Phase 3 Open-label, Multicenter, Randomized Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation
Phase: PHASE3
Conditions: AML With FLT3 Mutation
Sponsor: Astellas Pharma Inc

Sponsor: API 
ISN/Protocol 2215-CL-0303 
- CONFIDENTIAL - 
05 Jun 2023 
Astellas 
Page 1 of 147 
Version 7.0 
Phase 3 Open-label, Multicenter, Randomized Study 
of ASP2215 versus Salvage Chemotherapy in Patients with 
Relapsed or Refractory Acute Myeloid Leukemia (AML) 
with FLT3 Mutation 
Protocol for Phase 3 Study of ASP2215 
 
ISN/Protocol 2215-CL-0303 
Version 7.0 
Incorporating Substantial Amendment 3 
05 June 2023 
 
 
Sponsor: 
Astellas Pharma Inc. 
 
Protocol History:  
Version 1.0 [13Feb2017] 
Version 2.0 [29Jun2017] 
Version 3.0 [08Aug2018] 
Version 4.0 [10Oct2019] 
Version 5.0 [25Mar2020] 
Version 6.0 [18Feb2021] 
 
This confidential document is the property of the Sponsor. No unpublished information 
contained in this document may be disclosed without prior written approval of the Sponsor. 

Sponsor: API 
ISN/Protocol 2215-CL-0303 
- CONFIDENTIAL - 
05 Jun 2023 
Astellas 
Page 2 of 147 
Version 7.0 
Table of Contents 
I. 
SIGNATURES ································
································
······················
 9 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ································
·······  11 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ····························
 13 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················
 15 
IV. 
SYNOPSIS ································
································
··························
 19 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································
· 38 
1 
INTRODUCTION ································
································
·················
 53 
1.1 
Background ································
································
····················
 53 
1.2 
Non-clinical and Clinical Data ································
······························
 54 
1.2.1 
Non-clinical Data ································
································
········  54 
1.2.2 
Clinical Data ································
································
·············
 55 
1.2.2.1 
Clinical Pharmacokinetics and Pharmacodynamics ···························
 55 
1.2.2.2 
Clinical Efficacy ································
································
···  56 
1.3 
Summary of Key Safety Information for Study Drugs ································
···  56 
1.3.1 
ASP2215································
································
··················
 56 
1.3.1.1 
ASP2215 Non-clinical Data ································
······················
 57 
1.3.1.2 
ASP2215 Clinical Data ································
···························
 57 
1.3.2 
Comparative Chemotherapy Regimens ································
···············
 59 
1.4 
Risk-Benefit Assessment ································
································
·····  59 
2 
STUDY OBJECTIVES, DESIGN AND ENDPOINTS ································
·····  60 
2.1 
Study Objectives ································
································
··············
 60 
2.1.1 
Primary Objective ································
································
·······  60 
2.1.2 
Secondary Objectives ································
································
···  60 
2.1.3 
Exploratory Objectives ································
································
· 60 
2.2 
Study Design and Dose Rationale ································
···························
 61 
2.2.1 
Study Design ································
································
·············
 61 
2.2.2 
Dose Rationale ································
································
···········
 63 
2.2.2.1 
ASP2215 ································
································
············
 63 
2.2.2.2 
Comparator Chemotherapy Regimens ································
··········
 63 
2.3 
Endpoints ································
································
·······················
 64 
2.3.1 
Primary Endpoint ································
································
········  64 
2.3.2 
Secondary Endpoints ································
································
····  64 

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05 Jun 2023 
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Version 7.0 
2.3.3 
Exploratory Endpoints ································
································
··  64 
2.3.4 
Safety Endpoints ································
································
·········  64 
2.3.5 
Pharmacokinetics ································
································
········  64 
3 
STUDY POPULATION ································
································
··········
 65 
3.1 
Selection of Study Population ································
·······························
 65 
3.2 
Inclusion Criteria ································
································
··············
 65 
3.3 
Exclusion Criteria ································
································
·············
 66 
4 
TREATMENT(S) ································
································
··················
 68 
4.1 
Identification of Investigational Products ································
··················
 68 
4.1.1 
ASP2215································
································
··················
 68 
4.1.2 
Comparative Drug(s) ································
································
····  68 
4.2 
Packaging and Labeling ································
································
······  70 
4.3 
Study Drug Handling ································
································
·········  70 
4.4 
Blinding ································
································
························
 71 
4.5 
Assignment and Allocation ································
································
··  71 
5 
TREATMENTS AND EVALUATION ································
························
 71 
5.1 
Dosing and Administration of Study Drugs and Other Medications ····················
 71 
5.1.1 
Dose/Dose Regimen and Administration Period ································
····  71 
5.1.1.1 
ASP2215 ································
································
············
 71 
5.1.1.2 
Comparative Drugs ································
································
 71 
5.1.2 
Interruption, Reduction or Escalation in Dose of the Study Drug ·················
 72 
5.1.3 
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy) ································
································
··················
 74 
5.1.3.1 
ASP2215 Group Only ································
·····························
 74 
5.1.3.2 
ASP2215 Group and Chemotherapy Group ································
····  74 
5.1.4 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation ······  75 
5.1.5 
Treatment Compliance ································
································
··  75 
5.2 
Demographics and Baseline Characteristics ································
···············
 75 
5.2.1 
Demographics ································
································
············
 75 
5.2.2 
Medical History ································
································
··········
 75 
5.2.3 
Diagnosis of the Target Disease, Severity and Duration of Disease ··············
 76 
5.2.4 
FLT3 Mutation Status ································
································
···  76 
5.2.5 
Performance Status ································
································
······  76 
5.3 
Efficacy Assessment ································
································
··········
 77 

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5.3.1 
Response Definitions ································
································
···  77 
5.3.1.1 
Complete Remission ································
······························
 77 
5.3.1.2 
Complete Remission with Incomplete Platelet Recovery ·····················
 77 
5.3.1.3 
Complete Remission with Incomplete Hematologic Recovery ··············
 77 
5.3.1.4 
Composite Complete Remission Rate ································
···········
 77 
5.3.1.5 
Partial Remission ································
································
··  77 
5.3.1.6 
Relapse ································
································
··············
 78 
5.3.1.7 
Best Response ································
································
······  78 
5.3.2 
Survival Time, Duration and Other Efficacy Endpoints ····························
 78 
5.3.2.1 
Overall Survival ································
································
····  78 
5.3.2.2 
Event-free Survival ································
································
 78 
5.3.2.3 
Leukemia-free Survival ································
···························
 78 
5.3.2.4 
Duration of Remission ································
····························
 78 
5.3.2.5 
Transplantation Rate ································
······························
 79 
5.3.3 
Bone Marrow Aspiration and/or Biopsy ································
··············
 79 
5.3.4 
Survival Status and Subsequent Antileukemic Treatments and Their 
Outcomes ································
································
·················
 80 
5.3.5 
Pharmacokinetics Assessment ································
·························
 80 
5.4 
Safety Assessment ································
································
············
 81 
5.4.1 
Vital Signs ································
································
················
 81 
5.4.2 
Adverse Events ································
································
··········
 81 
5.4.2.1 
Adverse Events of Possible Hepatic Origin ································
····  81 
5.4.2.2 
Adverse Events during Hematopoietic Stem Cell Transplant ················
 82 
5.4.3 
Laboratory Assessments ································
································
 82 
5.4.4 
Physical Examination ································
································
···  82 
5.4.5 
Electrocardiogram ································
································
·······  82 
5.4.6 
Chest X-ray or Computed Tomography Scan ································
········  83 
5.4.7 
Multigated Acquisition Scan or Echocardiogram ································
···  83 
5.5 
Adverse Events and Other Safety Aspects ································
·················
 84 
5.5.1 
Definition of Adverse Events ································
··························
 84 
5.5.2 
Definition of Serious Adverse Events································
·················
 84 
5.5.3 
Special Situations ································
································
········  85 
5.5.4 
Criteria for Causal Relationship to the Study Drug ································
· 86 
5.5.5 
Criteria for Defining the Severity of an Adverse Event ····························
 86 
5.5.6 
Reporting of Serious Adverse Events ································
·················
 87 
5.5.7 
Follow-up of Adverse Events ································
··························
 88 

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5.5.8 
Monitoring of Common Serious Adverse Events ································
···  88 
5.5.9 
Procedure in Case of Pregnancy ································
·······················
 88 
5.5.10 
Emergency Procedures and Management of Overdose ·····························
 89 
5.5.11 
Supply of New Information Affecting the Conduct of the Study ··················
 89 
5.5.12 
Urgent Safety Measures ································
································
 89 
5.5.13 
Reporting Urgent Safety Measures ································
····················
 90 
5.6 
Test Drug Concentration ································
································
·····  90 
5.6.1 
Pharmacokinetics ································
································
········  90 
5.7 
Other Measurements, Assessments or Methods ································
···········
 90 
5.7.1 
Patient Reported Outcome Measures ································
·················
 90 
5.7.1.1 
Brief Fatigue Inventory ································
···························
 90 
5.7.1.2 
EuroQol Group-5 Dimension-5 Level Instrument ·····························
 91 
5.7.1.3 
Functional Assessment of Chronic Illness Therapy–Dyspnea-Short 
Forms ································
································
················
 91 
5.7.1.4 
Functional Assessment of Cancer Therapy-Leukemia ························
 91 
5.7.1.5 
Dizziness and Mouth Sores Items ································
···············
 92 
5.7.2 
Resource Utilization ································
································
····  92 
5.7.3 
Exploratory Biomarker Analysis ································
······················
 92 
5.7.4 
Whole Blood and Buccal Sample for Future Pharmacogenomics Analysis 
(Retrospective Pharmacogenomics Analysis) (Optional) ···························
 92 
5.8 
Total Amount of Blood ································
································
·······  93 
6 
DISCONTINUATION ································
································
············
 93 
6.1 
Discontinuation of Individual Subject(s) ································
···················
 93 
6.1.1 
Discontinuation Criteria from Treatment for Individual Subjects ·················
 94 
6.1.2 
Discontinuation Criteria from the Posttreatment Period for Individual 
Subjects ································
································
···················
 94 
6.2 
Discontinuation of the Site ································
································
···  94 
6.3 
Discontinuation of the Study ································
································
 95 
7 
STATISTICAL METHODOLOGY ································
···························
 95 
7.1 
Sample Size ································
································
····················
 95 
7.2 
Analysis Set ································
································
····················
 96 
7.2.1 
Intention to Treatment Set ································
······························
 96 
7.2.2 
Full Analysis Set ································
································
········  96 
7.2.3 
Safety Analysis Set ································
································
······  96 
7.2.4 
Pharmacokinetic Analysis Set ································
·························
 96 

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7.3 
Demographics and Other Baseline Characteristics ································
········  97 
7.3.1 
Demographics ································
································
············
 97 
7.3.2 
Medical History ································
································
··········
 97 
7.3.3 
Disease History ································
································
··········
 97 
7.3.4 
Previous and Concomitant Medications ································
··············
 97 
7.3.5 
Subject Disposition ································
································
······  97 
7.3.6 
Drug Exposure ································
································
···········
 97 
7.4 
Analysis of Efficacy ································
································
··········
 97 
7.4.1 
Analysis of Primary Endpoint ································
·························
 98 
7.4.2 
Analysis of Secondary Endpoints ································
·····················
 98 
7.4.2.1 
Key Secondary Efficacy Analysis ································
···············
 98 
7.4.2.2 
Secondary Efficacy Analyses ································
····················
 98 
7.4.3 
Analysis of Exploratory Endpoints ································
····················
 99 
7.4.4 
Subgroup Analysis ································
································
······  99 
7.5 
Analysis of Safety ································
································
·············
 99 
7.5.1 
Adverse Events ································
································
··········
 99 
7.5.2 
Laboratory Assessments ································
······························
 100 
7.5.3 
Vital Signs ································
································
··············
 100 
7.5.4 
Physical Examination ································
································
· 100 
7.5.5 
Electrocardiograms ································
································
····  100 
7.5.6 
ECOG Performance Scores ································
··························
 100 
7.6 
Analysis of Pharmacokinetics ································
······························
 100 
7.6.1 
Estimation of Pharmacokinetic Parameters ································
········  100 
7.7 
Protocol Deviations ································
································
··········
 101 
7.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················
 101 
7.9 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········  102 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ··················
 102 
8.1 
Procedure for Clinical Study Quality Control ································
············
 102 
8.1.1 
Data Collection ································
································
········  102 
8.1.2 
Specification of Source Documents ································
·················
 103 
8.1.3 
Clinical Study Monitoring ································
····························
 103 
8.1.4 
Direct Access to Source Data/Documents ································
··········
 103 
8.1.5 
Data Management ································
································
·····  104 
8.1.6 
Protocol Deviations ································
································
···  104 

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8.1.7 
End of Trial in All Participating Countries ································
·········  105 
8.2 
Ethics and Protection of Subject Confidentiality ································
·········  105 
8.2.1 
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities ································
································
··············
 105 
8.2.2 
Ethical Conduct of the Study ································
·························
 105 
8.2.3 
Informed Consent of Subjects ································
·······················
 105 
8.2.3.1 
Subject Information and Consent ································
··············
 105 
8.2.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ···························
 106 
8.2.4 
Subject Confidentiality ································
·······························
 106 
8.3 
Administrative Matters ································
································
······  106 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ···  106 
8.3.2 
Documents and Records Related to the Clinical Study ···························
 107 
8.3.3 
Protocol Amendment and/or Revision ································
··············
 108 
8.3.4 
Insurance of Subjects and Others ································
····················
 109 
8.3.5 
Signatory Investigator for Clinical Study Report ································
··  109 
9 
QUALITY ASSURANCE ································
································
······  109 
10 
STUDY ORGANIZATION ································
································
····  109 
10.1 
Independent Data-Monitoring Committee (IDMC) ································
······  109 
10.2 
Other Study Organization ································
································
···  110 
11 
REFERENCES ································
································
··················
 111 
12 
APPENDICES ································
································
···················
 113 
12.1 
List of Excluded and Cautionary Concomitant Medications ····························
 113 
12.2 
Liver Safety Monitoring and Assessment ································
·················
 118 
12.3 
Laboratory Tests ································
································
·············
 121 
12.4 
Common Serious Adverse Events ································
··························
 123 
12.5 
Retrospective PGx Sub-Study (Optional) ································
·················
 125 
12.6 
Definitions of Line of Therapy and Tools to Determine Study Eligibility ············
 127 
12.7 
Crossover Extension ································
································
·········  127 
12.7.1 
Rationale and design for COE portion of the study ·······························
 127 
12.7.2 
Inclusion Criteria ································
································
······  128 
12.7.3 
Exclusion Criteria ································
································
·····  129 
12.7.4 
Treatment of COE ································
································
·····  130 
12.7.5 
Schedule and Assessments ································
···························
 130 

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12.7.6 
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy) ································
································
················
 131 
12.7.7 
Duration of Treatment and Discontinuation Criteria ······························
 131 
12.7.8 
Statistical Methods ································
································
····  132 
12.8 
Continuation of Study Treatment with ASP2215 ································
········  132 
12.9 
Clinical Study Continuity ································
································
···  133 
13 
SPONSOR’S SIGNATURES ································
································
··  147 
 

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I. 
SIGNATURES 
1. SPONSOR’S SIGNATURE 
Required signatures (e.g., protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in [Section 13 Sponsor’s Signatures]; e-signatures (when applicable) are located at 
the end of this document. 

