, t1/2,z, tlast, CL/F, 
and Vz/F will be calculated by non-compartmental analysis using a PK 
analysis software for individual subjects. 
 CL/F/BW and Vz/F/BW will be calculated by dividing CL/F and Vz/F by 
baseline body weight (kg), respectively. 
 Cmax/D, AUC24h/D, AUCt/D, and AUC∞/D will be calculated by dividing 
Cmax, AUC24h, AUCt, and AUC∞ by the SGI-110 dose (mg/m2), 
respectively. 
 For AUC24h, AUCt, and AUC∞ ratios of decitabine to SGI-110, the 
AUCs (ng·h/mL) calculated from their respective mass concentrations 
(ng/mL) will be converted to a molar basis, and the molar AUC of the 
metabolite will be divided by the molar AUC of SGI-110. 
 R5,ac (AUC24h) and R5,ac (Cmax) will be calculated by dividing AUC24h 
and Cmax on Day 5 by AUC24h and Cmax on Day 1.  R10,ac (AUC24h) and 
R10,ac (Cmax) will be calculated by dividing AUC24h and Cmax on Day 12 
by AUC24h and Cmax on Day 1. 
 The ratio of AUC24h on Day 5 to AUC∞ on Day 1 will be calculated by 
dividing AUC24h on Day 5 by AUC∞ on Day 1.  The ratio of AUC24h on 
Day 12 to AUC∞ on Day 1 will be calculated by dividing AUC24h on 
Day 12 by AUC∞ on Day 1. 
 
4) Statistical analysis methods 
Descriptive statistics of the items mentioned in a) of 1) in Section 11.3.3 will be 
calculated by blood sampling timepoint, compound, and dose.  Descriptive 
statistics of the items mentioned in b) of 1) in Section 11.3.3 will be calculated by 
compound and dose.  Descriptive statistics of the items mentioned in c) of 1) in 
Section 11.3.3 will be calculated by dose.  Descriptive statistics of the items 
mentioned in d) and e) of 1) in Section 11.3.3 will be calculated by compound and 
dose.  Descriptive statistics to be calculated will be the number of subjects, 
arithmetic mean, standard deviation, coefficient of variation, minimum, median, 
and maximum for plasma drug concentrations and the number of subjects, 
arithmetic mean, standard deviation, coefficient of variation, geometric mean, 
minimum, median, and maximum for parameters other than plasma drug 
concentrations. 
11.3.4 
Pharmacodynamic Analysis 
1) Item 
Extent of DNA hypomethylation in LINE-1 
 


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2) Analysis set 
PD analysis set 
 
3) Analysis methods 
Descriptive statistics of the extent of DNA hypomethylation in LINE-1 (percent 
change in the extent of DNA methylation from baseline) at each timepoint will be 
calculated by cohort. 
Also, descriptive statistics of the extent of maximum DNA hypomethylation in 
LINE-1 (at the timepoint when a percent reduction from baseline is maximum) 
will be calculated. 
11.3.5 
Demographic and Other Baseline Characteristics 
1) Definition 
Age, sex, height, body weight, BSA, ECOG PS, diagnosis of AML, duration of 
illness, the presence or absence of hematopoietic stem cell transplantation for 
AML, the presence or absence of radiation therapy for AML, the presence or 
absence of other prior treatments for AML, karyotype at screening, the presence 
or absence of cytogenetic abnormalities, the presence or absence of 
extramedullary lesions after the diagnosis of AML, the proportion (maximum) of 
blast cells (leukemia cells) in the bone marrow after the diagnosis of AML, and 
baseline WBC count, neutrophil count and platelet count. 
 
2) Analysis set 
Safety analysis set (other analysis sets if necessary) 
 
3) Analysis method 
Calculation of frequency tabulation or descriptive statistics will be made by 
cohort according to the characteristics of each item. 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan 
When it is necessary to amend the statistical analysis plan, the timing, details, and reason 
for the amendment will be documented in the CSR. 
11.5 
Rationale for Target Number of Patients 
For Cohorts 1, 2, and 4, tolerability will be evaluated in at least 3 subjects per cohort 
based on the Guidelines for Clinical Evaluation of Antimalignant Tumor Drugs.  If DLTs 
are evaluated in 3 subjects in a cohort for the recommended dose and regimen, additional 
subjects will be enrolled for further safety evaluation in 6 subjects.  For Cohort 3, 
tolerability will be evaluated in 6 subjects. 
 


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12 
Quality Control and Quality Assurance for the Trial 
To ensure quality of the trial, trial sites, contract research organizations, laboratory 
performing drug concentration measurements, PD measurement laboratory, laboratories 
performing clinical tests, and the sponsor will perform quality control for the trial 
according to their respective Standard Operating Procedures. 
The audit division of the sponsor company will carry out audits within the company and, 
as necessary, at the trial site and contract research organizations or organizations 
entrusted to perform related activities, and check whether quality control of the trial is 
appropriately performed according to the Standard Operating Procedures. 
 
13 
General Items of Caution Pertaining to the Trial 
13.1 
Ethics and Good Clinical Practice Compliance 
This clinical trial is to be conducted in compliance with the ethical principles of the 
Declaration of Helsinki, the Pharmaceutical Affairs Law, the Ordinance on Good Clinical 
Practice (Ministry of Health and Welfare Ordinance No. 28 dated 27 Mar 1997), relevant 
notifications, and this trial protocol. 
13.2 
Institutional Review Board 
Prior to performance of this trial, the appropriateness of performance of this trial will be 
reviewed from ethical, scientific, and medical perspectives by the IRB designated by the 
trial site, and this trial will be commenced only after obtaining the approval of the IRB. 
13.3 
Subject Consent 
13.3.1 
Procedures for Obtaining Consent 
1) Prior to the start of the screening examination, the investigator or subinvestigator 
will fully explain the matters listed in Section 13.3.2 to each subject who will be 
included in the trial, using the written information for subjects and ICF, and give 
these documents to the subject.  The subject will be provided sufficient time to 
make a decision regarding participation.  After confirming that the subject has 
properly understood the explanation, the investigator or subinvestigator will 
obtain written voluntary consent for participation in the trial from the subject. 
2) The investigator or subinvestigator who has provided the explanation and the 
subject will each put their printed name and personal seal or signature on the ICF, 
and write the date on which they sign or stamp the form.  If a trial associate has 
provided a supplemental explanation of the trial, he/she will also put his/her 
printed name and personal seal or signature on the form and write the date on 
which he/she signs or stamps the form. 


