Conditions: Acute Myeloid Leukemia
Keywords: Oncology MDM2 Escalation with overdose control (EWOC)
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 14
Healthy volunteers: no

Brief summary:
This is a Phase 1, multicenter, open-label study to evaluate safety, tolerability and pharmacokinetics of milademetan in Japanese patients with relapsed or refractory acute myeloid leukemia. The milademetan initial dose will be Level 1: 90 mg. No increase in the milademetan dose will be made in the same participant. Dose-limiting toxicity associated with milademetan occurring at each level will be assessed, and the maximum tolerated dose (MTD) will be decided using a modified continuous reassessment method (mCRM).

Detailed description:

Arms:
arm 1: Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle. arm 2: Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle. arm 3: Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.

Interventions: intervention 1: Milademetan
Intervention descriptions: intervention 1: Milademetan was administered orally once daily on Days 1 to 14 in a 28-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
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Page 1
CLINICAL STUDY PROTOCOL
PHASE 1, OPEN-LABEL, DOSE ESCALATION 
STUDY OF DS-3032B, AN ORAL MDM2 INHIBITOR, 
TO ASSESS SAFETY, TOLERABILITY AND 
PHARMACOKINETICS IN JAPANESE PATIENTS 
WITH RELAPSED OR REFRACTORY ACUTE 
MYELOID LEUKEMIA
DS3032-A-J104
VERSION 01.4, 07 OCT 2019
DAIICHI SANKYO
CONFIDENTIALITY STATEMENT
Information contained in this document is proprietary to Daiichi Sankyo Co., Ltd.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or any
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo Co., Ltd.


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PROTOCOL SYNOPSIS
Protocol Number:
DS3032-A-J104
Investigational Substance Code: DS-3032b
Generic Name/INN:
milademetan
Study Title:
Phase 1, open-label, dose escalation study of DS-3032b, an oral 
MDM2 inhibitor, to assess safety, tolerability and 
pharmacokinetics in Japanese patients with relapsed or refractory 
acute myeloid leukemia
Study Phase:
Phase 1
Indication Under Investigation: Acute myeloid leukemia (AML)
Study Objectives:
Primary objective:
To evaluate the safety and tolerability of DS-3032b monotherapy 
administered as multiple doses and assess the maximum 
tolerated dose (MTD) in Japanese subjects with relapsed or 
refractory AML.
Secondary objectives:
x
To evaluate the pharmacokinetics of DS-3032a
x
To exploratively evaluate the antitumor effect of DS-3032b
Type of study objectives:
Efficacy, safety, pharmacodynamics, pharmacokinetics, 
tolerability, pharmacogenomics
Study Design:
Type of study: Interventional
Type of intervention: Pharmaceutical drugs
Type of proposed indications: Treatment
Study design: Single arm
Dose finding method:
An optimal dose of DS-3032b will be explored from among four 
doses (Subtrials A, B, C, and D) based on the fixed dosing 
schedule.  The study will be started from Subtrial A, and other 
subtrials will be conducted as necessary. Explorative assessment 
of MTD in each subtrial will be guided by a modified continual 
reassessment method (mCRM) using a Bayesian logistic 
regression model (BLRM) incorporating the escalation with 
overdose control (EWOC) principle.


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Combinations of Doses and Dosing Schedules
Subtrial C
Subtrial B
Subtrial A
Subtrial D
Dose (mg)
160
C-3
B-3
A-3
D-3
120
C-2
B-2
A-2
D-2
90
C-1
B-1
A-1
D-1
3/14 × 2
7/28
14/28
21/28
Dosing schedule (day/day)
Level of blinding: Open-label
Type and presence/absence of comparator: Not applicable
Add-on to standard therapy: None
Study Duration:
06 Jul 2018 to 31 Dec 2019
Location:
Japan
Study Centers:
Refer to Attachment 2.
Planned Sample Size:
9 to 24 subjects
Study Population
(Inclusion and Exclusion 
Criteria)
Inclusion criteria
1.
Provision of written informed consent for participation in 
this study.
2.
Age ≥20 years old upon enrollment in this study.
3.
Having AML (including those with a history of 
myelodysplastic syndrome [MDS]) satisfying either of the 
following:
x
Have failed to achieve remission with at least 1 cycle of 
prior induction therapy
x
Have relapsed after achieving remission with prior 
therapy
4.
Those who appear unable to achieve persistent remission 
with standard treatment, who failed to complete potentially 
curative treatment, or who have no treatment options with 
expected therapeutic efficacy.
5.
Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0 to 2 (refer to “Appendix 2”).
6.
Having laboratory data satisfying all of the following criteria 
in the measurement within 14 days before enrollment in this 
study.


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Laboratory Parameter
Requirement
AST
≤2.5 × the upper limit of normal of the 
center (ULN)
ALT
≤2.5 × ULN
Total bilirubin
≤1.5 × ULN
Serum creatinine
Creatinine clearance ≥60 mL/min, as 
calculated using the modified Cockcroft 
Gault equation*
In case of creatinine clearance ≥50 mL/min 
and <60 mL/min, as calculated using the 
above equation, the subject may be 
enrolled if the serum creatinine level is 
≤1.5 × ULN.
Prothrombin time-
international normalized ratio 
(PT-INR)
≤1.5 × ULN
Activated partial 
thromboplastin time (aPTT)
≤1.5 × ULN
*: ([140 −age (year)] × [actual weight (kg)]) / [72 × serum creatinine 
(mg/dL)] (× 0.85 [if female])
7.
Able to take the following interval during the period from 
the last dose or last procedure of prior therapy to the start 
day of treatment with the study drug (study treatment) in this 
study.
x
Cytotoxic drugs: 2 weeks (48 hours for 
hydroxycarbamide used for the purpose of controlling 
the increase in white blood cells)
x
Non-cytotoxic drugs: At least 5 times the half-life of the 
drug
8.
Women of childbearing potential must have a negative 
pregnancy test at screening and must be willing to use highly 
effective birth control (eg, barrier contraceptives with 
spermicides, intrauterine device) during the following 
period: Upon enrollment, during the treatment period, and 
for at least 95 days after the last dose of DS-3032b.
Women of childbearing potential are those in the period 
from first menstruation to menopause (no menstrual period 
for a minimum of 12 months). This, however, shall exclude 
permanently (surgically) sterile women.
9.
Males must be surgically sterile or willing to use highly 
effective birth control upon enrollment, during the treatment 
period, and for at least 95 days after the last dose of 
DS-3032b. Male subjects may not donate their sperm during 
the study period and for at least 95 days after the last dose of 
DS-3032b.
10. Able to be hospitalized during the dose-limiting toxicity 
(DLT) evaluation period.


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Study Population
(Inclusion and Exclusion 
Criteria)
Exclusion criteria
1.
Diagnosis of acute promyelocytic leukemia.
2.
Chronic myeloid leukemia in blast crisis (positive for a 
breakpoint cluster region- c-Abelson [BCR-ABL] fusion 
gene).
3.
History of or concurrent central nervous system leukemia.
4.
History of hematopoietic stem cell transplant (HSCT) and
meeting any of the following:
x
Transplantation within 60 days before the start of study 
treatment
x
Persistent graft-versus-host disease (GVHD) that is 
clinically significant, requires the start of treatment, or 
requires intensification of treatment within 21 days 
before informed consent
x
Persistent Grade ≥2 clinically significant or irreversible 
non-hematological toxicity related to transplantation
5.
Uncontrolled infection requiring intravenous antibiotics, 
antifungals, or antivirals.
6.
A positive test result for hepatitis C virus (HCV) antibody or 
human immunodeficiency virus (HIV) antibody within 90 
days before enrollment.
7.
A positive test result for hepatitis B surface (HBs) antigen
within 90 days before enrollment.
8.
A positive test result for hepatitis B core (HBc) antibody or 
HBs antibody with hepatitis B virus (HBV)-DNA levels 
≥2.1 log copies/mL, despite a negative test result for HBs 
antigen, within 90 days before enrollment.
9.
Receiving strong cytochrome P450 (CYP) 3A inhibitors 
within 7 days before the start of study treatment.
10. Receiving strong CYP3A inducers within 14 days before the 
start of study treatment.
11. History of or current cardiovascular disease as specified 
below:
x
QT corrected for heart rate using Fridericia’s method 
(QTcF) interval >450 ms, determined as the average of 
triplicate electrocardiogram (ECG) measurements taken 
within 14 days before enrollment in this study
x
Class III or more severe congestive heart failure 
according to “Appendix 3 New York Heart Association 
(NYHA) Functional Classification” within 6 months 
before enrollment in this study
x
History of myocardial infarction within 6 months before 
enrollment in this study
x
History of angina pectoris attack within 6 months before 
enrollment in this study


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x
History of arrhythmia requiring treatment within 6 
months before enrollment in this study
x
Need for a pacemaker or implantable cardioverter 
defibrillator
x
Diagnosed or suspected congenital long QT syndrome
x
History of life-threatening ventricular arrhythmia
(ventricular tachycardia, ventricular fibrillation, or 
torsades de pointes)
x
History of bradyarrhythmia (eg, atrioventricular block)
x
Clinically significant electrolyte abnormalities that can 
induce secondary long QT syndrome
x
Uncontrolled hypertension despite pharmacotherapy etc.
12. Adverse drug reactions (excluding alopecia) to previous 
therapy (treatment for AML and/or anticancer therapy),
which have not resolved or returned to Grade 1 or baseline.
Patients with chronic Grade 2 adverse drug reactions (eg, 
chemotherapy-induced neuropathy) may be eligible when the 
investigator or subinvestigator decides that there are no 
clinical safety concerns from the standpoint of the patient’s 
safety.
* The grade will be assessed according to the “Common 
Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0.”
13. History of another malignant tumor requiring treatment 
within 2 years before enrollment in this study.
However, patients whose disease is considered to have been 
cured by local treatment (eg, non-melanoma skin cancer, 
superficial bladder cancer, or carcinoma in situ of the cervix 
or breast) may be eligible for participation in the study.
14. Predisposition to serious infection (eg, cystic fibrosis, 
congenital or acquired immunologic disease, hemorrhagic 
disease, or cytopenia unrelated to AML).
15. Disseminated intravascular coagulation or other clinically 
significant coagulation abnormalities.
16. Extensive surgery within 28 days before the start of study 
treatment.
17. Radiation therapy within 28 days before the start of study 
treatment.
18. Any factor that could preclude adequate absorption of 
DS-3032b (eg, refractory nausea and vomiting, 
malabsorption, biliary shunt, significant bowel resection, 
and/or GVHD affecting the gut).
19. Pregnant or breastfeeding women.
20. Patients who are otherwise considered ineligible for the 
study in the opinion of the investigator or subinvestigator.




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x
From 14 days before the start of study treatment to the day of 
the Follow-up:
Strong CYP3A inducers and St. John’s wort-containing 
foods and supplements
x
From 7 days before the start of study treatment to the day of 
the Follow-up:
Strong CYP3A inhibitors and grapefruit-containing foods 
and beverages
Restricted concomitant drugs:
x
Hydroxycarbamide should be used as per the following 
instructions.
Use of hydroxycarbamide is prohibited during the period 
from 48 hours before treatment with DS-3032b to the start of 
treatment with DS-3032b.  It is, however, allowed to 
concomitantly use hydroxycarbamide to control white blood 
cell counts at doses up to 5 g/day for a total of 8 days or less 
only during the period from after the start of treatment with
DS-3032b to the end of the Follow-up.
x
Prophylactic treatment for the following symptom is 
prohibited during the DLT evaluation period. However, 
treatment given as supportive care for the following 
symptom is allowed.
Neutropenia: Granulocyte colony stimulating factor (G-CSF) 
products etc.
Study procedures:
Refer to Appendix 1.
Study Endpoints:
Safety endpoints:
Adverse events (AE), ECOG PS, laboratory data, body weight, 
vital signs, and 12-lead ECG
Efficacy endpoints:
Complete remission (CR), CR with incomplete hematological 
recovery (CRi), CR with partial hematological recovery (CRh),
partial remission (PR), morphologic leukemia-free state (MLFS),
stable disease (SD), progressive disease (PD), composite CR
(CRc) rate (CR + CRi + CRh), response rate (CRc + PR), and 
duration of CRc
Pharmacokinetic endpoints:
Plasma DS-3032a concentration and pharmacokinetic parameters 
(Subtrial A)
C1D1 (Cycle 1 Day 1): Cmax, Tmax, AUClast, AUC8h,
AUC24h, AUCinf*, Kel*, t1/2*, CL/F*, Vz/F*
C1D14 (Cycle 1 Day 14)**: Cmax, Ctrough, Cavg, Tmax,
AUC8h, AUC24h, Kel*, t1/2*, CLss/F***, Vz/F*,***, AR


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*: To be calculated only if possible.
**: To be read as C1D7 (Cycle 1 Day 7) in Subtrial B, C1D3
(Cycle 1 Day 3) in Subtrial C, and C1D15 (Day 15) in 
Subtrial D.
***: Not to be calculated because steady state will not be 
reached in Subtrial C.
Pharmacodynamic endpoints:
Tumor protein p53 gene (TP53) mutation and serum macrophage 
inhibitory cytokine-1 (MIC-1) level
Primary statistical analyses:
Safety analyses:
The DLT rate will be estimated for each dose using mCRM
based on DLT evaluation data of all evaluable subjects, and the 
MTD will then be determined.  AEs that occur or worsen after 
the start of study treatment will be summarized in frequency 
tables by event, causality with the study drug, and grade 
according to the CTCAE. For laboratory data, vital signs, body 
weight, and 12-lead ECGs, a frequency table or shift table will 
be prepared for categorical data and summary statistics will be 
calculated for quantitative data.  Also, frequency table(s) with 
detailed descriptions of DLTs (if any) will be prepared.
Efficacy analyses:
Frequency tables will be prepared for best response. The CRc 
rate, response rate, and transplantation rate will be calculated.
Summary statistics will be calculated for the duration of CRc.
Pharmacokinetic analyses:
Pharmacokinetics will be analyzed for each subtrial. Summary 
statistics of plasma concentrations of DS-3032a will be 
calculated by dose at each time point, and a plasma 
concentration-time profile will be prepared.
For the pharmacokinetic parameters that are calculated by the 
non-compartmental analysis, summary statistics will be 
calculated by dose.
Pharmacodynamic analyses:
For PDy values and PDy parameters, summary statistics will be 
calculated by treatment group.
Adaptive design: Present
Withdrawal Criteria of the 
Study:
Subjects will be withdrawn from the study for the following 
reasons.
1.
Apparent progression of the disease is found.
2.
It becomes difficult to continue the study treatment due to 


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AEs (refer to “Section 5.5 Actions to be Taken for Adverse 
Events”).
3.
A TP53 mutation is detected after study treatment and it is 
decided inappropriate to continue the study for the subject.
4.
The subject is found to be ineligible for the study after 
enrollment in the study.
5.
The subject withdraws his/her consent to participation in the 
study.
6.
The sponsor decides to prematurely terminate the study.
7.
The subject has received the study drug on less than 75% of 
the specified number of dosing days in Cycle 1.
8.
Other cases that the investigator or subinvestigator judges it 
inappropriate to continue the study for the subject.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................................2 
TABLE OF CONTENTS...............................................................................................................11 
LIST OF TABLES.........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................19 
LIST OF ABBREVIATIONS........................................................................................................19 
LIST OF PHARMACOKINETIC PARAMETERS......................................................................21 
LIST OF TERMS...........................................................................................................................22 
1. 
INTRODUCTION ........................................................................................................23 
1.1. 
Background of This Study ............................................................................................23 
1.2. 
Summary of Significant Findings Obtained from Nonclinical Studies ........................24 
1.2.1. 
Pharmacology................................................................................................................24 
1.2.2. 
Safety Pharmacology ....................................................................................................25 
1.2.3. 
Pharmacokinetics and Drug Metabolism ......................................................................26 
1.2.4. 
Toxicology ....................................................................................................................27 
1.3. 
Summary of Significant Findings Obtained from Previous Clinical 
Studies...........................................................................................................................28 
1.3.1. 
Overseas Phase 1 Studies (Study DS3032-A-U101 and Study 
DS3032-A-U102)..........................................................................................................28 
1.3.2. 
Japanese Phase 1 Study (Study DS3032-A-J103).........................................................29 
1.4. 
Known and Foreseeable Risks ......................................................................................30 
2. 
STUDY OBJECTIVES.................................................................................................32 
3. 
STUDY DESIGN..........................................................................................................33 
3.1. 
Starting Dose in Each Subtrial......................................................................................33 
3.2. 
Explorative Dose Finding in Each Subtrial...................................................................34 
4. 
STUDY POPULATION ...............................................................................................35 
4.1. 
Selection of Subjects.....................................................................................................35 
4.1.1. 
Inclusion Criteria...........................................................................................................35 
4.1.2. 
Exclusion Criteria .........................................................................................................36 
4.1.3. 
Registration of Subjects ................................................................................................39 
4.1.3.1. 
Flow of Subject Registration.........................................................................................39 


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4.1.3.2. 
Notifying Any Other Physicians Treating Subjects of Their Study 
Participation ..................................................................................................................40 
4.2. 
Subject Withdrawal Criteria and Procedure at Withdrawal..........................................40 
5. 
METHODOLOGY........................................................................................................41 
5.1. 
Study Drug ....................................................................................................................41 
5.1.1. 
Labeling and Packaging................................................................................................41 
5.1.2. 
Storage of the Study Drug.............................................................................................41 
5.2. 
Method of Study Treatment ..........................................................................................42 
5.2.1. 
Dose ..............................................................................................................................42 
5.2.2. 
Regimen ........................................................................................................................42 
5.2.3. 
Rationale for the Dose and Regimen ............................................................................43 
5.2.4. 
Randomization and Blinding ........................................................................................43 
5.3. 
Definition of Dose-limiting Toxicities and Maximum Tolerated Dose........................43 
5.3.1. 
Definition of Dose-limiting Toxicities..........................................................................43 
5.3.2. 
Definition of Maximum Tolerated Dose.......................................................................44 
5.3.3. 
Study Treatment to Subjects in Each Cohort and Procedure for 
Proceeding to the Next Cohort......................................................................................45 
5.4. 
Enrollment of Additional Subjects................................................................................45 
5.5. 
Actions to be Taken for Adverse Events ......................................................................45 
5.5.1. 
Occurrence of Dose-limiting Toxicities or Toxicities Equivalent to the 
Definition of Dose-limiting Toxicities after Cycle 1....................................................45 
5.5.2. 
Occurrence of the Following Toxicities Not Listed in Section 5.5.1 ...........................46 
5.6. 
Withdrawal Criteria.......................................................................................................46 
5.7. 
Prohibited Concomitant Drugs and Therapies, and Restricted 
Concomitant Drugs .......................................................................................................47 
5.7.1. 
Prohibited Concomitant Drugs and Therapies..............................................................47 
5.7.2. 
Restricted Concomitant Drugs......................................................................................47 
5.8. 
Symptomatic Therapy...................................................................................................48 
5.9. 
Management of Subjects...............................................................................................48 
6. 
STUDY PROCEDURES ..............................................................................................49 
6.1. 
List of Study Procedures...............................................................................................49 
6.2. 
Study Procedures before Registration of Subjects........................................................49 
6.3. 
Procedures During the Study Conduct Phase ...............................................................51 
6.3.1. 
Subtrial A (14/28 Day Schedule)..................................................................................51 


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6.3.2. 
Subtrial B (7/28 Day Schedule) ....................................................................................55 
6.3.3. 
Subtrial C (3/14 Day × 2 Schedule)..............................................................................59 
6.3.4. 
Subtrial D (21/28 Day Schedule)..................................................................................64 
6.4. 
Procedures at Study Discontinuation ............................................................................68 
6.5. 
Examination Items during the Follow-up Period and the Time Points.........................68 
6.6. 
Subsequent AML treatment ..........................................................................................69 
6.7. 
Pharmacokinetics ..........................................................................................................69 
6.8. 
Biomarker Study ...........................................................................................................73 
6.8.1. 
Handling of Specimens for Biomarker Study...............................................................74 
6.8.1.1. 
Blood and Bone Marrow...............................................................................................74 
6.8.1.2. 
Serum ............................................................................................................................74 
6.8.2. 
Anonymization, Storage, and Disposal of Specimens for Biomarker 
Study .............................................................................................................................75 
6.8.2.1. 
Anonymization of Specimens .......................................................................................75 
6.8.2.2. 
Storage of Specimens....................................................................................................75 
6.8.2.3. 
Disposal of Specimens..................................................................................................75 
6.9. 
Long-term Storage (Banking) of Clinical Specimens for Genome/Gene 
Analysis.........................................................................................................................76 
6.9.1. 
Specimens to be Banked ...............................................................................................76 
6.9.2. 
Collection of Oral Mucosa............................................................................................76 
6.9.3. 
Storage Period...............................................................................................................76 
6.9.4. 
Disclosure of Results of Genome/Gene Analysis Using Banking 
Specimens .....................................................................................................................77 
6.9.5. 
Disposal of Banking Specimens ...................................................................................77 
7. 
PHARMACOKINETIC ENDPOINTS.........................................................................78 
8. 
PHARMACODYNAMIC ENDPOINTS......................................................................79 
9. 
SAFETY ENDPOINTS ................................................................................................80 
9.1. 
Definition of Adverse Events........................................................................................80 
9.2. 
Definition of Serious Adverse Events...........................................................................80 
9.3. 
Adverse Event Information to be Reported ..................................................................81 
9.4. 
Definition of Adverse Drug Reactions..........................................................................83 
9.5. 
Actions to be Taken for Adverse Events ......................................................................83 
9.5.1. 
Recommended Action for Adverse Events...................................................................83 


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9.5.2. 
Action for Serious Adverse Events...............................................................................83 
9.6. 
Actions to be Taken in the Event That Information on Pregnancy, 
Pregnant and Parturient Women, and Delivery is Obtained .........................................83 
10. 
EFFICACY ENDPOINTS ............................................................................................84 
10.1. 
Definition of Efficacy Endpoints ..................................................................................84 
10.2. 
Best Response ...............................................................................................................85 
10.3. 
Duration of Composite Complete Remission ...............................................................85 
11. 
STATISTICAL ANALYSIS.........................................................................................86 
11.1. 
General Statistical Considerations ................................................................................86 
11.2. 
Analysis Sets.................................................................................................................86 
11.2.1. 
Safety Analysis Set .......................................................................................................86 
11.2.2. 
Maximum Tolerated Dose Analysis Set .......................................................................86 
11.2.3. 
Efficacy Analysis Set....................................................................................................87 
11.2.4. 
Pharmacokinetic Analysis Set.......................................................................................87 
11.2.5. 
Biomarker Analysis Set ................................................................................................87 
11.3. 
Data Handling ...............................................................................................................87 
11.4. 
Statistical Analysis Items and Methods ........................................................................87 
11.4.1. 
Baseline Subject Characteristics ...................................................................................87 
11.4.2. 
Safety Analysis .............................................................................................................87 
11.4.2.1. Adverse Events .............................................................................................................87 
11.4.2.2. Dose-limiting Toxicity..................................................................................................88 
11.4.2.3. Laboratory Data ............................................................................................................88 
11.4.2.4. Height, Body Weight, and Vital Signs (Blood Pressure, Pulse Rate, 
and Body Temperature) ................................................................................................88 
11.4.2.5. Electrocardiogram.........................................................................................................88 
11.4.3. 
Efficacy Analysis ..........................................................................................................89 
11.4.4. 
Pharmacokinetic Analysis.............................................................................................89 
11.4.5. 
Pharmacodynamic Analysis..........................................................................................89 
11.4.6. 
Other Analyses..............................................................................................................89 
11.5. 
Changes to the Analysis Plan........................................................................................89 
11.6. 
Planned Sample Size.....................................................................................................90 
11.7. 
Details of Modified Continual Reassessment Method..................................................90 
11.7.1. 
Bayesian Logistic Regression Model............................................................................90 