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2. INVESTIGATOR’S SIGNATURE 
Phase 3 Open-label, Multicenter, Randomized Study of ASP2215 versus Salvage 
Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia 
(AML) with FLT3 Mutation 
ISN/Protocol 2215-CL-0303 
Version 7.0/ 05 June 2023 
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents. 
Principal Investigator: 
 
Signature: 
 
Printed Name: 
Date (DD Mmm YYYY) 
Address: 
 
 
 
 
 
 
 
 
 

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Version 7.0 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Substantial Amendment 3 (Version 7.0) 
05 Jun 2023 
Substantial Amendment 2 (Version 6.0) 
18 Feb 2021 
Nonsubstantial Amendment 3 (Version 5.0) 
25 Mar 2020 
Nonsubstantial Amendment 2 (Version 4.0) 
10 Oct 2019 
Nonsubstantial Amendment 1 (Version 3.0) 
08 Aug 2018 
Substantial Amendment 1 (Version 2.0) 
29 Jun 2017 
Original Protocol  
13 Feb 2017 
Amendment 3 [Substantial] 05 Jun 2023 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament, the Council of the European Union and 
EU Clinical Trial Regulation. 
Overall Rationale for the Amendment: 
To provide access to study drug to subjects continuing to receive clinical benefit where 
applicable reimbursement of the marketed product cannot be established. 
Summary of Changes 
Substantial Changes 
Section Number 
Description of Change 
Brief Rationale 
IV, 2.2.1, 6, 6.1, 6.1.2, 
7.5.1, 12.8 
The study treatment continues until 
subjects meet the discontinuation 
criteria or applicable 
reimbursement becomes available 
in the country of residence. 
To provide access to 
study drug to subjects 
continuing to receive 
clinical benefit in 
countries where 
applicable 
reimbursement of the 
marketed product 
cannot be established 
yet. 
IV, V (Flow Chart and 
Table 5), 2.2.1, 5.1.2, 
5.3.4, 5.3.5, 5.5.2, 5.5.6, 
5.6.1, 7.5.1, 12.8 
After the subjects’ reconsent, the 
subject will be managed according 
to the local institution’s standard of 
care. Only SAEs will be collected 
and reported until 30 days after the 
last dose of study treatment. No 
data will be collected in the eCRF. 
To reduce subject’s 
burden for the study 
procedures, considering 
the subjects’ safety and 
efficacy. 
5.5.2 
Add important medical events to 
the list of events held by the 
Sponsor that may require 
additional information. 
To bring protocol 
2215-CL-0303 into 
alignment with other 
gilteritinib documents. 

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Non-substantial Changes 
Section Number 
Description of Change 
Brief Rationale 
II, 13 
 
 as the 
Clinical Research Contacts. 
Astellas Pharma China, Inc. is 
replaced by Astellas (China) 
Investment Co., Ltd.  
To provide corrected 
personnel information. 
II, 5.5.6 
Change the 24 h-Contact for 
Serious Adverse Events (SAEs) 
from Quintiles East Asia Pte Ltd 
(Singapore) to IQVIA RDS East 
Asia Pte Ltd. 
To update the safety 
reporting information.  
IV,2.2.1, 12.7, 12.7.1 
Update language to indicate the 
COE has been implemented. 
To bring protocol 
language up to date. 
IV, 7.1 
The planned sample size with EFS 
event is updated from 230 to 250. 
To correct an error 
aligning the latest SAP.  
12.1 
Add substrates of P-gp, BCRP and 
OCT1 to the list of excluded and 
cautionary concomitant 
medications. 
To bring protocol 
2215-CL-0303 into 
alignment with latest IB. 
Throughout 
Minor administrative-type changes, 
e.g., typos, format, numbering, 
consistency throughout the 
protocol. 
To provide clarifications 
to the protocol and to 
ensure complete 
understanding of study 
procedures. 
 
PPD

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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
24 h-Contact for Serious 
Adverse Events (SAEs) 
See Section 5.5.6 
 
 
Development Medical Department/ Development 
Division 
Astellas (China) Investment Co., Ltd. 
27th floor, Beijing IFC Tower, No.8 Jianguomenwai 
Avenue, Chaoyang District, Beijing 100022, P.R.C 
 
 
 
Please email the SAE Worksheet to: 
IQVIA Lifecycle Safety Department 
IQVIA RDS East Asia Pte. Ltd.  
Email address: QLS_ASP2215@iqvia.com 
 
For more information, please refer to the SAE worksheet 
completion guideline. 
Medical Monitor/Medical 
Expert 
 
 
Development Medical Department/ Development 
Division 
Astellas (China) Investment Co., Ltd.  
27th floor, Beijing IFC Tower, No.8 Jianguomenwai 
Avenue, Chaoyang District, Beijing 100022, P.R.C 
 
 
Clinical Research Contacts 
  
  
Development Clinical Department/ Development 
Division 
Astellas (China) Investment Co., Ltd. 
27th floor, Beijing IFC Tower, No.8 Jianguomenwai 
Avenue, Chaoyang District, Beijing 100022, P.R.C 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD

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Astellas Pharma, Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, 
103-8411, JAPAN 
 
 
 
PPD
PPD

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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of Abbreviations 
5HT1R 
5-hydroxytryptamine receptor 1 
5HT2BR 
5-hydroxytryptamine receptor 2B 
ΔQTcF 
Fridericia-corrected QT interval change from baseline 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
API 
Astellas Pharma Inc. 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AXL 
AXL tyrosine kinase 
BCRP 
Breast cancer resistance protein 
BFI 
Brief Fatigue Inventory 
Ca2+ 
Calcium 
CK 
Creatine kinase 
Cmax 
Maximum tissue concentration 
CMH 
Cochran-Mantel-Haenszel 
COE 
Crossover extension 
CR 
Complete remission 
CRc 
Composite complete remission 
CRF 
Case Report Form 
CRi 
Complete remission with incomplete hematologic recovery 
CRO 
Contract Research Organization 
CRp 
Complete remission with incomplete platelet recovery 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Observed trough concentration 
CYP 
Cytochrome P450 
DLT 
Dose limiting toxicity 
DTP 
Direct-to-Participant 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFS 
Event-free survival 
EGFR 
Epidermal Growth Factor Receptor 
EGFR m+ 
Epidermal Growth Factor Receptor Mutation positive 
EQ-5D-5L 
EuroQol Group-5 Dimension-5 Level Instrument 
FACIT-Dys-SF 
Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms 
FACT-Leu 
Functional Assessment of Cancer Therapy-Leukemia 
FAS 
Full Analysis Set 

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Abbreviations 
Description of Abbreviations 
FLAG 
Fludarabine, cytarabine and granulocyte colony-stimulating factor 
FLT3 
FMS-like tyrosine kinase 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GMP 
Good Manufacturing Practice 
GVHD 
Graft-versus-host disease 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard ratio 
HSCT 
Hematopoietic stem cell transplant 
IAP 
Interim Analysis Plan 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IEC 
Independent Ethics Committee 
IND 
Investigational new drug 
INR 
International normalization ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITD 
Internal tandem duplication 
ITT 
Intention to Treatment Set 
IV 
Intravenous 
LA-CRF 
Liver Abnormality-Case Report Form 
LFS 
Leukemia-free survival 
LFT 
Liver function tests 
LLN 
Lower limit of normal 
LoDAC 
Low-dose cytarabine 
LVEF 
Left ventricular ejection fraction 
MATE1 
Multidrug and toxin extrusion protein 1 
MDS 
Myelodysplastic syndrome 
MEC 
Mitoxantrone, etoposide and intermediate-dose cytarabine 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer  
NR 
No response 
NYHA 
New York Heart Association 
OATP 
Organic anion transporting polypeptide 
OS 
Overall survival 
PD 
Progressive disease 
PD 
Protocol deviation 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenomics 
PIA 
Plasma inhibitory assay 

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Abbreviations 
Description of Abbreviations 
PKAS 
Pharmacokinetic Analysis Set 
PPS 
Per Protocol Set 
PR 
Partial remission 
PRO 
Patient reported outcome 
PT 
Preferred term 
PT 
Prothrombin time 
QTc 
Corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAS 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOP 
Standard Operating Procedure 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TK 
Tyrosine kinase 
TKD 
Tyrosine kinase domain 
TLFs 
Tables, listings and figures 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WHO 
World Health Organization 
 

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Definition of Key Study Terms 
Terms 
Definition of Terms 
Baseline 
Observed values/findings which are regarded as the starting point for 
comparison. 
Enroll 
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject. 
Intervention 
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) is usually given to a subject, and continues until the last 
assessment after completing administration of the test drug or comparative 
drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Randomization 
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screen failure 
Potential subject who signed consent but did not meet 1 or more criteria 
required for participation in a trial and did not randomize to the trial. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the randomization. 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 

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IV. 
SYNOPSIS 
Date and Version # of Protocol Synopsis: 
05 Jun 2023/Version 7.0 
Sponsor: 
Astellas Pharma Inc. (API) 
Protocol Number: 
2215-CL-0303 
Name of Study Drug:  
ASP2215 
Phase of Development:  
Phase 3 
Title of Study: 
Phase 3 Open-Label, Multicenter, Randomized Study of ASP2215 versus Salvage 
Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
with FLT3 Mutation 
Planned Study Period: 
From June 2017 until last subject discontinuation of study treatment under local standard 
of care.   
Study Objective(s): 
The primary objective is to: 
• Determine the clinical benefit of ASP2215 therapy in subjects with FMS-like tyrosine 
kinase (FLT3) mutated AML who are refractory to or have relapsed after first-line 
AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. 
The key secondary objectives are to: 
• Determine the overall efficacy in event-free survival (EFS) of ASP2215 compared to 
salvage chemotherapy. 
• Determine the overall efficacy in complete remission (CR) rate of ASP2215 compared 
to salvage chemotherapy. 
The secondary objectives are to: 
Evaluate the safety and efficacy of ASP2215 therapy versus salvage chemotherapy in 
terms of:  
• leukemia-free survival (LFS) 
• duration of remission 
• composite complete remission (CRc) rate 
• transplantation rate 
• patient reported fatigue (Brief Fatigue Inventory [BFI]) 
• adverse events (AEs), safety labs, vital signs, electrocardiograms (ECGs) and Eastern 
Cooperative Oncology Group (ECOG) performance scores 
• evaluate the PK of ASP2215 therapy in Chinese population 

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The exploratory objectives are to: 
Evaluate the safety and efficacy of ASP2215 therapy versus salvage chemotherapy in 
terms of:  
• Pharmacogenomics (PGx) 
• FLT3 gene mutation status 
o mutation types and frequency 
o relationship to efficacy and safety 
• exploratory (predictive) biomarkers of ASP2215 activity 
• resource utilization in this study population including hospitalization, blood 
transfusion, antibiotic iv infusions, medication for AEs and opioid usage 
• patient reported dyspnea (Functional Assessment of Chronic Illness Therapy–Dyspnea-
Short Forms [FACIT-Dys-SF]) 
• patient reported signs, symptoms and impacts of AML (Functional Assessment of 
Cancer Therapy-Leukemia [FACT-Leu], dizziness and mouth sore items) 
• EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L) 
Planned Total Number of Study Centers and Location(s): 
Approximately 50 centers: 
China, Russia, Singapore, Thailand, and Malaysia 
Two (or more) study sites in China will be designated as a “pharmacokinetic cohort site” 
(PK cohort site) which will collect PK samples after single and multiple doses in Chinese 
subjects. The first 20 subjects (10 male and 10 female) randomized into ASP2215 arm at 
PK cohort sites will participate in PK cohort.  
Study Population: 
FLT3-mutated subjects with relapsed or refractory AML after first-line therapy. 
Number of Subjects to be Enrolled / Randomized:  
318 subjects will be randomized 
Among 318 subjects, approximately 20 Chinese subjects who are randomized into the 
ASP2215 arm will be allocated to the PK cohort. 
Study Design Overview:  
This is phase 3, open-label, multicenter, randomized study to compare the efficacy and 
safety of ASP2215 therapy to salvage chemotherapy in FLT3-mutated AML subjects who 
are refractory to or have relapsed after first-line AML therapy. 
Three hundred eighteen subjects will be randomized in a 1:1 ratio to receive ASP2215 or 
salvage chemotherapy.  
Among 318 subjects, approximately 20 Chinese subjects (10 male and 10 female subjects) 
who are randomized into the ASP2215 arm will be allocated to the PK cohort. Subjects in 
the PK cohort will be requested to be hospitalized from the date of randomization (Day 1) 
to at least the completion of all the assessments planned on Day 2. All subjects in the PK 
cohort will undergo blood sampling for PK measurement of ASP2215. Subjects in PK 
cohort will be administered the study drug in the same manner and undergo the same 

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efficacy and safety assessments as other subjects except for blood sampling for additional 
PK measurements. 
Subjects will enter the screening period up to 14 days prior to the start of treatment. Prior 
to randomization, the investigator will preselect a salvage chemotherapy regimen for each 
subject; options will include low-dose cytarabine (LoDAC), mitoxantrone, etoposide and 
intermediate-dose cytarabine (MEC) or fludarabine, high-dose cytarabine and granulocyte 
colony-stimulating factor (FLAG). The randomization will be stratified by response to 
first-line therapy and preselected salvage chemotherapy. Subjects will be administered 
treatment over continuous 28-day cycles and per institutional guidelines for chemotherapy 
product preparation and administration. The dose and duration of study treatments are 
outlined in [Section 5.1.1 Dose/Dose Regimen and Administration Period] of the protocol. 
For subjects taking ASP2215 or LoDAC, treatment should continue until the subject meets 
a treatment discontinuation criterion. 
Subjects receiving MEC or FLAG will receive 1 cycle of therapy and will be assessed for 
response on or after day 15, per institutional guidelines. If the bone marrow cellularity is 
20% or greater with at least a 50% reduction in blasts, the subject may receive a second 
cycle of the same chemotherapy. If bone cellularity is between 5% and 20%, the 
investigator should make the decision whether the subject should receive another treatment 
cycle or be observed for recovery. If marrow cellularity is 5% or less, the subject will be 
observed for recovery. Subjects achieving CR, complete remission with incomplete 
hematologic recovery (CRi) or complete remission with incomplete platelet recovery 
(CRp) may receive a second cycle of chemotherapy at the investigator’s discretion. 
Subjects with no response (NR) or progressive disease will discontinue study treatment 
following cycle 1. 
Dose adjustments for ASP2215 are described in [Section 5.1.2 Interruption, Reduction or 
Escalation in Dose of the Study Drug] of the protocol. 
Subjects who have a donor identified and achieve a response allowing them to undergo 
hematopoietic stem cell transplant (HSCT) per each institution’s assessment can undergo 
HSCT without leaving the study. However, ASP2215 should be stopped and a pre-HSCT 
visit should be performed prior to starting the conditioning regimen for HSCT. ASP2215 
can be resumed after stem cell transplantation if the following conditions are met: 
• Subject is between 30 - 90 days post HSCT 
• Subject has had successful engraftment as demonstrated by absolute neutrophil count 
(ANC) ≥ 500/mm3 and platelets ≥ 20000/mm3 without transfusions 
• Subject does not have ≥ grade 2 acute graft-versus-host disease (GVHD) 
• Subject is in CRc 
For subjects resuming treatment, subjects will follow the procedures listed under 
subsequent cycles day 1 in the Schedule of Assessments. Subjects who do not resume 
ASP2215 will be followed for primary endpoint.  
After treatment discontinuation, subjects will have an end of treatment visit within 7 days 
after treatment discontinuation, followed by a 30-day follow-up, in which a telephone 
contact with the subject is sufficient unless any assessment must be repeated for resolution 
of treatment-related AEs. After which the subjects will enter the long-term follow-up 