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3) The original of the ICF that was signed or stamped and dated will be retained by 
the investigator or subinvestigator according to the regulations of the trial site.  A 
copy of the original ICF will be given to the subject. 
4) After obtaining informed consent from a subject, the investigator or 
subinvestigator will write the date of informed consent acquisition and subject 
identification code in the documents for enrolled subjects (list of screened 
subjects and list of enrolled subjects). 
5) If new information becomes available that may influence the willingness of the 
subject to continue participation in the trial, the investigator or subinvestigator 
will promptly inform the subject of such information and confirm the willingness 
of the subject to continue participation in the trial, and then record the result in the 
subject’s medical records.  If there is guidance regarding the recording of re-
consent stipulated by the trial site, it will be followed. 
6) The investigator or subinvestigator will confirm the willingness of the subject to 
continue treatment in Course 2 and subsequent courses and obtain his/her consent 
between the visit on Day 22 of Course 1 and the start of Course 2. 
7) The investigator or subinvestigator will confirm the willingness of the subject to 
receive the IMP in the extended treatment part and obtain his/her consent before 
the start of a treatment course in the extended treatment part. 
13.3.2 
Contents of Written Information for Subjects and Informed 
Consent Form 
1) An explanation that the trial involves research 
2) The type of IRB that reviews the appropriateness of trial conduct, matters to be 
reviewed by the IRB, and other relevant descriptions of the activity of the IRB 
3) The objectives of the trial 
4) The trial procedures (including research-related aspects of the trial, inclusion 
criteria for subjects, and, if random allocation is performed, the probability of 
randomization to each treatment arm) 
5) The expected duration of the subject's participation in the trial 
6) The planned number of subjects involved in the trial 
7) The foreseeable IMP-related physical and mental benefits (if no benefits are 
expected, this should be indicated) as well as risks or inconveniences to the 
subject 
8) The existence of alternative treatments for the subject, and their important 
potential benefits and risks 
9) The treatment and compensation available to the subject in the event of trial-
related injury to health 
10) An explanation that the subject's participation in the trial is voluntary, and that the 
subject can refuse to participate or withdraw from the trial, at any time, without 
penalty or loss of benefits to which he or she would otherwise be entitled 


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11) An explanation that the subject will be informed in a timely manner if information 
becomes available that may be relevant to his or her willingness to continue 
participation in the trial 
12) The circumstances or reasons under which the subject's participation in the trial 
should be terminated 
13) An explanation that the monitors, the auditors, the IRB, and the regulatory 
authorities will be granted direct access to the subject's original medical records 
without violating the confidentiality of the subject, and that by signing the ICF, 
the subject is authorizing such access 
14) An explanation that if the results of the trial are published, the subject's identity 
will remain confidential 
15) The anticipated expenses to the subject for participating in the trial 
16) The anticipated payment, if any, to the subject for participating in the trial 
(agreements on payment, etc) 
17) The name, position, and contact address of the investigator or subinvestigator 
18) The persons at the trial site to contact for further information regarding the trial 
and the rights of trial subjects, and whom to contact in the event of trial-related 
injury to health 
19) Matters to be observed by subjects 
13.3.3 
Amendments to the Written Information for Subjects or Informed 
Consent Form 
If revision of the written information for subjects or ICF becomes necessary due to newly 
obtained information, the investigator will promptly revise the written information for 
subjects or ICF to include that information after conferring with the sponsor. 
The investigator, when revising the written information for subjects or ICF, will report 
this to the head of the trial site and submit the revised document to the IRB designated by 
the trial site to obtain its approval. 
If new information becomes available that may influence the willingness of subjects to 
continue participation in the trial and the written information for subjects or ICF has been 
revised according to the new information, the investigator or subinvestigator will again 
obtain subjects’ written informed consent to continue participation in the trial. 
13.4 
Management of Investigational Medicinal Products 
1) The sponsor will issue the “Procedures for Handling of Investigational Medicinal 
Products” to the persons designated by the trial site. 
2) The sponsor will issue the “Document on Investigational Medicinal Products 
Storage Conditions” to the investigator or subinvestigator, trial associates, and 
IMP manager. 
3) The sponsor will deliver the IMPs to the trial site following the start of the trial 
period contracted with the trial site. 


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4) The IMP manager will manage the IMPs appropriately according to the 
“Procedures for Handling of Investigational Medicinal Products” prepared by the 
sponsor. 
5) The IMP manager will prepare and retain the “Record of Management and 
Storage of Investigational Medicinal Products.” 
13.5 
Direct Access to Source Documents and Monitoring 
13.5.1 
Direct Access to Source Documents 
The head of the trial site and the investigator must accept monitoring and audits to be 
performed by the sponsor and inspection by the IRB and Japanese and foreign regulatory 
authorities, and must make source documents and all other trial-related records available 
to these agencies for direct access (including copying).  Subjects authorize such direct 
access by signing the written ICF. 
13.5.2 
Monitoring 
The sponsor bears responsibility for ethical, legal, and scientific conduct of the trial.  The 
sponsor will perform monitoring according to the “Procedures for monitoring” specified 
for this trial.  Monitoring includes periodic visits, phone calls, or other contact with the 
trial site for the provision, obtaining, and recording of updated trial-related information 
by monitors designated by the sponsor. 
The sponsor may entrust a portion of monitoring activity to a contract research 
organization. 
13.5.3 
Documents to Be Retained by the Investigator 
The trial-related documents to be retained by the investigator will be kept in the 
investigator’s file, which will be managed by the investigator. 
13.6 
Deviations From and Changes or Amendments to the Trial 
Protocol 
13.6.1 
Deviations From the Trial Protocol 
1) The investigator or subinvestigator should not deviate from the protocol or change 
it without prior written agreement between the investigator and the sponsor and 
the written approval of the IRB of the trial site based on prior review. 
2) In unavoidable medical circumstances such as the need to avoid emergent risk to 
a subject, the investigator or subinvestigator may deviate from the protocol or 
change the protocol without prior written agreement from the sponsor and prior 
approval of the IRB.  In such an event, the investigator will promptly submit a 
document providing the details of and reason for the deviation or change to the 
sponsor and the head of the trial site and obtain approval from the IRB.  In 