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11.7.2. 
Prior Distribution of Bayesian Logistic Regression Model..........................................90 
11.7.3. 
Recommended Dose for the Next Cohort by Bayesian Logistic 
Regression Model Incorporating the Escalation with Overdose Control 
Principle ........................................................................................................................91 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE............................................92 
13. 
PAYMENT FOR PARTICIPATION, COMPENSATION FOR 
STUDY-RELATED INJURIES, AND INSURANCE.................................................93 
13.1. 
Payment for Participation..............................................................................................93 
13.2. 
Compensation for Study-related Injuries ......................................................................93 
13.3. 
Insurance .......................................................................................................................93 
14. 
PUBLICATION POLICY.............................................................................................94 
15. 
STUDY ADMINISTRATIVE INFORMATION .........................................................95 
15.1. 
Ethics.............................................................................................................................95 
15.1.1. 
Ethical Conduct of the Study ........................................................................................95 
15.1.2. 
Institutional Review Board ...........................................................................................95 
15.2. 
Subject Confidentiality .................................................................................................95 
15.3. 
Procedures for Informed Consent .................................................................................95 
15.4. 
Informed Consent for Biomarker Study........................................................................97 
15.5. 
Informed Consent for Storage (Banking) of Specimens for 
Genome/Gene Analysis.................................................................................................98 
15.6. 
Provision of New Information Affecting the Conduct of the Study.............................98 
15.7. 
Planned Study Period....................................................................................................98 
15.8. 
Protocol Amendment ....................................................................................................99 
15.9. 
Permanent or Temporary Discontinuation of the Study ...............................................99 
15.10. 
Procedures for Preparing the Case Report Form and Remarks ....................................99 
15.10.1. Style of the Case Report Form......................................................................................99 
15.10.2. Completion of the Case Report Forms........................................................................100 
15.10.3. Signature or Seal with Printed Name Applied to the Case Report Form....................100 
15.10.4. Changes or Corrections to the Case Report Form.......................................................101 
15.11. 
Retention of Source Documents and Other Records ..................................................101 
15.11.1. Definition of Source Documents.................................................................................101 
15.11.2. Record Keeping...........................................................................................................101 
15.11.2.1. Institutional Review Board .........................................................................................101 
15.11.2.2. Study Center................................................................................................................101 


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15.11.2.3. Sponsor........................................................................................................................102 
15.12. 
Source Document Verification....................................................................................102 
15.13. 
Organization................................................................................................................102 
16. 
REFERENCES............................................................................................................103 
17. 
APPENDICES ............................................................................................................105 
Appendix 1...................................................................................................................................106 
Appendix 2...................................................................................................................................114 
Appendix 3...................................................................................................................................115 


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LIST OF TABLES
Table 5.1.1: Descriptions on the Labeling of the Study Drug.....................................................41 
Table 6.7.1: Blood Collection Points for Pharmacokinetic Assessment.....................................70 
Table 6.8.1: Serum Collection Points..........................................................................................74 
Table 9.3.1: Adverse Event Information to be Reported ............................................................82 
Table 10.1.1: Definition of Efficacy Endpoints ..........................................................................84 
Table 15.10.1: EDC System......................................................................................................100 


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LIST OF FIGURES
Figure 3.1: Combinations of Doses and Dosing Schedules ..........................................................33 
Figure 4.1-1: Subject Registration Procedure .............................................................................40 
Figure 5.2-1: Dosing Schedules in Each Subtrial........................................................................43 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
LIST OF ABBREVIATIONS
ABBREVIATION
DEFINITION
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BCR-ABL
breakpoint cluster region- c-Abelson
BLRM
Bayesian logistic regression model
BUN
blood urea nitrogen
CFU-GM
colony forming unit-granulocyte/macrophage
CHL
Chinese hamster lung
CML
chronic myelogenous leukemia
CR
complete remission
CRc
composite CR
CRh
CR with partial hematological recovery
CRi
CR with incomplete hematological recovery
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capturing
EWOC
escalation with overdose control
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI50
concentration causing 50% growth inhibition
GVHD
graft-versus-host disease


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ABBREVIATION
DEFINITION
HBc
hepatitis B core
HBs
hepatitis B surface
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-a-go-go related gene
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
HSCT
hematopoietic stem cell transplantation
ICa (IC50, IC75, IC90)
concentration causing a% inhibition
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IRB
Institutional Review Board
mCRM
modified continual reassessment method
MDM2
murine double minute 2
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MIC-1
macrophage inhibitory cytokine-1
MLFS
morphologic leukemia-free state
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
NOAEL
no observed adverse effect level
NRU
neutral red uptake
NYHA
New York Heart Association
PD
progressive disease 
PDy
pharmacodynamic(s)
PGx
pharmacogenomic(s)
PIF
photo irritation factor
PK
pharmacokinetic(s)
PR
partial remission
PS
performance status
PT
preferred term
PT-INR
prothrombin time-international normalized ratio


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ABBREVIATION
DEFINITION
qd
once daily
QT
interval between the start of the Q wave and the end of the T wave
QTcB
QT corrected for heart rate using Bazett’s formula
QTcF
QT corrected for heart rate using Fridericia’s method
RP2D
recommended phase 2 dose
SAVER
serious adverse event report
SD
stable disease
SOC
system organ class
STD10
severely toxic dose in 10% of the animals
TEAE
treatment emergent adverse event
TP53
tumor protein p53 gene
WHO
World Health Organization
LIST OF PHARMACOKINETIC PARAMETERS
ABBREVIATION
DEFINITION
AR
observed accumulation ratio
AUC
area under the plasma concentration-time curve
AUC8h
area under the plasma concentration-time curve during 8 hours
AUC24h
area under the plasma concentration-time curve during 24 hours
AUCinf
area under the plasma concentration-time curve up to infinity
AUClast
area under the plasma concentration-time curve up to the last 
quantifiable time
Cavg
average plasma concentration
Cmax
maximum plasma concentration
Ctrough
trough plasma concentration
CL/F
apparent total body clearance
CLss/F
apparent total body clearance at steady state
Kel
apparent terminal elimination rate constant
t1/2
terminal elimination half-life
Tmax
time to reach maximum plasma concentration
Vz/F
apparent volume of distribution based on the terminal phase


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LIST OF TERMS
TERMS
DEFINITION
DS-3032b
Development code of milademetan
DS-3032a
Free form of DS-3032b
DOHH-2
B-cell lymphoma cell line
MOLM-13
Human acute myeloid leukemia cell line
RG7112
MDM2 antagonist
RG7388
MDM2 antagonist
SAR405838
MDM2 antagonist
SJSA-1
Osteosarcoma cell line
WM-115
Melanoma cell line


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1.
INTRODUCTION
1.1.
Background of This Study
Acute myeloid leukemia (AML) is a hematological malignant tumor characterized by 
autonomous growth of myeloid blast cells (myeloblasts) that are unable to differentiate or 
further develop into mature white blood cells, and its clinical presentation is diverse.1
According to “Cancer Registration and Statistics” of the Cancer Information Service, 
National Cancer Center, the crude prevalence rate of leukemia is 9.6 (11.4 for males and 
7.9 for females) per 100,000 people in 2011 and it is increasing each year.2 The 
prevalence rate of AML by itself is unknown; however, acute leukemia accounts for 
about 80% of all leukemias, and AML accounts for approximately 80% of adult acute 
leukemia cases and 20% of pediatric acute leukemia cases.3 While AML has become a 
disease that is considered curable in recent years, the long-term survival rate after 
complete remission (CR) with chemotherapy in AML patients remains low at about 
40%.4 At present, there are no molecular targeting drugs that can be used for newly 
diagnosed AML patients, and the relapse rate still remains high. In Japan, relapsed or 
refractory AML patients are treated with monotherapy or combination therapy with 
cytarabine, mitoxantrone, etoposide, fludarabine, aclarubicin, gemtuzumab ozogamicin, 
and others.  None of these therapies, however, provide an adequate therapeutic effect, or 
no standard treatment has been established for these patients.5 Accordingly, how to 
prevent relapse is a major concern for chemotherapy.
The tumor suppressor protein p53 plays an essential role in preventing neoplasia by 
inducing cell cycle arrest or apoptosis in cells undergoing various types of physiological 
stress.  The activity of p53 can be lost due to its mutations or defects but is frequently 
inhibited by intermolecular interactions between p53 and murine double minute 2 
(MDM2) in human tumors harboring wild-type p53. In normal cells, p53 is controlled by
MDM2. MDM2 promotes p53 nuclear export or degradation of p53 through the 
ubiquitin proteasome pathway, and thereby maintains low levels of p53 activity.6 It has 
also been reported that p53 becomes activated in the presence of stress, and subsequently 
acts as a transcription factor that modulates the expression of a variety of genes, 
including MDM2.7
In humans, the balance between MDM2 and p53 is disrupted by overexpression and/or 
oncogenic activation of MDM2, which reduces p53 function, potentially allowing 
tumorigenesis and tumor growth.  Pharmacologic inhibition of the interaction between 
MDM2 and p53 in tumor cells harboring wild-type p53 could therefore result in a
sustained increase in p53 activity and subsequent antitumor effects.8,9 Therefore, MDM2
is considered to become a treatment target for various forms of malignant tumors.10
Approximately 90% of AML patients retain wild-type tumor protein p53 gene (TP53) in 
their leukemia cells, in which p53 activity is maintained at a low level by binding of 
overexpressed MDM2.11
DS-3032b is a small-molecule inhibitor of MDM2 that disrupts interactions between 
MDM2 and the tumor suppressor protein p53 in tumor cells, and is being developed as an 
oral drug for the treatment of cancer by Daiichi Sankyo Co., Ltd.


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In vitro studies demonstrated that DS-3032b inhibits the MDM2-p53 interaction and 
induces p53 target gene expression.  In the study of DS-3032b for tumor growth 
inhibition in 6 human cancer cell lines with different p53 status, DS-3032b exhibited p53 
status-dependent antitumor effects.  DS-3032b demonstrated more potent antitumor 
effects in the p53 wild-type cell line than the positive control Nutlin-3a, known as a 
small-molecule MDM2 inhibitor.  In in vivo studies in male nude mice subcutaneously 
inoculated with SJSA-1 human osteosarcoma cell line, orally given DS-3032b exhibited 
dose-dependent antitumor effects.  In a study that evaluated the antitumor effects of 
DS-3032b in combination with either quizartinib or 5-azacytidine in male mice 
subcutaneously inoculated with human acute myeloid leukemia cell line (MOLM-13),
DS-3032b exhibited antitumor effects when used as a single agent or in combination with 
quizartinib or 5-azacytidine.
Based on the above results, DS-3032b is considered to have the potential to become a 
new drug for the treatment of hematological cancers including AML, and a clinical study 
was planned. A Phase 1 study of DS-3032b in subjects with advanced hematological 
cancers including AML is currently underway in the US.  To date, decreases in 
myeloblasts and CR have been achieved in several subjects treated with DS-3032b
monotherapy in the study.
Accordingly, it was decided to start clinical development of DS-3032b in Japan, and this 
study was planned to evaluate the safety and pharmacokinetics of DS-3032b
monotherapy in subjects with relapsed or refractory AML.
1.2.
Summary of Significant Findings Obtained from Nonclinical 
Studies
1.2.1.
Pharmacology
In vitro studies demonstrated that DS-3032b inhibits the MDM2-p53 interaction and 
induces p53-dependent gene expression.  In the study that evaluated potential tumor 
growth inhibition of DS-3032b in 6 human cancer cell lines with different p53 status,
DS-3032b exhibited superior growth inhibitory effects in the human p53 wild-type acute 
leukemia cell line (MOLM-13), B-cell lymphoma cell line (DOHH-2), osteosarcoma cell 
line (SJSA-1), and melanoma cell line (WM-115) at lower doses, compared with Nutlin-
3a.  On the other hand, no growth inhibition of DS-3032b was observed in the 
p53 mutant or null cell line.  These results demonstrated that DS-3032b exhibits 
antitumor effects p53 status-dependently and exerts more potent antitumor effects than 
Nutlin-3a in cancer cells harboring wild-type p53.
In vivo studies in male nude mice subcutaneously inoculated with SJSA-1 human
osteosarcoma cell line demonstrated that DS-3032b exhibits dose-dependent antitumor 
effects.  In the study that evaluated schedule-dependent effects (3 dosing schedules of
DS-3032b at a total of 250 mg/kg [25 mg/kg once daily for 10 days [qd × 10],
62.5 mg/kg every 3 days, 4 times in 12 days [q3d × 4], or 125 mg/kg every 7 days, twice
in 2 weeks [q7d × 2]), DS-3032b exhibited antitumor effects with all the dosing 
schedules, with no difference in the antitumor effects among the dosing schedules.


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Furthermore, DS-3032b was assessed for potential in vivo antitumor effects when used in 
combination with either quizartinib or 5-azacytidine in male mice subcutaneously 
inoculated with MOLM-13. In the assessment of the combination of DS-3032b and 
quizartinib both given orally once daily for 11 days (qd × 11), tumor growth inhibition of 
DS-3032b as a single agent was 27.3% and 60.5% in the 25 mg/kg/dose and 
50 mg/kg/dose groups, respectively.  Tumor growth inhibition of quizartinib as a single 
agent was 17.8% and 53.3% in the 0.5 mg/kg/dose and 1 mg/kg/dose groups, respectively.  
Tumor growth inhibition of DS-3032b in combination with quizartinib was 61.7% in the 
25 mg/kg/dose + 0.5 mg/kg/dose group, 91.2% in the 50 mg/kg/dose + 0.5 mg/kg/dose
group, 85.6% in the 25 mg/kg/dose + 1 mg/kg/dose group, and 97.5% in the 
50 mg/kg/dose + 1 mg/kg/dose group.  Estimated tumor volume was significantly lower
in individual DS-3032b and quizartinib combination groups than in individual single gent 
groups of DS-3032b and quizartinib.
In the assessment of the combination of DS-3032b (orally given once daily for 11 days) 
and 5-azacytidine (intravenously given once daily for 5 days), tumor growth inhibition of 
DS-3032b as a single agent was 46.4% and 80.3% in the 25 mg/kg/dose and
50 mg/kg/dose groups, respectively, and tumor growth inhibition of 5-azacytidine as a 
single agent (4 mg/kg/dose) was 49.9%. Tumor growth inhibition of DS-3032b in
combination with 5-azacytidine was 75.4% in the 25 mg/kg/dose + 4 mg/kg/dose group 
and 94.8% in the 50 mg/kg/dose + 4 mg/kg/dose group.  Estimated tumor volume was 
significantly lower in individual DS-3032b and 5-azacytidine combination groups than in 
individual single agent groups of DS-3032b and 5-azacytidine.
1.2.2.
Safety Pharmacology
DS-3032b was assessed for potential effects on the cardiovascular, respiratory, and 
central nervous systems.
In the study that assessed the potential effects of DS-3032b on the cardiovascular system,
DS-3032b inhibited the human ether-a-go-go related gene (hERG) current at a
concentration of 2.6 μM, inferring that the concentration causing 50% inhibition (IC50) of
DS-3032b against hERG current is greater than 2.6 μM.  The statistically significant 
hERG current inhibitory concentration (2.6 μM) was approximately 200 times the 
maximum plasma concentration (Cmax; 0.013 μM) at the lethal dose of DS-3032a (free 
form), 460 times the IC50 value of DS-3032b for the MDM2-p53 interaction in vitro 
(0.00557 μM), and 9 to 60 times the concentration causing 50% growth inhibition (GI50)
values in in vitro pharmacology studies (0.043 μM to 0.276 μM). Moreover, the hERG 
channel was not significantly inhibited at 0.8 μM (approximately 60 times the free form 
Cmax at the lethal dose).  In telemeterized male beagle dogs, no effects on clinical signs,
or hemodynamic and electrocardiogram (ECG) parameters through 25 hours post-dose 
were observed at doses up to 10 mg/kg (lethal dose in a 4-week repeated-dose toxicity 
study). In addition, no effects on ECG parameters, heart rate, or waveform morphology 
(including corrected QT interval), as determined by surface leads, were seen in male or
female dogs given repeated oral doses of 3 mg/kg/day for 3 months.  These in vitro and 
in vivo data suggest a low potential risk on cardiovascular function in humans at 
DS-3032a exposures expected to be associated with clinical efficacy.


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Effects of DS-3032b on the central nervous system (CNS) were assessed on Day 3 in 
male Sprague Dawley rats given up to 1000 mg/kg/day. Transient and reversible 
DS-3032b-related effects on motor activity were observed in male rats given 
1000 mg/kg/day. However, the changes were relatively mild and were therefore assessed 
to be toxicologically insignificant.
Effects of DS-3032b on the pulmonary system were assessed on Day 1 in male Sprague 
Dawley rats given up to 1000 mg/kg/day.  Transient and reversible increases in 
respiratory rate were observed in male rats given 1000 mg/kg/day.  However, this effect 
was considered incidental because it was mild in severity and no statistically significant 
DS-3032b-related effects on minute volume were noted.
1.2.3.
Pharmacokinetics and Drug Metabolism
In pharmacokinetic studies, plasma DS-3032a concentrations were assessed in male and 
female Sprague Dawley rats and beagle dogs orally given DS-3032a or DS-3032b.
Exposures increased dose-dependently, and no accumulation of DS-3032a was noted 
after multiple dosing in either species, or rather, a decrease in exposures was found over 
time.
Pharmacokinetic exposures of DS-3032b in combination with anticancer drugs 
(quizartinib or 5-azacytidine) were assessed in in vivo pharmacology studies.  Following 
administration of DS-3032b in combination with quizartinib in tumor-bearing mice, 
exposures increased with increasing dose of both DS-3032a and quizartinib.  No apparent 
effect of drug-drug interactions between DS-3032a and quizartinib on exposures was 
observed.  Exposures to each of DS-3032a and quizartinib tended to decrease after 
multiple doses.  Following administration of DS-3032b in combination with 5-
azacytidine in tumor-bearing mice, exposures to DS-3032a increased with increasing 
dose.  No apparent effect of DS-3032b administration on 5-azacytidine exposure was 
observed.  DS-3032a exposures tended to decrease by 5-azacytidine administration.
DS-3032a highly binds to proteins in mouse, rat, dog, and human plasma.  Plasma protein 
binding was lowest in human plasma and was not concentration-dependent in all tested 
species.
DS-3032b was assessed for inhibition potential of human cytochrome P450 (CYP)
isoforms by measuring metabolic activity of isoform-specific substrates using pooled 
human liver microsomes.  DS-3032b showed direct inhibitory effects on CYP2A6, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, but not on CYP1A2
or CYP2E1.  DS-3032b also showed mild-to-moderate, metabolism-dependent inhibitory
effects on CYP3A4/5 but not on the other CYP isoforms tested in this study. Meanwhile,
DS-3032b was assessed for induction potential of CYP3A4, CYP1A2, and CYP2B6 
using freshly isolated human hepatocytes from 3 individual donors. DS-3032b did not 
markedly change the messenger ribonucleic acid (mRNA) levels or enzyme activity of 
CYP1A2.  DS-3032b weakly induced CYP3A4 as measured by mRNA levels and 
enzyme activity in 1 of 3 donors.  As for CYP2B6, treatment with DS-3032b did not 
increase the mRNA levels or the enzyme activity, but rather decreased both levels.  These 
data suggest that coadministered of DS-3032b with strong CYP3A4/5 inducers or 
inhibitors should be avoided in this Phase 1 study.