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period for collection of patient reported outcome (PRO) using EQ-5D-5L, subsequent 
AML treatment, remission status and survival (cause of death and date of death). The 
long-term follow-up will be every 3 months, for up to 3 years from the subject’s end of 
treatment visit until the implementation and reconsent of the current protocol version 7.0, 
at which time they will discontinue from the study.  
A formal interim analysis by an Independent Data Monitoring Committee (IDMC) will be 
done when approximately 50% of deaths by any cause have occurred. This analysis will be 
utilized to determine whether the study should be terminated earlier than planned if 
ASP2215 has more favorable or harmful outcome than the salvage chemotherapy group. If 
the interim analysis demonstrates a more favorable outcome for ASP2215, enrollment to 
the study may be stopped in advance. If it demonstrates a harmful outcome, the enrollment 
will be stopped. However, any subject continuing to derive clinical benefit from ASP2215 
as assessed by the investigator will be allowed to continue treatment until they meet a 
discontinuation criterion as outlined in [Section 6 Discontinuation]or upon marketing 
authorization, commercial availability and applicable reimbursement of ASP2215 in the 
country of residence. 
Subjects will be managed per the local institution’s standard of care for safety and efficacy 
assessments while on study treatment after subjects reconsent under this protocol version 
7.0. No data (including PK assessment) will be collected in the Electronic Case Report 
Forms after the subject reconsents under this protocol version 7.0. Only SAEs, as defined 
in [Section 5.5.2 Definition of Serious Adverse Events], will be collected and reported as 
outlined in [Section 5.5.6 Reporting of Serious Adverse Events]. SAE data will be reported 
in the safety database. SAE collection will continue until 30 days after last dose of study 
treatment. Once subjects receiving study treatment meet the study discontinuation criteria 
or upon marketing authorization and commercial availability and applicable 
reimbursement of ASP2215 in the country of residence, subjects will be discontinued from 
the study.  
Subjects in long-term follow-up who are no longer receiving study treatment will be 
followed every 3 months for up to 3 years until implementation and reconsent of the 
current protocol version 7.0, at which time they will discontinue from the study. 
The detailed assessments and procedures are presented in [Appendix 12.8 Continuation of 
Study Treatment with ASP2215].   
The study planned interim analysis demonstrated superior OS outcome for the ASP2215 
arm compared to the Salvage chemotherapy arm. The IDMC concluded that the primary 
endpoint of OS crossed the predefined efficacy stopping boundary and recommended that 
the study should stop for efficacy. According to IDMC’s recommendation, the sponsor 
determined that no further screening/enrollment is required. In addition, the Crossover 
Extension (COE) is implemented to allow active salvage chemotherapy arm subjects and 
salvage chemotherapy arm subjects in follow to receive ASP2215 treatment on the study 
based on the investigators’ discretion. 
All eligible subjects must be evaluated and meet the eligibility criteria for COE. 
Subjects on active salvage chemotherapy arm who are participating in COE, will have an 
end of treatment visit within 7 days after treatment discontinuation, followed by a 30-day 

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follow-up, in which a telephone contact with the subject is sufficient unless any assessment 
must be repeated for resolution of treatment-related AEs. 
Day 1 of the COE will occur after COE informed consent form is signed and eligibility is 
confirmed.  
In COE portion of the study, subjects will receive treatment with ASP2215 over 
continuous 28-day cycles. Subjects taking ASP2215 should continue until the subject 
meets a treatment discontinuation criterion. The subjects will have an end of treatment visit 
within 7 days after treatment discontinuation, followed by a 30-day follow-up, in which a 
telephone contact with the subject is sufficient unless any assessment must be repeated for 
resolution of treatment-related AEs. Dose interruption and reduction due to adverse events 
related to ASP2215 must be followed [Table 9] 
Study procedures during the COE will be limited to safety data collection including 
AE/SAE collection/assessment, clinical laboratory, ECGs, physical exams, vital signs and 
concomitant treatment as detailed in the schedule of assessment [Table 4 and Table 6]. 
Inclusion/Exclusion Criteria: 
Inclusion: 
Subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB) -/Independent Ethics Committee (IEC) -approved 
written Informed Consent and privacy language as per national regulations must be 
obtained from the subject or legally authorized representative prior to any study-
related procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject is considered an adult according to local regulation (e.g., age ≥ 18 years old in 
China) at the time of signing informed consent. 
3. Subject has a diagnosis of primary AML or AML secondary to myelodysplastic 
syndrome (MDS) according to World Health Organization classification [Swerdlow et 
al, 2008] as determined by pathology review at the treating institution. 
4. Subject is refractory to or relapsed after first-line AML therapy (with or without 
HSCT) (see definition of line of therapy in Appendix 12.6). 
• Refractory to first-line AML therapy is defined as: 
a. Subject did not achieve CR/CRi/CRp under initial therapy. A subject eligible 
for standard therapy must receive at least 1 cycle of an anthracycline 
containing induction block in standard dose for the selected induction 
regimen. A subject not eligible for standard therapy must have received at 
least 1 complete block of induction therapy seen as the optimum choice of 
therapy to induce remission for this subject as per investigator’s assessment. 
• Untreated first hematologic relapse is defined as: 
a. Subject must have achieved a CR/CRi/CRp (criteria as defined by [Cheson et 
al, 2003], see [Section 5.3 Efficacy Assessment]) with first-line treatment and 
has hematologic relapse. 
5. Subject is positive for FLT3 mutation in bone marrow or whole blood as determined 
by the central lab. In the investigator’s opinion, a subject with rapidly proliferative 

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disease and unable to wait for the central lab results can be enrolled based on a local 
test performed after completion of the last interventional treatment. Subjects can be 
enrolled from a local test result if they have any of the following FLT3 mutations: 
FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD)/D835 
or FLT3-TKD/I836. 
6. Subject has an ECOG performance status ≤ 2. 
7. Subject is eligible for preselected salvage chemotherapy according to investigator 
assessment. 
8. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
• Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit 
of normal (ULN) 
• Serum total bilirubin ≤ 1.5 x ULN 
• Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of 
> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation 
[Levey et al, 1999]. 
9. Subject is suitable for oral administration of study drug. 
10. Female subject must either: 
• Be of non-childbearing potential: 
• Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or 
• Documented as surgically sterile (at least 1 month prior to screening) 
• Or, if of childbearing potential,  
• Agree not to try to become pregnant during the study and for 60 days after the 
final study drug administration 
• And have a negative serum or urine pregnancy test at screening 
• And, if heterosexually active, agree to consistently use highly effective 
contraception per locally accepted standards in addition to barrier method 
starting at screening and throughout the study period and for 60 days after the 
final study drug administration. 
11. Female subject must agree not to breastfeed at screening and throughout the study 
period and for 60 days after the final study drug administration. 
12. Female subject must not donate ova starting at screening and throughout the study 
period and for 60 days after the final study drug administration. 
13. Male subject and their female spouse/partners who are of childbearing potential must 
be using highly effective contraception per locally accepted standards in addition to a 
barrier method starting at screening and continue throughout the study period and for 
120 days after the final study drug administration. 
14. Male subject must not donate sperm starting at screening and throughout the study 
period and  
for 120 days after the final study drug administration. 
15. Subject agrees not to participate in another interventional study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed. 

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Inclusion for COE portion: 
Subject is eligible for the COE if they meet the following criteria when the subject is 
evaluated for eligibility to participate in the COE portion of the study: 
1. Institutional Review Board (IRB) -/Independent Ethics Committee (IEC) -approved 
written Informed Consent and privacy language as per national regulations must be 
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject has received study treatment of either LoDAC, MEC or FLAG and has no 
response or progressive disease.  
3. Subject has not received other antileukemic therapy after EoT (hydroxyurea is allowed 
for the control of peripheral leukemic blasts in patients with leukocytosis). 
4. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
• Serum AST and ALT ≤ 2.5 x upper limit of normal (ULN) 
• Serum total bilirubin ≤ 1.5 x ULN 
• Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of 
> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation 
[Levey et al, 1999]. 
• Serum potassium ≥ lower limit of normal (LLN) (Repletion of potassium levels 
prior to C1D1 of COE is allowed). 
• Serum magnesium ≥ LLN (Repletion of magnesium levels prior to C1D1 of COE 
is allowed). 
5. Subject has an ECOG performance status ≤ 2. 
6. Female subject must either: 
• Be of non-childbearing potential: 
• Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or 
• Documented as surgically sterile (at least 1 month prior to screening) 
• Or, if of childbearing potential,  
• Agree not to try to become pregnant during the study and for 60 days after the 
final study drug administration 
• And have a negative serum or urine pregnancy test at screening 
• And, if heterosexually active, agree to consistently use highly effective 
contraception per locally accepted standards in addition to barrier method 
starting at screening and throughout the study period and for 60 days after the 
final study drug administration. 
7. Female subject must agree not to breastfeed at screening and throughout the study 
period and for 60 days after the final study drug administration. 
8. Female subject must not donate ova starting at screening and throughout the study 
period and for 60 days after the final study drug administration. 
9. Male subject and their female spouse/partners who are of childbearing potential must 
be using highly effective contraception per locally accepted standards in addition to a 
barrier method starting at screening and continue throughout the study period and for 
120 days after the final study drug administration. 

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10. Male subject must not donate sperm starting at screening and throughout the study 
period and for 120 days after the final study drug administration. 
11. Subject agrees not to participate in another interventional study while on treatment. 
Waivers to the COE inclusion criteria will NOT be allowed. 
Exclusion: 
Subject will be excluded from participation if any of the following apply: 
1. Subject was diagnosed as acute promyelocytic leukemia. 
2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast 
crisis). 
3. Subject has AML secondary to prior chemotherapy for other neoplasms (except for 
MDS). 
4. Subject is in second or later hematologic relapse or has received salvage therapy for 
refractory disease. 
5. Subject has clinically active central nervous system leukemia. 
6. Subject has been diagnosed with another malignancy, unless disease-free for at least 
5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this 
study if definitive treatment for the condition has been completed. Subjects with 
organ-confined prostate cancer with no evidence of recurrent or progressive disease 
are eligible if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
7. Subject has received prior treatment with ASP2215 or other FLT3 inhibitors (with the 
exception of sorafenib and midostaurin used in first-line therapy regimen as part of 
induction, consolidation and/or maintenance). 
8. Subject has clinically significant abnormality of coagulation profile, such as 
disseminated intravascular coagulation. 
9. Subject has had major surgery within 4 weeks prior to the first study dose. 
10. Subject has radiation therapy within 4 weeks prior to the first study dose.  
11. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 
or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, 
unless a screening echocardiogram performed within 1 month prior to study entry 
results in a left ventricular ejection fraction (LVEF) that is ≥ 45%. 
12. Subject with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at 
Screening based on central reading. 
13. Subject with Long QT Syndrome at Screening. 
14. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below 
lower limit of normal [LLN]). 
15. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 
16. Subject requires treatment with concomitant drugs that are strong inhibitors or 

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inducers of P-glycoprotein (P-gp) with the exception of drugs that are considered 
absolutely essential for the care of the subject. 
17. Subject requires treatment with concomitant drugs that target serotonin 5-
hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) 
or sigma nonspecific receptor with the exception of drugs that are considered 
absolutely essential for the care of the subject. 
18. Subject has an active uncontrolled infection. 
19. Subject is known to have human immunodeficiency virus infection. 
20. Subject has active hepatitis B or C or other active hepatic disorder. 
21. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
22. Subject has active clinically significant GVHD or is on treatment with systemic 
corticosteroids for GVHD. 
23. Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 
or FLT3-TKD/I836 
Waivers to the exclusion criteria will NOT be allowed. 
Exclusion for COE portion: 
Subject will be excluded from participation in the COE if any of the following apply when 
the subject is evaluated for eligibility to participate in the COE portion of the study: 
1. Subject has been diagnosed with another malignancy, unless disease-free for at least 
5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this 
study if definitive treatment for the condition has been completed. Subjects with 
organ-confined prostate cancer with no evidence of recurrent or progressive disease 
are eligible if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
2. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 
or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, 
unless a screening echocardiogram performed within 1 month prior to study entry 
results in a left ventricular ejection fraction (LVEF) that is ≥ 45%. 
3. Subjects with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at 
COE Screening based on central reading.  
4. Subject has clinically active central nervous system leukemia. 
5. Subject has clinically significant abnormality of coagulation profile, such as 
disseminated intravascular coagulation. 
6. Subject has had major surgery within 4 weeks prior to the first study dose. 
7. Subject has radiation therapy within 4 weeks prior to the first study dose.  
8. Subject with Long QT Syndrome at Screening. 
9. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below 
lower limit of normal [LLN]). 
10. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 

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11. Subject requires treatment with concomitant drugs that are strong inhibitors or 
inducers of P-glycoprotein (P-gp) with the exception of drugs that are considered 
absolutely essential for the care of the subject. 
12. Subject requires treatment with concomitant drugs that target serotonin 5-
hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B 
(5HT2BR) or sigma nonspecific receptor with the exception of drugs that are 
considered absolutely essential for the care of the subject. 
13. Subject has an active uncontrolled infection. 
14. Subject is known to have human immunodeficiency virus infection. 
15. Subject has active hepatitis B or C or other active hepatic disorder. 
16. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
Waivers to the COE exclusion criteria will NOT be allowed. 
Investigational Product: 
ASP2215 tablets containing 40 mg of active ingredient. 
Dose: 
ASP2215 120 mg will be administered once daily. 
Mode of Administration: 
ASP2215 will be administered orally. 