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addition, the investigator will obtain written approval from the head of the trial 
site and the written agreement of the sponsor by way of the head of the trial site. 
3) The investigator or subinvestigator will record all deviations from the protocol. 
13.6.2 
Amendments to the Trial Protocol 
1) The investigator will promptly submit to the sponsor, the head of the trial site, and 
the IRB by way of the head of the trial site, a written report on any changes in the 
trial that may significantly affect conduct of the trial or increase risks to the trial 
subjects. 
2) The sponsor, after conferring with the investigator, will agree with the 
investigator on the contents of the revised protocol and compliance with the 
revised protocol. 
3) The sponsor will promptly submit the revised protocol to the head of the trial site. 
13.7 
Archiving of Records 
1) The trial site will retain all the trial-related documents and records for the period 
of time indicated in a) or b) below, whichever is longer.  However, if the sponsor 
requires a longer period of archiving, the head of the trial site will consult with the 
sponsor on the period and procedures of record retention. 
a) The date an Application for Approval of a Pharmaceutical Product for the 
IMP is granted; or, if the head of the trial site receives notification from the 
sponsor that development has been terminated or that results of the trial will 
not be submitted with the approval application, the date 3 years after receipt of 
such notification. 
b) The date 3 years after termination or completion of the trial. 
2) The investigator will retain the trial-related documents and records as directed by 
the head of the trial site. 
3) If it becomes no longer necessary to retain the trial-related documents and records 
at the trial site, the sponsor will notify the head of the trial site. 
13.8 
Termination or Interruption of Part or All of the Trial 
13.8.1 
Termination or Interruption of the Trial at Individual Trial Sites 
1) In the event of termination or interruption of the trial, the investigator will 
promptly provide the head of the trial site with written notification and a written 
explanation of the details of the termination or interruption of the trial. 
2) When the sponsor has been informed by the head of a trial site that the 
investigator has terminated or interrupted the trial, the sponsor will obtain a 
detailed written explanation of the termination or interruption of the trial from the 
head of the trial site. 
13.8.2 
Termination or Interruption of the Entire Trial 
1) When the entire trial is to be terminated or interrupted by the sponsor, the sponsor 
will promptly provide the heads of all trial sites involved in the trial and the 


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regulatory authority with written notification and a detailed written explanation of 
the reason for the termination or interruption of the trial. 
2) When the investigator has received notification of termination or interruption of 
the entire trial by the sponsor from the head of the trial site, the investigator will 
obtain a detailed written explanation of the termination or interruption of the trial 
from the head of the trial site, promptly notify the trial subjects currently 
receiving IMP administration, and take necessary measures such as switching to 
appropriate alternative treatment(s). 
3) When development of the IMP is terminated by the sponsor, the sponsor will 
promptly provide the heads and the investigators of all trial sites involved in the 
trial and the regulatory authority with written notification and a detailed written 
explanation of the reason for the termination of development. 
13.9 
Protection of Subjects’ Personal Information 
In completion and handling of CRFs, the investigator and subinvestigator will take 
adequate care to ensure protection of the personal information of subjects.  Individual 
subjects will be identified by subject numbers and subject identification codes.  The 
sponsor will not provide the information obtained to any third party. 
13.10 
Compensation for Injury to Health 
Trial subjects will be compensated for health damages according to the criteria 
established by the trial sponsor with reference to the “Guidelines for Health Damage 
Compensation to Trial Subjects” (revised 25 Nov 2009) of the Japan Pharmaceutical 
Industry Legal Affairs Association.  Compensation for this trial will comprise medical 
costs and medical benefits. 
13.11 
Agreement on Publication 
The sponsor may use the findings obtained from this trial for purposes such as an 
“Application for Approval of a Pharmaceutical Product” for the IMP. 
When the results of this trial and relevant data are to be published in scientific journals or 
at academic meetings, the investigator will obtain prior written approval from the sponsor. 
 
14 
Trial Administrative Structure 
The administrative structure of this trial is shown in Annex 1, Annex 2, and Annex 3. 
 


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15 
Scheduled Duration of the Trial 
Overall trial duration:  01 Oct 2014 to 31 Dec 2019 
1) Cohorts 1, 2, and 4  
(Primary Evaluation Part [Cohorts 1, 2, and 4]) 
01 Oct 2014 to 31 May 2016 
(Extended Treatment Part [Cohorts 1, 2, and 4]) 
01 Jun 2016 to 31 Dec 2019 
2) Cohort 3 
(Primary Evaluation Part [Cohort 3]) 
01 Sep 2016 to 30 Nov 2017 
(Extended Treatment Part [Cohort 3]) 
01 Dec 2017 to 31 Dec 2019 
 
16 
References 
1 
Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. Compound monograph for SGI-
110:  DNA methyltransferase inhibitor oncolytic. Drugs Future. 2013 Aug;38(8):535-43. 
2 
Japanese Society of Hematology, editors. Clinical practice guidelines of hematopoietic tumor 
2013. 
3 
Nishiyama H, Mokuno J, Inoue T. Relative frequency and mortality rate of various types of 
leukemia in Japan [abstract]. Gann 1969 Feb;60(1):71-81. 
4 
Weiss NS. Geographical variation in the incidence of the leukemias and lymphomas [abstract]. 
Natl Cancer Inst Monogr. 1979 Nov;(53):139-42. 
5 
Akazaki K, Wakasa H. Frequency of lymphoreticular tumors and leukemias in Japan [abstract]. J 
Natl Cancer Inst. 1974 Feb;52(2):339-43. 
6 
Kizaki M, editor. Leukemia, lymphomas, and myeloma – Today’s diagnosis and treatment – 
Fourth edition. Chugai-Igakusha; 2011. 
7 
Leopold HL, Willemze R. The treatment of acute myeloid leukemia in first relapse:  a 
comprehensive review of the literature. Leuk Lymphoma. 2002 Sep;43(9):1715-27. 
8 
Kantarjian HM, Roboz GJ, Rizzieri DA, Stock W, O’Connell CL, et al. Results from the dose 
escalation phase of a randomized phase 1-2 first-in-human (FIH) study of SGI-110, a novel low 
volume stable subcutaneous (SC) second generation hypomethylating agent (HMA) in patients 
with relapsed/refractory MDS and AML. Blood (ASH Annual Meeting Abstracts). 2012 
Nov;120:414. 
9 
O’Connell C, Tibes R, Walsh K, Rizzieri D, Yee K, Stock W, et al. Outcomes of intermediate or 
high risk myelodysplastic syndromes (MDS) patients post azacitidine and/or decitabine treatment 
failures with SGI-110, a novel second generation hypomethylating agent (HMA). Poster 


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Version 8 
presented at:  18th Congress of the European Hematology Association (EHA) 2013 Jun 13-16; 
Stockholm, Sweden. Abstract #189. 
10 
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. 
11 
Kantarjian H, Jabbour E, Yee K, Kropf P, O'Connell C, Stock W, et al. First Clinical Results of a 
Randomized Phase 2 Study of SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent 
(HMA), In Adult Patients With Acute Myeloid Leukemia (AML). Blood. 2013;122(21):497. 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Phase 1 Study of SGI-110 in Patients with Acute Myeloid Leukemia 
 