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1.2.4.
Toxicology
No serious toxicological changes were observed in rats given once-daily repeated oral 
doses up to 1000 mg/kg for 4 weeks.  All changes in blood chemistry tests and organ 
weight measurement were fairly mild, with no histopathological findings.  Therefore,
these changes were considered to be toxicologically insignificant and were reversible
during the recovery period.  In rats given repeated oral doses for 4 weeks, the no 
observed adverse effect level (NOAEL) of DS-3032b was 1000 mg/kg/day. At this dose, 
Cmax of DS-3032b on Day 28 of the dosing period was 4820 ng/mL in males and 
6627 ng/mL in females, and AUC24h was 57,719 ng·h/mL in males and 73,440 ng·h/mL
in females.  The severely toxic dose in 10% of the animals (STD10) of DS-3032b was 
considered to be greater than 1000 mg/kg/day in rats.
In a 3-month repeated-dose toxicity study in rats, weight loss and decreased food 
consumption were observed in males given 1000 mg/kg.  No treatment-related adverse
changes were observed in any of the other examinations or in females.  The NOAEL was 
300 mg/kg/day for males and 1000 mg/kg/day for females.  At the NOAEL, the mean 
Cmax and AUC24h values of DS-3032a on Day 91 of the dosing period were 
2700 ng/mL and 24,800 ng·h/mL, respectively, in males, and 5050 ng/mL and 
66,400 ng·h/mL, respectively, in females.
No serious toxicological changes were observed in dogs given once-daily, repeated oral 
doses up to 3 mg/kg for 4 weeks. In dogs given 10 mg/kg, weight loss was observed 
during the first week of the dosing period and clinical signs of toxicity (eg, emaciation, 
dehydration, hypoactivity, hunched position, decreased/no food consumption, 
liquid/unformed feces, and pyrexia) were also noted, and they were moribund and 
sacrificed on Day 11 or Day 12 of the dosing period, or on Day 4 of the recovery period.
In dogs sacrificed on Day 11 or Day 12, neutropenia was observed, and clinical 
pathology findings included pancytopenia with bone marrow suppression, hemorrhage in 
multiple organs, and lymphocyte depletion in lymphoid organs.  At lower doses 
(≤3 mg/kg), minimally to mildly decreased reticulocyte and platelet counts in males and 
females and transient decreases in white blood cell, neutrophil, and monocyte counts in 
males were observed on Day 12.  These changes were not observed on Day 19 or Day 26
of the dosing period or during the recovery period.  These slight and transient changes 
were therefore considered to be toxicologically insignificant. In dogs given repeated oral 
doses for 4 weeks, the NOAEL and the highest nonseverely toxic dose (HNSTD) of 
DS-3032b were 3 mg/kg/day. At this dose, Cmax of DS-3032b at Week 4 of the dosing 
period was 99.3 ng/mL in males and 84.9 ng/mL in females, and AUC24h was
973 ng·h/mL in males and 880 ng·h/mL in females.
In a 3-month repeated-dose toxicity study in dogs, one male in the 3 mg/kg group was 
found to have deteriorating conditions from Day 24 and was sacrificed on Day 27 of the
dosing period. Suppression of the bone marrow and immune system was detected as test
article-related histopathological changes, and this was considered to have caused
hematological changes including decreases in leukocyte parameters and platelet count,
and pathological changes including hemorrhage in several organs.  In surviving male and 
female animals, a decrease in platelet count was noted in the 3 mg/kg group. In dogs 
given once-daily, repeated oral doses for 3 months, the NOAEL of DS-3032b was 


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determined to be 1 mg/kg/day in both males and females.  The HNSTD of DS-3032b was 
considered to be 1 mg/kg/day for males and 3 mg/kg/day for females.  At the NOAEL, 
the mean Cmax and AUC24h values of DS-3032a on Day 91 of the dosing period were 
92.4 ng/mL and 1360 ng·h/mL, respectively, in males, and 94.7 ng/mL and 
1170 ng·h/mL, respectively, in females.
DS-3032b showed negative results in all genotoxicity studies, including the bacterial 
reverse mutation study, in vitro micronucleus study in Chinese hamster lung (CHL) cells, 
and in vivo rat bone marrow micronucleus study.  Accordingly, DS-3032b was concluded 
to have no genotoxic potential.
DS-3032b was found to be non-phototoxic in mouse (BALB/c 3T3 clone A31) 
fibroblasts using the neutral red uptake (NRU) assay, with a photo irritation factor (PIF)
value of 1.396.
DS-3032b was assessed for myelotoxic potential in an in vitro progenitor cell (colony 
forming unit-granulocyte/macrophage [CFU-GM]) toxicity study in canine and human 
bone marrow specimens.  DS-3032b inhibited CFU-GM with an IC50 of 32.2 nM, IC75 of
58.1 nM, and IC90 of 103.1 nM in canine bone marrow cultures, and with an IC50 of
220.2 nM, IC75 of 392.1 nM, and IC90 of 617.3 nM in human bone marrow cultures.  
Canine bone marrow was approximately 6- to 7-fold more sensitive to DS-3032b than
human bone marrow.
1.3.
Summary of Significant Findings Obtained from Previous 
Clinical Studies
1.3.1.
Overseas Phase 1 Studies (Study DS3032-A-U101 and Study 
DS3032-A-U102)
DS3032-A-U101 is a Phase 1, multicenter, open-label study of DS-3032b in subjects 
with solid tumors or lymphomas, which are refractory to standard therapies or for which 
no standard treatment is available.  This study consists of Part 1 (dose escalation) and 
Part 2 (dose expansion).  The objectives of Part 1 were to evaluate the safety and 
tolerability of DS-3032b and assess the maximum tolerated dose (MTD) or the 
recommended phase 2 dose (RP2D) of DS-3032b.  The objectives of Part 2 were to
evaluate preliminary tumor response in subjects with advanced melanoma and subjects 
with diffuse large B-cell lymphoma (DLBCL). As of 31 Oct 2016, 69 subjects have been 
treated with DS-3032b in this study (49 subjects in the dose escalation part [Part 1] and 
20 subjects in the dose expansion part [Part 2]), and 9 subjects are ongoing in the study.
In Part 1, DS-3032b was administered once daily on Days 1 to 21, followed by a 7-day 
rest, in a 28-day cycle (qd 21/28 day schedule), starting from 15 mg and escalating 
through 30, 60, 120, 160 and 240 mg, guided by a modified continual reassessment 
method (mCRM) incorporating the escalation with overdose control (EWOC) principle.
Dose-limiting toxicities (DLTs) were reported as Grade 4 thrombocytopenia and Grade 4
febrile neutropenia in 1 subject treated at 240 mg, and the study was continued at a 
reduced dose of 160 mg.  At 160 mg, DLTs were reported as Grade 3 anorexia, nausea, 
and vomiting in 1 subject and Grade 4 neutropenia and Grade 2 thrombocytopenia in 1 
subject.  As a result, the study was continued at a further reduced dose of 120 mg.  At 


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120 mg, DLTs were reported as Grade 4 thrombocytopenia in 1 subject and Grade 2
thrombocytopenia requiring dose interruption for more than 7 days in 1 subject.12 Based 
on these results, the MTD for the qd 21/28 day schedule was determined to be 120 mg.
Another dosing schedule was also evaluated in parallel where DS-3032b was 
administered in a 90 mg qd 28/28 day schedule.  Grade 3 thrombocytopenia was reported 
as DLT in 1 subject treated on this dosing schedule.12 The MTD for the qd 28/28 day 
schedule was therefore determined to be 90 mg. In the efficacy assessment, the best 
tumor response was stable disease (SD) in 27 of 35 subjects in Part 1 who had at least 
one post-dose tumor assessment.  However, none of the subjects in this study have 
achieved an objective response (CR or partial remission [PR]) to date.
DS3032-A-U102 was a Phase 1, multicenter, open-label study of DS-3032b.  This study,
consisting of Part 1 (dose escalation) and Part 2 (dose expansion), was conducted in 
subjects with advanced hematological malignant tumors (AML, acute lymphocytic 
leukemia [ALL], chronic myelogenous leukemia [CML], and high-risk myelodysplastic 
syndrome [MDS]) to evaluate the safety and tolerability of DS-3032b, to assess the MTD 
or RP2D of DS-3032b, and to evaluate the pharmacokinetics/pharmacodynamics of
DS-3032b. As of 17 Oct 2016, 37 subjects with AML or high-risk MDS have been
enrolled and treated with DS-3032b in the dose escalation part (Part 1), and the study is 
currently underway.  In Part 1, DS-3032b was administered once daily on Days 1 to 21,
followed by a 7-day rest, in a 28-day cycle (qd 21/28 day schedule), starting from 60 mg
and escalating through 90, 120, 160 and 210 mg, guided by mCRM with EWOC. DLTs
were reported as Grade 3 hypokalemia in 1 subject and Grade 3 diarrhea in 1 subject at 
160 mg.  At 210 mg, DLTs were reported as Grade 2 acute renal failure (less than 75% of 
the specified number of dosing days in Cycle 1), Grade 3 nausea and vomiting, and 
Grade 3 fatigue and anorexia in 1 subject each.13 Based on these results, MTD for the qd 
21/28 day schedule was determined to be 160 mg.  In the efficacy assessment, a decrease 
in bone marrow blasts (≥50% decrease from baseline in 10 of 15 subjects) was observed 
in 15 of 26 subjects who underwent bone marrow assessment 28 days after the first dose 
of DS-3032b (after the end of the first cycle).  CR was achieved in 2 subjects with 
relapsed or refractory AML who were treated with DS-3032b at 120 mg qd for 4 months 
or 160 mg qd for 13 months, and CR as determined by bone marrow assessment was 
achieved in 1 subject with high-risk MDS who was treated with DS-3032b at 120 mg qd
for 4 months.13
1.3.2.
Japanese Phase 1 Study (Study DS3032-A-J103)
DS3032-A-J103 is a Phase 1 dose-ascending study of DS-3032b in Japanese subjects 
with advanced solid tumors or lymphomas.  The objectives of the study were to evaluate
the safety and tolerability of DS-3032b, assess the MTD or RP2D of DS-3032b, and 
evaluate the pharmacokinetics and pharmacodynamics of DS-3032b.
In this study, DS-3032b was administered once daily on Days 1 to 21, followed by a 7-
day rest, in a 28-day cycle (qd 21/28 day schedule), starting from 60 mg and escalating 
through 90 mg and 120 mg, guided by mCRM with EWOC.  As of 31 Oct 2016, a total 
of 18 subjects have been enrolled and treated in the study, and the study is currently 
underway. DLTs were reported in subjects treated at 120 mg, and the MTD for the qd 
21/28 day schedule was determined to be 90 mg.


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1.4.
Known and Foreseeable Risks
DS-3032b was studied for potential toxicity in rats and dogs.  In the 4-week repeated-
dose toxicity study in rats, DS-3032b was well tolerated up to 1000 mg/kg (the highest 
dose tested).  In the 3-month oral dose study, DS-3032b was well tolerated up to 
300 mg/kg in males and 1000 mg/kg (the highest dose tested) in females. Weight loss 
and decreased food consumption were observed in males at 1000 mg/kg. In the 4-week 
repeated-dose toxicity study in dogs, DS-3032b was well tolerated at 3 mg/kg given as 
repeated oral doses.  DS-3032b given as repeated oral doses of 10 mg/kg/day (the highest 
dose tested) was associated with moribund condition in the observation of clinical signs, 
with neutropenia, moderate to severe pancytopenia with bone marrow suppression, 
hemorrhage in multiple organs, and lymphocyte depletion in lymphoid organs.  Effects 
on bone marrow and lymphoid tissues were predictable from pharmacology studies of 
DS-3032b.  These results showed the primary target effects of DS-3032b on the 
hematopoietic/lymphoid system in dogs.  In the 3-month repeated-dose toxicity study in 
dogs, DS-3032b was given as repeated oral doses of 3 mg/kg (the highest dose tested), 
and pancytopenia, suppression of the bone marrow and immune system, and hemorrhages 
in several organs were observed in 1 sacrificed male. In the surviving animals, a
decrease in platelet counts was noted in males and females in the 3 mg/kg group.
Several reports are available for clinical studies using drugs that inhibit the MDM2-p53
interaction.  According to published clinical data of MDM2 antagonists such as 
RG7112,14 RG7388,15 and SAR405838,16 adverse events (AE) of blood and lymphatic 
system disorders and gastrointestinal disorders have been reported.
In DS3032-A-U101, an overseas study in subjects with advanced solid tumors or 
lymphomas, treatment emergent adverse events (TEAEs) reported in more than 10% of a 
total of 69 subjects who have been treated as of 31 Oct 2016 were nausea in 47 subjects 
(68.1%), thrombocytopenia in 22 subjects (31.98%), platelet count decreased in 22
subjects (31.9%), fatigue in 35 subjects (50.7%), anaemia in 30 subjects (43.5%), 
diarrhoea in 27 subjects (39.1%), decreased appetite in 26 subjects (37.7%), white cell 
count decreased in 19 subjects (27.5%), leukopenia in 5 subjects (7.2%), neutropenia in 9
subjects (13.0%), neutrophil count decreased in 11 subjects (15.9%), vomiting in 20
subjects (29%), constipation in 16 subjects (23.2%), dysgeusia in 14 subjects (20.3%), 
cough in 14 subjects (20.3%), dyspnoea in 12 subjects (17.4%), headache in 11 subjects 
(15.9%), abdominal pain in 10 subjects (14.5%), dizziness and alopecia in 7 subjects 
(10.1%) each, and dry mouth and peripheral oedema in 9 subjects (13.0%) each.
Reported DLTs were Grade 4 thrombocytopenia and Grade 4 febrile neutropenia in 1 
subject in the 240 mg qd group (21/28 day schedule), and Grade 3 anorexia, nausea, and 
vomiting in 1 subject and Grade 4 neutropenia and Grade 2 thrombocytopenia in 1 
subject in the 160 mg qd group (21/28 day schedule). DLTs reported in the 120 mg qd
group (21/28 day schedule) were Grade 4 thrombocytopenia in 1 subject and Grade 2 
thrombocytopenia requiring dose interruption for more than 7 days in 1 subject.  Grade 3
thrombocytopenia was also reported in 1 subject in the 90 mg qd 28/28 day schedule.12
In DS3032-A-U102, an overseas study in subjects with advanced hematological 
malignant tumors, TEAEs reported in more than 10% of a total of 37 subjects who have 
been treated as of 17 Oct 2016 were nausea in 28 subjects (75.7%), diarrhoea in 21


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subjects (56.8%), fatigue in 16 subjects (43.2%), vomiting in 13 subjects (35.1%), 
thrombocytopenia in 13 subjects (35.1%), anaemia in 12 subjects (32.4%), decreased 
appetite in 10 subjects (27%), hypotension in 10 subjects (27%), hypokalaemia in 9
subjects (24.3%), neutropenia in 9 subjects (24.3%), febrile neutropenia,  pneumonia, 
hypomagnesaemia, and peripheral oedema in 6 subjects (16.2%) each, asthenia, dizziness,
and dyspnoea in 5 subjects (13.5%) each, and pyrexia, dehydration, and hyperuricemia in 
4 subjects (10.8%) each.  DLTs reported in the 160 mg qd group (21/28 day schedule) 
were Grade 3 hypokalemia in 1 subject and Grade 3 diarrhea in 1 subject.  DLTs reported 
in the 210 mg group (21/28 day schedule) were Grade 2 acute renal failure (less than 
75% of the specified number of dosing days in Cycle 1), Grade 3 nausea and vomiting, 
and Grade 3 fatigue and anorexia in 1 subject each.13 In DS3032-A-J103, a Japanese 
study in subjects with advanced solid tumors or lymphomas, TEAEs reported in more
than 10% of a total of 18 subjects who have been treated as of 31 Oct 2016 were nausea 
in 13 subjects (72.2%), decreased appetite in 11 subjects (61.1%), fatigue in 9 subjects 
(50%), white blood cell count decreased in 9 subjects (50%), hypoalbuminaemia in 7
subjects (38.9%), anaemia in 6 subjects (33.3%), platelet count decreased in 6 subjects
(33.3%), constipation, diarrhoea, and vomiting in 5 subjects (27.8%) each, hyponatremia, 
ALT increased, and AST increased in 4 subjects (22.2%) each, thrombocytopenia,
pyrexia, lymphocyte count decreased, neutrophil count decreased, and hypophosphatemia 
in 3 subjects (16.7%) each, and insomnia, cough, dry skin, proteinuria, and weight 
decreased in 2 subjects (11.1%) each. It is predicted from these results that DS-3032b
may cause AEs of gastrointestinal disorders and blood and lymphatic system disorders.  
Patients treated with DS-3032b should therefore be closely monitored throughout the 
study period, and if any of these AEs occur, measures should be taken immediately.
Nonclinical data also suggest that coadministration of DS-3032b with CYP3A4/5
inhibitors or inducers may confound the metabolism of DS-3032b.  Concomitant use of 
CYP3A4/5 inhibitors and inducers is therefore prohibited in this study.


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2.
STUDY OBJECTIVES
Primary Objective:
To evaluate the safety and tolerability of DS-3032b monotherapy administered as 
multiple doses and assess the MTD in Japanese subjects with relapsed or refractory AML.
Secondary Objectives:
x
To evaluate the pharmacokinetics of DS-3032a
x
To exploratively evaluate the antitumor effect of DS-3032b
Exploratory Objectives:
x
To evaluate the pharmacodynamic effect of DS-3032b on macrophage 
inhibitory cytokine-1 (MIC-1) levels in serum
x
To confirm if a TP53 mutation is present or not using bone marrow and blood 
specimens
x
To evaluate biomarker candidates related to the action mechanism of 
DS-3032b using bone marrow and blood specimens
x
To assess the recommended dose in subsequent phases of development


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3.
STUDY DESIGN
This is a Phase 1, multicenter, open-label uncontrolled study.  Combinations of doses and 
dosing schedules are shown in “Figure 3.1 Combinations of Doses and Dosing 
Schedules.” Four dose-finding Subtrials (Subtrials A, B, C, and D) of DS-3032b will be 
conducted by fixing the dosing schedule. The study will be started from Subtrial A, and 
other subtrials will be conducted as necessary.
In Subtrials A, B, and D, the study drug will be administered once daily (qd) on Days 1 to 
14, Days 1 to 7, and Days 1 to 21, followed by a 14-day, 21-day, and 7-day rest,
respectively, in a 28-day cycle.  In Subtrial C, the study drug will be administered once 
daily (qd) on Days 1 to 3, followed by a 11-day rest, in a 14-day subcycle, which will be 
repeated twice in a 28-day cycle.
Subjects must be hospitalized in Cycle 1, which is the DLT evaluation period.  The 
number of treatment cycles will not be specified, and the study treatment for each subject 
will be continued unless the criteria provided in “Section 5.6 Withdrawal Criteria ” are 
met.
The MTD will be determined for each subtrial (see “Section 5.3.2 Definition of 
Maximum Tolerated Dose”).
Figure 3.1:
Combinations of Doses and Dosing Schedules
Subtrial C
Subtrial B
Subtrial A
Subtrial D
Dose (mg)
160
C-3
B-3
A-3
D-3
120
C-2
B-2
A-2
D-2
90
C-1
B-1
A-1
D-1
3/14 × 2
7/28
14/28
21/28
Dosing schedule (day/day)
3.1.
Starting Dose in Each Subtrial
The dose of DS-3032b for Cohort 1 in Subtrial A will be 90 mg (see “Section 5.2.3
Rationale for the Dose and Regimen”).
The starting dose in the subtrial that has a smaller number of dosing days than the subtrial
in which the MTD has been determined will be equal to or lower than the MTD in the 
subtrial in which the MTD has been determined.  For instance, when the MTD in Subtrial 
A is determined to be 120 mg, the starting dose in Subtrial B will be 120 mg or 90 mg.
The starting dose in the subtrial that has a greater number of dosing days than the subtrial 
in which the MTD has been determined will be lower than the MTD in the subtrial in 
which the MTD has been determined.  For instance, when the MTD in Subtrial A is 
determined to be 160 mg, the starting dose in Subtrial D will be 120 mg or 90 mg.  When 
the MTD has not been reached in Subtrial A, the starting dose in Subtrial D will be equal 
to or lower than the maximum dose used in Subtrial A.


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3.2.
Explorative Dose Finding in Each Subtrial
After confirming the DLT rate in Cycle 1 in each cohort in accordance with 
“Section 5.3.1 Definition of Dose-limiting Toxicities,” the dose for the next and 
subsequent cohorts will be determined, in consideration of the following i) and ii).  As a 
rule, each cohort consists of 3 to 6 subjects, and if “Section 5.4 Enrollment of Additional 
Subjects ” is applicable, enrollment of additional subjects will be considered.
i)
Recommended dose, guided by mCRM using a Bayesian logistic regression 
model (BLRM) incorporating the EWOC principle
ii) Clinical evaluation of the toxicological profile and information on 
pharmacokinetics/pharmacodynamics (PK/PDy)
Rationale:
The study design was selected in reference to the “Guidelines for Clinical Evaluation of 
Anticancer Drugs.17”  The Bayesian statistical analysis methods are specified in 
“Section 11.7 Details of Modified Continual Reassessment Method.”


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4.
STUDY POPULATION
4.1.
Selection of Subjects
Subjects who satisfy all of the following inclusion criteria and do not meet any of the 
exclusion criteria are eligible for this study.
4.1.1.
Inclusion Criteria
1. Provision of written informed consent for participation in this study.
2. Age ≥20 years old upon enrollment in this study.
3. Having AML (including those with a history of MDS) satisfying either of the 
following:
i)
Have failed to achieve remission with at least 1 cycle of prior induction 
therapy
ii) Have relapsed after achieving remission with prior therapy
4. Those who appear unable to achieve persistent remission with standard treatment, 
who failed to complete potentially curative treatment, or who have no treatment 
options with expected therapeutic efficacy.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 
(refer to “Appendix 2”).
6. Having laboratory data satisfying all of the following criteria in the measurement 
within 14 days before enrollment in this study.
Laboratory Parameter
Requirement
AST
≤2.5 × the upper limit of normal of the center (ULN)
ALT
≤2.5 × ULN
Total bilirubin
≤1.5 × ULN
Serum creatinine
Creatinine clearance ≥60 mL/min, as calculated using 
the modified Cockcroft Gault equation*
In case of creatinine clearance ≥50 mL/min and 
<60 mL/min, as calculated using the above equation, 
the subject may be enrolled if the serum creatinine 
level is ≤1.5 × ULN.
Prothrombin time-
international normalized 
ratio (PT-INR)
≤1.5 × ULN
Activated partial 
thromboplastin time (aPTT)
≤1.5 × ULN
*: ([140 −age (year)] × [actual weight (kg)]) / [72 × serum creatinine (mg/dL)] (× 0.85 [if 
female])


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7. Able to take the following interval during the period from the last dose or last 
procedure of prior therapy to the start day of treatment with the study drug (study
treatment) in this study.
i)
Cytotoxic drugs: 2 weeks (48 hours for hydroxycarbamide used for the 
purpose of controlling the increase in white blood cells)
ii) Non-cytotoxic drugs: At least 5 times the half-life of the drug
8. Women of childbearing potential must have a negative pregnancy test at 
screening and must be willing to use highly effective birth control (eg, barrier 
contraceptives with spermicides, intrauterine device) during the following period: 
Upon enrollment, during the treatment period, and for at least 95 days after the 
last dose of DS-3032b. Women of childbearing potential are those in the period 
from first menstruation to menopause (no menstrual period for a minimum of 12 
months).  This, however, shall exclude permanently (surgically) sterile women.
9. Males must be surgically sterile or willing to use highly effective birth control 
upon enrollment, during the treatment period, and for at least 95 days after the last 
dose of DS-3032b.  Male subjects may not donate their sperm during the study 
period and for at least 95 days after the last dose of DS-3032b.
10. Able to be hospitalized during the DLT evaluation period.
Rationale:
1. To ensure the eligibility of study subjects, and in consideration of ethics.
2. The lower limit of age is 20 years at which each subject can provide informed 
consent appropriately based on his/her own judgment.
3, 5, 10.
To appropriately evaluate the safety of DS-3032b.
4. As recommended in the Guidelines for the Clinical Evaluation of Anticancer 
Drugs.17
6. To confirm that the subjects have adequate organ functions for appropriate 
evaluation of the subject’s safety, as recommended in the Guidelines for the 
Clinical Evaluation of Anticancer Drugs.17
7. To confirm that the subjects are in a stable physiological condition at registration, 
as recommended in the Guidelines for the Clinical Evaluation of Anticancer 
Drugs.17
8, 9.
Since an effect of DS-3032b on fetuses or infants cannot be ruled out.  
Breastfeeding women are not allowed to participate in this study independent 
of whether or not they temporarily discontinue breastfeeding.
4.1.2.
Exclusion Criteria
1. Diagnosis of acute promyelocytic leukemia.