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Comparative Drugs: 
The specific regimen will be preselected by the investigator prior to randomization of each 
subject. All regimens will be administered as 28-day cycles and per institutional guidelines 
for chemotherapy product preparation and administration. 
Options for comparative salvage chemotherapies are limited to the following (all dose 
levels as defined below must be followed): 
LoDAC [Burnett & Knapper, 2007]  
● 
20 mg cytarabine will be administered twice daily by SC or IV injection for 10 days. 
MEC Induction Chemotherapy [Amadori et al, 1991] 
● 
Mitoxantrone 6 mg/m2 per day will be administered by IV for 5 days (days 1 through 
5). 
● 
Etoposide 100 mg/m2 per day will be administered by IV for 5 days (days 1 through 
5). 
● 
Cytarabine 1000 mg/m2 per day will be administered by IV for 5 days (days 1 through 
5). 
FLAG Induction Chemotherapy [Montillo et al, 1998] 
● 
Granulocyte colony-stimulating factor (G-CSF) 300 µg/m2 per day will be 
administered by SC/IV for 5 days (days 1 through 5). Additional G-CSF by SC/IV is 
recommended 7 days after completing chemotherapy until ANC > 0.5 x 109/L. 
● 
Fludarabine 30 mg/m2 per day will be administered by IV for 5 days (days 2 through 
6). 
● 
Cytarabine 2000 mg/m2 per day will be administered by IV for 5 days (days 2 through 
6). 
Concomitant Medication Restrictions or Requirements: 
ASP2215 group only:  
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. 
Treatment with concomitant drugs that are strong inhibitors or inducers of P-gp and 
concomitant drugs that target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor 
are to be avoided with the exception of drugs that are considered absolutely essential for 
the care of the subject. Treatment with concomitant drugs that are strong inhibitors of 
CYP3A should be avoided with the exception of antibiotics, antifungals and antivirals that 
are used as standard of care to prevent or treat infections. If CYP3A inhibitors are used 
concomitantly, subjects should be monitored for AEs. 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are 
known to prolong QT or QTc intervals. 
ASP2215 group and chemotherapy group: 
Any other treatments of AML (including but not limited to chemotherapy, radiotherapy, 
surgery, immunotherapy or cellular therapy) are prohibited during therapy with the 
exception of hydroxyurea daily for up to 2 weeks to keep the absolute blast count below 
50 x 109/L and prophylactic intrathecal chemotherapy, cranial radiation, and donor 
lymphocyte infusion as part of the HSCT treatment plan. Participating in another 

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interventional study while on treatment is prohibited. 
COE receiving ASP2215 group: 
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. 
Treatment with concomitant drugs that are strong inhibitors or inducers of P-gp and 
concomitant drugs that target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor 
are to be avoided with the exception of drugs that are considered absolutely essential for 
the care of the subject. Treatment with concomitant drugs that are strong inhibitors of 
CYP3A should be avoided with the exception of antibiotics, antifungals and antivirals that 
are used as standard of care to prevent or treat infections. If CYP3A inhibitors are used 
concomitantly, subjects should be monitored for AEs. 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are 
known to prolong QT or QTc intervals. 
In addition, any other treatments of AML (including but not limited to chemotherapy, 
radiotherapy, surgery, immunotherapy or cellular therapy) are prohibited during therapy 
with the exception of hydroxyurea daily for up to 2 weeks to keep the absolute blast count 
below 50 x 109/L and prophylactic intrathecal chemotherapy, cranial radiation, and donor 
lymphocyte infusion as part of the HSCT treatment plan. Prior to starting protocol 
treatment, hydroxyurea is allowed for the control of peripheral leukemic blasts in patients 
with leukocytosis (e.g., white blood cell [WBC] counts > 30 x 109/L). Participating in 
another interventional study while on treatment is prohibited. 
Duration of Treatment:  
For subjects taking ASP2215, LoDAC, treatment should continue until the subject meets a 
treatment discontinuation criterion. 
• Subjects receiving MEC or FLAG will receive 1 cycle of therapy and will be assessed 
for response on or after day 15, per institutional guidelines. If the bone marrow 
cellularity is 20% or greater with at least a 50% reduction in blasts, the subject may 
receive a second cycle of the same chemotherapy. If bone cellularity is between 5% 
and 20%, the investigator should make the decision whether the subject should receive 
another treatment cycle or be observed for recovery. If marrow cellularity is 5% or less, 
the subject will be observed for recovery. Subjects achieving CR, CRi or CRp may 
receive a second cycle of chemotherapy at the investigator’s discretion. Subjects with 
NR or progressive disease following cycle 1 will discontinue study treatment. 

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Discontinuation Criteria  
Subjects will be eligible to continue receiving treatment in this study until they meet a 
discontinuation criterion as outlined below or upon marketing authorization, commercial 
availability and applicable reimbursement of ASP2215 in the country of residence. Once a 
subject(s) transitions to commercial supply, the subject(s) will be discontinued from the 
study. 
Discontinuation Criteria from Treatment for Individual Subjects: 
• Subject declines further study participation (i.e. withdrawal of consent). 
• Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment. 
• Subject is found to have significantly deviated from any 1 of the inclusion or exclusion 
criteria after enrollment (subjects having clinical benefit may be kept in the study after 
discussion with the medical monitor). 
• Subject develops an intolerable or unacceptable toxicity. 
• Subject receives any antileukemic therapy other than the assigned treatment, with the 
exceptions of hydroxyurea up to 2 weeks, prophylactic intrathecal chemotherapy or 
cranial irradiation, and donor lymphocyte infusion as part of the HSCT treatment plan. 
• Investigator/sub-investigator determines that the continuation of the study treatment 
will be detrimental to the subject. 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
• Subject is receiving MEC or FLAG and has NR or progressive disease following 
cycle 1. 
• Subject is receiving LoDAC or ASP2215 and has progressive disease or NR and the 
subject, in the opinion of the investigator, is no longer deriving clinical benefit. 
• Subject is in comparator group (chemotherapy) and goes on for HSCT. 
• Female subject becomes pregnant. 
• Death. 
Discontinuation Criteria for COE group 
Subjects will be eligible to continue receiving treatment in this study until they meet a 
discontinuation criterion as outlined below or upon marketing authorization, commercial 
availability and applicable reimbursement of ASP2215 in the country of residence. Once a 
subject(s) transitions to commercial supply, the subject(s) will be discontinued from the 
study. 
Discontinuation Criteria from Treatment for Individual Subjects: 
• Subject declines further study participation (i.e. withdrawal of consent). 
• Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment. 
• Subject is found to have significantly deviated from any 1 of the inclusion or exclusion 
criteria after enrollment (subjects having clinical benefit may be kept in the study after 
discussion with the medical monitor). 
• Subject develops an intolerable or unacceptable toxicity. 
• Subject receives any antileukemic therapy other than the assigned treatment, with the 

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exceptions of hydroxyurea up to 2 weeks, prophylactic intrathecal chemotherapy or 
cranial irradiation, and donor lymphocyte infusion as part of the HSCT treatment plan. 
• Investigator/sub-investigator determines that the continuation of the study treatment 
will be detrimental to the subject. 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
• Subject is receiving ASP2215 and has progressive disease or NR and the subject, in the 
opinion of the investigator, is no longer deriving clinical benefit. 
• Female subject becomes pregnant. 
• Death. 
• ASP2215 reimbursement becomes available in the country of residence. 
The subject will be discontinued from the post treatment period if any of the following 
occur: 
• Subject declines further study participation (i.e., withdraws consent). 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
• More than 3 years has passed from the subject’s end of treatment visit.  
• The implementation and reconsent of protocol version 7.0. 
• Death. 
Endpoints for Evaluation: 
Primary Efficacy Endpoint: 
• OS 
Key Secondary Efficacy Endpoints: 
• EFS 
• CR 
Secondary Efficacy Endpoints: 
• LFS 
• Duration of remission 
• CRc (CR + CRi + CRp)  
• Transplantation  
• BFI 
Exploratory Endpoints: 
• Pharmacogenomics (PGx) 
• FLT3 gene mutation status 
o mutation types and frequency 
o relationship to efficacy and safety 

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• Exploratory (predictive) biomarkers of ASP2215 activity 
• Resource utilization including hospitalization, blood transfusion, antibiotic iv 
infusions, medication for AEs and opioid usage 
• FACIT-Dys-SF 
• FACT-Leu and dizziness and mouth sore items 
• EQ-5D-5L 
Safety endpoints 
• AEs 
• Serum chemistry, hematology, coagulation and urinalysis 
• Vital signs 
• ECGs 
• ECOG performance scores 
Pharmacokinetics 
• ASP2215 concentration in blood 
• Pharmacokinetic parameters of ASP2215 in Chinese population 
Statistical Methods: 
Sample Size Justification: 
This is a group sequential design using the O’Brien-Fleming boundaries as implemented 
by Lan-DeMets alpha spending method (East®). One interim analysis and 1 final analysis 
are planned. The interim and final analyses will be performed after the prespecified 
number of death events. All statistical tests of treatment effects will be conducted at the 
2-sided 0.05 level of significance. 
Approximately 318 subjects (the planned sample size with 10% dropout rate) will be 
randomized in a 1:1 ratio to receive ASP2215 or salvage chemotherapy (159 subjects in 
the ASP2215 treatment arm and 159 subjects in the salvage chemotherapy arm). The 
planned 230 events during the study will provide 90% power to detect a difference in OS 
between the ASP2215 arm with 7.7 months median survival time and salvage 
chemotherapy arm with 5 months median survival time (hazard ratio = 0.65) at the overall 
2-sided 0.05 significance level. 
The planned sample size with 250 EFS events will provide 90% power to detect the 
difference in EFS (6 months median EFS for ASP2215 arm and 3.9 months for salvage 
chemotherapy arm with hazard ratio = 0.65) and > 90% power to detect a difference in CR 
rate between ASP2215 with 25% CR rate and the salvage chemotherapy with 10% CR 
rate. 

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Randomization will be stratified by response to first-line AML therapy and preselected 
salvage chemotherapy: 
Response to first-line therapy: 
• 
Relapse within 6 months after allogeneic HSCT 
• 
Relapse after 6 months after allogeneic HSCT 
• 
Primary refractory without HSCT 
• 
Relapse within 6 months after CRc and no HSCT 
• 
Relapse after 6 months after CRc and no HSCT 
Preselected chemotherapy: 
• 
High intensity chemotherapy (FLAG or MEC) 
• 
Low intensity chemotherapy (LoDAC) 
Primary Efficacy Analysis: 
The primary efficacy endpoint of OS will be analyzed using the stratified Cox proportional 
hazard model with strata to control for response to first-line AML therapy and preselected 
salvage chemotherapy on the Intention to Treatment Set (ITT). The ITT is defined as all 
randomized subjects. 
The hypothesis testing on the primary analysis will be performed at overall 2-sided 
0.05 significance level to test the null hypothesis that OS is equal between the 2 treatment 
arms versus the alternative hypothesis that OS is different between the ASP2215 arm 
versus the salvage chemotherapy arm.  
The sensitivity analysis for the primary efficacy endpoint will be performed on the Full 
Analysis Set (FAS), which includes all randomized subjects who are FLT3-mutated 
subjects based on the central test. The sensitivity analysis for OS with censoring at the time 
of HSCT for subjects who undergo HSCT will be conducted on the ITT. If the 
FLT3-mutated subjects constitute less than 90% of the total number of randomized 
subjects, the difference in the primary efficacy endpoint will be evaluated between 
FLT3-mutated subjects and FLT wild type subjects per central lab test. 
Key Secondary Efficacy Analysis: 
The key secondary efficacy endpoint of EFS will be analyzed using the stratified Cox 
proportional hazard model with strata to control for response to first-line AML therapy and 
preselected salvage chemotherapy on the ITT. To maintain the overall Type I error rate at 
the 0.05 significance level, the hypothesis testing on EFS will be performed only if the null 
hypothesis on the primary analysis is rejected at the overall 2-sided 0.05 significance level. 
The key secondary efficacy endpoint of CR rate will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test to control for response to first-line AML therapy and 
preselected salvage chemotherapy on the ITT. To maintain the overall Type I error rate at 
the 0.05 significance level, the hypothesis testing on CR rate will be performed only if the 
null hypothesis on EFS is rejected at the overall  
2-sided 0.05 significance level. 
The sensitivity analysis for the key secondary efficacy endpoints will be performed on the 
FAS, which included all randomized subjects who are FLT3-mutated subjects based on the 
central test. Additional sensitivity analysis will be performed to evaluate the impact on the 

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analysis of EFS due to any missing data/assessments and any loss to follow-up or 
discontinuation of assessments of EFS not due to an event. 
Secondary Efficacy Analyses: 
The statistical analyses on secondary efficacy endpoints include: 
• 
Stratified Cox proportional hazard model on duration of remission and LFS 
• 
CMH method on the CRc rate and transplantation rate 
• 
Analysis of variance (ANOVA) model to analyze the change in the BFI global fatigue 
score (average of all 9 items) from baseline to post-baseline visits 
Safety Analyses: 
The Safety Analysis Set (SAS) is defined as all subjects who received at least 1 dose of 
study treatment (ASP2215 or salvage chemotherapy). 
The safety evaluation will be based mainly on AEs, clinical laboratory, vital signs, ECG 
and ECOG. Descriptive statistics will be used to summarize safety data.  All safety data 
will be summarized by treatment. 
All summaries of AEs will include only treatment-emergent events unless otherwise stated. 
AEs will be categorized by SOC and preferred term using MedDRA and will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4.03. 
Since the cross-over choice of chemotherapy patients were introduced as a result of the 
interim analysis of the efficacy, the main statistical analysis of efficacy and safety should 
be conducted on the data up to the implementation of this choice to maintain the integrity 
of the study conclusion. 
All eligible salvage chemotherapy arm subjects who cross to COE ASP2215 treatment will 
be summarized separately to support the safety conclusion for the ASP2215. More details 
will be included in the SAP. 
Pharmacokinetics Analyses: 
Population pharmacokinetic modeling will be conducted for ASP2215 using nonlinear 
mixed effects methodology. Data from this study may be pooled with other studies for 
analysis. A covariate analysis will be performed to relate the effect of intrinsic and 
extrinsic subject factors to exposure. After the subject reconsents under this protocol 
version 7.0, no PK assessments will be performed. 
Plasma concentrations and PK parameters will be summarized using descriptive statistics, 
including number of subjects, mean, standard deviation, minimum, median, maximum, and 
coefficient of variation (CV) of the mean. Time-course of drug concentrations will be 
plotted as appropriate. 
Subjects with sufficient PK samples will have PK parameter estimates for ASP2215 
including calculation of AUC24, Cmax, Ctrough and tmax using standard NCA 
(non-compartmental analysis). 
Pharmacodynamics Analyses: 
Not applicable 

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Exploratory Analyses: 
An exploratory analysis of FLT3 mutation status and clinical efficacy will be conducted. 
FLT3 mutation status, including subgroups of FLT3 internal tandem duplication mutation,  
D835/I836 tyrosine kinase domain mutations and allelic ratio, will be analyzed. 
CMH method will be used for resource utilization status (hospitalization, blood 
transfusion, antibiotic iv infusions, medication for AEs and opioid medication); and 
ANOVA model will be used for resource utilization counts (hospital stays, duration of 
medications, blood transfusions, antibiotic iv infusions, medication for AEs and opioid 
medication). 
ANOVA model will be used to analyze the change in the FACIT-Dys-SF domain scores 
from baseline to post-baseline visits. 
ANOVA model will be used to evaluate change from baseline to post-baseline visits for 
the global and domain scores, individual items and item clusters of the FACT-Leu. The 
same analytic approach will be used for the dizziness and mouth sore items. 
ANOVA model will be used for the change from baseline of EQ-5D-5L visual analogue 
scale (VAS) and shift table for the 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression) baseline to post-baseline visits. 
Interim Analysis: 
To evaluate whether ASP2215 is particularly beneficial or harmful compared to the 
salvage chemotherapy group while the study is ongoing, a formal interim analysis is 
planned when approximately 50% of the planned death events have occurred in the study. 
A group sequential design using the O’Brien-Fleming type alpha-spending function [Lan 
& DeMets, 1983] will be used to control the overall 2-sided 0.05 significance level 
(East®).  
The IDMC may recommend terminating the trial for favorable or unfavorable results at the 
interim analysis. In the case of favorable results, the 2-sided significance levels for 
superiority are 0.0031 for the interim analysis and 0.0490 for the final analysis. If the 
estimated hazard ratio (HR) is less than 1 and the 2-sided P of the interim analysis is less 
than 0.0031, the IDMC may recommend terminating the trial for success. In the case of 
unfavorable results in the interim analysis, the 2-sided significance level for futility 
(nonbinding) is 0.8458. If the estimated HR is less than 1 and the 2-sided P of the interim 
analysis is greater than 0.8458 or the estimated HR is greater than 1, the IDMC may 
recommend terminating the trial for futility. 
The decision rules based on the P and estimated HR at the formal interim analysis are 
further described in the table below. 
Decision Rules based on P Value and HR obtained at Interim Analysis 
● 
HR < 1 
o P value < 0.0031 
 
: Termination due to success 
o 0.0031 ≤ P value ≤ 0.8458 
: Continuation of study 
o P value > 0.8458 
 
: Termination due to futility 
● 
HR ≥ 1 
o Termination due to futility 

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Details for the interim analysis, monitoring subject safety, enrollment rates and event 
(death) rates will be contained in the Interim Analysis Plan (IAP) and IDMC Charter. 
Recommendations regarding study conduct will be made by the IDMC based on their 
assessment of these rates. If the study is not stopped after the interim analysis, a final 
analysis will occur after 100% of events have been observed. 
 