 
 
 
NCT Number: NCT02293993 
PRT NO.: 343-14-001 
Version Date: 15 February 2018 (Version 3.0) 


 
Phase 1 Study of SGI-110 in Patients with Acute 
Myeloid Leukemia 
 
 
 
 
 
 
Statistical Analysis Plan 
Protocol No.: 343-14-001 
 
Confidential 
 
 
 
 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
 
Version 3.0: 2018/02/15
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 343-14-001
16.1.9 Documentation of Statistical Methods
2


 
2
Table of Contents 
1 
Introduction .......................................................................................... 5 
2 
Trial Objectives .................................................................................... 6 
3 
Trial Design ........................................................................................... 7 
4 
Implementation of Planned Analyses ............................................... 10 
5 
Statistical Analysis Sets ...................................................................... 11 
5.1.1 
Safety Analysis Set ......................................................................................... 11 
5.1.1.1 
Dose-limiting Toxicity Analysis Set .......................................................... 11 
5.1.2 
Efficacy Analysis Set ..................................................................................... 11 
5.1.3 
Pharmacokinetic Analysis Set ........................................................................ 11 
5.1.4 
Pharmacodynamic Analysis Set ..................................................................... 11 
6 
Considerations for Data Analysis ..................................................... 12 
6.1 
Software ............................................................................................................ 12 
6.2 
Data Conversion and Calculation ..................................................................... 12 
6.2.1 
Conversion of Duration .................................................................................. 12 
6.2.2 
Time since Initial Diagnosis ........................................................................... 12 
6.2.3 
Complete Remission Rate .............................................................................. 12 
6.2.4 
Composite Complete Remission Rate ............................................................ 12 
6.2.5 
Overall Remission Rate .................................................................................. 12 
6.2.6 
Duration of Composite Complete Remission ................................................. 13 
6.2.7 
Overall Survival ............................................................................................. 13 
6.3 
Handling of Time Points ................................................................................... 14 
6.4 
Handling of Missing Values and Outliers ......................................................... 14 
6.5 
Significance Level and Confidence Coefficient ............................................... 14 
6.5.1 
Multiple Comparisons and Multiplicity ......................................................... 14 
7 
Disposition of Subjects ....................................................................... 15 
7.1 
Disposition of Subjects ..................................................................................... 15 
7.2 
Statistical Analysis Sets .................................................................................... 15 
8 
Description of Analysis Datasets ....................................................... 16 
8.1 
Demographics and Baseline Characteristics ..................................................... 16 
8.2 
Status of Trial Conduct ..................................................................................... 17 
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3
8.2.1 
Investigational Medicinal Product Compliance ............................................. 17 
8.2.2 
Use of Medication Other Than Investigational Medicinal Product ............... 17 
8.2.3 
Number of Blood Transfusion........................................................................ 18 
9 
Safety Analysis .................................................................................... 19 
9.1 
Extent of Exposure ............................................................................................ 19 
9.2 
Primary Endpoints ............................................................................................ 19 
9.3 
Secondary Endpoints ........................................................................................ 19 
9.3.1 
Adverse Events ............................................................................................... 19 
9.3.2 
Death, Other Serious Adverse Events, CTCAE Grade 3 or above 
Adverse Events, and Other Significant Adverse Events ................................ 20 
9.3.3 
Clinical Laboratory Tests ............................................................................... 20 
9.3.4 
Vital Signs and Body Weight ......................................................................... 21 
9.3.5 
ECG (12-Lead ECG) ...................................................................................... 21 
9.3.6 
ECOG PS ........................................................................................................ 21 
9.3.7 
Chest X-ray .................................................................................................... 22 
10 
Efficacy Analysis ................................................................................. 23 
10.1 
Complete Remission Rate, Composite Complete Remission Rate, Overall 
Remission Rate ................................................................................................. 23 
10.2 
Duration of Composite Complete Remission ................................................... 23 
10.3 
Overall Survival ................................................................................................ 23 
10.4 
Adjustment for Covariates ................................................................................ 23 
10.5 
Subgroup Analysis ............................................................................................ 23 
11 
Pharmacodynamic Analysis .............................................................. 24 
11.1 
DNA Methylation Inhibition............................................................................. 24 
12 
Rationale for Target Number of Subjects ........................................ 25 
13 
Changes From Analyses Planned in the Protocol ........................... 26 
14 
References ........................................................................................... 27 
15 
Revision History ................................................................................. 28 
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4
List of Abbreviations and Definition of Terms 
 