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2. Chronic myeloid leukemia in blast crisis (positive for a breakpoint cluster region-
c-Abelson [BCR-ABL] fusion gene).
3. History of or concurrent central nervous system leukemia.
4. History of hematopoietic stem cell transplant (HSCT) and meeting any of the 
following:
i)
Transplantation within 60 days before the start of study treatment
ii) Persistent graft-versus-host disease (GVHD) that is clinically significant, 
requires the start of treatment, or requires intensification of treatment within 
21 days before informed consent
iii) Persistent Grade ≥2 clinically significant or irreversible non-hematological
toxicity related to transplantation
5. Uncontrolled infection requiring intravenous antibiotics, antifungals, or antivirals.
6. A positive test result for hepatitis C virus (HCV) antibody or human 
immunodeficiency virus (HIV) antibody within 90 days before enrollment.
7. A positive test result for hepatitis B surface (HBs) antigen within 90 days before 
enrollment.
8. A positive test result for hepatitis B core (HBc) antibody or HBs antibody with 
hepatitis B virus (HBV)-DNA levels ≥2.1 log copies/mL, despite a negative test 
result for HBs antigen, within 90 days before enrollment.
9. Receiving strong CYP3A inhibitors within 7 days before the start of study 
treatment.
10. Receiving strong CYP3A inducers within 14 days before the start of study 
treatment.
11. History of or current cardiovascular disease as specified below:
i)
QT corrected for heart rate using Fridericia’s method (QTcF) interval 
>450 ms, determined as the average of triplicate ECG measurements taken 
within 14 days before enrollment in this study
ii)
Class III or more severe congestive heart failure according to “Appendix 3
New York Heart Association (NYHA) Functional Classification” within 6 
months before enrollment in this study
iii) History of myocardial infarction within 6 months before enrollment in this 
study
iv)
History of angina pectoris attack within 6 months before enrollment in this 
study
v)
History of arrhythmia requiring treatment within 6 months before enrollment 
in this study
vi)
Need for a pacemaker or implantable cardioverter defibrillator
vii) Diagnosed or suspected congenital long QT syndrome


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viii) History of life-threatening ventricular arrhythmia (ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
ix)
History of bradyarrhythmia (eg, atrioventricular block)
x)
Clinically significant electrolyte abnormalities that can induce secondary 
long QT syndrome
xi)
Uncontrolled hypertension despite pharmacotherapy etc.
12. Adverse drug reactions (excluding alopecia) to previous therapy (treatment for 
AML and/or anticancer therapy), which have not resolved or returned to Grade 1 
or baseline.  Patients with chronic Grade 2 adverse drug reactions (eg, 
chemotherapy-induced neuropathy) may be eligible when the investigator or 
subinvestigator decides that there are no clinical safety concerns from the 
standpoint of the patient’s safety.
* The grade will be assessed according to the “Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0.”
13. History of another malignant tumor requiring treatment within 2 years before 
enrollment in this study.
However, patients whose disease is considered to have been cured by local 
treatment (eg, non-melanoma skin cancer, superficial bladder cancer, or 
carcinoma in situ of the cervix or breast) may be eligible for participation in the 
study.
14. Predisposition to serious infection (eg, cystic fibrosis, congenital or acquired 
immunologic disease, hemorrhagic disease, or cytopenia unrelated to AML).
15. Disseminated intravascular coagulation or other clinically significant coagulation
abnormalities.
16. Extensive surgery within 28 days before the start of study treatment.
17. Radiation therapy within 28 days before the start of study treatment.
18. Any factor that could preclude adequate absorption of DS-3032b (eg, refractory 
nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, 
and/or GVHD affecting the gut).
19. Pregnant or breastfeeding women.
20. Patients who are otherwise considered ineligible for the study in the opinion of 
the investigator or subinvestigator.
Rationale:
1 to 18.
To appropriately evaluate the safety of DS-3032b.
19. Since an effect of DS-3032b on fetuses or infants cannot be ruled out.  
Breastfeeding women are not allowed to participate in this study independent of 
whether or not they temporarily discontinue breastfeeding.


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20. To allow the investigator or subinvestigator to determine the subject’s eligibility 
for participation in the study from a comprehensive standpoint, including careful 
consideration of the subject’s safety.
4.1.3.
Registration of Subjects
Subjects will be registered in the study according to the procedure described below.
4.1.3.1.
Flow of Subject Registration
After obtaining written informed consent from subjects, the investigator or 
subinvestigator will assign a subject identification code to each of the subjects.  The 
investigator or subinvestigator will fill out the Subject Registration Form for subjects 
who are assessed to be eligible for the study among the above subjects and send it by fax 
to the sponsor.
The sponsor will confirm the eligibility of the concerned subjects against the inclusion 
and exclusion criteria for this study based on the information in the received Subject 
Registration Form.  If there are any questions about the information in the Subject 
Registration Form, the sponsor will immediately contact the investigator or 
subinvestigator for confirmation.  Subjects who are assessed to be eligible for the study 
by the sponsor will be registered in this study and assigned a subject number.
The sponsor will immediately fax the registration confirmation form with the result of 
eligibility assessment to the investigator; the confirmation form should include the date 
of registration, subject number, and dose of the study drug for subjects assessed to be 
eligible, and the fact that the subject is not eligible and the reason for subjects assessed to 
be ineligible.  The investigator or subinvestigator will explain the reason for ineligibility 
to subjects who are assessed to be ineligible for the study by the sponsor.
Address for sending the Subject Registration Form
(the sponsor’s address)
Working hours: Monday to Friday, 9:00 to 17:30
(closed on Saturdays, Sundays, and public holidays)
FAX: 
TEL: 
The investigator or subinvestigator must not prescribe the study drug before registration 
of subjects.
If there is any subject who has provided informed consent, but is not registered in the 
study, the investigator or subinvestigator will record the reason why the concerned 
subject has not been registered in the medical record.  Such a subject will not be included 
in the number of subjects enrolled in this study.
If a subject who has provided informed consent, but is assessed to be ineligible for the 
study at the time of eligibility confirmation and for whom a Subject Registration Form 
has not been faxed to the sponsor, is confirmed to satisfy the eligibility criteria at a later 
date, the investigator or subinvestigator may fax the Subject Registration Form to the 
PPD
PPD




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5.
METHODOLOGY
5.1.
Study Drug
For the details of the study drug and its handling, see the “Investigator’s Brochure” and 
“Procedure for Study Drug Management.”
1. Investigational substance code: DS-3032b
2. Generic name: milademetan
3. Content and dosage form:
White opaque capsules, each of which contains 30 mg of DS-3032b as the free 
form of its drug substance, or white opaque, red-lined capsules, each of which 
contains 100 mg of DS-3032b as the free form of its drug substance.
4. Lot number: Lot numbers are listed in the “Procedure for Study Drug 
Management.”
5.1.1.
Labeling and Packaging
Thirty five capsules of the study drug are packed with a desiccant agent in a plastic bottle.
The information that should be included on the label is provided in Table 5.1.1
Descriptions on the Labeling of the Study Drug.
Table 5.1.1:
Descriptions on the Labeling of the Study Drug
Labeled as “For Clinical Trial Use Only”
Study drug name
Protocol number
Study drug lot number
Storage conditions
Statement, “Do not discard but store unused study drug tablets; they will be collected later.”
Name of the sponsor
Address of the sponsor
5.1.2.
Storage of the Study Drug
After concluding the clinical study contract, the sponsor will distribute the study drug to 
the study center.  The study drug manager will store and manage the study drugs, which 
are placed with a desiccant agent in plastic bottles, at up to 25°C (excursions permitted 
up to 30°C). The study drug will be managed and collected in accordance with the 
“Procedure for Study Drug Management.”


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5.2.
Method of Study Treatment
5.2.1.
Dose
The starting dose of DS-3032b in Subtrial A will be 90 mg.  The subsequent doses will
be determined, taking the following into consideration.
i)
Recommended dose, guided by mCRM using a BLRM incorporating the 
EWOC principle
ii) Clinical evaluation of the toxicological profile and information on PK/PDy
Dose increments should be at least 1.3-fold in order to make a distinction among the dose 
cohorts, considering inter-subject variability in exposure.  Even if the recommended dose 
for the next cohort calculated by the model is more than 2-fold, the dose should be no 
more than 2-fold.
5.2.2.
Regimen
In Subtrial A, the study drug will be administered once daily on Days 1 to 14, followed 
by a 14-day rest, in a 28-day cycle (14/28 schedule).  Each cycle is 28 days long.
Capsules with two different strengths will be used as the study drug (30 mg and 100 mg).
As a rule, subjects will orally take the study drug once daily every morning under fasting 
conditions. Meal consumption should be avoided from 2 hours before dosing to 1 hour 
after dosing.
The first dose of the study drug will be started within 7 days of the day of registration.  If 
the study treatment is started on Day 8 or later from the day of registration, the first dose 
of the study drug should be started only after the subject’s eligibility has been confirmed 
again before the start of the study treatment (see “Section 6.2 Study Procedures before 
Registration of Subjects”).  Day 1 of Cycle 3 and subsequent cycles may be rescheduled 
within + 3 days of the originally scheduled date. If the schedule of Day 1 is changed, all 
subsequent scheduled dates will be changed accordingly.
If a subject vomits after taking the study drug, it is not allowed to take another dose of the 
study drug on the same day.
Other dosing schedules (Subtrials B, C, and D) will be assessed if it becomes necessary 
in order to evaluate the safety of DS-3032b. Dosing schedules in each subtrial are shown
in “Figure 5.2-1 Dosing Schedules in Each Subtrial.”




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x
Grade 3 AST/ALT lasting ≥3 days, Grade 3 AST/ALT with Grade ≥2 total 
bilirubin
x
Unable to complete at least 75% of the prescribed doses of DS-3032b in Cycle
1 (28 days) as a result of Grade ≥2 events
2.
The following events will not be assessed as DLTs:
x
Grade 3 fatigue lasting <3 days
x
Grade 3 nausea or vomiting that has resolved to Grade ≤2 within 48 hours 
after antiemetic therapy
x
Grade 3 diarrhea that has resolved to Grade ≤2 within 48 hours after 
antidiarrheal therapy
x
Alopecia
x
Febrile neutropenia
x
Transient laboratory abnormalities that do not involve clinical symptoms and 
do not require continuous treatment (≥Grade 3 ALP, uric acid, amylase, and 
lipase, hyponatremia that has resolved within 72 hours after onset, etc.)
The following hematological toxicities will be assessed as DLTs.
x
Failure to recover neutrophil count to ≥500 /mm3 and platelet count to
≥20,000 /mm3, leading to a delay in starting Cycle 2 for more than 2 weeks
5.3.2.
Definition of Maximum Tolerated Dose
If any of the following completion criteria are met, the MTD will be determined based on 
comprehensive evaluation of the recommended dose guided by mCRM incorporating the
EWOC principle, and safety and PK/PDy information of DS-3032b.
Completion criteria:
x
DLT evaluation is completed in at least 15 subjects in the entire study and in 
at least 6 subjects in the cohort of the dose selected to be the dose for the next 
cohort by mCRM.
x
DLT evaluation is completed in at least 6 subjects in the cohort of the dose 
selected to be the dose for the next cohort by mCRM, with at least 50% 
posterior probability for the DLT rate ranging between 16% and 33%.
x
DLT evaluation is completed in at least 3 subjects in the cohort of each dose, 
with no DLTs reported.
x
The posterior probability for the DLT rate of 33% or higher in the 90 mg
cohort is at least 60%.


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5.3.3.
Study Treatment to Subjects in Each Cohort and Procedure for 
Proceeding to the Next Cohort
In the cohort of the first dose, study treatment for the second subject must be started after 
an at least 1-week interval from the first dose of treatment in the first subject. In the 
subsequent cohorts, study treatment for the next subject may be started on the following 
day of the start day of study treatment in the first subject.
If proceeding to the next cohort involves an increase in the dose, study treatment for the
first subject in the new cohort will be started after the end of the DLT evaluation period 
in at least 3 subjects in the ongoing cohort.  If a DLT occurs in 2 subjects before 
registration of the third subject, the dose for the third subject will be reviewed by using 
the mCRM incorporating the EWOC principle.
5.4.
Enrollment of Additional Subjects
If there is a subject who cannot be evaluated for DLTs because of withdrawal from the 
study before the end of Cycle 1 for any reason during the study, additional subjects will 
be enrolled.  In other cases where enrollment of additional subjects is considered 
necessary, whether or not to enroll additional subjects will be considered through 
discussion between the investigator and the sponsor.  The medical expert may join the 
discussion as necessary.
5.5.
Actions to be Taken for Adverse Events
If a toxicity that falls under the following definition occurs, dose interruption,
postponement of the start of the next cycle (hereinafter, postponement), or dose reduction 
should be performed as shown below.
5.5.1.
Occurrence of Dose-limiting Toxicities or Toxicities Equivalent to the 
Definition of Dose-limiting Toxicities after Cycle 1
If a DLT occurs or a treatment-related toxicity falling under the definition of DLTs
occurs after Cycle 1, the investigator or subinvestigator should interrupt, postpone, or
discontinue the study treatment.  If the toxicity improves to Grade ≤1 or the subject 
recovers to the baseline condition, the investigator or subinvestigator will consider 
resuming the study treatment at a one-level reduced dose from the dose used in his/her 
participating cohort (in the case of the 90 mg cohort, resumption at a dose of 90 mg
should be considered), only when it is considered beneficial to the subject.  Once the dose 
is reduced, the dose should not be increased again.
The duration of dose interruption must not exceed 4 weeks.  If the subject does not 
recover 4 weeks or more after the onset of the toxicity, the subject should be withdrawn 
from the study.  In case a Grade ≥3 toxicity or a serious adverse event (SAE) that is 
apparently attributable to the primary disease occurs, the study treatment may be 
interrupted or postponed until the toxicity or the event improves to Grade ≤1 or until the 
subject recovers to the baseline condition.


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5.5.2.
Occurrence of the Following Toxicities Not Listed in Section 5.5.1
If any of the following toxicities, not listed in “Section 5.5.1 Occurrence of Dose-limiting 
Toxicities or Toxicities Equivalent to the Definition of Dose-limiting Toxicities after 
Cycle 1,” occur, the investigator or subinvestigator will continue the study treatment if 
the toxicity can be controlled by appropriate intervention.
x
Grade ≥2 non-hematological toxicity (excluding alopecia) unrelated to the 
primary disease, Grade ≥3 fatigue lasting >48 hours
x
Grade ≥2 laboratory abnormalities not falling under the definition of DLTs
x
Hypoplastic marrow (neutrophil count <500 /mm3 and platelet count
<20,000 /mm3)
When it is considered necessary to interrupt or postpone the study treatment, interruption 
or postponement of the study treatment until the toxicity resolves to the following 
conditions will be considered.  Resumption of the study treatment may be considered if 
the toxicity is confirmed to have improved or resolved within 4 weeks.  When the study 
treatment is resumed, a reduction to the dose in the cohort that is one-level lower than the
dose the pertinent subject was receiving before experiencing the toxicity will be 
considered.
x
Neutrophil count ≥500 /mm3
x
Platelet count ≥20,000 /mm3
x
Grade ≥2 non-hematological toxicities (excluding alopecia) that have 
improved to Grade ≤1 or have resolved to baseline levels
5.6.
Withdrawal Criteria
Subjects will be withdrawn from the study for the following reasons.
1. Apparent progression of the disease is found.
2. It becomes difficult to continue the study treatment due to AEs (refer to 
“Section 5.5 Actions to be Taken for Adverse Events”).
3. A TP53 mutation is detected after study treatment and it is decided inappropriate 
to continue the study for the subject.
4. The subject is found to be ineligible for the study after enrollment in the study.
5. The subject withdraws his/her consent to participation in the study.
6. The sponsor decides to prematurely terminate the study.
7. The subject has received the study drug on less than 75% of the specified number 
of dosing days in Cycle 1.
8. Other cases that the investigator or subinvestigator judges it inappropriate to 
continue the study for the subject.


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If a subject is withdrawn from the study treatment, the investigator or subinvestigator will 
provide appropriate care to the subject, and record the date and reason of withdrawal in 
the case report form.  The date of withdrawal from the study treatment will not be the 
date when the event leading to withdrawal occurs, but the date when the investigator or 
subinvestigator decides on withdrawal.
If a subject is withdrawn due to an AE, the investigator or subinvestigator will provide 
appropriate treatment to the subject and continue follow-up until resolution or relief of 
the AE as far as possible.
5.7.
Prohibited Concomitant Drugs and Therapies, and Restricted 
Concomitant Drugs
5.7.1.
Prohibited Concomitant Drugs and Therapies
x
From informed consent to the day of the Follow-up:
Anticancer treatment other than the study drug (excluding hydroxycarbamide), 
other investigational products, and investigational medical devices
x
From 14 days before the start of study treatment to the day of the Follow-up:
Strong CYP3A inducers and St. John’s wort-containing foods and 
supplements
x
From 7 days before the start of study treatment to the day of the Follow-up:
Strong CYP3A inhibitors and grapefruit-containing foods and beverages
Rationale:
These specifications are provided with safety and ethical considerations for patients, and 
also to eliminate the effects of other drugs on this study as far as possible.  Since 
nonclinical data indicate that DS-3032b is mainly metabolized by CYP3A, these 
specifications are necessary for the appropriate evaluation of the pharmacokinetics and 
safety of the study drug.
5.7.2.
Restricted Concomitant Drugs
x
Hydroxycarbamide should be used as per the following instructions.
Use of hydroxycarbamide is prohibited during the period from 48 hours 
before treatment with DS-3032b to the start of treatment with DS-3032b.  It is, 
however, allowed to concomitantly use hydroxycarbamide to control white 
blood cell counts at doses up to 5 g/day for a total of 8 days or less only 
during the period from after the start of treatment with DS-3032b to the end of 
the Follow-up.
x
Prophylactic treatment for the following symptom is prohibited during the 
DLT evaluation period.  However, treatment given as supportive care for the 
following symptom is allowed.


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x
Neutropenia: Granulocyte colony stimulating factor (G-CSF) products etc.
Rationale:
This is set in consideration of the safety of subjects and for the appropriate safety 
evaluation of DS-3032b.
5.8.
Symptomatic Therapy
There are no regulations on symptomatic therapy in this study.
5.9.
Management of Subjects
The investigator or subinvestigator will make efforts to maximize the subject’s safety 
throughout the study period.  Subjects must be hospitalized during the DLT evaluation
period (refer to “Section 5.3.1 Definition of Dose-limiting Toxicities”).  The investigator 
or subinvestigator may allow subjects to temporarily stay out overnight if it is considered 
feasible after carefully examining the subjects during hospitalization.  If a subject stays 
out overnight, the study center will provide the subject with an instruction beforehand on
how to communicate in an emergency.
If an AE occurs during hospitalization and the event is not confirmed to have resolved or 
be resolving before the scheduled day of hospital discharge, the investigator or 
subinvestigator will decide whether to continue hospitalization or not, taking the 
subject’s safety into consideration.


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6.
STUDY PROCEDURES
6.1.
List of Study Procedures
Study procedures specified in the protocol are shown in “Appendix 1.”
In the study, the period from the day of informed consent through the end day of the
Follow-up is defined as the “study period” for each subject.  However, if follow-up of a 
subject at the study center becomes difficult for such reasons as transfer to another 
hospital or that the subject refuses to visit the site after the last dose of DS-3032b then the 
study duration for the pertinent subject will be terminated on the relevant day.
6.2.
Study Procedures before Registration of Subjects
The following examinations and assessments, etc. will be performed and the results will 
be recorded in the case report form.
Data collected before informed consent can also be used if they are obtained within the 
acceptable limit for each item.
If the study treatment is started on Day 8 or later based on the day of registration defined 
as Day 0, the patient’s eligibility should be assessed again on the preceding day or the 
start day (before administration) of study treatment.
1. Items confirmed after informed consent obtainment but before the start of subject 
registration
x
Date of informed consent to participate in this study
x
Subject identification code
x
Date of birth
x
Sex
x
Race
x
Height
x
Eligibility
x
Medical history and complications
Symptoms that are expressed at the time of informed consent will be recorded 
as complications.
Regarding medical history, only symptoms/diseases that were cured at the 
time of informed consent and are considered necessary to be reported at the 
investigator’s or subinvestigator’s discretion will be recorded.
x
Information on the underlying disease (AML)
Collect data on the date of the first diagnosis, the World Health Organization 
(WHO) classification, and the date of relapse.


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x
Prior therapy
The following items will be confirmed:
x
Medications for AML: Drug name, stop date, best response, number of 
courses
x
Radiation therapy for AML: Purpose, location, stop date, best response
x
Hematopoietic stem cell transplantation: Details, date of transplantation
x
Others: Details, stop date
x
Assessment of SAEs
Information on SAEs that occur from after informed consent to before the first 
dose of the study drug will be collected.  Information on non-SAEs is not 
subject to collection during this period.
2. Items performed within 14 days before the day of registration (screening tests) 
*Performed on a day as close as possible to the day of registration
x
Vital sign measurement
Axillary body temperature, pulse rate, and systolic and diastolic blood 
pressure will be measured at rest.
x
Body weight measurement
x
ECOG PS assessment
Subject’s general condition will be assessed in accordance with the criteria 
provided in “Appendix 2.”
x
12-lead ECG measurement (including evaluation of QTcF)
A 12-lead ECG will be performed in the supine position after a 10-minute rest.  
Each measurement will be performed in triplicate at approximately 1- to 5-
minute intervals.
x
Laboratory tests
Laboratory Parameters
Hematology test
Red blood cell count, reticulocyte ratio, hemoglobin, 
hematocrit, white blood cell count, white blood cell differential 
count (neutrophils, basophils, eosinophils, lymphocytes, 
monocytes), platelet count, PT-INR, and aPTT
Blood chemistry 
test
Total protein, albumin, total bilirubin, direct bilirubin, AST, 
ALT, ALP, BUN, serum creatinine, uric acid, glucose, 
electrolytes (K, Na, Cl, Ca, P, Mg), and CRP
Urinalysis
Occult blood, glucose, and protein 


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x
Assessment of bone marrow findings
Assessment will be made based on bone marrow findings and peripheral
blood results (neutrophil count, platelet count, and number of blasts) in 
accordance with “Section 10.1 Definition of Efficacy Endpoints.”
It is desired to obtain bone marrow specimens by bone marrow aspiration and 
biopsy.  If the investigator or subinvestigator considers that the antitumor 
effect of DS-3032b can be assessed adequately using specimens obtained by 
bone marrow aspiration only, bone marrow biopsy may be skipped.
x
Pregnancy test
A urine or serum pregnancy test will be performed in female subjects.
A pregnancy test is not necessary in women who have been amenorrheic for at 
least 12 months after the last menstruation and who are considered to have no 
childbearing potential, or women who are not of childbearing potential after 
permanent surgical sterilization, etc.  In this case, the information and reason 
will be recorded in the case report form.
A pregnancy test must be performed in women who have been amenorrheic 
for at least 12 months for medical reasons other than surgical sterilization (eg, 
medication) because they are considered to have childbearing potential.
3. Items confirmed within 90 days before the day of registration
x
HBs antigen, HBs antibody, HBc antibody, HBV-DNA level, HCV antibody, 
HIV antibody
6.3.
Procedures During the Study Conduct Phase
The following examinations and assessments, etc. will be performed and the results will 
be recorded in the case report form.  The details of the procedures are the same as those 
described in “Section 6.2 Study Procedures before Registration of Subjects.”
6.3.1.
Subtrial A (14/28 Day Schedule)
1. Confirmation of treatment compliance
x
Whether to have taken the drug or not
x
Date of administration
x
Time of administration
x
Dose (mg/day)
x
Whether or not the study treatment was interrupted or postponed, or the dose 
was reduced, and if there was any intervention, the details and reason.