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Flow Chart for Crossover Extension 
 
 
Salvage 
Chemotherapy*** 
COE 
ASP2215 
Continuous 28-day cycles until 
meets treatment discontinuation 
criteria 
NR/PD 
30-Day 
Follow-up 
*** Active salvage chemotherapy arm subjects who are 
participating in COE, will have an end of treatment visit 
within 7 days after treatment discontinuation, followed by a 
30-day follow-up for salvage chemotherapy arm. 30-day 
follow-up assessment on salvage chemotherapy arm shold 
be completed even if the subjects are in COE.  

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Table 1 
Schedule of Assessments for ASP2215 Arm 
Activity 
Screening 
(Day -14 
to -1) 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
Signed ICF 
X 
 
 
 
 
 
 
 
 
Medical and Disease History 
X 
 
 
 
 
 
 
 
 
Randomization 
 
Xo 
 
 
 
 
 
 
 
Physical Examinationb 
X 
Xa 
X 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
Xa 
X 
X 
 
X 
X 
X 
X 
ECOG Performance 
X 
Xa 
 
 
 
X 
X 
X 
X 
Prior and Concomitant Medications 
Xc 
X 
X 
X 
 
X 
X 
X 
X 
Pregnancy Test for Woman of Childbearing Potential 
Xd 
X 
 
 
 
 
X 
 
X 
Chest X-ray (or CT of chest)n 
X 
 
 
 
 
 
 
 
 
12-lead ECGe 
Xg 
X 
 
Xr 
Xr 
X 
X 
 
X 
Clinical Laboratory Tests (chemistry, hematology, coagulation, 
urinalysis)f 
Xg 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Tests 
X 
 
 
 
 
 
 
 
Xs 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
 
MUGA or ECHOh 
X 
 
 
 
 
 
 
 
 
FLT3 Mutation Statusi (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xj 
 
 
 
 
 
Xj 
 
Xj 
AE/SAE Assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
PK (whole blood samples for plasma PK) 
 
Xk 
 
Xk 
 
Xk 
Xk 
 
Xk 
PGxl 
 
X 
 
 
 
 
 
 
 
Patient Reported Outcome Toolsp, q 
 
Xa 
 
Xp 
 
Xp 
X 
Xp 
X 
EQ-5D-5Lq 
 
Xa 
 
 
 
 
X 
 
X 
Resource Utilization 
 
Xa 
 
 
 
 
X 
 
X 
IRT Transaction Requiredo 
X 
X 
 
 
 
 
X 
 
X 
ASP2215 Dosing at the Clinicm 
 
X 
X 
X 
 
X 
X 
X 
X 
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with incomplete hematologic recovery; CRp: complete remission with 
incomplete platelet recovery; CT: computed tomography; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EDTA: 
ethylenediaminetetraacetic acid; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level Instrument; FLAG: fludarabine, cytarabine and granulocyte colony-stimulating factor; FLT3: FMS-
like tyrosine kinase; ICF: Informed Consent Form; INR: international normalization ratio; IRT: interactive response technology; LoDAC: low-dose cytarabine; MEC: mitoxantrone, 
etoposide and intermediate-dose cytarabine; MUGA: multigated acquisition scan; PGx: pharmacogenomics; PK: pharmacokinetic; PT: prothrombin time; SAE: serious adverse event 
Footnotes continued on next page 

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a. 
Obtained predose. 
b. 
Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
c. 
Includes medications taken within 28 days prior to cycle 1 day 1. 
d. 
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
e. 
Screening ECG is required. ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 8, cycle 1 day 15 and day 1 of each subsequent cycle. Predose assessments 
should be taken within 1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 
5 minutes apart per time point) and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for final 
treatment decisions and AE reporting. If the mean of the triplicate QTcF is > 500 ms at any time point (by either value on ECG tracing printout or central reading), then triplicate 
ECGs will be repeated (within 2 hours if based on value on ECG tracing printout and as soon as possible if based on central reading). If the repeat ECG confirms a mean of the 
triplicate QTcF > 500 ms, dosing of ASP2215 will be interrupted for up to 14 days. While ASP2215 may be interrupted temporarily based on value on ECG tracing printout, the 
central reading should be used for final treatment decisions. Cardiology consult will be obtained as medically indicated. If QTcF resolves to ≤ 480 ms (grade 1 or less) by central 
reading within 14 days, the subject may resume dosing at the reduced dose. 
f. 
Urinalysis only required at screening. Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard 
of care. 
g. 
Subjects may be screened and randomized from local labs only. However, samples must also be submitted for central lab. Labs and/or ECG can be repeated during screening 
period. 
h. 
MUGA scans or ECHO (per standard of care) are to be performed at screening for subjects with history of congestive heart failure New York Heart Association Class 3 or 4 
(unless MUGA scans or ECHO performed either within 1 month prior revealed left ventricular ejection fraction ≥ 45%). 
i. 
FLT3 mutation status will be assessed from bone marrow sample taken at the screening visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood sample taken 
at the screening visit will be used. Subjects must be screened by the central laboratory. All subjects including those with rapidly proliferative disease must have screening sample 
sent to the central lab. If central result is negative, central FLT3 testing can be repeated during screening period. Bone marrow sample before the informed consent date may be 
used for screening if the patient has already performed bone marrow assessment within 14 days prior to the planned Cycle 1 Day 1, and the sample should be stored at 2˚C to 8˚C 
and can be started testing within 7 days after sample collection. 
j. 
Bone marrow samples are required during screening, cycle 2 day 1 and cycle 3 day 1. For subjects who do not achieve a CRc (CR, CRp or CRi), the bone marrow assessments 
will be repeated at day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), bone marrow sampling will be repeated on 1 month after the date of 
remission and every 3 subsequent cycles, or if there is suspicion of relapse in the whole blood. Bone marrow samples are also required at the pre-HSCT visit /end of treatment 
visit and as clinically indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of whole blood should be collected instead. Bone marrow 
aspirate is required, and bone marrow biopsy is preferred. In case of inadequate aspirate, bone marrow biopsy is required. Bone marrow assessment for blasts counts and cell 
counts and flow cytometry will be conducted at local lab. Bone marrow assessment data before the IC date may be used for screening if the patient has already performed bone 
marrow assessment 14 days prior to the planned Cycle 1 Day 1. 
k. 
PK samples for ASP2215 will be collected on cycle 1 day 1 predose, cycle 1 day 8 predose, and at cycle 1 day 15 and day 1 predose of each subsequent cycle (within 1 hour 
before drug administration). See Section 7.6. 
l. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomics study. Optional pharmacogenomics study is not conducted in China. 
m. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 

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n. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
o. 
For the purposes of drug preparation and dispensing activities, IRT transaction may be done prior to the visit and do not need to fall within the protocol visit window. 
p. 
Includes Brief Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness 
and mouth sores items. The Brief Fatigue Inventory will be administered at cycle 1 day 1 predose, cycle 1 day 8 (± 1 day), day 15 (± 1 day), cycle 2 day 1 (± 2 days), 
day 15 (± 1 day) and all subsequent cycles day 1 (± 2 days). Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-
Leukemia and dizziness and mouth sores items will be administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days). 
q. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
r. 
A cycle 1 day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on cycle 
1 day 9 if the mean QTcF from cycle 1 day 1 to cycle 1 day 8 has increased > 30 ms with no other known etiology, based on the central read ECG. On cycle 1 day 8, it is 
recommended that the ECG is taken as early as possible in the morning and transmitted immediately. In addition, it is recommended that the cycle 1 day 9 visit is scheduled later 
in the day in order to allow for receipt and assessment of the cycle 1 day 8 central read ECG.  This also allows for a subject to be contacted if the cycle 1 day 9 ECG is no longer 
required. If the cycle 1 day 9 ECG is still required, the result of the central read ECG will be received on cycle 1 day 10, in which the investigator should assess if the ASP2215 
dose modification should occur as per the dose interruption or reduction guideline in [Section 5.1.2 Interruption, Reduction or Escalation in Dose of the Study Drug]. 
s. 
Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
 
 

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Table 2 
Schedule of Assessments for ASP2215 Arm in PK cohort 
Activity 
Screening 
(Day -14 
to -1) 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
Signed ICFa 
X 
 
 
 
 
 
 
 
 
Hospitalizationb 
 
X 
 
 
 
X 
 
 
 
Medical and Disease History 
X 
 
 
 
 
 
 
 
 
Randomization 
 
Xr 
 
 
 
 
 
 
 
Physical Examinationd 
X 
Xc 
X 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
Xc 
X 
X 
 
X 
X 
X 
X 
ECOG Performance 
X 
Xc 
 
 
 
X 
X 
X 
X 
Prior and Concomitant Medications 
Xe 
X 
X 
X 
 
X 
X 
X 
X 
Pregnancy Test for Woman of Childbearing Potential 
Xf 
X 
 
 
 
 
X 
 
X 
Chest X-ray (or CT of chest)q 
X 
 
 
 
 
 
 
 
 
12-lead ECGg 
Xi 
X 
 
Xu 
Xu 
Xv 
X 
 
X 
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)h 
Xi 
Xc 
Xc 
Xc 
 
Xc 
Xc 
Xc 
Xc 
Thyroid Function Test 
X 
 
 
 
 
 
 
 
Xw 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
 
MUGA or ECHOj 
X 
 
 
 
 
 
 
 
 
FLT3 Mutation Statusk (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xl 
 
 
 
 
 
Xl 
 
Xl 
AE/SAE Assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
PK (whole blood samples for plasma PK) 
 
Xm, n 
 
Xm 
 
Xm, n 
Xm 
 
Xm 
PGxo 
 
X 
 
 
 
 
 
 
 
Patient Reported Outcome Toolss, t 
 
Xc 
 
Xs 
 
Xs 
X 
Xs 
X 
EQ-5D-5Lt 
 
Xc 
 
 
 
 
X 
 
X 
Resource Utilization 
 
Xc 
 
 
 
 
X 
 
X 
IRT Transaction Requiredr 
X 
X 
 
 
 
 
X 
 
X 
ASP2215 Dosing at the Clinicp 
 
X 
X 
X 
 
X 
X 
X 
X 
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with incomplete hematologic recovery; CRp: complete remission with 
incomplete platelet recovery; CT: computed tomography; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EDTA: 
ethylenediaminetetraacetic acid; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level Instrument; FLAG: fludarabine, cytarabine and granulocyte colony-stimulating factor; FLT3: FMS-
like tyrosine kinase; FMS-like tyrosine kinase; ICF: Informed Consent Form; INR: international normalization ratio; IRT: interactive response technology; LoDAC: low-dose 
cytarabine; MEC: mitoxantrone, etoposide and intermediate-dose cytarabine; MUGA: multigated acquisition scan; PGx: pharmacogenomics; PK: pharmacokinetic; PT: prothrombin 
time; SAE: serious adverse event 
Footnotes continued on next page 

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a. 
For the subjects who will be enrolled at a PK cohort site, specific informed consent form (to explain additional blood sampling for PK measurement in the ASP2215 arm)  
b. 
The subjects who are randomized to ASP2215 will be requested to be hospitalized from the date of C1D1 and C1D15 to at least the completion of PK sample collection at 
24 hours post dose planned on C1D2 and C1D16, respectively. 
c. 
Obtained predose. 
d. 
Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
e. 
Includes medications taken within 28 days prior to cycle 1 day 1. 
f. 
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
g. 
Screening ECG is required. ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 8, cycle 1 day 15 and day 1 of each subsequent cycle. Predose assessments 
should be taken within 1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 
5 minutes apart per time point) and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for final 
treatment decisions and AE reporting. If the mean of the triplicate QTcF is > 500 ms at any time point (by either value on ECG tracing printout or central reading), then triplicate 
ECGs will be repeated (within 2 hours if based on value on ECG tracing printout and as soon as possible if based on central reading). If the repeat ECG confirms a mean of the 
triplicate QTcF > 500 ms, dosing of ASP2215 will be interrupted for up to 14 days. While ASP2215 may be interrupted temporarily based on value on ECG tracing printout, the 
central reading should be used for final treatment decisions. Cardiology consult will be obtained as medically indicated. If QTcF resolves to ≤ 480 ms (grade 1 or less) by central 
reading within 14 days, the subject may resume dosing at the reduced dose. 
h. 
Urinalysis only required at screening. Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard 
of care. 
i. 
Subjects may be screened and randomized from local labs only. However, samples must also be submitted for central lab. Labs and/or ECG can be repeated during screening 
period. 
j. 
MUGA scans or ECHO (per standard of care) are to be performed at screening for subjects with history of congestive heart failure New York Heart Association Class 3 or 4 
(unless MUGA scans or ECHO performed either within 1 month prior revealed left ventricular ejection fraction ≥ 45%). 
k. 
FLT3 mutation status will be assessed from bone marrow sample taken at the screening visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood sample taken 
at the screening visit will be used. Subjects must be screened by the central laboratory. All subjects including those with rapidly proliferative disease must have screening sample 
sent to the central lab. If central result is negative, central FLT3 testing can be repeated during screening period. Bone marrow sample before the informed consent date may be 
used for screening if the patient has already performed bone marrow assessment within 14 days prior to the planned Cycle 1 Day 1, and the sample should be stored at 2˚C to 8˚C 
and can be started testing within 7 days after sample collection. 
l. 
Bone marrow samples are required during screening, cycle 2 day 1 and cycle 3 day 1. For subjects who do not achieve a CRc (CR, CRp or CRi), the bone marrow assessments 
will be repeated at day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), bone marrow sampling will be repeated on 1 month after the date of 
remission and every 3 subsequent cycles or if there is suspicion of relapse in the whole blood. Bone marrow samples are also required at the pre-HSCT visit /end of treatment visit 
and as clinically indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of whole blood should be collected instead. Bone marrow aspirate is 
required, and bone marrow biopsy is preferred. In case of inadequate aspirate, bone marrow biopsy is required. Bone marrow assessment for blasts counts and cell counts and flow 
cytometry will be conducted at local lab. Bone marrow assessment data before the IC date may be used for screening if the patient has already performed bone marrow assessment 
14 days prior to the planned Cycle 1 Day 1. 