List of Abbreviations 
Abbreviation 
Expansion 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AMLSG 
Acute myeloid leukemia study group 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
Cr 
Creatinine 
CR 
Complete remission 
CRi 
Complete remission with incomplete blood count recovery 
CRp 
Complete remission with incomplete platelet recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram, electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
IMP 
Investigational medicinal product 
LINE-1 
Long interspersed nucleotide element-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NE 
Not evaluable 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PS 
Performance status 
PT 
Preferred term 
QTcF interval 
QT interval as corrected by Fridericia’s formula 
RBC 
Red blood cell 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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5
1 
Introduction 
This statistical analysis plan (SAP) describes the methods of summary/analysis or 
assessment of the data collected in this trial.  This SAP was prepared based on protocol 
version 8 (Protocol No.: 343-14-001) prepared on 13 Oct 2017. 
The analysis methods for the pharmacokinetic (PK) evaluation are not described in this 
SAP, as a PK analysis plan will be prepared as a separate document.  By-subject listings 
are not included in this SAP unless stated otherwise. 
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6
2 
Trial Objectives 
Primary objective: 
To evaluate the tolerability of SGI-110 when administered subcutaneously to Japanese 
patients with acute myeloid leukemia (AML) 
Secondary objectives: 
 To perform PK evaluation of plasma SGI-110 and decitabine 
 To evaluate efficacy (complete remission rate, composite complete remission rate, 
overall remission rate, overall survival, composite complete remission duration) 
 To evaluate safety through observed adverse events (AEs) and examinations 
Exploratory objective: 
To perform pharmacodynamics (PD) evaluation of the extent of deoxyribonucleic acid 
(DNA) hypomethylation 
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7
3 
Trial Design 
This is a phase 1, multicenter, open-label study to evaluate the tolerability of SGI-110 in 
Japanese patients with relapsed or refractory AML after undergoing standard therapy or 
Japanese patients with AML aged 65 years or older who are not eligible for standard 
chemotherapy. 
This trial consists of a screening period, dose limiting toxicity (DLT) evaluation period, 
and withdrawal examination.  Subjects who complete investigational medicinal product 
(IMP) administration and all observations during the DLT evaluation period, and who do 
not have any apparent progression of AML, will be permitted to continue treatment with 
IMP following the DLT evaluation period if they wish.  The primary evaluation data for 
Cohorts 1, 2, and 4 will have a cut-off date of 31 May 2016 and the primary evaluation 
data for Cohort 3 will have a cut-off date of 30 Nov 2017.  The period up until the data 
cut-off will be defined as the primary evaluation part.  This will be followed by an 
extended treatment part to assess long-term safety, which will include those subjects on 
IMP treatment who have consented to participate in the extended treatment part.  
Transition from the primary evaluation part to the extended treatment part will take place 
at the start of the next course after the data cut-off. 
Administration of the IMP will be started in Cohort 1 (36 mg/m2 in 5-day regimen) and 3 
subjects will receive the IMP in this cohort.  If none of the 3 subjects has a DLT during 
the DLT evaluation period, the study will proceed to the next cohort.  If one of the 3 
subjects experiences a DLT, 3 additional subjects will be enrolled and DLTs will be 
evaluated in a total of 6 subjects.  The study will proceed to the next cohort only if no 
more than one of the 6 subjects has a DLT.  If the number of subjects exhibiting a DLT 
within a cohort is ≥ 2/3 or ≥ 2/6, there will be no dose escalation. 
In Cohort 2 (60 mg/m2 in 5-day regimen) and Cohort 4 (90 mg/m2 in 5-day regimen), 
DLTs will be assessed in the same manner.  However, even if none of the first 3 
subjects enrolled has a DLT, a total of 6 subjects will be enrolled in each of Cohorts 2 
and 3 of which the dose has been determined as the recommended dose for a next phase 
study. 
Based on the occurrence of DLTs, the tolerability at the recommended dose for a next 
phase study will be confirmed in Japanese subjects as well. 
The sponsor will review safety data obtained from the previous cohort(s) and judge the 
transition to the next cohort, including selection of a cohort to proceed to, based on the 
advice of the Independent Data Monitoring Committee. 
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8
If the number of subjects exhibiting DLT within a cohort is ≥ 2/3 or ≥ 2/6, then there will 
be no transition to the next cohort, and the maximum tolerated dose (MTD) will be 
determined as follows: 
≥ 2/3 or ≥ 2/6 subjects with DLT 
MTD 
In Cohort 1 
< 36 mg/m2 in 5-day regimen 
In Cohort 2 
36 mg/m2 in 5-day regimen 
In Cohort 4 
60 mg/m2 in 5-day regimen 
If the incidence of DLT does not reach either ≥ 2/3 or ≥ 2/6 in any of the cohorts in the 
table above, the MTD will not be determined in this study.  For Cohort 3 (60 mg/m2 in 
10-day regimen), DLT will be evaluated but the MTD of 10-day regimen will not be 
determined from the incidence of DLT. 
 
The DLT evaluation period will be from the start of administration in Course 1 to the 
examination scheduled for Day 29 of Course 1.  However, for subjects who have 
postponed the start of IMP administration scheduled for Day 1 of Course 2 (extended 
treatment period), the DLT evaluation period will last until the start of IMP 
administration in Course 2. 
Subjects will be hospitalized for treatment during Course 1.  Subjects will be required to 
remain hospitalized until the examination scheduled for Day 29 of Course 1 if they 
complete the trial in Course 1 (until the withdrawal examination if they are withdrawn 
during Course 1) and until the start of IMP administration in Course 2 if they proceed to 
the extended treatment period of Course 2 and the subsequent courses. 
Dose-limiting toxicity shall be defined as any of the following AEs occurring during 
Course 1 for which there is a reasonable probability or possibility of a causal relationship 
with the IMP (being related to the IMP) if it cannot be reasonably explained by 
underlying disease, intercurrent illness, or concomitant medications.  The severity of 
AEs will be graded in accordance with Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. 
 Non-hematologic toxicity of Grade 3 or higher, except for the following: 
 Nausea, vomiting, or diarrhea of Grade 3 that is controllable by optimal 
therapy 
 Grade 3 laboratory findings other than serum creatinine (Cr), bilirubin, 
aspartate aminotransferase (AST), or alanine aminotransferase (ALT), that 
are not associated with clinical manifestations 
 Grade 4 thrombocytopenia that was not present at study entry and that is not 
resolved within 7 days 
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9
 Grade 4 neutropenia that was not present at study entry and that is not resolved 
within 7 days 
 Febrile neutropenia* 
If the febrile neutropenia is not resolved or improved during the DLT evaluation 
period, it shall be defined as DLT.  If the febrile neutropenia is resolved or 
improved during the DLT evaluation period, it shall be judged whether it is 
defined as DLT based on the background of the subject and through consultation 
with the Independent Data Monitoring Committee. 
 Any AE that results in a delay of > 4 weeks in starting the next treatment course 
*In this trial, febrile neutropenia is defined as a neutrophil count of < 500/μL 
accompanied by a fever of ≥ 38°C 
The DLT evaluation period will be for the duration of Course 1.  Subjects who complete 
IMP administration and all observations during the DLT evaluation period, and who do 
not have any apparent progression of AML, will be permitted to continue treatment with 
IMP following the DLT evaluation period if they wish. 
 
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4 
Implementation of Planned Analyses 
One interim analysis for cohort 1, 2 and 4 of this study will be take place that the data 
will be locked on 25Aug2017.  And one final analysis for cohort 1, 2, 3 and 4 of this 
study will take place for final locked. 
SAP will be fixed before lock of database. 
After confirmation of which subjects are to be included in the statistical analyses and how 
to handle the data in the statistical analyses and discussion of how to deal with problems 
unexpected at the time of planning, final analysis will be done based on the SAP by using 
the final data. 
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5 
Statistical Analysis Sets 
5.1.1 
Safety Analysis Set 
The safety analysis set will include subjects who have received at least one dose of the 
IMP. 
5.1.1.1 
Dose-limiting Toxicity Analysis Set 
The DLT analysis set will include subjects in whom tolerability has been assessed in 
Cohorts 1 to 4 (subjects who have received all doses and completed all assessments 
scheduled for the DLT evaluation period). 
5.1.2 
Efficacy Analysis Set 
The efficacy analysis set will include subjects who have received at least one dose of the 
IMP and have data of the efficacy endpoints after the start of IMP administration. 
5.1.3 
Pharmacokinetic Analysis Set 
The PK analysis set will include subjects whose plasma drug concentrations have been 
measured. 
5.1.4 
Pharmacodynamic Analysis Set 
The PD analysis set will include subjects in whom the extent of DNA hypomethylation in 
long interspersed nucleotide element-1(LINE-1) has been measured. 
 