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2. Vital signs measurement
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 2
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 14
Pre-dose and 3 h post-dose (±10 min)
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 14 (−4 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
3. Body weight measurement, ECOG PS assessment
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 14
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 14 (−4 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose


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4. 12-lead ECG
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 2
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 14
Pre-dose and 3 h post-dose (±10 min)
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 14 (−4 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
5. Laboratory tests
For clinical laboratory parameters, the reference rage of the institution that 
performs the measurements will be used. When screening tests are performed 
within 24 hours before the first dose of the study drug, the tests before 
administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 2
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 14
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 14 (−4 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
6. Pregnancy test
A urine or serum pregnancy test will be performed in female subjects.


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A pregnancy test is not necessary in women who have been amenorrheic for at 
least 12 months after the last menstruation and who are considered to have no 
childbearing potential, or women who are not of childbearing potential after 
permanent surgical sterilization, etc.  In this case, the information and reason will 
be recorded in the case report form.
A pregnancy test must be performed in women who have been amenorrheic for at 
least 12 months for medical reasons other than surgical sterilization (eg, 
medication) because they are considered to have childbearing potential.
Cycle 3
Day 1 (−4 days)
Pre-dose
7. Evaluation method of the antitumor effect
Assessment will be made based on bone marrow findings and peripheral blood 
results (neutrophil count, platelet count, and number of blasts) in accordance with 
“Section 10.1 Definition of Efficacy Endpoints.”
It is desired to obtain bone marrow specimens by bone marrow aspiration and 
biopsy.  If the investigator or subinvestigator considers that the antitumor effect of 
DS-3032b can be assessed adequately using specimens obtained by bone marrow 
aspiration only, bone marrow biopsy may be skipped.
Cycle 2 
and
thereafter
Day 25 of the previous cycle to pre-dose on Day 1 of the present cycle
* After CR is achieved, assessment based on bone marrow findings may 
be skipped until blasts are observed in the peripheral blood.
8. Confirmation of concomitant drugs and therapies
x
Concomitant drugs and therapies
The following information on concomitant drugs and therapies other than the 
study drug, which are used during the period from the day of the first dose of 
the study drug to the visit day of the Follow-up period will be confirmed.  As 
for concomitant drugs or therapies that are newly started after the following
day of the last dose of the study drug, those used only for the treatment of AEs
will be confirmed as to the following information.
x
Name of drug (therapy), dose, unit, mode of administration, and dosage
x
Start and end dates of drug (therapy)
x
Reason for use (application)
The following items need not to be recorded in the case report form, except 
when a relationship between the AEs occurring in subjects during their
participation in the study and the study drug cannot be ruled out:
x
Antiseptic solutions


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x
Heparin for heparin lock flush
x
Test drugs or treatment drugs used for tests including bone marrow
aspiration or biopsy
x
Transfusion
The following information on transfusion that is introduced during the period 
from the day of the first dose of the study drug to the visit day of the Follow-
up period will be confirmed.  As for transfusion that is newly started after the 
following day of the last dose of the study drug, only cases of use for the 
treatment of AEs will be confirmed for the following information.
x
Type of blood products (whole blood, red blood cells, plasma, platelets, 
others)
x
Start date, end date, amount of use (unit)
x
Reason for use
9. Assessment of AEs
10. Collection of specimens for pharmacokinetic assessment and the biomarker study
Refer to “Section 6.7 Pharmacokinetics” and “Section 6.8 Biomarker Study”
6.3.2.
Subtrial B (7/28 Day Schedule)
1. Confirmation of treatment compliance
x
Whether to have taken the drug or not
x
Date of administration
x
Time of administration
x
Dose (mg/day)
x
Whether or not the study treatment was interrupted or postponed, or the dose 
was reduced, and if there was any intervention, the details and reason.


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2. Vital signs measurement
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 2
Pre-dose
Day 7
Pre-dose and 3 h post-dose (±10 min)
Day 15 (±2 days)
Specified day
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 7 (−2 days)
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
3. Body weight measurement, ECOG PS assessment
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 7
Pre-dose
Day 15 (±2 days)
Specified day
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 7 (−2 days)
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose


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4. 12-lead ECG measurement
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 2
Pre-dose
Day 7
Pre-dose and 3 h post-dose (±10 min)
Day 15 (±2 days)
Specified day
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 7 (−2 days)
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
5. Laboratory tests
For clinical laboratory parameters, the reference rage of the institution that 
performs the measurements will be used. When screening tests are performed 
within 24 hours before the first dose of the study drug, the tests before 
administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 2
Pre-dose
Day 7
Pre-dose
Day 15 (±2 days)
Specified day
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 7 (−2 days)
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose


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6. Pregnancy test
A urine or serum pregnancy test will be performed in female subjects.
A pregnancy test is not necessary in women who have been amenorrheic for at 
least 12 months after the last menstruation and who are considered to have no 
childbearing potential, or women who are not of childbearing potential after 
permanent surgical sterilization, etc.  In this case, the information and reason will 
be recorded in the case report form.
A pregnancy test must be performed in women who have been amenorrheic for at 
least 12 months for medical reasons other than surgical sterilization (eg, 
medication) because they are considered to have childbearing potential.
Cycle 3
Day 1 (−4 days)
Pre-dose
7. Evaluation method of the antitumor effect
Assessment will be made based on bone marrow findings and peripheral blood 
results (neutrophil count, platelet count, and number of blasts) in accordance with 
“Section 10.1 Definition of Efficacy Endpoints.”
It is desired to obtain bone marrow specimens by bone marrow aspiration and 
biopsy.  If the investigator or subinvestigator considers that the antitumor effect of 
DS-3032b can be assessed adequately using specimens obtained by bone marrow 
aspiration only, bone marrow biopsy may be skipped.
Cycle 2 
and
thereafter
Day 25 of the previous cycle to pre-dose on Day 1 of the present cycle
* After CR is achieved, assessment based on bone marrow findings may 
be skipped until blasts are observed in the peripheral blood.
8. Confirmation of concomitant drugs and therapies
x
Concomitant drugs and therapies
The following information on concomitant drugs and therapies other than the 
study drug, which are used during the period from the day of the first dose of 
the study drug to the visit day of the Follow-up period will be confirmed.  As 
for concomitant drugs or therapies that are newly started after the following 
day of the last dose of the study drug, those used only for the treatment of AEs
will be confirmed as to the following information.
x
Name of drug (therapy), dose, unit, mode of administration, and dosage
x
Start and end dates of drug (therapy)
x
Reason for use (application)


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The following items need not to be recorded in the case report form, except 
when a relationship between the AEs occurring in subjects during their 
participation in the study and the study drug cannot be ruled out:
x
Antiseptic solutions
x
Heparin for heparin lock flush
x
Test drugs or treatment drugs used for tests including bone marrow 
aspiration or biopsy
x
Transfusion
The following information on transfusion that is introduced during the period 
from the day of the first dose of the study drug to the visit day of the Follow-
up period will be confirmed.  As for transfusion that is newly started after the 
following day of the last dose of the study drug, only cases of use for the 
treatment of AEs will be confirmed for the following information.
x
Type of blood products (whole blood, red blood cells, plasma, platelets, 
others)
x
Start date, end date, amount of use (unit)
x
Reason for use
9. Assessment of AEs
10. Collection of specimens for pharmacokinetic assessment and the biomarker study
Refer to “Section 6.7 Pharmacokinetics” and “Section 6.8 Biomarker Study”
6.3.3.
Subtrial C (3/14 Day × 2 Schedule)
1. Confirmation of treatment compliance
x
Whether to have taken the drug or not
x
Date of administration
x
Time of administration
x
Dose (mg/day)
x
Whether or not the study treatment was interrupted or postponed, or the dose 
was reduced, and if there was any intervention, the details and reason.
2. Vital signs measurement
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.


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Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 3
Pre-dose and 3 h post-dose (±10 min)
Day 8 (±2 days)
Specified day
Day 15
Pre-dose and 3 h post-dose (±10 min)
Day 17
Pre-dose and 3 h post-dose (±10 min)
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 3
Pre-dose
Day 15
Pre-dose
Day 17
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
3. Body weight measurement, ECOG PS assessment
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 3
Pre-dose
Day 8 (±2 days)
Specified day
Day 15
Pre-dose
Day 17
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 3
Pre-dose
Day 15
Pre-dose
Day 17
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose


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4. 12-lead ECG measurement
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 3
Pre-dose and 3 h post-dose (±10 min)
Day 8 (±2 days)
Specified day
Day 15
Pre-dose and 3 h post-dose (±10 min)
Day 17
Pre-dose and 3 h post-dose (±10 min)
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 3
Pre-dose
Day 15
Pre-dose
Day 17
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
5. Laboratory tests
For clinical laboratory parameters, the reference rage of the institution that 
performs the measurements will be used. When screening tests are performed 
within 24 hours before the first dose of the study drug, the tests before 
administration on Day 1 of Cycle 1 are not necessary.


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Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 3
Pre-dose
Day 8 (±2 days)
Specified day
Day 15
Pre-dose
Day 17
Pre-dose
Day 22 (±2 days)
Specified day
Cycle 2
Day 1
Pre-dose
Day 3
Pre-dose
Day 15
Pre-dose
Day 17
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
6. Pregnancy test
A urine or serum pregnancy test will be performed in female subjects.
A pregnancy test is not necessary in women who have been amenorrheic for at 
least 12 months after the last menstruation and who are considered to have no 
childbearing potential, or women who are not of childbearing potential after 
permanent surgical sterilization, etc.  In this case, the information and reason will 
be recorded in the case report form.
A pregnancy test must be performed in women who have been amenorrheic for at 
least 12 months for medical reasons other than surgical sterilization (eg, 
medication) because they are considered to have childbearing potential.
Cycle 3
Day 1 (−4 days)
Pre-dose
7. Evaluation method of the antitumor effect
Assessment will be made based on bone marrow findings and peripheral blood 
results (neutrophil count, platelet count, and number of blasts) in accordance with 
“Section 10.1 Definition of Efficacy Endpoints.”
It is desired to obtain bone marrow specimens by bone marrow aspiration and 
biopsy.  If the investigator or subinvestigator considers that the antitumor effect of 
DS-3032b can be assessed adequately using specimens obtained by bone marrow 
aspiration only, bone marrow biopsy may be skipped.


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Cycle 2
Day 25 of the previous cycle to pre-dose on Day 1 of the present cycle
* After CR is achieved, assessment based on bone marrow findings may 
be skipped until blasts are observed in the peripheral blood.
8. Confirmation of concomitant drugs and therapies
x
Concomitant drugs and therapies
The following information on concomitant drugs and therapies other than the 
study drug, which are used during the period from the day of the first dose of 
the study drug to the visit day of the Follow-up period will be confirmed.  As 
for concomitant drugs or therapies that are newly started after the following 
day of the last dose of the study drug, those used only for the treatment of AEs
will be confirmed as to the following information.
x
Name of drug (therapy), dose, unit, mode of administration, and dosage
x
Start and end dates of drug (therapy)
x
Reason for use (application)
The following items need not to be recorded in the case report form, except 
when a relationship between the AEs occurring in subjects during their 
participation in the study and the study drug cannot be ruled out:
x
Antiseptic solutions
x
Heparin for heparin lock flush
x
Test drugs or treatment drugs used for tests including bone marrow 
aspiration or biopsy
x
Transfusion
The following information on transfusion that is introduced during the period 
from the day of the first dose of the study drug to the visit day of the Follow-
up period will be confirmed.  As for transfusion that is newly started after the 
following day of the last dose of the study drug, only cases of use for the 
treatment of AEs will be confirmed for the following information.
x
Type of blood products (whole blood, red blood cells, plasma, platelets, 
others)
x
Start date, end date, amount of use (unit)
x
Reason for use
9. Assessment of AEs


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10. Collection of specimens for pharmacokinetic assessment and the biomarker study
Refer to “Section 6.7 Pharmacokinetics” and “Section 6.8 Biomarker Study”
6.3.4.
Subtrial D (21/28 Day Schedule)
1. Confirmation of treatment compliance
x
Whether to have taken the drug or not
x
Date of administration
x
Time of administration
x
Dose (mg/day)
x
Whether or not the study treatment was interrupted or postponed, or the dose 
was reduced, and if there was any intervention, the details and reason.
2. Vital signs measurement
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 2
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 15
Pre-dose
Day 21
Pre-dose and 3 h post-dose (±10 min)
Cycle 2
Day 1
Pre-dose
Day 15 (±2 days)
Pre-dose
Day 21 (−2 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose


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3. Body weight measurement, ECOG PS assessment
When screening tests are performed within 24 hours before the first dose of the 
study drug, the tests before administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 15
Pre-dose
Day 21
Pre-dose
Cycle 2
Day 1
Pre-dose
Day 15 (±2 days)
Pre-dose
Day 21 (−2 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
4. 12-lead ECG measurement
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose and 3 h post-dose (±10 min)
Day 2
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 15
Pre-dose
Day 21
Pre-dose and 3 h post-dose (±10 min)
Cycle 2
Day 1
Pre-dose
Day 15 (±2 days)
Pre-dose
Day 21 (−2 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
5. Laboratory tests
For clinical laboratory parameters, the reference rage of the institution that 
performs the measurements will be used. When screening tests are performed 


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within 24 hours before the first dose of the study drug, the tests before 
administration on Day 1 of Cycle 1 are not necessary.
Cycle 1
Day 1
* Day of the first 
dose of the study 
drug
Pre-dose
Day 2
Pre-dose
Day 8 (±2 days)
Pre-dose
Day 15
Pre-dose
Day 21
Pre-dose
Cycle 2
Day 1
Pre-dose
Day 15 (±2 days)
Pre-dose
Day 21 (−2 days)
Pre-dose
Cycle 3 
and
thereafter
Day 1 (−4 days)
Pre-dose
6. Pregnancy test
A urine or serum pregnancy test will be performed in female subjects.
A pregnancy test is not necessary in women who have been amenorrheic for at 
least 12 months after the last menstruation and who are considered to have no 
childbearing potential, or women who are not of childbearing potential after 
permanent surgical sterilization, etc.  In this case, the information and reason will 
be recorded in the case report form.
A pregnancy test must be performed in women who have been amenorrheic for at 
least 12 months for medical reasons other than surgical sterilization (eg, 
medication) because they are considered to have childbearing potential.
Cycle 3
Day 1 (−4 days)
Pre-dose
7. Evaluation method of the antitumor effect
Assessment will be made based on bone marrow findings and peripheral blood 
results (neutrophil count, platelet count, and number of blasts) in accordance with 
“Section 10.1 Definition of Efficacy Endpoints.”
It is desired to obtain bone marrow specimens by bone marrow aspiration and 
biopsy.  If the investigator or subinvestigator considers that the antitumor effect of 
DS-3032b can be assessed adequately using specimens obtained by bone marrow 
aspiration only, bone marrow biopsy may be skipped.


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Cycle 2 
and
thereafter
Day 25 of the previous cycle to pre-dose on Day 1 of the present cycle
* After CR is achieved, assessment based on bone marrow findings may 
be skipped until blasts are observed in the peripheral blood.
8. Confirmation of concomitant drugs and therapies
x
Concomitant drugs and therapies
The following information on concomitant drugs and therapies other than the 
study drug, which are used during the period from the day of the first dose of 
the study drug to the visit day of the Follow-up period will be confirmed.  As 
for concomitant drugs or therapies that are newly started after the following 
day of the last dose of the study drug, those used only for the treatment of AEs
will be confirmed as to the following information.
x
Name of drug (therapy), dose, unit, mode of administration, and dosage
x
Start and end dates of drug (therapy)
x
Reason for use (application)
x
The following items need not to be recorded in the case report form, except 
when a relationship between the AEs occurring in subjects during their 
participation in the study and the study drug cannot be ruled out:
x
Antiseptic solutions
x
Heparin for heparin lock flush
x
Test drugs or treatment drugs used for tests including bone marrow 
aspiration or biopsy
x
Transfusion
The following information on transfusion that is introduced during the period 
from the day of the first dose of the study drug to the visit day of the Follow-
up period will be confirmed.  As for transfusion that is newly started after the 
following day of the last dose of the study drug, only cases of use for the 
treatment of AEs will be confirmed for the following information.
x
Type of blood products (whole blood, red blood cells, plasma, platelets, 
others)
x
Start date, end date, amount of use (unit)
x
Reason for use
9. Assessment of AEs


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10. Collection of specimens for pharmacokinetic assessment and the biomarker study
Refer to “Section 6.7 Pharmacokinetics” and “Section 6.8 Biomarker Study”
6.4.
Procedures at Study Discontinuation
The investigator or subinvestigator will perform the following examinations and 
assessments, etc. on the day when discontinuation of the study is determined (±3 days).
If the study is discontinued after 25 days from the last dose of the study drug with the day 
of the last dose set as 0 for any reason, examinations and assessments, etc. specified in 
this section will be omitted, and examinations and assessments, etc. presented in 
“Section 6.5 Examination Items during the Follow-up Period and the Time Points” will 
be performed immediately instead.
The details of the procedures are the same as those described in “Section 6.2 Study 
Procedures before Registration of Subjects” and “Section 6.3 Procedures During the 
Study Conduct Phase.”
x
Date of discontinuation of the study and reason for discontinuation
x
Vital signs measurement
x
Body weight measurement
x
ECOG PS assessment
x
12-lead ECG measurement
x
Laboratory tests
x
Assessment of bone marrow findings (It is desired to obtain bone marrow 
specimens by bone marrow aspiration and biopsy.  If the investigators 
consider that the antitumor effect of DS-3032b can be assessed adequately 
using specimens obtained by bone marrow aspiration only, bone marrow 
biopsy may be skipped.)
x
Confirmation of concomitant drugs and therapies
x
Assessment of AEs
x
Collection of biomarker specimens (blood and bone marrow)
6.5.
Examination Items during the Follow-up Period and the Time 
Points
The following examinations and assessments, etc. will be performed after 30 days (±5 
days) from the last dose of the study drug with the day of the last dose set as 0. If a 
subsequent AML treatment is introduced, Follow-up will be performed before the start of 
the subsequent AML treatment.
The end day of the Follow-up period is the day when all examinations and assessments,
etc. are completed.


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If any AE is persistent on the end day of the Follow-up period, follow-up investigation 
will be performed until the AE is confirmed to have resolved or be resolving as far as 
possible.
x
Confirmation of survival (the last date of confirming survival) or death (the 
date of death)
x
Vital signs measurement
x
Body weight measurement
x
ECOG PS assessment
x
12-lead ECG measurement
x
Laboratory tests
x
Confirmation of concomitant drugs and therapies
x
Assessment of AEs
x
Subsequent AML treatment after discontinuation of treatment with DS-3032b
x
AML relapsed or not, if relapsed, the date of relapse
x
[If the assessment at withdrawal is omitted (if the study is discontinued after 
25 days from the last dose of the study drug with the day of the last dose set as 
0 for any reason)] Assessment of bone marrow findings (It is desired to 
obtain bone marrow specimens by bone marrow aspiration and biopsy.  If the 
investigators consider that the antitumor effect of DS-3032b can be assessed 
adequately using specimens obtained by bone marrow aspiration only, bone 
marrow biopsy may be skipped.)
x
[If the assessment at withdrawal is omitted (if the study is discontinued after 
25 days from the last dose of the study drug with the day of the last dose set as 
0 for any reason)] Collection of biomarker specimens (blood and bone 
marrow)
6.6.
Subsequent AML treatment
“Subsequent AML treatment” is defined as treatment introduced for the AML after the 
day of the last dose of the study drug, including HSCT, chemotherapy, immunotherapy, 
radiation therapy, and surgery, etc.
Subsequent AML treatment should not be initiated before the end day of the Follow-up
period in this study as far as possible.  If a subsequent AML treatment is introduced 
before the end of the Follow-up period for an unavoidable reason, the content of the
subsequent AML treatment and the start date will be recorded in the case report form.
6.7.
Pharmacokinetics
Plasma specimen will be obtained using a blood collection tube provided by the sponsor 
according to “Table 6.7.1 Blood Collection Points for Pharmacokinetic Assessment.”  
The plasma specimens will be stored in a frozen state and be sent to the central laboratory 


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contracted by the sponsor.  The details will be specified in separate procedures. Residual 
specimens collected in accordance with the procedures related to this study may be 
archived for a maximum of 15 years with the patient’s consent for future biomarker 
assessment.
The time of each dosing and each blood collection will be recorded in the case report 
form.
Table 6.7.1:
Blood Collection Points for Pharmacokinetic Assessment
Subtrial A (14/28 Day Schedule)
Treatment 
Cycle
Treatment Day
Blood Collection Point (Acceptable Time Window)
Cycle 1
Day 1
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 2
Pre-dose
Day 8
Pre-dose
Day 14
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Cycle 2
Day 1
Pre-dose
3 h post-dose (±10 min)


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Subtrial B (7/28 Day Schedule)
Treatment 
Cycle
Treatment Day
Blood Collection Point (Acceptable Time Window)
Cycle 1
Day 1
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 2
Pre-dose
Day 7
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 8
24 h post-dose (±15 min) of Day 7
Cycle 2
Day 1
Pre-dose
3 h post-dose (±10 min)


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Subtrial C (3/14 × 2 Day Schedule)
Treatment 
Cycle
Treatment Day
Blood Collection Point (Acceptable Time Window)
Cycle 1
Day 1
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 2
Pre-dose
Day 3
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 4
24 h post-dose (±15 min) of Day 3
Day 15
Pre-dose
Day 16
Pre-dose
Day 17
Pre-dose
Cycle 2
Day 1
Pre-dose
3 h post-dose (±10 min)


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Subtrial D (21/28 Day Schedule)
Treatment 
Cycle
Treatment Day
Blood Collection Point (Acceptable Time Window)
Cycle 1
Day 1
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 2
Pre-dose
Day 8
Pre-dose
Day 15
Pre-dose
1 h post-dose (±10 min)
2 h post-dose (±10 min)
3 h post-dose (±10 min)
6 h post-dose (±10 min)
8 h post-dose (±10 min)
Day 21
Pre-dose
Cycle 2
Day 1
Pre-dose
3 h post-dose (±10 min)
Rationale
The results of the preceding overseas Phase 1 study showed that the median Tmax of 
DS-3032a following single and multiple oral doses of DS-3032b at 90 mg to 160 mg was 
approximately 3 hours post-dose.  Referring to “Clinical Pharmacokinetic Studies of 
Pharmaceuticals,18” the blood collection time points required for pharmacokinetic 
evaluation of DS-3032a in this study were determined to be one time point immediately 
before administration, one time point before Tmax, and two time points around Tmax.  
Three time points of 6 hours, 8 hours, and 24 hours post-dose were also set in the 
elimination phase.  Furthermore, to assess the time when the pharmacokinetics of 
DS-3032a reaches a steady state, two time points, namely, before administration on Day 
2 of Cycle 1 and before administration on Day 8 of Cycle 1, were also set.
6.8.
Biomarker Study
The biomarker study will be conducted in subjects who provide written informed consent 
for this clinical study.  In the clinical study, blood, bone marrow, and serum will be 
collected to explore biomarkers potentially related to the mechanism of efficacy of 
DS-3032b.