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m. 
PK samples for ASP2215 will be collected on cycle 1 day 1 predose, cycle 1 day 8 predose, and at cycle 1 day 15 and day 1 predose of each subsequent cycle (within 1 hour 
before drug administration). See [Section 7.6 Analysis of Pharmacokinetics]. 
n. 
For the subjects who are randomized to ASP2215 arm at a PK cohort site, PK samples will be collected additionally at 0.5, 1, 2, 3, 4, 6, 10, 24 hours post dose on C1D1 and 
C1D15. PK sample collection at 24 hours post dose should be done prior to ASP2215 administration on C1D2 and C1D16. 
o. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomics study. Optional pharmacogenomics study is not conducted in China. 
p. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
q. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
r. 
For the purposes of drug preparation and dispensing activities, IRT transaction may be done prior to the visit and do not need to fall within the protocol visit window. 
s. 
Includes Brief Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness 
and mouth sores items. The Brief Fatigue Inventory will be administered at cycle 1 day 1 predose, cycle 1 day 8 (± 1 day), day 15 (± 1 day), cycle 2 day 1 (± 2 days), 
day 15 (± 1 day) and all subsequent cycles day 1 (± 2 days). Functional Assessment of Chronic Illness Therapy-Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-
Leukemia and dizziness and mouth sores items will be administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days). 
t. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
u. 
A cycle 1 day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on cycle 
1 day 9 if the mean QTcF from cycle 1 day 1 to cycle 1 day 8 has increased > 30 ms with no other known etiology, based on the central read ECG. On cycle 1 day 8, it is 
recommended that the ECG is taken as early as possible in the morning and transmitted immediately. In addition, it is recommended that the cycle 1 day 9 visit is scheduled later 
in the day in order to allow for receipt and assessment of the cycle 1 day 8 central read ECG. This also allows for a subject to be contacted if the cycle 1 day 9 ECG is no longer 
required. If the cycle 1 day 9 ECG is still required, the result of the central read ECG will be received on cycle 1 day 10, in which the investigator should assess if the ASP2215 
dose modification should occur as per the dose interruption or reduction guideline in [Section 5.1.2 Interruption, Reduction or Escalation in Dose of the Study Drug]. 
v. 
A cycle 1 day 15 ECG will be taken predose and 4 hours post dose on C1D15. 
w. 
Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
 
 

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Table 3 
Schedule of Assessments for Chemotherapy Arm 
Activity 
Screening 
(Day -14 to -1) 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
Signed ICF 
X 
 
 
 
 
 
 
 
Medical and Disease History 
X 
 
 
 
 
 
 
 
Randomization 
 
Xo 
 
 
 
 
 
 
Physical Examinationb 
X 
Xa 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
Xa 
X 
X 
X 
X 
X 
X 
ECOG Performance 
X 
Xa 
 
 
X 
X 
X 
X 
Prior and Concomitant Medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test for Woman of Childbearing Potential 
Xd 
X 
 
 
 
X 
 
X 
Chest X-ray (or CT of chest)n 
X 
 
 
 
 
 
 
 
12-lead ECGe 
Xg 
X 
 
 
X 
X 
 
X 
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)f 
Xg 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Testr 
X 
 
 
 
 
 
 
Xr 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
MUGA or ECHOh 
X 
 
 
 
 
 
 
 
FLT3 Mutation Statusi (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xj 
 
 
 
Xj 
Xj 
 
Xj 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
PGxk 
 
X 
 
 
 
 
 
 
Patient Reported Outcome Toolsp,q  
 
Xa 
 
Xp 
Xp 
X 
Xp 
X 
EQ-5D-5Lq 
 
Xa 
 
 
 
X 
 
X 
Resource Utilization 
 
Xa 
 
 
 
X 
 
X 
IRT Transaction Requiredo 
X 
X 
 
 
 
X 
 
X 
LoDAC Dosing  
 
See Footnotel 
MEC or FLAG Dosing 
 
See Footnotem 
 
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with incomplete hematologic recovery; CRp: complete remission with 
incomplete platelet recovery; CT: computed tomography; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EDTA: 
ethylenediaminetetraacetic acid; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level Instrument; FLAG: fludarabine, cytarabine and granulocyte colony-stimulating factor; FLT3: FMS-
like tyrosine kinase; ICF: Informed Consent Form; INR: international normalization ratio; IRT: interactive response technology; LoDAC: low-dose cytarabine; MEC: mitoxantrone, 
etoposide and intermediate-dose cytarabine; MUGA: multigated acquisition scan; PGx: pharmacogenomics; PT: prothrombin time; SAE: serious adverse event 
Footnotes continued on next page  

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a. 
Obtained predose. 
b. 
Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
c. 
Includes medications taken within 28 days prior to cycle 1 day 1. 
d. 
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
e. 
Screening ECG is required. ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 15 and day 1 each subsequent cycle. Predose assessments should be taken 
within 1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 5 minutes apart per 
time point) and transmitted electronically for central reading. See [Section 7.5.5 Electrocardiograms]. 
f. 
Urinalysis only required at screening. Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard 
of care. 
g. 
Subjects may be screened and randomized from local labs only. However, samples must also be submitted for central lab. Labs and/or ECG can be repeated during Screening 
period. 
h. 
MUGA scans or ECHO (as per standard of care) are to be performed at screening for subjects with history of congestive heart failure New York Heart Association Class 3 or 4 
(unless MUGA scans or ECHO performed either within 1 month prior revealed left ventricular ejection fraction ≥ 45%). 
i. 
FLT3 mutation status will be assessed from bone marrow sample taken at the screening visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood sample taken 
at the screening visit will be used. Subjects must be screened by the central laboratory. All subjects including those with rapidly proliferative disease must have screening sample 
sent to the central lab. If central result is negative, central FLT3 testing can be repeated during screening period. Bone marrow sample before the informed consent date may be 
used for screening if the patient has already performed bone marrow assessment within 14 days prior to the planned Cycle 1 Day 1, and the sample should be stored at 2˚C to 8˚C 
and can be started testing within 7 days after sample collection. 
j. 
For MEC and FLAG, bone marrow samples are required during screening and at cycle 2 day1. Also, an additional bone marrow sample is required at cycle 1 day 15 or later, per 
institutional guidelines, to assess the need for a second cycle. For LoDAC, bone marrow samples are required during screening and at cycle 2 day 1 and at cycle 3 day1. For 
subjects who do not achieve a CRc (CR, CRp or CRi), the bone marrow assessments will be repeated at day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, 
CRp or CRi), bone marrow sampling will be repeated at 1 month after the date of remission and at every 3 subsequent cycles or if there is suspicion of relapse in the whole blood. 
Bone marrow samples are also required at the end of treatment visit and as clinically indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of 
whole blood should be collected instead. Bone marrow aspirate is required, and bone marrow biopsy is preferred. In case of inadequate aspirate, bone marrow biopsy is required. 
Bone marrow assessment for blasts counts and cell counts and flow cytometry will be conducted at local lab. Bone marrow assessment data before the IC date may be used for 
screening if the patient has already performed bone marrow assessment 14 days prior to the planned Cycle 1 Day 1. 
k. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomics study. Optional pharmacogenomics study is not conducted in China. 
l. 
LoDAC dosing may continue past cycle 2. 
m. 
Additional clinic visits are allowed per institutional guidelines for subjects receiving MEC (days 1 through 5) or FLAG (days 1 through 6). MEC and FLAG are administered for 
up to 2 cycles depending on response and safety assessments as described in [Section 5.1 Dosing and Administration of Study Drugs and Other Medications]. 
n. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
o. 
For the purposes of drug preparation and dispensing activities, IRT transaction may be done prior to the visit and do not need to fall within the protocol visit window. 

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p. 
Includes Brief Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness 
and mouth sores items. The Brief Fatigue Inventory will be administered at cycle 1 day 1 predose, cycle 1 day 8 (± 1 day), day 15 (± 1 day), cycle 2 day 1 (± 2 days), 
day 15 (± 1 day) and all subsequent cycles day 1 (± 2 days). Functional Assessment of Chronic Illness Therapy-Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-
Leukemia and dizziness and mouth sores items will be administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days). 
q. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
r. 
For subjects receiving LoDAC, thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
 
 

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Table 4 
Treatment Schedule of Assessments for Crossover Extension 
Activity 
Screeningl 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
Signed ICF for COE portion of the study 
X 
 
 
 
 
 
 
 
 
Physical Examinationb 
X 
Xa 
X 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
Xa 
X 
X 
 
X 
X 
X 
X 
ECOG Performance 
X 
Xa 
 
 
 
X 
X 
X 
X 
Prior and Concomitant Medications 
Xc 
X 
X 
X 
 
X 
X 
X 
X 
Pregnancy Test for Woman of Childbearing Potential 
X 
Xd 
 
 
 
 
X 
 
X 
12-lead ECGe 
X 
Xg 
 
Xj 
Xj 
X 
X 
 
X 
Clinical Laboratory Tests (chemistry, hematology, 
coagulation, urinalysis)f 
X 
Xa,g 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Testk 
X 
 
 
 
 
 
 
 
X 
AE/SAE Assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
Enrollment and IRT Transaction Requiredh 
 
X 
 
 
 
 
X 
 
X 
ASP2215 Dosing at the Clinici 
 
X 
X 
X 
 
X 
X 
X 
X 
AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; ICF: Informed Consent Form; IRT: interactive response technology; SAE: serious adverse 
event 
a. 
Obtained predose. 
b. 
Weight measurement should be performed at day 1 of each cycle. 
c. 
Includes medications taken within 28 days prior to C1D1. If EoT was performed within 28 days prior to C1D1, only includes medication after EoT of salvage chemotherapy arm 
and prior to C1D1. 
d. 
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
e. 
ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 8, cycle 1 day 15 and day 1 of each subsequent cycle. Predose assessments should be taken within 
1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 5 minutes apart per time 
point) and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for final treatment decisions and AE 
reporting. If the mean of the triplicate QTcF is > 500 ms at any time point (by either value on ECG tracing printout or central reading), then triplicate ECGs will be repeated 
(within 2 hours if based on value on ECG tracing printout and as soon as possible if based on central reading). If the repeat ECG confirms a mean of the triplicate QTcF > 500 ms, 
dosing of ASP2215 will be interrupted for up to 14 days. While ASP2215 may be interrupted temporarily based on value on ECG tracing printout, the central reading should be 
used for final treatment decisions. Cardiology consult will be obtained as medically indicated. If QTcF resolves to ≤ 480 ms (grade 1 or less) by central reading within 14 days, 
the subject may resume dosing at the reduced dose. 
f. 
Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard of care. 

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g. 
Subjects may be enrolled from local labs only. However, samples must also be submitted for central lab.  
h. 
For the purposes of drug preparation and dispensing activities, IRT transaction may be done prior to the visit and do not need to fall within the protocol visit window. 
i. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
j. 
A cycle 1 day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on cycle 
1 day 9 if the mean QTcF from cycle 1 day 1 to cycle 1 day 8 has increased > 30 ms with no other known etiology, based on the central read ECG. On cycle 1 day 8, it is 
recommended that the ECG is taken as early as possible in the morning and transmitted immediately. In addition, it is recommended that the cycle 1 day 9 visit is scheduled later 
in the day in order to allow for receipt and assessment of the cycle 1 day 8 central read ECG.  This also allows for a subject to be contacted if the cycle 1 day 9 ECG is no longer 
required. If the cycle 1 day 9 ECG is still required, the result of the central read ECG will be received on cycle 1 day 10, in which the investigator should assess if the ASP2215 
dose modification should occur as per the dose interruption or reduction guideline in [Section 5.1.2 Interruption, Reduction or Escalation in Dose of the Study Drug]. 
k. 
Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
l. 
Screening assessment can be performed from the results of the assessments of the EOT of salvage chemotherapy arm if the EOT was performed within 14 days of the planned 
start of COE C1D1. Eligibility assessments (clinical labs and ECG) can be repeated to ensure the subject meets eligibility for COE. The start of COE can be extended to repeat 
safety assessments with the approval of the Medical Monitor. 
 
 

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Table 5 
Post-treatment Schedule of Assessments for ASP2215 Arm and Chemotherapy Arm 
Activity 
pre-HSCT Visit / 
End of Treatment Visita 
30-Day 
Follow-up (+ 7 days) 
Long-term Follow-up 
(+/- 7 days) g 
Physical Examination 
Xb 
 
 
Vital Signs 
Xb 
 
 
ECOG Performance 
Xb 
 
 
Concomitant Medications 
X 
 
 
Pregnancy Test for Woman of Childbearing Potential 
X 
 
 
12-lead ECG 
X 
 
 
Clinical Laboratory Tests (chemistry, hematology, coagulation) 
Xb 
 
 
Thyroid Function Tests 
X 
 
 
Bone Marrow Aspiration and/or Biopsy  
Xc 
 
 
Patient Reported Outcome Toolsh, i 
X 
 
 
EQ-5D-5Li 
X 
X 
X 
Resource Utilization 
X 
 
 
AE/SAE Assessmentj 
X 
Xd, e 
Xf 
IRT Transaction Required  
X 
 
 
Survival and Subsequent Antileukemic Treatments and Their Outcomes 
 
Xf 
X 
AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EDTA: ethylenediaminetetraacetic acid; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level 
Instrument; FLT3: FMS-like tyrosine kinase; HSCT: hematopoietic stem cell transplant; IRT: interactive response technology; SAE: serious adverse event 
a. End of treatment visit is to be performed within 7 days after treatment discontinuation, and before initiation of any other systemic antileukemic treatment or conditioning regimen 
for HSCT. Once protocol version 7.0 has been implemented, no follow-up visits are required after the end of treatment. Subjects in long-term follow-up will discontinue from the 
study, as further survival data are no longer needed. 
b. Does not need to be repeated if collected at a regularly scheduled visit within 3 days of the end of treatment visit. 
c. Bone marrow aspiration and/or biopsy for morphology are preferred, but biopsy may be omitted if the aspirate is considered to be adequate. If bone marrow aspirate is 
unobtainable (e.g., dry tap), an additional EDTA tube of peripheral blood should be collected instead. Bone marrow assessment for blasts counts and cell counts and flow 
cytometry will be conducted at local lab. 
d. AE collection will continue during HSCT for subjects who plan to resume ASP2215 treatment after HSCT. 
e. Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
f. 
Only SAE data that are related to ASP2215 will be collected. 
g. Telephone contact every 3 months. Ad hoc contact will be required during interim analysis. Long-term Follow-up is not applicable for the subjects enters COE. 
h. Includes Brief Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness 
and mouth sores items. The Brief Fatigue Inventory will be administered at preHSCT/end of treatment visit. Functional Assessment of Chronic Illness Therapy–Dyspnea-Short 
Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness and mouth sores items will be administered at preHSCT/end of treatment visit. 
i. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 

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Table 6 
Post-treatment Schedule of Assessments for Crossover Extension 
Activity 
pre-HSCT Visit / 
End of Treatment Visita 
30-Day 
Follow-up (+ 7 days) 
Physical Examination 
Xb 
 
Vital Signs 
Xb 
 
ECOG Performance 
Xb 
 
Concomitant Medications 
X 
 
Pregnancy Test for Woman of Childbearing Potential 
X 
 
12-lead ECG 
X 
 
Clinical Laboratory Tests (chemistry, hematology, coagulation) 
Xb 
 
Thyroid Function Tests 
X 
 
AE/SAE Assessment 
X 
Xc,d 
IRT Transaction Required  
X 
 
AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HSCT: hematopoietic stem cell transplant; IRT: interactive response technology; SAE: 
serious adverse event 
a. End of treatment visit is to be performed within 7 days after treatment discontinuation, and before initiation of any other systemic antileukemic treatment or conditioning regimen 
for HSCT. 
b. Does not need to be repeated if collected at a regularly scheduled visit within 3 days of the end of treatment visit. 
c. AE collection will continue during HSCT for subjects who plan to resume ASP2215 treatment after HSCT. 
d. Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. SAE data that is related to ASP2215 will be 
collected after 30-Day Follow-up as well. 
 