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12 
6 
Considerations for Data Analysis 
6.1 
Software 
The following software (including versions) will be used in the analyses. 
 SAS 9.4 (SAS Institute Inc.) 
 
6.2 
Data Conversion and Calculation 
6.2.1 
Conversion of Duration 
1 month will be considered with 30 days for the analysis. 
 
6.2.2 
Time since Initial Diagnosis 
Time since initial diagnosis will be calculated as [the date of first dose of IMP - 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 1 is used.  If the year is missing, the date is left as missing. 
 
6.2.3 
Complete Remission Rate 
Complete remission will be defined as follows. 
 Complete remission (CR) 
 
6.2.4 
Composite Complete Remission Rate 
Composite complete remission will be defined as follows. 
 CR 
 Complete remission with incomplete platelet recovery (CRp) 
 Complete remission with incomplete blood count recovery (CRi) 
 
6.2.5 
Overall Remission Rate 
Overall remission will be defined as follows. 
 CR 
 CRp 
 CRi 
 Partial response (PR) 
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13 
 
The investigator or subinvestigator will evaluate response in each course in accordance 
with the response criteria in following table, which is based on the response criteria for 
AML treatment established by an international working group1.   
 
Bone Marrow 
Peripheral Blood 
CR 
 
Blast cells < 5% 
 
Neutrophil count > 1,000/μL 
 
Platelet count ≥ 100,000/μL 
 
No blast cell 
 
Transfusion independence 
CRp 
 
Blast cells < 5% 
 
Neutrophil count > 1,000/μL 
 
Platelet count < 100,000/μL 
 
No blast cell 
 
Red blood cell (RBC) transfusion 
independence 
Morphologic CRi 
 
Blast cells < 5% 
 
Neutrophil count < 1,000/μL 
 
No blast cell 
PR 
 
Rate of decrease in blast 
cells in the bone marrow 
≥ 50% and ratio of blast 
cells of 5% to 25% 
 
Neutrophil count > 1,000/μL 
 
Platelet count ≥ 100,000/μL 
 
No blast cell 
Relapse 
 
Leukemia cells (blast cells) ≥ 5% in the bone marrow or presence 
of leukemia cells (blast cells) in the peripheral blood are 
manifested again after CR, CRi, or CRp has been achieved. 
 
Leukemia cells with abnormal chromosomes are revealed again in 
chromosomal testing. 
 
6.2.6 
Duration of Composite Complete Remission 
Duration of composite complete remission (in number of days) is calculated from the first 
time a composite complete remission is observed to time of relapse defined as above 
table. 
The duration of composite complete remission will be calculated to the last available time 
point in the case that relapse was not observed. 
Duration of composite complete remission will be summarized for subjects who achieved 
complete remission during the study. 
 
6.2.7 
Overall Survival 
Overall survival is defined as the number of days from the day the subject received the 
first dose of IMP to the date of death (regardless of cause). 
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14 
Survival time will be censored on the last date of survival confirmation if a subject is 
alive or lost to follow-up. 
 
6.3 
Handling of Time Points 
Data recorded at the time points specified in the case report form will be summarized for 
the respective time points.  If data at the time of withdrawal or unspecified time points 
are within the acceptable time window specified in the protocol, they will be used as the 
data at that time point.  If there are 2 or more data in a specific time window, the closest 
data to the scheduled visit date will be used for the analysis.  If there are 2 data with 
same interval from the scheduled visit date, one before the scheduled visit date and the 
other after the scheduled visit date, the data from after the scheduled visit date will be 
used for the analysis.  If 2 or more data are collected on the same date, the mean value 
of these data will be used for the analysis. 
Baseline is defined as last available data before the first dose of IMP. 
Time point of Cohort 3 vital sign data will be handled same as the time point of Cohorts 1, 
2 and 4. 
6.4 
Handling of Missing Values and Outliers 
No imputation of missing values or exclusion of outliers will be performed. 
 
6.5 
Significance Level and Confidence Coefficient 
No significance level or confidence coefficient will be set, since statistical tests and 
interval estimations will not be performed. 
 
6.5.1 
Multiple Comparisons and Multiplicity 
No multiple comparisons and multiplicity will be considered, since statistical tests will 
not be performed. 
 
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15 
7 
Disposition of Subjects 
Subjects who gave informed consent will be used in the statistical analyses.  Data will 
be summarized by cohort and overall (Cohorts 1, 2, and 4). 
7.1 
Disposition of Subjects 
Subject disposition will be summarized.  The frequency distribution (number of subjects 
and incidence rate [the same applies hereafter]) of subjects who gave informed consent, 
screen failures, subjects who were administered the IMP, subjects who completed course 
1, and subjects who discontinued the study will be determined.  In addition, the 
frequency distribution of study discontinuation will also be determined by primary reason 
for discontinuation. 
Frequency distribution will be summarized for course 1 and on or after course 2.  Only 
the subjects who continue IMP administration on or after course 2 will be included in the 
frequency distribution for on or after course 2. 
7.2 
Statistical Analysis Sets 
The frequency distribution of subjects included or excluded in each analysis set will be 
determined for subjects who were administered the IMP.
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16 
8 
Description of Analysis Datasets 
The safety analysis set will be used in the statistical analyses.  The following analyses 
will be performed by cohort and overall (Cohorts 1, 2, and 4). 
8.1 
Demographics and Baseline Characteristics 
Demographic and other baseline characteristics are as follows; 
1) Age (< 65 years, ≥ 65 and < 75 years, ≥ 75 years, calculated relative to date of 
informed consent) 
2) Sex (Male, Female)  
3) Height (cm) 
4) Weight (kg) 
5) Body surface area (m2) 
6) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0, 1 or 2) 
7) Diagnosis of AML 
8) Time since initial diagnosis (calculated relative to date of first dose of IMP) 
9) Hematopoietic stem cell transplantation history (Yes, No) and type of 
transplantation 
10) De novo or secondary AML (De novo AML, secondary AML) 
11) Prior radiotherapy history (Yes, No) 
12) Chemotherapy history including induction therapy history and consolidation 
therapy history 
13) Poor type category of Karyotype at screening (Better risk, Intermediate risk, Poor 
risk, Unknown) 
14) Cytogenetic abnormalities (Yes, No, Unknown) and detail of abnormality 
15) Extra medullary lesions found after diagnosis of AML (Yes, No) 
16) Maximum proportion of blast cells (leukemic cells) in the bone marrow after 
diagnosis of AML 
17) Baseline leukocytes (≥ 20.0 × 109/L, ≥ 2.0 and < 20.0 × 109/L, ≥ 1.0 and < 2.0 × 
109/L, < 1.0 × 109 /L) 
18) Baseline neutrophil (≥ 1.0 × 109/L, ≥ 0.5 and < 1.0 × 109/L, < 0.5 × 109/L) 
19) Baseline platelets (≥ 50.0 × 109/L, ≥ 25.0 to < 50.0 × 109/L, < 25.0 × 109/L) 
 