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6.8.1.
Handling of Specimens for Biomarker Study
6.8.1.1.
Blood and Bone Marrow
Whether a mutation in the TP53 gene is present or not will be confirmed using blood and
bone marrow in this study.  When the result becomes available, the Investigator and the 
subject will be immediately notified of the information.  If a TP53 mutation is detected
after the start of study treatment, the treatment will be discontinued unless it can be 
beneficial to the subject.
Blood and bone marrow will be collected at screening tests (within 14 days before the 
day of registration) and at the time of withdrawal.  If the assessment at withdrawal is
omitted (if the study is discontinued after 25 days from the last dose of the study drug 
with the day of the last dose set as 0 for any reason), they will be collected at the Follow-
up. The details for submission will be specified in a separate procedure.
6.8.1.2.
Serum
Serum MIC-1 levels will be measured to assess the effect of DS-3032b on MIC-1
induction because MIC-1 in serum is considered to be a major pharmacodynamic 
parameter of DS-3032b. Blood will be collected in accordance with “Table 6.8.1 Serum 
Collection Points.”  Obtained serum specimens will be immediately stored frozen and the
specimens will be submitted to the specimen collection agency contracted by the sponsor.
The details will be specified in separate procedures.
Table 6.8.1:
Serum Collection Points
Subtrial A (14/28 Day Schedule)
Cycle
Day
Blood Collection Point
Cycle 1
Day 1
Pre-dose
Day 2
Pre-dose
Day 8
Pre-dose
Day 14
Pre-dose
Day 22
Specified day
Cycle 2
Day 1
Pre-dose
Subtrial B (7/28 Day Schedule)
Cycle
Day
Blood Collection Point
Cycle 1
Day 1
Pre-dose
Day 2
Pre-dose
Day 7
Pre-dose
Cycle 2
Day 1
Pre-dose


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Subtrial C (3/14 × 2 Day Schedule)
Cycle
Day
Blood Collection Point
Cycle 1
Day 1
Pre-dose
Day 2
Pre-dose
Day 3
Pre-dose
Day 15
Pre-dose
Day 16
Pre-dose
Day 17
Pre-dose
Cycle 2
Day 1
Pre-dose
Subtrial D (21/28 Day Schedule)
Cycle
Day
Blood Collection Point
Cycle 1
Day 1
Pre-dose
Day 2
Pre-dose
Day 15
Pre-dose
Day 21
Pre-dose
Cycle 2
Day 1
Pre-dose
6.8.2.
Anonymization, Storage, and Disposal of Specimens for Biomarker Study
6.8.2.1.
Anonymization of Specimens
The specimens to be submitted will be anonymized using subject identification codes to 
prevent subjects’ personal information from being identified.  The correspondence table 
between the subject identification codes and the subjects’ personal information will be 
strictly stored at the study center, so that neither the sponsor, nor the specimen collection 
agency or the biomarker laboratory can identify a subjects’ personal information.  The 
sponsor will be able to link the results of the biomarker study with the subject 
identification code and the subjects’ study data.
6.8.2.2.
Storage of Specimens
In consideration of the possibility that the relationship between the efficacy or safety of 
DS-3032b and the biomarkers is additionally analyzed based on the newly obtained 
knowledge, the submitted specimens will be stored for a maximum of up to 15 years after 
the time of submission of the clinical trial plan notification.
6.8.2.3.
Disposal of Specimens
At the expiration of the storage period, the biomarker laboratory will dispose of all 
specimens according to the sponsor’s directions.


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When a subject withdraws consent for the biomarker study, the specimens will be 
disposed of, depending on the location of the specimens at the time of the request, 
according to the procedure listed below.  If biomarker analysis has already been 
performed by the biomarker laboratory at the time of the subject’s withdrawal of consent, 
the data will not be destroyed.
1. In cases where the specimens are temporarily stored at the study center:
The investigator or subinvestigator will identify the specimens of the subject and 
dispose of them.
2. In case the specimens are stored in the specimen collection agency:
The investigator or subinvestigator will report the subject identification code of 
the pertinent subject to the sponsor.  The sponsor will direct the agency to dispose 
of the specimens of the subject.
6.9.
Long-term Storage (Banking) of Clinical Specimens for 
Genome/Gene Analysis
In preparation for future research to analyze the relationship between the
pharmacokinetics, pharmacodynamics, and safety of DS-3032b and genomes and/or
genes, specimens of DNA extracted from oral mucosa of subjects will be archived over a 
long period of time (banking) in accordance with the following procedures. The details 
of handling specimens will be specified separately in the “Procedure for Banking.”
6.9.1.
Specimens to be Banked
Subjects will be explained about banking as per procedure given in “Section 15.5
Informed Consent for Storage (Banking) of Specimens for Genome/Gene Analysis.”  
Specimens obtained from subjects who have provided informed consent for banking will 
be banked.  The investigator or subinvestigator will record the date of informed consent 
of subjects providing consent for specimen banking in the case report form.  In subjects 
with a medical history, etc. that may affect genomic or genetic information (eg, allogenic 
bone marrow transplantation), the information should also be recorded in the case report 
form.
6.9.2.
Collection of Oral Mucosa
Oral mucosa will be collected before the first dose of the study drug and stored frozen 
(−20°C or below) until transportation.  The investigator or subinvestigator will record the 
date of collection in the case report form.  The specimens should be managed by 
attaching a code unrelated to the subjects to avoid leaking of subjects’ personal 
information.
6.9.3.
Storage Period
The storage period of the banking specimens will be up to a maximum of 15 years after 
the day of submission of the clinical trial plan notification.


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6.9.4.
Disclosure of Results of Genome/Gene Analysis Using Banking Specimens
The timing, methods, accuracy of the results, and clinical significance of the 
genome/gene analysis using banked specimens remain unknown at present. In this 
context, disclosure of the results of genome/gene analysis to investigators and subjects is 
not planned.
6.9.5.
Disposal of Banking Specimens
After the expiration of the storage period or at the time of a subject’s withdrawal of 
consent during the storage period, the banking specimens will be disposed of without 
delay.  If the gene analysis has been performed before the expiration of the storage period 
or before the subject’s withdrawal of consent, the data will not be destroyed.


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7.
PHARMACOKINETIC ENDPOINTS
The pharmacokinetic parameters listed below will be calculated from plasma 
concentrations of DS-3032a using the non-compartmental analysis.
Pharmacokinetic parameters (Subtrial A):
C1D1 (Cycle 1 Day 1): Cmax, Tmax, AUClast, AUC8h, AUC24h, AUCinf*, Kel*,
t1/2*, CL/F*, Vz/F*
C1D14 (Cycle 1 Day 14)**: Cmax, Ctrough, Cavg, Tmax, AUC8h, AUC24h, Kel*,
t1/2*, CLss/F***, Vz/F*,***, AR
*:
To be calculated only if possible.
**:
To be read as C1D7 (Cycle 1 Day 7) in Subtrial B, C1D3 (Cycle 1 Day 3) in 
Subtrial C, and C1D15 (Day 15) in Subtrial D.
***:
Not to be calculated because steady state will not be reached in Subtrial C.
The details of the method of calculation of pharmacokinetic parameters are specified in 
the Statistical Analysis Plan.
Rationale:
To evaluate the pharmacokinetics of DS-3032b administered as a single dose or multiple 
doses, general pharmacokinetic parameters after oral dosing are selected.


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8.
PHARMACODYNAMIC ENDPOINTS
The following pharmacodynamic parameters will be analyzed:
x
TP53 mutation
x
Serum MIC-1 level
Rationale:
These pharmacodynamic parameters that can be drug-related markers will be measured to 
assess the pharmacological or clinical effect of DS-3032b in each individual.


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9.
SAFETY ENDPOINTS
Safety endpoints will be AEs, ECOG PS, laboratory data, body weight, vital signs, and 
12-lead ECG.
9.1.
Definition of Adverse Events
An AE is any untoward or unintended sign (including an abnormal change in laboratory 
data or vital signs), symptom, or disease noted in subjects who received the study drug, 
whether it is considered to be related to the study drug or not.
A symptom or disease preexisting before the start of study treatment will be handled as a 
complication, not as an AE.  However, complications that have worsened during the 
study treatment will be handled as AEs, and the date when worsening is confirmed will 
be used as the date of onset of the relevant event.
It is the responsibility of investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory data which should be considered 
as AEs.
Progression of the primary disease (AML) will be handled as follows:
x
Tumor progression will not be considered as an AE.  However, if tumor 
progression results in death during the AE collection period, it will be handled 
as an SAE (this should be recorded as “disease progression” for the event term 
and “fatal” for the outcome).
x
Worsening of signs or symptoms resulting from tumor progression will be 
handled as AEs.
9.2.
Definition of Serious Adverse Events
An SAE is any AE that:
x
results in death,
x
is life-threatening,
x
requires inpatient hospitalization or prolongation of existing hospitalization 
for treatment,
x
is a disability or incapacity,
x
may lead to a disability or incapacity,
x
represents other medically important condition, or
x
is a congenital anomaly or birth defect.
SAEs that occurs after the informed consent will be collected.


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9.3.
Adverse Event Information to be Reported
If an AE occurs during the study, the items shown in “Table 9.3.1 Adverse Event 
Information to be Reported” will be investigated and recorded in the case report form.  If 
a medical interview is used to investigate symptoms, questions that specify symptoms 
should not be used.  If a subject has two or more signs (including symptoms and 
abnormal changes in laboratory data) that are correlated with each other and can be 
considered part of one diagnosis, they will be regarded as one single event, and the 
diagnosis will be recorded as an AE in the case report form.  Only the highest grade 
observed in the course of each AE should be recorded as the severity in the case report 
form.
AEs will be graded according to the “CTCAE Version 5.0.”  AEs that are not listed in the 
CTCAE Version 5.0 will be graded according to the definitions provided in “Table 9.3.1
Adverse Event Information to be Reported.”


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Table 9.3.1:
Adverse Event Information to be Reported
Item
Details to be Assessed
AE
Name of AE, date of onset
Action taken for AE
Whether or not action was taken (including the modification of administration of the study 
drug), and if taken, details of the action.
Outcome
Outcome category, date of outcome assessment, date of resolution
Outcome 
category
Recovered/
Resolved
The AE has resolved, and the subject has recovered to the pre-event 
condition.
Recovering/
Resolving
The AE has almost resolved, and the subject has nearly recovered to the 
pre-event condition.
Not recovered/
Not resolved
The AE has not resolved, and the condition of the subject is similar to that 
at onset (unchanged).
Recovered/
Resolved with 
sequelae/
residual effect(s) 
present
The AE has resolved, but the subject has sequelae.
Fatal
Tumor progression will not be handled as an AE.  However, tumor 
progression leading to a fatal outcome during the AE collection period 
should be handled as a SAE (with the name and outcome of the event 
recorded as “disease progression” and “fatal,” respectively).
Unknown
Outcome is unknown because of lack of information.
Severity
To be assessed according to the CTCAE Version 5.0.
The severity of AEs not included in the CTCAE Version 5.0 will be assessed according to the 
following grades:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
Seriousness
Serious/Nonserious
Causality with the 
study drug
Classification of the relationship (in accordance with the following classification of the 
relationship), reason for the assessment
Causality 
category
Related
x
There is a reasonable temporal relationship between the onset of the 
adverse event and administration of the study drug, it is not 
reasonable to assess that the adverse event is attributable to the 
subject’s condition or other factors than the study drug (underlying 
disease, complications, concomitant drugs, etc.), and a relationship 
with the study drug cannot be ruled out.
x
There is a reasonable temporal relationship between the onset of the 
adverse event and administration of the study drug, and the adverse 
event can be explained by known actions or the pharmacological 
action of the study drug or similar analogues.
Unrelated
x
There is no reasonable temporal relationship between the onset of 
the AE and administration of the study drug, it is reasonable to 
assess that the AE is attributable to the subject’s condition or other 
factors than the study drug (underlying disease, complications, 
concomitant drugs, etc.), and a relationship with the study drug can 
be ruled out.


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9.4.
Definition of Adverse Drug Reactions
AEs that are assessed as “related” to the study drug will be handled as adverse drug 
reactions.
9.5.
Actions to be Taken for Adverse Events
9.5.1.
Recommended Action for Adverse Events
If any adverse event has occurred, the investigator or subinvestigator will provide 
appropriate medication, notify the sponsor as required, and continue follow-up until the 
subject recovers to the pre-event condition with resolution or relief of the adverse event 
as far as possible, even after the end of this study.  However, even if the adverse event is 
not confirmed to have resolved or relieved, if it is judged that the subject’s condition 
remains stable and the safety can be assured, the investigator or subinvestigator will 
explain the matter to the subject, and the follow-up of the study will be completed 
(treatment of the relevant symptom will be continued).
9.5.2.
Action for Serious Adverse Events
If an SAE has occurred, the investigator or subinvestigator will provide appropriate 
medication, and report the details of the SAE to the sponsor by telephone or fax within 24 
hours of learning of the occurrence.  The investigator will also record the necessary 
information in the “Serious Adverse Event Report (SAVER)” Form, sign it with the date 
of confirmation, and immediately report it to the sponsor.  A written report to the head of 
the study center will be made in accordance with the procedures and format specified by 
the study center.
9.6.
Actions to be Taken in the Event That Information on 
Pregnancy, Pregnant and Parturient Women, and Delivery is 
Obtained
If information on the pregnancy of a subject or a subject’s female partner is obtained 
during the study period or within 95 days after the last dose of the study drug, the 
investigator or subinvestigator will investigate the information on the pregnancy through 
delivery, and report it to the sponsor using the format provided by the sponsor.  
Pregnancy will not be handled as an AE; however, if the outcome of the pregnant woman 
falls under the definition of SAEs (congenital anomaly in the fetus [including suspected 
cases], stillbirth, abortion, etc.), the investigator or subinvestigator must report it to the 
sponsor in accordance with the procedures for reporting SAEs specified in “Section 9.5.2
Action for Serious Adverse Events,” independent of whether it is during the study period 
or not.


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10.
EFFICACY ENDPOINTS
The antitumor effect of DS-3032b will be evaluated based on bone marrow findings and 
peripheral blood results (neutrophil count, platelet count, and number of blasts), as 
specified in “Table 10.1.1 Definition of Efficacy Endpoints.”
10.1.
Definition of Efficacy Endpoints
The response criteria are defined as follows.
Table 10.1.1: Definition of Efficacy Endpoints
Complete remission: CR*
Bone marrow blasts <5%, neutrophil count ≥1000 /mm3, and platelet 
count ≥100,000 /mm3 in the absence of RBC or platelet transfusion 
(4 weeks for RBC transfusion, 1 week for platelet transfusion);
absence of Auer rods; absence of extra-medullary leukemia.
Absence of peripheral blasts.
CR with incomplete hematological recovery:
CRi
All CR criteria are met, except for neutrophil count <1000 /mm3 and 
platelet count ≥100,000 /mm3 or neutrophil count ≥1000 /mm3 and 
platelet count <100,000 /mm3.
CR with partial hematological recovery: 
CRh**
All CR criteria are met, except for neutrophil count >500 /mm3 and
platelet count >50,000 /mm3.
Partial remission: PR
Neutrophil count ≥1000 /mm3 and platelet count ≥100,000 /mm3 in 
the absence of RBC or platelet transfusion (4 weeks for RBC 
transfusion, 1 week for platelet transfusion); decrease in bone 
marrow blast percentage by at least 50% and total bone marrow blast 
percentage of 5% to 25%.
Morphologic leukemia-free state: MLFS
Bone marrow blasts <5% in the absence of blasts with Auer rods; 
absence of extra-medullary leukemia.  The presence/absence of 
hematological recovery or blood transfusion is not considered.
Stable disease: SD
Absence of CR, CRi, CRh, PR, or MLFS; and criteria for PD not met.
Progressive disease: PD
When any of the following apply:
>1.5-fold increase in bone marrow blasts over baseline (eg, increase 
in blast count from 35% to >52.5%).  At least 15% point increase in 
bone marrow blasts in cases with <30% blasts at baseline (eg, 
increase in blast count from 20% to 35%).  Persistent bone marrow 
blast percentage of >70% over at least 3 months.  Cases with
improvement in neutrophil count to ≥500 /mm3 and/or improvement 
in platelet count to ≥50,000 /mm3 (without transfusion) are excluded.
>1.5-fold increase in peripheral blasts (WBC × % blasts) to
>25,000 /mm3, in the absence of differentiation syndrome.
New extra-medullary leukemia.
Relapse
Relapse after CR, CRi, or CRh (except in case the criteria for MLFS 
are also met):
Either of appearance of peripheral blasts, bone marrow blast
percentage ≥5%, or relapsed or new extra-medullary leukemia.
Unknown
No post-baseline evaluation.
*
If a subject meets the criteria for both CR and CRh, the outcome should be captured in the case report form as CR.
** If a subject meets the criteria for both CRi and CRh or for both CRh and MLFS, the outcome should be captured in 
the case report form as CRh.


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10.2.
Best Response
Best response is defined as the best measured response over all response assessments (CR, 
CRi, CRh, PR, MLFS, SD, or PD) at all time points after the start of study treatment.
The best response will be SD if the response is assessed as SD three or more times
consecutively in the protocol-specified evaluation of the antitumor effect.  If the response 
is not assessed as SD three or more times consecutively, the best response will be Not 
Applicable (unconfirmed SD).
10.3.
Duration of Composite Complete Remission
The duration of composite CR (CRc) is defined as the length of time from the time when 
the criteria for CRc (CR + CRi + CRh) are first met to the time when a relapse was first 
confirmed.


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11.
STATISTICAL ANALYSIS
An outline of the statistical and pharmacokinetic analyses is provided below.  Statistical 
methods will be specified in more details in the separately prepared Statistical Analysis 
Plan.
11.1.
General Statistical Considerations
Patients treated with the same dose level and schedule will be pooled into a single 
treatment group. All statistical analyses will be performed by treatment group, unless 
otherwise noted.  Subjects whose dose is reduced will be analyzed in the dose group 
before dose reduction.
Baseline values of each subject, unless otherwise specified, will be the last observed 
values that are available before the first dose of the study drug.
Unless otherwise noted, continuous variables will be summarized by the number of
subjects analyzed, arithmetic mean, standard deviation, minimum, median, and maximum, 
whereas categorical variables will be summarized by frequency and proportion.  
Analyses of changes from baseline (eg, absolute change, shift table) will be performed 
for subjects with the baseline value and at least one value available after treatment. Two-
sided 95% confidence interval (CI) will be determined, unless otherwise noted.
11.2.
Analysis Sets
The sponsor will define the criteria for inclusion of subjects in each analysis set in the 
Statistical Analysis Plan, and will determine whether each subject should be included or 
not according to the criteria. Subjects with major Good Clinical Practice (GCP) 
violations (eg, a violation of informed consent procedure, a major violation of study 
procedures) will be excluded from all analysis sets.
11.2.1.
Safety Analysis Set
The safety analysis set will include subjects enrolled in the study but will exclude 
“subjects who have not received any dose of the study drug.”
11.2.2.
Maximum Tolerated Dose Analysis Set
The MTD analysis set will include all subjects who received at least one dose of the 
study drug but will exclude subjects who have missing data of one or more examination 
or observation items during the DLT evaluation period for other reasons than adverse 
drug reactions (worsening of clinical conditions due to progression of the primary disease, 
AEs for which a relationship with the study drug is ruled out, etc.) and whose DLT 
evaluation could not be performed appropriately. The MTD analysis set will also include 
subjects who have experienced DLT in Cycle 1 and subjects who have received the study 
drug on at least 75% of the specified days in Cycle 1 in the absence of DLT.
Subjects for whom the study treatment is postponed due to a DLT occurring during the 
DLT evaluation period, and the study treatment is then resumed at a reduced dose will be 


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handled as those included in the MTD analysis set for the dose level at the first dose of
the study drug.
11.2.3.
Efficacy Analysis Set
The efficacy analysis set will include all subjects who received at least one dose of the 
study drug and who underwent efficacy evaluation after administration at least once.
11.2.4.
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set will include subjects who received at least one dose of 
the study drug, whose specimens for pharmacokinetics have been collected at least once
after the start of treatment, and who have available data of the measurement.
11.2.5.
Biomarker Analysis Set
The biomarker analysis set will include subjects who received at least one dose of the 
study drug, whose specimens for biomarker research have been collected, and who have 
available data of the measurement.
11.3.
Data Handling
The sponsor will decide the handling of individual data in consultation with the medical 
expert as needed, and lock data.
11.4.
Statistical Analysis Items and Methods
11.4.1.
Baseline Subject Characteristics
For baseline subject characteristics (demographic variables and baseline values),
distributions and summary statistics will be calculated.  Frequency tables will be prepared 
for categorical data and summary statistics will be calculated for quantitative data.  
Analyses will be performed in the safety analysis set, MTD analysis set, efficacy analysis 
set, pharmacokinetic analysis set, and biomarker analysis set.
11.4.2.
Safety Analysis
Safety will be analyzed in the safety analysis set, unless otherwise noted. AEs that occur 
or worsen relative to the pre-treatment state after the start of study treatment (TEAEs) 
will be tabulated. AE terms will be converted using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology developed by the ICH.  Individual AEs
will be grouped by organ system using the system organ classes (SOC) of MedDRA, and 
be summarized in the preferred term (PT) level.
11.4.2.1.
Adverse Events
For TEAEs and TEAEs assessed as “related” to the study drug, frequency tables will be 
prepared as classified below.  The grade of AEs will be assessed according to the 
CTCAE Version 5.0.  In the tabulation by grade, only the highest-grade event in each 
subject will be counted for tabulation.