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1 
INTRODUCTION 
1.1 
Background 
Over 90% of leukemia cases are diagnosed in adults 20 years of age and older, among whom 
the most common types are chronic lymphocytic leukemia (35%) and acute myeloid leukemia 
(AML) (32%) [American Cancer Society, 2014]. The median age at diagnosis is 67 years of 
age, with 54% of patients diagnosed at 65 years or older [O’Donnell et al, 2012]. It was 
estimated that 18860 people (11530 men and 7330 women) were to be diagnosed with AML, 
and 10460 were to die from the disease in 2014 in the United States [American Cancer Society, 
2014]. While 60% to 80% of younger patients achieve a complete remission (CR) with 
standard therapy, only about 30% to 40% of the overall patient population has long-term 
disease-free survival [Tallman, 2005]. Outcomes are worse for patients aged 60 years or over, 
with CR rates in the range of 40% to 55% and poor long-term survival rates. 
Along with age, remission rates and overall survival (OS) depend on a number of other 
factors, including cytogenetics, previous bone marrow disorders (such as myelodysplastic 
syndrome [MDS]) and comorbidities. Currently, there is no effective cure for the disease. 
FMS-like tyrosine kinase (FLT3) is a member of the class III receptor tyrosine kinase (TK) 
family that is normally expressed on the surface of hematopoietic progenitor cells. FLT3 and 
its ligand play an important role in proliferation, survival and differentiation of multipotent 
stem cells. FLT3 is overexpressed in the majority of AML cases. In addition, activated FLT3 
with internal tandem duplication (ITD) in and around the juxtamembrane domain and 
tyrosine kinase domain (TKD) mutations at around D835 in the activation loop are present in 
28% to 34% and 11% to 14% of AML cases, respectively [Schlenk & Döhner, 2009]. These 
activated mutations in FLT3 are oncogenic and show transforming activity in cells 
[Yamamoto et al, 2001]. Patients with FLT3-ITD mutation show poor prognosis in clinical 
studies, with a higher relapse rate, a shorter duration of remission from initial therapy 
(6 months versus 11.5 months for those without FLT3-ITD mutations) as well as reduced 
disease-free survival (16% to 27% versus 41% at 5 years) and OS (15% to 31% versus 42% 
at 5 years) [Patel et al, 2012; Gale et al, 2008; Yanada et al, 2005; Tiesmeier et al, 2004; 
Moreno et al, 2003]. The incidence of relapse after hematopoietic stem cell transplant 
(HSCT) is also higher for patients with FLT3-ITD (30% versus 16% at 2 years for those 
without FLT3-ITD mutations) [Brunet et al, 2012]. Similar to their prognosis for first line 
therapy, patients with relapsed/refractory FLT3-mutation positive AML have lower remission 
rates with salvage chemotherapy, shorter durations of remission to second relapse and 
decreased OS relative to FLT3-mutation negative patients [Konig & Levis, 2015; Chevallier 
et al, 2011; Levis et al, 2011]. 
AXL tyrosine kinase (AXL) is a member of TAM family (Tyro-3, AXL and Mer) receptor 
TKs and is normally expressed in cells of mesenchymal origin, such as osteoblasts, fibroblasts 
and blood cells. AXL has been reported to be overexpressed or activated in many cancers, 
including AML [Linger et al, 2008]. AXL overexpression in AML confers drug resistance 
[Hong et al, 2008] and is associated with adverse prognosis [Ben-Batalla et al, 2013; Rochlitz 
et al, 1999]. AXL inhibition suppresses the growth of human FLT3-positive AML in vivo 

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[Park et al, 2013]. In addition, AXL inhibition is also effective against FLT3-negative AML 
expressing AXL in vivo [Ben-Batalla et al, 2013]. 
ASP2215 is a new chemical entity discovered by Astellas Pharma Inc. in collaboration with 
Kotobuki Pharmaceutical Co., Ltd. ASP2215 has an inhibitory effect on TKs, mainly FLT3, 
AXL and anaplastic lymphoma kinase (ALK). ASP2215 demonstrated favorable efficacy in a 
non-clinical AML model, with complete regression of tumors in the xenograft model mice 
transplanted with MV4-11, human AML cell line expressing FLT3-ITD, by repeated oral 
doses. In addition, ASP2215 inhibited the growth of cells expressing either FLT3-ITD, 
FLT3-D835Y or FLT3-ITD-D835Y. 
There is no universally accepted standard chemotherapy regimen for patients with relapsed or 
refractory AML and the National Comprehensive Cancer Network (NCCN) guideline for 
AML strongly recommends clinical trial as the first option for any patient. The guidelines 
also provide a list of commonly used regimens for relapsed/refractory AML. The choice of 
specific regimen is based on factors such as prior treatment, eligibility for allogeneic HSCT 
and institutional preference. Additionally, there are no definitive studies that demonstrated 
superiority of any single regimen. In this study, a limited list of regimens listed in NCCN 
guidelines are provided as comparator chemotherapy regimens for the investigators to choose 
from. Similar to the guidelines, both aggressive (mitoxantrone, etoposide and intermediate-
dose cytarabine [MEC] and fludarabine, cytarabine and granulocyte colony-stimulating factor 
[FLAG]) and less-aggressive (low-dose cytarabine [LoDAC]) regimens are included in the 
study. 
1.2 
Non-clinical and Clinical Data 
1.2.1 
Non-clinical Data 
ASP2215 inhibited activities of FLT3, nucleophosmin-1 gene-ALK, leukocyte receptor TK, 
ALK and AXL kinases at 1 and 5 nmol/L and tropomyosin receptor kinase A, ROS, RET and 
MER kinases at 5 nmol/L by over 50%. ASP2215 inhibited FLT3, echinoderm microtubule-
associated protein-like 4-ALK variant 1 and KIT kinase activities with the half maximal 
inhibitory concentration (IC50) values of 0.291, 1.2 and 229 nmol/L, respectively. 
ASP2215 inhibited each radioligand binding to adenosine A1 receptor (rat), serotonin 
5-hydroxytryptamine receptor 1 (5HT1R) (nonselective, rat), serotonin 5-hydroxytryptamine 
receptor 2B (5HT2BR) (human) and sigma receptor (nonselective, guinea pig) with IC50 
values of 4.57, 4.90, 0.190 and 0.615 μmol/L, respectively. 
ASP2215 inhibited human 5HT2BR function in a cell function assay with an IC50 value of 
5.82 μmol/L without showing agonistic activity. 
ASP2215 inhibited the cell growth of Ba/F3 cells expressing FLT3-ITD, FLT3-D835Y and 
FLT3-ITD-D835Y with IC50 values of 1.8, 1.6 and 2.1 nmol/L, respectively. ASP2215 
inhibited the growth of MV4-11 cells with IC50 value of 0.92 nmol/L. In MV4-11 cells, 
treatment of ASP2215 at 0, 0.1, 1 and 10 nmol/L resulted in FLT3 phosphorylation of 100%, 
86%, 19% and 7%, respectively. 

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ASP2215 induced significant growth inhibition of MV4-11 tumors and tumor regression in 
vivo. Further, ASP2215 at 6 and 10 mg/kg per day induced complete tumor regression for 
4 and 6 out of 6 mice, respectively. Body weight of the mice treated with ASP2215 was not 
affected at any tested doses. 
These results indicate ASP2215 should show the antitumor efficacy against AML subjects 
with FLT3-ITD and FLT3 mutation at D835. 
The IC50 value of ASP2215 against FLT3 kinase was about 800-fold lower than that against 
KIT kinase, and neutropenia was not observed in the toxicity studies in rats and dogs. 
In Caco-2 cells, the permeability of ASP2215 was between that of known low and high 
permeability markers. ASP2215 was a substrate for P-glycoprotein (P-gp), but not a substrate 
for breast cancer resistance protein (BCRP), organic anion transporting polypeptide 
(OATP)1B1, OATP1B3 or organic cation transporter 1. ASP2215 demonstrated a potential to 
inhibit BCRP and multidrug and toxin extrusion protein 1 (MATE1) at clinically relevant 
concentrations of ASP2215. However, preliminary results from the drug-drug interaction 
assessment of coadministration of ASP2215 and cephalexin, a MATE1 substrate, in 
Relapse/Refractory AML subjects indicate lack of a clinically-significant interaction between 
ASP2215 and MATE1 substrate [see Section 1.2.2.1 Clinical Pharmacokinetics and 
Pharmacodynamics]. 
No major human-specific ASP2215 metabolites were formed by liver microsomes or 
hepatocytes. The main enzyme involved in the metabolism of ASP2215 was estimated to be 
cytochrome P450 (CYP)3A4. ASP2215 has a potential to induce CYP enzyme activities 
(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5) and messenger RNA 
levels (CYP2B6, CYP2C8, CYP2C9 and CYP3A4). However, these results should be 
interpreted with caution because these effects were not uniformly observed in all donor 
samples and the concentration-dependency of these effects could not be evaluated. For 
CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2D6 inhibition, IC50 values were 
> 100 μmol/L. Very weak direct inhibition of CYP2C19 and CYP3A was observed. Overall, 
ASP2215 showed minimal direct inhibition of CYP enzymes at clinically relevant 
concentrations. 
1.2.2 
Clinical Data 
1.2.2.1 Clinical Pharmacokinetics and Pharmacodynamics 
The pharmacokinetic parameters of unchanged drug after single and multiple dosing of 
ASP2215 to AML subjects were investigated in the dose escalation cohort of 
Study 2215-CL-0101. Assessment of observed trough concentration (Ctrough) over time for 
individual subjects (both dose escalation and dose expansion cohorts) showed that in most 
subjects, the trough concentration of ASP2215 appeared to reach steady state by day 15 of 
multiple administrations of ASP2215 from 20 to 120 mg once daily. 
Plasma inhibitory assay (PIA) from the samples collected predose and postdose on days 1, 8, 
15 and 29 demonstrated sustained inhibition of phospho-FLT3 at doses 80 mg and higher. 

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The effect of strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers on 
ASP2215 exposure was assessed in Relapse/Refractory AML subjects (Study 2215-CL-0101) 
and healthy subjects (Study 2215-CL-0108). In Relapse/Refractory AML subjects, there was 
a less than 2-fold increase in ASP2215 exposure when ASP2215 was coadministered with 
moderate or strong CYP3A4 inhibitors. In healthy subjects, ASP2215 exposure increased 
approximately 2-fold when ASP2215 was coadministered with itraconazole, a strong 
CYP3A4 and P-gp inhibitor. Coadministration of ASP2215 with rifampicin, a strong 
CYP3A4 inducer, resulted in an approximate 70% decrease in ASP2215 exposure. 
Collectively, these data support monitoring subjects who require concomitant medications 
that are strong CYP3A4 inhibitors and restricting use of concomitant medications that are 
strong CYP3A4 inducers. 
Preliminary results from a drug-drug interaction assessment in a subset of Relapse/Refractory 
AML subjects (2215-CL-0101) indicate cephalexin (MATE 1 substrate) exposure was 
comparable after single dose administration of cephalexin alone and in combination with 
ASP2215 (administered once daily). These results suggest coadministration of MATE1 
substrates and ASP2215 is not expected to result in a clinically-relevant drug-drug 
interaction. 
1.2.2.2 Clinical Efficacy 
As of the cutoff date of 01 April 2016, a clinical study in AML patients and 3 studies in 
healthy volunteers are complete. In addition, 1 study in patients with solid tumors, 4 studies 
in AML patients and 1 study in combination with erlotinib in patients with Non-small cell 
lung cancer (NSCLC) whose tumors harbor an Epidermal Growth Factor Receptor (EGFR) 
activating mutation (EGFR mutation positive (EGFRm+) NSCLC) are ongoing. Overall, 
147 healthy volunteers and 319 patients have received at least 1 dose of gilteritinib. 
Data from Study 2215-CL-0101 as of the cutoff date of 24 November 2015, a phase 1/2 study 
in patients with relapsed/refractory AML are provided. Patients were assessed for FLT3 
mutational status by local lab at the screening visit. 
Primary analysis results from Study 2215-CL-0101 indicate that of the 252 patients who 
received at least 1 dose of gilteritinib, the majority of composite complete remission (CRc) 
and partial remission (PR) events were observed in FLT3-mutation positive patients in dose 
groups of 80 mg and greater. The derived response rate (CRc + PR) at the end of treatment in 
the 191 FLT3-mutation positive patients was 48.7% overall and 66.7%, 55.4%, 47.2%, 
60.0% and 50.0% in the 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups, 
respectively. 
1.3 
Summary of Key Safety Information for Study Drugs 
1.3.1 
ASP2215 
The non-clinical and clinical studies which are referred to in this section are described in 
more detail in the ASP2215 Investigator’s Brochure [2016]. 