1) will be summarized with descriptive statistics in addition to categorical summary.  3), 
4), 5), 8) and 16) will be summarized with descriptive statistics.  Others will be 
summarized categorically. 
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17 
In detail, poor-risk cytogenetics is defined based on the National Comprehensive Cancer 
Network (NCCN) Guidelines® (2014)2 as follows: 
Risk Status Based on Cytogenetics1 
Risk Status 
Cytogenetics 
Better-risk 
inv(16)2,3 or t(16;16)2 
t(8;21)2 
t(15;17) 
Intermediate-risk 
Normal cytogenetics 
+8 alone 
t(9;11) 
Other non-defined 
Poor-risk 
Complex (≥3 clonal chromosomal abnormalities) 
Monosomal karyotype 
-5, 5q-, -7, 7q- 
11q23 - non t(9;11) 
inv(3), t(3;3) 
t(6;9) 
t(9;22)4 
1 
The molecular abnormalities included in this table reflect those for which 
validated assays are available in standardized commercial laboratories. Given 
the rapidly evolving field, risk stratification should be modified based on 
continuous evaluation of research data. Other novel genetic mutations have 
been identified that may have prognostic significance. 
2  
Other cytogenetic abnormalities in addition to these findings do not alter better 
risk status. 
3 
Paschka P, Du J, Schlenk RF, et al. Secondary genetic lesions in acute 
myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian 
AML study group (AMLSG). Blood 2013;121:170-177. 
4 
For Philadelphia+ AML t(9;22), manage as myeloid blast crisis in chronic 
myeloid leukemia, with addition of tyrosine kinase inhibitors. 
Source: NCCN Guidelines: Acute Myeloid Leukemia. Version 2.2014. NCCN.org. 
 
8.2 
Status of Trial Conduct 
8.2.1 
Investigational Medicinal Product Compliance 
Not applicable. 
8.2.2 
Use of Medication Other Than Investigational Medicinal Product 
Medications will be coded using World Health Organization Drug Dictionary 
(WHO-DD) version 01MAR2014. 
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18 
The frequency distribution for the use of medications other than the IMP will be 
determined by therapeutic subgroup [Anatomical Therapeutic Chemical (ATC) level 2] 
and preferred term. 
 Medications used before the start of IMP administration 
 Medications used during the trial period (from the start of IMP administration to the 
end-of-trial assessment) 
 
8.2.3 
Number of Blood Transfusion 
Frequency distribution of the number of subjects who received transfusion by the type of 
blood transfusion for each course including baseline will be summarized by cohort and 
overall (Cohorts 1, 2, and 4). 
The number of blood transfusions (units/ month) over the treatment period will be 
calculated by the type of blood transfusion and subjects and will be summarized by 
cohort and overall (Cohorts 1, 2, and 4). 
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9 
Safety Analysis 
The safety analysis set or DLT evaluation analysis set will be used in safety analyses.  
The following analyses will be conducted by cohort and overall (Cohorts 1, 2, and 4) for 
subjects receiving IMP. 
9.1 
Extent of Exposure 
Safety analysis set will be used for the analysis. 
The following items will be tabulated. 
 Frequency distribution of the number of IMP administrations on course 1. 
 Frequency distribution of the number of IMP dosed subjects for each course 
 Number of IMP administration courses for each subject will be summarized with 
descriptive statistics for the overall treatment period. 
 
9.2 
Primary Endpoints 
DLT is the primary endpoint of this trial. 
DLT evaluation analysis set will be used for the analysis. 
 DLTs [preferred term (PT)] which observed on course 1 will be tabulated (number of 
subjects and incidence rate) by DLT criteria and Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class (SOC) and PT. 
 
9.3 
Secondary Endpoints 
The safety analysis set will be used for the analysis. 
9.3.1 
Adverse Events 
AEs will be coded using MedDRA version 20.0. 
 The number of subjects and incidence will be summarized for all treatment-emergent 
AEs (TEAEs). 
 The number of subjects and incidence will be summarized for all TEAEs by 
MedDRA SOC and PT. 
 The number of subjects and incidence will be summarized for all TEAEs by 
MedDRA SOC, PT, and CTCAE grade.  If a subject experiences the same TEAE 2 
or more times, the most severe grade occurrence will be used for the analysis. 
 The number of subjects and incidence will be summarized for all TEAEs by the 
timing of AE occurrence (in course 1, in or after course 2, and overall), MedDRA 
SOC and PT.  AEs which had occurred in Course 1 and continued beyond course 2 
will be included in “in or after course 2” category. 
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 TEAEs that DLTs and correspond to DLTs (preferred term) which were observed in 
course 1, in or after course 2, and overall will be tabulated (number of subjects and 
incidence rate).  AEs which had occurred in Course 1 and continued beyond course 
2 will be included in “in or after course 2” category. 
Adverse drug reactions (TEAEs for which a causal relationship with the IMP are 
suspected adverse reaction) will be summarized in the same manner as above. 
9.3.2 
Death, Other Serious Adverse Events, CTCAE Grade 3 or above 
Adverse Events, and Other Significant Adverse Events 
The following TEAEs will be summarized in the same manner as in first bullet of Section 
9.3.1 Adverse Events.  Also the following TEAEs, excluding TEAEs of grade ≥ 3, will 
be summarized in the same manner as in second bullet of Section 9.3.1 Adverse Events. 
 Serious TEAEs 
 TEAEs leading to death 
 TEAEs leading to discontinuation in course 1, in or after course 2, and overall 
 TEAEs of grade ≥ 3 
 TEAEs leading to postponement of the start of the next course 
 TEAEs leading to skipping of IMP administration 
Adverse drug reactions (TEAEs for which a causal relationship with the IMP are 
suspected adverse reaction) will be summarized in the same manner as above. 
9.3.3 
Clinical Laboratory Tests 
The following items will be tabulated by cohort and overall (Cohorts 1, 2, and 4) for 
hematological and biochemical tests performed at each time point. 
 Descriptive statistics of the measured values 
 Descriptive statistics of the change from baseline 
 Shift tables comparing the baseline grade with last grade, worst grade through all 
courses and worst grade of each course categorized by CTCAE grade 
 Shift tables comparing the baseline values with last value, worst value through all 
courses and worst value of each course by using the normality judgment (high, 
normal, low) 
If the laboratory test parameter has both upper limit of normal and lower limit of normal, 
larger difference one from median of normal range will be taken as worst value. 
The following item will be tabulated by cohort and overall (Cohorts 1, 2, and 4) for the 
urinalysis. 
 Shift tables comparing the baseline values with last value, worst value through all 
courses and worst value of each course. 
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Also, some of laboratory test parameter will be figured by subject performed at each time 
point of course 1 and all courses. 
 