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x
Subjects with TEAEs (by grade; including events classified as Grade ≥3)
x
Subjects with serious TEAEs
x
Subjects who have interrupted study treatment because of a TEAE
x
Subjects withdrawn from study treatment because of a TEAE
For TEAEs and TEAEs assessed as “related” to the study drug, frequency tables will be 
prepared by event as classified below.  The grade of AEs will be assessed according to 
the CTCAE Version 5.0.  If a subject reports a single event two or more times, only the
highest-grade event will be counted for tabulation.
x
TEAEs
x
TEAEs by grade (including events classified as Grade ≤2 and Grade ≥3)
x
Serious TEAEs
x
TEAEs leading to interruption of study treatment
x
TEAEs leading to discontinuation of study treatment
11.4.2.2.
Dose-limiting Toxicity
Frequency table(s) with detailed descriptions of DLTs (if any) will be prepared.
11.4.2.3.
Laboratory Data
For hematology and blood chemistry tests, summary statistics of measured values and 
changes from baseline will be calculated at each scheduled time point.  For urinalysis 
(qualitative data), shift tables of measured values at baseline and those at each time point 
will be prepared.  For urinalysis (quantitative data), summary statistics will be calculated 
at each time point.
11.4.2.4.
Height, Body Weight, and Vital Signs (Blood Pressure, Pulse Rate, and 
Body Temperature)
For blood pressure (systolic and diastolic), pulse rate, body temperature, and body weight, 
summary statistics of measured values and changes from baseline will be calculated at 
each time point.
11.4.2.5.
Electrocardiogram
In the 12-lead ECG analysis on PR, QRS, RR, and QT intervals, QT corrected for heart 
rate using Bazett’s method (QTcB), QTcF, and heart rate, summary statistics of measured 
values and changes from baseline will be calculated at each time point. For QTcF, 
frequency tables will be prepared according to the following categories:
Absolute QTcF:
x
QTcF >450 ms
x
QTcF >480 ms
x
QTcF >500 ms


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Changes in QTcF from baseline:
x
Increase in QTcF from baseline >30 ms
x
Increase in QTcF from baseline >60 ms
11.4.3.
Efficacy Analysis
The efficacy analyses will be performed on the efficacy analysis set, unless otherwise 
noted.
For the best response (CR, CRi, CRh, PR, MLFS, SD, and PD), frequency tables will be 
prepared. The point estimate and the 95% CI will be calculated for the CRc rate, 
response rate, and transplantation rate (as a subsequent AML treatment).
For the duration of CRc, summary statistics will be calculated using the Kaplan-Meier 
method.
11.4.4.
Pharmacokinetic Analysis
Pharmacokinetics will be analyzed for each subtrial in the pharmacokinetic analysis set.
Summary statistics of plasma concentrations of DS-3032a will be calculated by dose at
each time point, and a plasma concentration-time profile will be prepared.
For the pharmacokinetic parameters that are calculated by the non-compartmental 
analysis, summary statistics will be calculated by dose.  The relationship between dose 
and each pharmacokinetic parameter will also be assessed.
11.4.5.
Pharmacodynamic Analysis
For PDy values and PDy parameters, summary statistics will be calculated by treatment 
group.  The time profile of PDy values will be prepared.
11.4.6.
Other Analyses
Analyses using modeling and simulation, including population pharmacokinetic analysis 
and pharmacokinetic/pharmacodynamic analysis, will be performed using plasma
DS-3032a concentration data, where appropriate.  If the analyses are performed, the
results will be separately reported.
11.5.
Changes to the Analysis Plan
When it is considered necessary to change the analysis plan, the sponsor will discuss the 
appropriateness of the change and potential influences on evaluations in the study, and 
determine whether the change is feasible or not.  The sponsor will clearly document and 
retain the content of the discussion about the change in the analysis plan, whether the 
change was made or not, and the reason for the change if it is made.  The details of all 
changes in the analysis plan that have been made will be documented with the reasons in 
the clinical study report.


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11.6.
Planned Sample Size
9 to 24 subjects
Rationale:
In this study, DLT evaluation will be conducted in at least 3 subjects per cohort in
principle, and the safety of DS-3032b at doses up to 160 mg will be confirmed in Subtrial
A unless the completion criteria provided in “Section 5.3.2 Definition of Maximum 
Tolerated Dose” are met.  If no DLT occurs in any of the cohorts before the 160 mg
cohort, the total number of subjects in this study will be the minimum.  In this case, a 
total number of 9 subjects, consisting of 3 subjects each in the 90 mg, 120 mg, and 
160 mg cohorts, will participate in the study.  For instance, if 6 subjects participate in 
each of the 90 mg, 120 mg, and 160 mg cohorts, the total number of subjects 
participating in the study will be 18.  Also, if two or more dosing schedules are assessed, 
the total number of subjects may be further increased.
11.7.
Details of Modified Continual Reassessment Method
The details of mCRM used for explorative dose finding in Subtrial A will be provided in
this section, unless otherwise noted.
11.7.1.
Bayesian Logistic Regression Model
The following BLRM will apply to the dose-response relationship for DLTs:
logit(π(d)) = log(α) + β log(d/d*), α>0, β>0,
where logit(π(d)) = ln (π(d) / (1 − π(d))), π(d) is the DLT rate at a dose of d, and d* is 
160 mg. As a consequence, log(α) is equal to logit(π(d*)) at the dose of d*.  Note that if
the dose is zero, the DLT rate is also zero.  If other dosing schedules are assessed, d* will 
be set separately based on the information obtained up to that time.
11.7.2.
Prior Distribution of Bayesian Logistic Regression Model
Assuming that BLRM model parameters log(α) and log(β) follow bivariate normal 
distribution, a minimally informative prior distribution is set as follows.  If other dosing 
schedules are assessed, each parameter will be set separately based on the information 
obtained up to that time.
Parameter
Mean
Standard Deviation
Correlation 
Coefficient
log(α), log(β)
(−1.8999, 1.3484)
(2.2792, 1.3727)
−0.3157
The above parameters for a prior distribution will be calculated as shown below.


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x
Based on the overseas Phase 1 study (U102), the median probability of the 
DTL rate was estimated to be 5% and 20% for the 120 mg qd 21/28 day 
schedule and the 160 mg qd 21/28 day schedule, respectively.
x
From the ratio (0.67) of the dosing days in this study to U102, the median 
probability of the DTL rate is assumed to be 3% and 13% at doses of 120 mg
and 160 mg, respectively, in this study.
x
Based on the median probability of the DTL rate at the above doses,
parameters of the bivariate normal distribution will be calculated to generate 
vague prior Bayesian intervals (to minimize prior information) using minimal 
information beta distribution.
11.7.3.
Recommended Dose for the Next Cohort by Bayesian Logistic Regression 
Model Incorporating the Escalation with Overdose Control Principle
The recommended dose in the next cohort is decided based on posterior distribution of 
the DLT rate at planned doses (90 mg, 120 mg, and 160 mg). After completing DLT 
evaluation in 3 subjects per cohort in principle, posterior distribution of the DLT rate at 
each planned dose will be estimated using BLRM based on the results of DLT evaluation
and prior distribution set in “Section 11.7.2 Prior Distribution of Bayesian Logistic 
Regression Model,” and posterior probability of the DLT rate falling under the following
four intervals will then be calculated for each planned dose.  The following posterior 
probabilities can also be calculated for other doses than the planned, as long as the dose is 
more than 1.3 times but not more than 2 times of the dose in the concerned cohort.
x
[0, 16%]: DLT rate interval for under-dosing
x
(16, 33%]: target DLT rate interval
x
(33, 60%]: DLT rate interval for excessive toxicity
x
(60, 100%]: DLT rate interval for unacceptable toxicity
Among the planned doses and additional candidate doses, the dose with posterior 
probability of 25% for the DLT rate exceeding 33% (probability for excessive and 
unacceptable toxicity) (according to the EWOC principle) and with the highest posterior 
probability for the DLT rate being more than 16% and 33% or less (probability for target 
DLT rate interval) will be chosen as the recommended dose for the next cohort.  The 
EWOC principle will apply from the third cohort.  Dose increments for the next cohort 
should be within the 1.3-fold and 2-fold range.


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12.
QUALITY CONTROL AND QUALITY ASSURANCE
The sponsor will implement the quality assurance and quality control system in 
accordance with the standard operating procedures specified by the sponsor to ensure that 
the implementation of the study and the generation, recording, and reporting of data are 
in compliance with the following:
1. The clinical study protocol
2. Standards stipulated in Article 14, Paragraph 3 and Article 80-2 of the Act on 
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics (hereinafter referred to as the PMD Act)
3. GCP ordinance
In addition, the sponsor will perform quality control at each stage of data handling to 
ensure the reliability and proper processing of all study-related data.  The methods for 
quality control will be prepared in advance in accordance with the standard operating 
procedure specified by the sponsor, and the implementation will be recorded.
The sponsor’s responsible auditor will perform GCP auditing as part of quality assurance 
operations to determine whether the study is conducted in compliance with GCP, the 
clinical study protocol, and the written procedures independently and separately from the 
regular monitoring and study quality control operations.


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13.
PAYMENT FOR PARTICIPATION, COMPENSATION FOR 
STUDY-RELATED INJURIES, AND INSURANCE
13.1.
Payment for Participation
As compensation to reduce the subject’s burden, etc., the study center will pay subjects 
an amount from the funds paid by the sponsor to the study center according to the 
separately specified regulations of the study center.
13.2.
Compensation for Study-related Injuries
If a subject experiences any study-related injury resulting from participation in the study, 
the investigator or subinvestigator will take the necessary actions, including treatment.  If 
the subject makes a claim for study-related injury, the sponsor will be promptly notified.  
The sponsor will specify the procedures for compensation for study-related injury 
resulting from participation in the study and take actions such as purchase of an insurance 
policy.  In the event of any study-related injury occurring in a subject, the sponsor will 
bear the expenses that are paid by the subject for treatment of the injury, excluding the 
amount covered by health insurance, etc.  For injuries that are as severe as requiring 
hospitalization, the sponsor will also pay a medical allowance based on the amount set in 
the Relief System for Sufferers from Adverse Drug Reactions.  However, this will not 
apply to study-related injuries in case:
1. If there is clear evidence of any other cause of study-related injury.
2. If there is no reasonable temporal relationship between administration of the study 
drug and the occurrence of the study-related injury.
3. If a perpetrator has been identified (for instance, traffic accident).
4. If there were no therapeutic benefits because of lack of efficacy.
5. If a subject or a subject’s partner is found to be pregnant during the study.
6. If there is any protocol violation without due reason.
If a study-related injury is caused by an intentional act or gross negligence on the part of 
the study center or the subject, compensation may not be paid or may be reduced.
13.3.
Insurance
In case of compensation for study-related injury, the sponsor will purchase an insurance 
policy as required.  In case of study-related injury due to medical malpractice, the study 
center will purchase an insurance policy and take other measures as required.


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14.
PUBLICATION POLICY


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15.
STUDY ADMINISTRATIVE INFORMATION
15.1.
Ethics
15.1.1.
Ethical Conduct of the Study
This study will be conducted in compliance with the standards stipulated in Article 14, 
Paragraph 3 and Article 80-2 of the PMD Act and the “Ordinance on Good Clinical 
Practice” (MHW Ordinance No. 28, dated 27 Mar 1997) (hereinafter, the GCP ordinance).  
It will also be conducted in compliance with the ethical principles of the Declaration of 
Helsinki to ensure that the human rights, wellbeing, and safety of subjects are protected 
to the maximum extent.
Genome/gene analysis to be performed during the study, banking of clinical specimens 
for the genome/gene analysis, and a research study using the specimens will be 
performed in accordance with “Ethical Guidelines for Human Genome/Gene Analysis 
Research19” and “Ethical Guidelines for Clinical Studies20” in addition to the above (only
at the study centers that are granted approval for the conduct of genome/gene analysis or 
banking for genome/gene analysis).
15.1.2.
Institutional Review Board
Prior to the start of the study, it must be reviewed and approved by the Institutional 
Review Board (IRB) specified in Section 27 of the GCP ordinance.  During the course of 
the study, the appropriateness of study continuation will be reviewed annually, or more 
frequently upon the IRB’s request.  The appropriateness of study continuation will also 
be reviewed if any information that may affect the safety of subjects or the conduct of the 
study is obtained.
15.2.
Subject Confidentiality
To protect the privacy of individual subjects, the subject identification code or subject 
number, rather than the name or medical chart number, which may lead to personal 
identification, will be used to identify subjects in the documents submitted outside the 
study center.  Any personal information obtained in the course of the study will be kept 
confidential.
15.3.
Procedures for Informed Consent
The investigator or subinvestigator will explain the details of the study listed below to 
subject candidates who have applied to participate in the study in a readily 
understandable way using the informed consent documents, before any screening tests 
are performed, and will obtain written informed consent to participate in the study from 
subjects on their free will.  Before obtaining consent, the investigator or subinvestigator 
should give the subject ample time and opportunity to ask questions to decide whether to 
participate in the study, and should answer the questions to the satisfaction of the subject.


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Identification of TP53 mutation is not necessarily required before the first dose of the 
study drug; however, if the test result becomes available during the study, the 
Investigator and the subject will be immediately notified.  If a TP53 mutation is detected 
after the start of treatment, the treatment will be continued only when it is considered
clinically meaningful.
The investigator or subinvestigator should adequately explain this matter to subjects and 
obtain written informed consent from the subjects based on their free will.
The investigator or subinvestigator who has provided an explanation and the subject who 
has given consent will sign and date the consent form.  If study staff personnel have 
provided a supplementary explanation to the subject, the study staff should also sign and 
date the form.  A copy of the consent form along with the subject information form will 
be provided to the subject, and the original consent form will be retained at the study 
center.  The investigator or subinvestigator will document (eg, in the original consent 
form or medical record) that a copy of the consent form and subject information form 
have been provided to the subject.
[Items to be explained to the subjects]
1. That the study involves research
2. Study objectives
3. Study methods (including experimental aspect of the study, inclusion criteria for 
subjects and, if subjects are randomized to treatment arms, the probability of 
randomization to each treatment)
4. Planned duration of participation in the study
5. Planned number of subjects in the study
6. Foreseeable physical and mental benefits (or if no such benefit, a statement to that 
effect) and risks associated with the study drug
7. Whether or not there are other treatment methods, and if any, expected important 
benefits and risks of the methods
8. Compensation and treatment that the subject can receive if any study-related 
injury occurs as a result of participation in the study
9. Statements that participation in the study is based on the subject’s own free will; 
that the subject can refuse to participate in, or withdraw from, the study at any 
time; that he/she will not be disadvantaged even if he/she refuses to participate in 
or withdraw from the study; and that he/she will not lose any benefits that would 
have been given, even if he/she does not participate in the study
10. A statement that the subject will be promptly informed if any information that 
may affect his/her willingness to continue participation in the study is obtained
11. Conditions or reasons for withdrawal from the study
12. Statements that the Clinical Research Associates, responsible auditors, IRB, and 
regulatory authorities can access source documents; that in such a case, the 


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subject’s privacy will be protected; and that the subject is deemed to have 
consented to such access by writing his/her name and affixing his/her seal on or 
signing the consent form
13. A statement that the subject’s privacy will be protected even if the results of the 
study are published
14. Details of expenses the subject needs to pay, if any
15. Details of payment to the subject, if any
16. Name, title, and contact information of the investigator or subinvestigator
17. Contact information of the study center in the event that the subject requires 
further information regarding the study or the rights of subjects, or in the event of 
study-related injury
18. Responsibilities of subjects
19. The type of IRB that evaluates and reviews the appropriateness of the study, etc., 
items to be evaluated and reviewed by the IRB, and other matters regarding the 
IRB in relation to the study
15.4.
Informed Consent for Biomarker Study
The investigator or subinvestigator will explain the details of the study listed below to 
subjects in a readily understandable way to confirm their willingness to provide consent 
to participate in the biomarker research on their free will, and obtain the result in writing.  
The investigator or subinvestigator will ensure that the subject’s decision on the consent 
has been entered in the concerned section of the informed consent form.
1. Characteristics and properties of genetic information
2. Study objectives
3. Study methods
4. Foreseeable physical and mental benefits and risks associated with the study
5. Statements that participation in the biomarker study is based on the subject’s own 
free will and that the subject can refuse to participate in, or withdraw from, the 
study at any time; that he/she will not be disadvantaged even if he/she withdraws 
his/her consent
6. Handling of specimens and data after withdrawal of consent
7. Matters on the method of handling, duration of storage, and disposal of specimens
8. Compensation that the subject can receive
9. Disclosure of study results and to whom the results belong
10. Details of expenses the subject needs to pay, if any
11. A statement that no payment is made for specimens provided by the subject
12. Protection of human rights, including the subject’s privacy


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15.5.
Informed Consent for Storage (Banking) of Specimens for 
Genome/Gene Analysis
The investigator or subinvestigator will explain the items relating to banking listed below,
in addition to the information given in “Section 15.3 Procedures for Informed Consent” 
and “Section 15.4 Informed Consent for Biomarker Study,” to subjects who have 
provided informed consent for this clinical study in a readily understandable way using 
the informed consent form for storage (banking) of specimens for genome/gene analysis,
and will obtain written informed consent for banking on their free will, separately from 
consent to participate in the clinical study.
1. Characteristics and properties of genetic information
2. Policy for specimen and data handling in the case of consent withdrawal
3. Policy for specimen handling after the completion of genotyping
4. Procedures for handling banked specimens and banking period
5. Disclosure of genotyping results
Even if subjects refuse to participate in or have withdrawn from banking, they may
continue participating in the clinical study unless their willingness to participate in any 
part of the study except for banking is changed. Subjects may refuse to participate or 
withdraw from banking without penalty or loss of benefits to which they are otherwise 
entitled.
15.6.
Provision of New Information Affecting the Conduct of the 
Study
If any information that may affect the subject’s willingness to continue participation in 
the study is obtained, the investigator or subinvestigator will promptly inform the subject 
and confirm the subject’s willingness to continue participation in the study.  The 
investigator or subinvestigator will also document (eg, in the medical record) the date of 
explanation, the person who has given the explanation, the details of the explanation, the 
subject’s decision, and the date of confirmation.  The investigator will also promptly 
revise the consent form and subject information form, as necessary, and submit them to 
the sponsor.  The investigator will also report the revised forms to the head of the study 
center and request review and approval by the IRB.  For subjects who are already 
participating in the study, their consent to remain in the study should be obtained in the 
same manner as the above-mentioned informed consent procedure using the revised 
consent form and subject information form.  A copy of the said consent form and subject 
information form will be provided to the subject.  The investigator or subinvestigator will 
document (eg, in the original consent form or medical record) that a copy of the consent 
form and subject information form have been provided to the subject.
15.7.
Planned Study Period
06 Jul 2018 to 31 Dec 2019


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15.8.
Protocol Amendment
If any amendment has to be made to the clinical study protocol after the start of the study, 
the sponsor will examine the appropriateness of the amendment and potential influences 
on the evaluations in the study, and after discussion with the medical expert, etc., if 
necessary, determine whether to make the amendment or not.  The sponsor will clearly 
document and retain the content of the discussion, whether to amend the protocol or not
and the reason, etc.
The sponsor will promptly notify the investigator of the specific details of the amendment 
to the protocol.  If the protocol is updated to a new version, the sponsor will newly obtain 
written agreement of the investigator and implement the procedures specified by the 
study center.
15.9.
Permanent or Temporary Discontinuation of the Study
If any of the following occur and the sponsor judges that continuation of the study is 
difficult, the sponsor will temporarily discontinue the study at that time.  The sponsor 
will then determine whether to permanently discontinue the entire study, and document 
the decision.
1. If any new safety information regarding the study drug, or information regarding 
SAEs is obtained
2. If any major GCP violation or significant protocol deviation is committed by the 
sponsor, the study center, or the investigator
3. If any other new information of such relevance is obtained during the study
If the sponsor decides to discontinue the study entirely after consultation with the medical 
expert, etc., the sponsor will promptly notify the head of the study center in writing with 
the reason for the discontinuation. The head of the study center will promptly notify the 
investigator and the IRB in writing of the discontinuation and the reason for 
discontinuation.
If the study is discontinued permanently or temporarily for any reason, the investigator 
will promptly notify the subjects participating in the study of the fact, and take 
appropriate actions and perform the necessary tests to verify the safety of subjects.
15.10.
Procedures for Preparing the Case Report Form and Remarks
In this study, case report forms will be prepared by the investigator, and measurement 
reports of 12-lead ECGs, pharmacokinetics, and biomarkers will be prepared at each 
measurement facility.  The preparation method of each measurement result report, etc. 
will be separately specified.
15.10.1.
Style of the Case Report Form
In this study, an electronic case report form will be recorded using the electronic data 
capturing (EDC) system (Table 15.10.1 EDC System), which is designed to prepare 
electronic case report forms.  The case report form (including an audit trail) will be 


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prepared for each subject and the one that was signed by the investigator will be handled 
as the original.  A validated EDC system will be used in the study.
Table 15.10.1:
EDC System
EDC system name
Medidata Rave®
EDC system 
development 
corporation
Medidata Solutions, Inc.
How to enter data
Data entry via the web interface
Terminal for data entry
PC at the study center
OS prohibited
None
Browser
Medidata Rave supports any browser that conforms to HTML 4, 
HTML 5, and CSS2.  JavaScript needs to be enabled in the browser.
Recommended screen 
resolution
1024 × 764 resolution or higher
Recommended 
connection speed
128 kbps or higher
Others
Adobe Flash Player: Version 10 or higher
15.10.2.
Completion of the Case Report Forms
The investigator will take an electronic signature training program prior to preparation of 
the case report form and the training record will supersede the list of signatures and 
printing of seals.
1. The case report form will be completed for subjects who provide informed 
consent.
2. The investigator or subinvestigator will complete the case report form in
accordance with the “Guidance for Completing and Making Corrections to the 
Case Report Form” provided by the sponsor.
3. The study staff will follow the instructions of the investigator or subinvestigator 
when assisting with the completion of the case report form.
4. The investigator will submit the case report form to the sponsor and retain a copy 
of the case report form.
5. If there are any inconsistencies between the data in the case report form and the 
source documents, the investigator will separately prepare a record explaining the 
reason and submit it to the sponsor, and retain a copy of the record.
15.10.3.
Signature or Seal with Printed Name Applied to the Case Report Form
The investigator will check all case report forms prepared at the study center, and affix 
his/her electronic signature to them.


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15.10.4.
Changes or Corrections to the Case Report Form
1. Any corrections to the case report form will be made by the investigator, 
subinvestigator, or study staff in accordance with the “Guidance for Completing 
and Making Corrections to the Case Report Form” provided by the sponsor.
2. The investigator is responsible for the descriptions in the case report form, and 
will retain copies of all records, including changes or corrections.
15.11.
Retention of Source Documents and Other Records
15.11.1.
Definition of Source Documents
Source documents shall refer to original documents, data, and records set forth in ICH-
GCP 1.52, or their certified copies, and include records (source data) necessary to 
reproduce and evaluate the factual progress of the study.  Source documents include 
hospital records, medical records, test records, memoranda, subject diary or check lists 
for evaluation, administration records, data recorded by automated measuring instruments, 
reproductions or transcripts verified as precise copies, microfiches, photographic 
negatives, microfilms or magnetic media, X-ray films, subject files, and records kept at 
either a pharmacy, laboratory, or medical technology department involved in the study, 
etc.
15.11.2.
Record Keeping
15.11.2.1. Institutional Review Board
The founder of the IRB will retain the standard operating procedures, member list, 
documents submitted, minutes and summaries of meetings, letters, etc., until the date 
specified in 1) or 2) below, whichever is later.  However, if longer retention is requested 
by the sponsor, the duration and method of retention will be discussed with the sponsor.
1. Date of approval of DS-3032b (or if clinical development is discontinued, 3 years 
after the date of notification of the discontinuation by the sponsor)
2. Three years after discontinuation or completion of the study
15.11.2.2. Study Center
The head of the study center or the person responsible for record keeping will retain the 
“documents or records related to the clinical study” to be retained by the study center 
until the date specified in 1) or 2) below, whichever is later.  However, if longer retention 
is requested by the sponsor, the duration and method of retention will be discussed with 
the sponsor.  A person responsible for record keeping will be designated for each set of 
records.
The head of the study center or the person responsible for record keeping will take 
measures to prevent loss or disposal of these records during the relevant period and 
provide immediate access to them upon request.
1. Date of approval of the DS-3032b (or if clinical development is discontinued, 3 
years after the date of notification of the discontinuation from the sponsor)


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2. Three years after discontinuation or completion of the study
To respond to subject’s withdrawal of consent for long-term storage (banking) of 
specimens for genome/gene analysis, which may arise after the end of the study, the
study center will retain the subject screening list for up to 20 years after the end of the 
study.
15.11.2.3. Sponsor
The sponsor will retain the “documents or records related to the clinical study” to be 
retained until the date specified in 1) or 2) below, whichever is later.
1. Five years after the date of approval of the DS-3032b (or if clinical development 
is discontinued, 3 years after the date of the decision on discontinuation) or the 
date of completion of the reexamination, whichever is later
2. Three years after discontinuation or completion of the study
15.12.
Source Document Verification
The head of the study center and the investigator will provide direct access to all study-
related documents, including source documents, at the implementation of monitoring and 
auditing by the sponsor as well as inspections by the regulatory authorities and the IRB.  
The sponsor will have direct access to all study-related documents, including source 
documents, at the study center when performing monitoring and auditing to ensure 
appropriate implementation of the study and the reliability of the data. The sponsor will 
confer with the investigator in advance regarding the procedures for source document 
verification.
15.13.
Organization
The study organization is given in Attachment 1.


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16.
REFERENCES
1. Japanese Society of Hematology. Guideline on Hematopoietic Malignant Tumors 
2013 Edition. [Internet]. 2013 [Last access date: 25 May 2018]. Available from: 
http://www.jshem.or.jp/gui-hemali/1_1.html
2. Matsuda A, Matsuda T, Shibata A, et al.; Japan Cancer Surveillance Research 
Group. Cancer incidence and incidence rates in Japan in 2008: a study of 25 
population-based cancer registries for the monitoring of cancer incidence in Japan 
(MCIJ) project. Jpn J Clin Oncol. 2014;44(4):388-96.
3. Ohno R. 4 Incidence of leukemia. Easy-to-understand descriptions about 
leukemia – For patients and their family − (October 2011; 5th rev.) [Internet]. 
Japan Adult Leukemia Study Group. 2011 [Last access date: 09 May 2018]. 
Available from. https://www.jalsg.jp/leukemia/frequency.html
4. Ohtake S, Miyawaki S, Kiyoi H, et al. Randomized trial of response-oriented 
individualized versus fixed-schedule induction chemotherapy with idarubicin and 
cytarabine in adult acute myeloid leukemia: the JALSG AML95 study. Int J 
Hematol. 2010;91(2):276-83.
5. Ohtake S, Miyawaki S. Treatment protocol for acute myeloid leukemia.
Miyawaki S, Nakao S (eds.). Therapeutic manual of leukemia. 3rd rev. Nankodo; 
2009. p.27-41.
6. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-
protein interaction to reactivate p53 function: a novel approach for cancer therapy. 
Annu Rev Pharmacol Toxicol. 2009;49:223-41.
7. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat
Rev Cancer. 2009;9(10):749-58.
8. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by 
small-molecule antagonists of MDM2. Science. 2004;303(5659):844-8.
9. Shangary S, Qin D, McEachern D, et al. Temporal activation of p53 by a specific
MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor 
growth inhibition. PNAS. 2008;105(10):3933-8.
10. Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med 
2007;13(1):23-31.
11. Bueso-Ramos CE, Yang Y, deLeon E, et al. The human MDM-2 oncogene is 
overexpressed in leukemias. Blood. 1993;82(9):2617-23.
12. Mrinal MG, Todd MB, Gary KS, et al. A phase 1 study of the MDM2 inhibitor 
DS-3032b in patients (pts) with advanced solid tumors and lymphomas. J Clin 
Oncol. 2016;34(15 suppl; abstract 2581).
13. DiNardo CD, Rosenthal J, Andreeff M, et al. Phase 1 dose escalation study of 
MDM2 inhibitor DS-3032b in patients with hematological malignancies -
preliminary results. Blood. 2016;128(22 suppl; abstract 593).


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14. Kurzrock R, Blay J-Y, Nguyen BB, et al. A phase 1 study of MDM2 antagonist 
RG7112 in patients (pts) with relapsed/refractory solid tumors. J Clin Oncol. 
2012;30(15 suppl; abstract e13600).
15. Siu LL, Italiano A, Miller WH, et al. Phase 1 dose escalation, food effect and 
biomarker study of RG7388, a more potent second-generation MDM2 antagonist, 
in patients (pts) with solid tumors. J Clin Oncol. 2014;32(15 suppl; abstract 2535).
16. de Weger V, Lolkema MP, Dickson M, et al. A fırst-in-human (FIH) safety and 
pharmacological study of SAR405838, a novel HDM2 antagonist, in patients with 
solid malignancies. Eur J Cancer. 2014;50(6 suppl; abstract 378):121-122.
17. Revision of the “Guidelines for Clinical Evaluation of Anticancer Drugs.”
PFSB/ELD Notification No. 1101001 (01 Nov 2005).
18. Director of the Evaluation and Licensing Division, Pharmaceutical and Medical 
Safety Bureau,Ministry of Health, Labour and Welfare. Clinical Pharmacokinetic 
Studies of Pharmaceuticals. PMSB/ELD Notification No. 796 (01 Jun 2001).
19. Ministry of Education, Culture, Sports, Science and Technology; Ministry of 
Health, Labour and Welfare; Ministry of Economy, Trade and Industry. Ethical 
Guidelines for Human Genome/Gene Analysis Research. (established on 29 Mar 
2001, fully revised on 28 Dec 2004, partially revised on 29 Jun 2005, partially 
revised on 01 Dec 2008, fully revised on 08 Feb 2013).
20. Ministry of Health, Labour and Welfare. Ethical Guidelines for Clinical Studies 
(established on 30 Jul 2003, fully revised on 28 Dec 2004, fully revised on 31 Jul 
2008).


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17.
APPENDICES
Appendix 1
Schedule of Study Procedures
Appendix 2
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Appendix 3
New York Heart Association (NYHA) Functional Classification


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Appendix 1
Schedule of Study Procedures and Specimen Collection (Subtrial A: 14/28 Day Schedule)
Cyclea
Screen-
ing
Cycle 1
Cycle 2
Cycle 
3
Cycle 4
and 
there-
after
Assess-
ment at
with-
drawalb
Follow-
upc
Study treatment
Subjects will take the study drug once daily on Days 1 to 14 of each cycle.
(Meal consumption should be avoided from 2 hours pre-dose to 1 hour post-dose.)
Cycle Day
1
2
8
14
22
1
14
1
1
Acceptable time window (day)
−14
±2
±2
−4
−4
−4
±3
±5
Elapsed time from administration
(hours)
Pre-
dose
1
2
3
6
8
Pre-
dose
Pre-
dose
Pre-
dose
1
2
3
6
8
Pre-
dose
3
Pre-
dose
Pre-
dose
Pre-
dose
Informed consentd
z
Baseline subject characteristics
z
Confirmation of medical history/
complications
z
Confirmation of inclusion/exclusion criteriae
z
Viral marker testf
z
Pregnancy testg
z
z
Assessment of AEsh
Confirmation of concomitant drugs/
therapies
ECOG PS assessment, body weight 
measurement
z
zi
z
z
z
z
z
z
z
z
z
Height measurement
z
Vital signs measurementj
z
zi
z
z
z
z
z
z
z
z
z
z
z
z
Laboratory tests
(Hematology test, blood biochemistry test, 
coagulation test, urine collection)
z
zi
z
z
z
z
z
z
z
z
z
z
12-lead ECG measurementk
(including evaluation of QTcF)
z
z
z
z
z
z
z
z
z
z
z
z
z
z
Bone marrow and peripheral blood 
assessment
z
zl
zl
zl
zl
{m
Biomarkers
Serum
z
z
zn
z
zn
z
Blood and bone marrow
z
z
{m
Collection of specimens for PGxo
z
Blood collection for pharmacokinetics
z
z z z z z
z
zp
z
z z z z z
z
z


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a Each cycle is 28 days long, and DLT evaluation will be conducted at the end of Cycle 1.
b Examinations and assessments will be performed on the day (±3 days) when the investigator or subinvestigator decides subject’s withdrawal from the study.
When the subject withdraws from the study on Day 25 or later based on the day of the last dose of the study drug defined as Day 0, examinations and assessments will be omitted
and Follow-up will be performed immediately.
c Examinations and assessments will be performed on Day 30 (±5 days) based on the day of the last dose of the study drug defined as Day 0. If a subsequent AML treatment is
introduced, Follow-up will be performed before the start of the subsequent AML treatment.
d Will be obtained before screening tests.
e If the study treatment is started on Day 8 or later based on the day of registration defined as Day 0, the subject’s eligibility should be assessed again on the preceding day or the 
start day (before administration) of study treatment.
f Will be confirmed within 90 days before the day of registration.
g Will be performed only for female subjects of childbearing potential (using urine or serum specimens).
h SAEs will be collected (non-SAEs will not be collected) during the period from informed consent obtainment to before the first dose of the study drug.
i Examinations and assessments on Day 1 of Cycle 1 are not necessary when they are performed within 24 hours before the first dose of the study drug.
j Axillary body temperature, pulse rate, and systolic and diastolic blood pressure will be measured at rest.
k A 12-lead ECG will be performed in the supine position after a 10-minute rest.  Each measurement will be performed in triplicate at approximately 1- to 5-minute intervals.
l The acceptable time window for bone marrow and peripheral blood assessment on Day 1 of Cycle 2 and thereafter is Day 25 of the previous cycle to pre-dose on Day 1 of the 
present cycle. After CR is achieved, assessment based on bone marrow findings may be skipped until blasts are observed in the peripheral blood.
m Will be performed when the assessment at withdrawal is omitted.
n The acceptable time window for blood collection for biomarkers on Day 8 of Cycle 1 and Day 22 of Cycle 1 is ±0 days.
o Will be performed only for subjects who have provided informed consent for the PGx study.
p The acceptable time window for blood collection for pharmacokinetics on Day 8 of Cycle 1 is ±0 days.


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Schedule of Study Procedures and Specimen Collection (Subtrial B: 7/28 Day Schedule)
Cyclea
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
there-
after
Assess-
ment at 
with-
drawalb
Follow-
upc
Study treatment
Subjects will take the study drug once daily on Days 1 to 7 of each cycle.
(Meal consumption should be avoided from 2 hours pre-dose to 1 hour post-dose.)
Cycle Day
1
2
7
8
15
22
1
7
22
1
1
Acceptable time window (day)
−14
±2
±2
−2
±2
−4
−4
±3
±5
Elapsed time from administration
(hours)
Pre-
dose
1
2
3
6
8
Pre-
dose
Pre-
dose
1
2
3
6
8
Pre-
dose 3
Pre-
dose
Pre-
dose
Pre-
dose
Informed consentd
z
Baseline subject characteristics
z
Confirmation of medical history/
complications
z
Confirmation of inclusion/
exclusion criteriae
z
Viral marker testf
z
Pregnancy testg
z
z
Assessment of AEsh
Confirmation of concomitant drugs/
therapies
ECOG PS assessment, body weight 
measurement
z
zi
z
z
z
z
z
z
z
z
z
z
Height measurement
z
Vital signs measurementj
z
zi
z
z
z
z
z
z
z
z
z
z
z
z
z
Laboratory tests
(Hematology test, blood 
biochemistry test, coagulation test, 
urine collection)
z
zi
z
z
z
z
z
z
z
z
z
z
z
12-lead ECG measurementk
(including evaluation of QTcF)
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
Bone marrow and peripheral blood 
assessment
z
zl
zl
zl
zl
{m
Biomarkers
Serum
z
z
z
z
Blood and bone 
marrow
z
z
{m
Collection of specimens for PGxn
z
Blood collection for 
pharmacokinetics
z
z z z z z
z
z
z z z z z zo
z
z


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a Each cycle is 28 days long, and DLT evaluation will be conducted at the end of Cycle 1.
b Examinations and assessments will be performed on the day (±3 days) when the investigator or subinvestigator decides subject’s withdrawal from the study.
When the subject withdraws from the study on Day 25 or later based on the day of the last dose of the study drug defined as Day 0, examinations and assessments will be omitted
and Follow-up will be performed immediately.
c Examinations and assessments will be performed on Day 30 (±5 days) based on the day of the last dose of the study drug defined as Day 0.  If a subsequent AML treatment is
introduced, Follow-up will be performed before the start of the subsequent AML treatment.
d Will be obtained before screening tests.
e If the study treatment is started on Day 8 or later based on the day of registration defined as Day 0, the subject’s eligibility should be assessed again on the preceding day or the 
start day (before administration) of study treatment.
f Will be confirmed within 90 days before the day of registration.
g Will be performed only for female subjects of childbearing potential (using urine or serum specimens).
h SAEs will be collected (non-SAEs will not be collected) during the period from informed consent obtainment to before the first dose of the study drug.
i Examinations and assessments on Day 1 of Cycle 1 are not necessary when they are performed within 24 hours before the first dose of the study drug.
j Axillary body temperature, pulse rate, and systolic and diastolic blood pressure will be measured at rest.
k A 12-lead ECG will be performed in the supine position after a 10-minute rest.  Each measurement will be performed in triplicate at approximately 1- to 5-minute intervals.
l The acceptable time window for bone marrow and peripheral blood assessment on Day 1 of Cycle 2 and thereafter is Day 25 of the previous cycle to pre-dose on Day 1 of the 
present cycle. After CR is achieved, assessment based on bone marrow findings may be skipped until blasts are observed in the peripheral blood.
m Will be performed when the assessment at withdrawal is omitted.
n Will be performed only for subjects who have provided informed consent for the PGx study.
o Will be performed at 24 h post-dose of Day 7.


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Schedule of Study Procedures and Specimen Collection (Subtrial C: 3/14 Day × 2 Schedule)
Cyclea
Screen-
ing
Cycle 1
Cycle 2
Cycle 
3
Cycle 
4 and 
there-
after
Assess-
ment at 
with-
drawalb
Follow-
upc
Study treatment
Subjects will take the study drug once daily on Days 1 to 3 and Days 15 to 17 of each cycle.
(Meal consumption should be avoided from 2 hours pre-dose to 1 hour post-dose.)
Cycle Day
1
2
3
4
8
15
16
17
22
1
3
15
17
1
1
Acceptable time window (day)
−14
±2
±2
−4
−4
±3
±5
Elapsed time from 
administration (hours)
Pre-
dose 1 2 3 6 8 Pre-
dose
Pre-
dose 1 2 3 6 8
Pre-
dose 3 Pre-
dose
Pre-
dose 3
Pre-
dose 3 Pre-
dose
Pre-
dose
Pre-
dose
Pre-
dose
Informed consentd
z
Baseline subject characteristics
z
Confirmation of medical history/
complications
z
Confirmation of inclusion/
exclusion criteriae
z
Viral marker testf
z
Pregnancy testg
z
z
Assessment of AEsh
Confirmation of concomitant 
drugs/therapies
ECOG PS assessment, body 
weight measurement
z
zi
z
z
z
z
z
z
z
z
z
z
z
z
Height measurement
z
Vital signs measurementj
z
zi
z
z
z
z
z
z
z
z z
z
z
z
z
z
z
z
Laboratory tests
(Hematology test, blood 
biochemistry test, coagulation 
test, urine collection)
z
zi
z
z
z
z
z
z
z
z
z
z
z
z
12-lead ECG measurementk
(including evaluation of QTcF)
z
z
z
z
z
z
z
z
z
z z
z
z
z
z
z
z
z
Bone marrow and peripheral 
blood assessment
z
zl
zl
zl
zl
{m
Biomarkers
Serum
z
z
z
z
z
z
z
Blood and bone 
marrow
z
z
{m
Collection of specimens for PGxn
z
Blood collection for 
pharmacokinetics
z
z z z z z
z
z
z z z z z zo
z
z
z
z
z


Protocol DS3032-A-J104
Version 01.4, 07 Oct 2019
Proprietary and Confidential
Page 111
a Each cycle is 28 days long, and DLT evaluation will be conducted at the end of Cycle 1.
b Examinations and assessments will be performed on the day (±3 days) when the investigator or subinvestigator decides subject’s withdrawal from the study.
When the subject withdraws from the study on Day 25 or later based on the day of the last dose of the study drug defined as Day 0, examinations and assessments will be omitted
and Follow-up will be performed immediately.
c Examinations and assessments will be performed on Day 30 (±5 days) based on the day of the last dose of the study drug defined as Day 0.  If a subsequent AML treatment is
introduced, Follow-up will be performed before the start of the subsequent AML treatment.
d Will be obtained before screening tests.
e If the study treatment is started on Day 8 or later based on the day of registration defined as Day 0, the subject’s eligibility should be assessed again on the preceding day or the 
start day (before administration) of study treatment.
f Will be confirmed within 90 days before the day of registration.
g Will be performed only for female subjects of childbearing potential (using urine or serum specimens).
h SAEs will be collected (non-SAEs will not be collected) during the period from informed consent obtainment to before the first dose of the study drug.
i Examinations and assessments on Day 1 of Cycle 1 are not necessary when they are performed within 24 hours before the first dose of the study drug.
j Axillary body temperature, pulse rate, and systolic and diastolic blood pressure will be measured at rest.
k A 12-lead ECG will be performed in the supine position after a 10-minute rest.  Each measurement will be performed in triplicate at approximately 1- to 5-minute intervals.
l The acceptable time window for bone marrow and peripheral blood assessment on Day 1 of Cycle 2 and thereafter is Day 25 of the previous cycle to pre-dose on Day 1 of the 
present cycle. After CR is achieved, assessment based on bone marrow findings may be skipped until blasts are observed in the peripheral blood.
m Will be performed when the assessment at withdrawal is omitted.
n Will be performed only for subjects who have provided informed consent for the PGx study.
o Will be performed at 24 h post-dose of Day 3.


Protocol DS3032-A-J104
Version 01.4, 07 Oct 2019
Proprietary and Confidential
Page 112
Schedule of Study Procedures and Specimen Collection (Subtrial D: 21/28 Day Schedule)
Cyclea
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
there-
after
Assess-
ment at 
with-
drawalb
Follow-
upc
Study treatment
Subjects will take the study drug once daily on Days 1 to 21 of each cycle.
(Meal consumption should be avoided from 2 hours pre-dose to 1 hour post-dose.)
Cycle Day
1
2
8
15
21
1
15
21
1
1
Acceptable time window (day)
−14
±2
±2
−2
−4
−4
±3
±5
Elapsed time from 
administration (hours)
Pre-
dose 1
2
3
6
8
Pre-
dose
Pre-
dose
Pre-
dose 1
2
3
6
8
Pre-
dose
3
Pre-
dose
3
Pre-
dose
Pre-
dose
Pre-
dose
Pre-
dose
Informed consentd
z
Baseline subject characteristics
z
Confirmation of medical history/
complications
z
Confirmation of inclusion/
exclusion criteriae
z
Viral marker testf
z
Pregnancy testg
z
z
Assessment of AEsh
Confirmation of concomitant drugs/
therapies
ECOG PS assessment, body weight 
measurement
z
zi
z
z
z
z
z
z
z
z
z
z
Height measurement
z
Vital signs measurementj
z
zi
z
z
z
z
z
z
z
z
z
z
z
z
z
Laboratory tests
(Hematology test, blood 
biochemistry test, coagulation test, 
urine collection)
z
zi
z
z
z
z
z
z
z
z
z
z
z
12-lead ECG measurementk
(including evaluation of QTcF)
z
z
z
z
z
z
z
z
z
z
z
z
z
z
z
Bone marrow and peripheral blood 
assessment
z
zl
zl
zl
zl
{m
Biomarkers
Serum
z
z
z
z
z
Blood and bone 
marrow
z
z
{m
Collection of specimens for PGxn
z
Blood collection for 
pharmacokinetics
z
z z z z z
z
zo
z
z z z z z
z
z
z


Protocol DS3032-A-J104
Version 01.4, 07 Oct 2019
Proprietary and Confidential
Page 113
a Each cycle is 28 days long, and DLT evaluation will be conducted at the end of Cycle 1.
b Examinations and assessments will be performed on the day (±3 days) when the investigator or subinvestigator decides subject’s withdrawal from the study.
When the subject withdraws from the study on Day 25 or later based on the day of the last dose of the study drug defined as Day 0, examinations and assessments will be omitted
and Follow-up will be performed immediately.
c Examinations and assessments will be performed on Day 30 (±5 days) based on the day of the last dose of the study drug defined as Day 0.  If a subsequent AML treatment is
introduced, Follow-up will be performed before the start of the subsequent AML treatment.
d Will be obtained before screening tests.
e If the study treatment is started on Day 8 or later based on the day of registration defined as Day 0, the subject’s eligibility should be assessed again on the preceding day or the 
start day (before administration) of study treatment.
f Will be confirmed within 90 days before the day of registration.
g Will be performed only for female subjects of childbearing potential (using urine or serum specimens).
h SAEs will be collected (non-SAEs will not be collected) during the period from informed consent obtainment to before the first dose of the study drug.
i Examinations and assessments on Day 1 of Cycle 1 are not necessary when they are performed within 24 hours before the first dose of the study drug.
j Axillary body temperature, pulse rate, and systolic and diastolic blood pressure will be measured at rest.
k A 12-lead ECG will be performed in the supine position after a 10-minute rest.  Each measurement will be performed in triplicate at approximately 1- to 5-minute intervals.
l The acceptable time window for bone marrow and peripheral blood assessment on Day 1 of Cycle 2 and thereafter is Day 25 of the previous cycle to pre-dose on Day 1 of the 
present cycle. After CR is achieved, assessment based on bone marrow findings may be skipped until blasts are observed in the peripheral blood.
m Will be performed when the assessment at withdrawal is omitted.
n Will be performed only for subjects who have provided informed consent for the PGx study.
o The acceptable time window for blood collection for pharmacokinetics on Day 8 of Cycle 1 is ±0 days.


Protocol DS3032-A-J104
Version 01.4, 07 Oct 2019
Proprietary and Confidential
Page 114
Appendix 2
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Score
ECOG PS
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 (eg, light housework, 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.
EOCG


Protocol DS3032-A-J104
Version 01.4, 07 Oct 2019
Proprietary and Confidential
Page 115
Appendix 3
New York Heart Association (NYHA) Functional Classification
Class
Symptoms
Class I
Patients with cardiac disease but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort is 
increased.