Line plots will be used to assess hemoglobin, red blood cell, white blood cell, 
neutrophil, lymphocytes and platelet. 
 
9.3.4 
Vital Signs and Body Weight 
The following vital signs (blood pressure, pulse rate, body temperature) and body weight 
will be tabulated at each time point. 
 Descriptive statistics of the measured values 
 Descriptive statistics of the change from baseline 
 
9.3.5 
ECG (12-Lead ECG) 
Electrocardiographic (ECG) assessment by site investigator will be used for the analysis. 
The following items will be tabulated for heart rate, PR interval, RR interval, QRS 
interval, QT interval, and QT interval as corrected by Fridericia’s formula (QTcF 
interval) at each time point. 
 Descriptive statistics of the measured values 
 Descriptive statistics of the change from baseline 
 
The number of subjects and incidence of the following items will be tabulated by cohort 
for QTcF interval of last value and worst value (maximum value obtained after the start 
of IMP administration). 
 Measured values will be classified as “greater than 450 ms”, “greater than 480 ms”, 
and “greater than 500 ms” for tabulation. 
 Changes from baseline will be classified as “greater than 30 ms” and “greater than 60 
ms” for tabulation. 
 
The following item will be tabulated by cohort using the normality judgment (normal or 
abnormal) for the electrocardiogram at each time point. 
 Shift table from baseline 
 
9.3.6 
ECOG PS 
The following item will be tabulated for the ECOG PS at each time point. 
 Frequency distribution of each ECOG PS score 
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9.3.7 
Chest X-ray 
The following item will be tabulated using the normality judgment (normal or abnormal) 
for the chest x-ray at each time point. 
 Shift table from baseline
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10 
Efficacy Analysis 
The efficacy analysis set will be used in efficacy analyses.  The following analyses will 
be performed by cohort and overall (Cohorts 1, 2, and 4). 
10.1 
Complete Remission Rate, Composite Complete Remission Rate, 
Overall Remission Rate 
The following analysis will be conducted by cohort and overall (Cohorts 1, 2, and 4). 
 Distribution of remission in each course [CR, CRp, CRi, PR No response, progressive 
disease, and not evaluable (NE)] 
 Distribution of the best overall remission: complete remission rate (CR), composite 
complete remission rate (CR + CRp + CRi), overall remission rate (CR + CRp + CRi 
+ PR) 
 
10.2 
Duration of Composite Complete Remission 
The following analysis will be conducted by cohort and overall (Cohorts 1, 2, and 4) for 
the subjects with composite complete remission. 
 Summary of duration of composite complete remission using descriptive statistics. 
 
10.3 
Overall Survival 
The following analysis will be conducted by cohort and overall (Cohorts 1, 2, and 4) in 
the efficacy analysis set.  Also, same analysis will be conducted for responders, 
non-responders, and overall in efficacy analysis set.  Responders will be defined as 
those subjects who meet the criteria of overall remission. 
 Kaplan–Meier plots with median survival time 
 
10.4 
Adjustment for Covariates 
No adjustment for covariates will be considered, since statistical tests and interval 
estimations will not be performed. 
10.5 
Subgroup Analysis 
No subgroup analysis will be conducted, since the number of subjects in this study will 
be very limited. 
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11 
Pharmacodynamic Analysis 
The PD analysis set will be used for pharmacodynamics analyses.  The following 
analyses will be performed by cohort and overall (Cohorts 1, 2, and 4). 
11.1 
DNA Methylation Inhibition 
The following analysis will be conducted by cohort and overall (Cohorts 1, 2, and 4) for 
the subjects with the measurement of the degree of DNA methylation inhibition of 
LINE-1. 
 Descriptive statistics of the DNA LINE-1 demethylation (defined as percent change 
from baseline in methylation value) at each time point.  Also, line plots will be used 
to assess DNA LINE-1 demethylation [Mean ± Standard deviation (SD)] at each time 
point. 
 Summary of the maximum DNA LINE-1 demethylation (defined as the largest 
percent decrease from baseline in methylation values within a subject between Day 8 
and Day 29 of the first treatment course) using the descriptive statistics.  Also, bar 
charts will be used to assess the maximum DNA LINE-1 demethylation within a 
subject between Day 8 and Day 29 of the first treatment course. 
 Line plots of DNA LINE-1 demethylation will be produced for responders, 
non-responders, and overall in the pharmacodynamics analyses set.  Responders will 
be defined as those subjects who meet the criteria of overall remission. 
 
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12 
Rationale for Target Number of Subjects 
For Cohorts 1, 2, and 4, tolerability will be evaluated in at least 3 subjects per cohort 
based on the Guidelines for Clinical Evaluation of Antimalignant Tumor Drugs.  If 
DLTs are evaluated in 3 subjects in a cohort for the recommended dose and regimen, 
additional subjects will be enrolled for further safety evaluation in 6 subjects.  For 
Cohort 3, tolerability will be evaluated in 6 subjects. 
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13 
Changes From Analyses Planned in the Protocol 
Categorization of urinalysis in shift tables was changed from CTCAE grade to qualitative 
value. 
One interim analysis for cohort 1, 2 and 4 of this study will take place that the data will 
be locked on 25Aug2017. 
Kaplan-Meier plots of overall survival with median survival time will be produced 
regardless of number of subjects in each cohort. 
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14 
References 
1 Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. 
Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 
15;21(24):4642-9. 
2 NCCN Guidelines: Acute Myeloid Leukemia. Version 2.2014. NCCN.org.
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