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1.3.1.1 ASP2215 Non-clinical Data 
Major findings in the safety pharmacology studies were vomiting, positive fecal occult blood 
and increased/decreased blood Ca2+ in dogs, and decreased urination and defecation in rats.  
In the oral 13-week repeated dose toxicity study in rats, and the 4- and 13-week repeated dose 
toxicity studies in dogs, mortality occurred at 20 mg/kg per day, and at 10 and 5 mg/kg per 
day, respectively.  With respect to other major target organ toxicities, effects on the urinary 
bladder, epithelial tissue, gastrointestinal tract, lymphohematopoietic system, eye, liver, 
kidney and/or lung were observed in rats and dogs at 2.5 mg/kg per day or more.  All major 
findings were reversible and monitorable.  
Gilteritinib has a potential to induce genotoxicity in vivo.   
Gilteritinib showed suppressed fetal growth, embryo-fetal deaths and teratogenicity in the 
embryo-fetal development study in rats.   
Gilteritinib showed no potential to induce phototoxicity in cultured mammalian cells. 
When gilteritinib was dosed to juvenile rats from PND 4 to 42, the minimum lethal dose level 
was 2.5 mg/kg per day and this dose level was lower than that (20 mg/kg per day) in adult 
rats in the 13-week dose study.  In the preliminary (non-GLP) dose range finding study 
(dosing from PND 4 to 21), gastrointestinal bleeding indicated as abnormal stool color (dark 
red) were noted at 10 mg/kg per day and higher, which was not noted in adult rats in the 
13-week dose study. 
1.3.1.2 ASP2215 Clinical Data 
As of the cutoff date of 01 April 2016, a clinical study in AML patients and 3 studies in 
healthy volunteers are complete. In addition, 1 study in patients with solid tumors, 4 studies 
in AML patients and 1 study in combination with erlotinib in patients with NSCLC whose 
tumors harbor an EGFR activating mutation (EGFRm+ NSCLC) are ongoing. Overall, 
147 healthy volunteers and 319 patients have received at least 1 dose of gilteritinib. 
The majority of the 249 patients (98.8%) in Study 2215-CL-0101 who received at least 
1 dose of gilteritinib experienced at least 1 treatment-emergent adverse event (TEAE), and 
74.6% of patients experienced at least 1 TEAE considered by the Investigator to be possibly 
or probably related to study drug. Common TEAEs (occurring in at least 10% of patients) 
included febrile neutropenia, thrombocytopenia, constipation, diarrhea, nausea, stomatitis, 
vomiting, asthenia, fatigue, peripheral edema, pyrexia, pneumonia, sepsis, fall, increased 
alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased 
blood alkaline phosphatase, increased blood creatinine, decreased neutrophil count, decreased 
platelet count, decreased appetite, hypoalbuminemia, hypocalcaemia, hypokalemia, 
hypomagnesaemia, hyponatraemia, arthralgia, acute myeloid leukaemia, dizziness, dysgeusia, 
headache, cough, dyspnea, epistaxis, hypoxia and hypotension. No clear dose-dependent 
patterns were observed for overall TEAEs, TEAEs of grade 3 or higher, drug-related TEAEs, 
serious TEAEs or drug-related serious TEAEs. Ninety-five patients experienced TEAEs 
leading to death. The incidence of deaths in the 20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 
300 mg and 450 mg dose groups was 31.3%, 37.5%, 45.8%, 30.0%, 41.7%, 40.0% and 

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33.3%, respectively. Twenty-eight patients experienced dose-limiting toxicities (DLTs). 
None of the doses below 450 mg met the criteria for pausing enrollment. Thus, the maximum 
tolerated dose (MTD) in Study 2215-CL-0101 is considered to be 300 mg. 
Additionally, primary analysis of the relationship between gilteritinib plasma concentration 
and Fridericia-corrected QT interval (QTcF) change from baseline (ΔQTcF) was performed 
on data from the 2215-CL-0101 study. This assessment included 1801 observations from 
249 patients. A concentration related increase in ΔQTcF was observed; however, the mean 
ΔQTcF at the mean steady-state Cmax was predicted to be less than 10 msec and the upper 
1-sided 95% confidence interval were predicted to be less than 10 msec and not considered as 
clinically significant. Additionally, less than 5% of relapse/refractory subjects had a 
maximum post baseline QTcF interval > 500 msec and approximately 8% of subjects had a 
> 60 msec change in their maximum Corrected QT interval (QTc) relative to baseline. 
Although these data indicate clinically relevant QTc prolongation is not anticipated, the 
sponsor has implemented additional eligibility criteria for enrollment in gilteritinib clinical 
trials (exclusion of subjects with QTcF > 450 ms, long QT syndrome, hypokalemia, or 
hypomagnesemia) and electrocardiogram (ECG) assessments at multiple timepoints. Astellas 
will continue to monitor for arrhythmias and clinically significant QT prolongation during the 
conduct of gilteritinib clinical trials. 
An exposure-related increase was observed between gilteritinib plasma concentration and 
Creatine kinase (CK) change from baseline (ΔCK) in patients with relapsed/refractory AML 
based on pharmacokinetic/ pharmacodynamic modeling that included 1519 time-matched 
data points (n = 243 patients). Additionally, the incidence of higher Common Terminology 
Criteria for Adverse Events (CTCAE) grades related to elevated CK appears to have 
increased with increasing gilteritinib dose. However, almost all of the observed elevations in 
CK laboratory values were grade 1 and grade 2, and the incidence of grade ≥ 3 related 
adverse events reported in the study population was low (4.4%). The preferred term of blood 
creatine phosphokinase increased has been identified as an expected Adverse Drug Reaction 
(ADR) of gilteritinib. 
There was a trend towards an increasing incidence of AEs and shifts in laboratory values 
related to hepatotoxicity with increasing gilteritinib doses as well. Similar to ΔCK, an 
exposure-related increase was observed between gilteritinib plasma concentration and AST 
change from baseline (ΔAST) based on pharmacokinetic/pharmacodynamic modeling that 
included 1517 time-matched data points (n = 243) with low incidence of Grade ≥ 3 related 
adverse events observed (6.0%). The preferred terms of alanine aminotransferase increased 
and aspartate aminotransferase increased have been identified as expected ADRs. 
Twenty-eight patients experienced DLTs as of the data cutoff; most (26/28) patients were in 
the dose expansion cohort. One patient in the 20 mg dose group experienced grade 5 
intracranial hemorrhage. One patient in the 40 mg dose group experienced grade 3 toxic 
shock syndrome. Two patients in the 80 mg dose group experienced DLTs including grade 3 
conjunctival edema and grade 5 septic shock. Seven patients in the 120 mg dose group 
experienced the following DLTs: grade 3 hypoxia and pleural effusion; grade 3 hematochezia 

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and lower gastrointestinal hemorrhage; grade 5 ventricular fibrillation; grade 4 renal tubular 
necrosis; grade 3 hyperbilirubinemia; grade 3 blood lactate dehydrogenase increased; and 
grade 3 liver function test abnormal. Twelve patients in the 200 mg dose group experienced 
DLTs including: grade 3 transaminases increased (2 patients); grade 3 abdominal pain; 
grade 3 hematochezia; grade 3 intestinal perforation; grade 3 blood creatine phosphokinase 
increased; grade 3 electrocardiogram QT prolonged, grade 4 hypoxia and grade 3 acute 
promyelocytic leukemia differentiation syndrome; grade 3 gamma-glutamyltransferase 
increased; grade 3 hypotension; grade 3 dizziness and myalgia; and grade 3 hypotension and 
acidosis and grade 4 hypoxia. Three patients in the 300 mg dose group experienced the 
following DLTs: grade 3 disseminated intravascular coagulation, grade 3 gastrointestinal 
hemorrhage, grade 3 hypertension and grade 3 aspartate aminotransferase increased; grade 5 
pulmonary embolism; and grade 4 blood creatine phosphokinase increased and grade 3 
rhabdomyolysis. Two patients in the 450 mg dose group experienced DLTs including grade 3 
diarrhea and grade 3 aspartate aminotransferase increased. The MTD in Study 2215-CL-0101 
is considered to be 300 mg. 
Expected adverse drug reactions for ASP2215 include (by preferred term) diarrhea, 
peripheral edema, increased blood creatine phosphokinase, electrocardiogram QT prolonged, 
increased ALT, increased AST, myopathy, and posterior reversible encephalopathy 
syndrome. 
There were 2 patients who experienced retinoic acid syndrome (differentiation syndrome) 
that was considered by the investigator to be related to ASP2215. FLT3 inhibitors may 
differentiate leukemic blasts to mature neutrophils. Patients who develop differentiation 
syndrome may present with increases in neutrophil counts, unexplained fever, acute 
respiratory distress with interstitial pulmonary infiltrates, and/or vascular capillary leak 
syndrome. 
1.3.2 
Comparative Chemotherapy Regimens 
Detailed information on the toxicities and common AEs associated with the comparative 
chemotherapy regimens can be found within the Package Insert, Summary of Product 
Characteristics or local product information. 
1.4 
Risk-Benefit Assessment 
Approximately 30% of adult AML subjects are refractory to induction therapy. Furthermore, 
of those who achieve CR, approximately 75% will relapse. Subjects with AML with FLT3 
mutations comprise an especially poor prognosis group. Generally, there is no established 
standard for relapsed subjects with FLT3 mutations and less than 20% will achieve CR with 
subsequent treatment. Duration of remission for the small minority who achieve remission is 
also limited with most of the subjects relapsing. 
In phase 1/2 Study (2215-CL-0101), ASP2215 has resulted in CRc in over 40% of subjects 
receiving 80 mg or higher dose. The median survival was over 7 months in 120 mg dose 
level. The majority of subjects in the trial have received multiple treatments prior to receiving 
ASP2215. Furthermore, ASP2215 was well tolerated at the proposed doses in this study. 

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Subjects with AML who relapse or do not respond to initial treatment have a very poor 
prognosis. Although there are various chemotherapy options available, they are by no means 
curative. The response to salvage chemotherapy is poor, and especially for subjects with FLT3 
mutation. Although it is not known whether response to ASP2215 treatment would lead to 
longer survival, in light of the very poor prognosis of relapsed or refractory AML subjects with 
FLT3 mutations, the potential for ASP2215 to improve outcome outweighs the risk of potential 
toxicities. 
2 
STUDY OBJECTIVES, DESIGN AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective  
The primary objective is to determine the clinical benefit of ASP2215 therapy in subjects 
with FLT3-mutated AML who are refractory to or have relapsed after first-line AML therapy 
as shown with OS compared to salvage chemotherapy. 
2.1.2 
Secondary Objectives 
The key secondary objectives are to: 
● 
Determine the overall efficacy in event-free survival (EFS) of ASP2215 compared to 
salvage chemotherapy. 
● 
Determine the overall efficacy in CR rate of ASP2215 compared to salvage chemotherapy. 
The secondary objectives are to evaluate the safety and efficacy of ASP2215 therapy versus 
salvage chemotherapy in terms of: 
● 
leukemia-free survival (LFS) 
● 
duration of remission 
● 
CRc rate 
● 
transplantation rate 
● 
patient reported fatigue (Brief Fatigue Inventory [BFI]) 
● 
adverse events (AEs), safety labs, vital signs, electrocardiograms (ECGs) and Eastern 
Cooperative Oncology Group (ECOG) performance scores 
● 
evaluate the PK of ASP2215 therapy in the Chinese population 
2.1.3 
Exploratory Objectives 
Evaluate the safety and efficacy of ASP2215 therapy versus salvage chemotherapy in terms of: 
● 
Pharmacogenomics (PGx) 
● 
FLT3 gene mutation status 
o mutation types and frequency 
o relationship to efficacy and safety 
● 
exploratory (predictive) biomarkers of ASP2215 activity 

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● 
resource utilization in this study population including hospitalization, blood transfusion, 
antibiotic iv infusions, medication for AEs and opioid usage  
● 
patient reported dyspnea (Functional Assessment of Chronic Illness Therapy-Dyspnea-
Short Forms [FACIT-Dys-SF]) 
● 
patient reported signs, symptoms and impacts of AML (Functional Assessment of Cancer 
Therapy-Leukemia [FACT-Leu], dizziness and mouth sore items) 
● 
EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L) 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is phase 3, open-label, multicenter, randomized study to compare the efficacy and safety 
of ASP2215 therapy to salvage chemotherapy in FLT3-mutated AML subjects who are 
refractory to or have relapsed after first-line AML therapy. Approximately 50 centers in 
China, Russia, Singapore, Thailand, and Malaysia will participate in this study. 
Three hundred eighteen subjects will be randomized. The randomization of the 318 subjects 
will be in a 1:1 ratio to receive ASP2215 or salvage chemotherapy. Subjects will enter the 
screening period up to 14 days prior to the start of treatment. Prior to randomization, the 
investigator will preselect a salvage chemotherapy regimen for each subject; options will 
include LoDAC, MEC or FLAG. The randomization will be stratified by response to first-line 
therapy and preselected salvage chemotherapy. Subjects will be administered treatment over 
continuous 28-day cycles and per institutional guidelines for chemotherapy product preparation 
and administration. The dose and duration of study treatments are outlined in [Section 5.1.1 
Dose/Dose Regimen and Administration Period] of the protocol. 
Two (or more) study sites in China will be designated as a “pharmacokinetic analysis site” (PK 
analysis site). Approximately 20 Chinese subjects (10 male and 10 female subjects) (they will 
be included in 318 subjects) at PK analysis sites, who are randomized to the ASP2215 arm will 
be allocated to the “PK cohort”. Subjects in the PK cohort will be requested to be hospitalized 
on Day 1 and Day15 until the completion of all the assessments. Subjects in the PK cohort will 
be administered ASP2215 in the same manner and undergo the same efficacy and safety 
assessments as other subjects except for blood sampling for additional PK analysis. For 
subjects in the PK cohort, written informed consent must be obtained by the specific informed 
consent form (ICF) explaining that more frequent blood sampling will be done. 
The first 20 subjects (10 male and 10 female) randomized into ASP2215 arm at PK cohort sites 
will participate in PK cohort.   
For subjects taking ASP2215 or LoDAC, treatment should continue until the subject meets a 
treatment discontinuation criterion. 
Subjects receiving MEC or FLAG will receive 1 cycle of therapy and will be assessed for 
response on or after day 15, per institutional guidelines. If the bone marrow cellularity is 20% 
or greater with at least a 50% reduction in blasts, the subject may receive a second cycle of 
the same chemotherapy. If bone cellularity is between 5% and 20%, the investigator should 

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make the decision whether the subject should receive another treatment cycle or be observed 
for recovery. If marrow cellularity is 5% or less, the subject will be observed for recovery. 
Subjects achieving CR, CRi or CRp may receive a second cycle of chemotherapy at the 
investigator’s discretion. Subjects with no response (NR) or progressive disease following 
cycle 1 will discontinue study treatment. 
Dose adjustments for ASP2215 are described in [Section 5.1.2 Interruption, Reduction or 
Escalation in Dose of the Study Drug] of the protocol. 
Subjects who have a donor identified and achieve a response allowing them to undergo 
HSCT per each institution’s assessment can undergo HSCT without leaving the study. 
However, ASP2215 should be stopped and a pre-HSCT visit should be performed prior to 
starting the conditioning regimen for HSCT. ASP2215 can be resumed after stem cell 
transplantation if the following conditions are met: 
● 
Subject is between 30 - 90 days post HSCT 
● 
Subject has had successful engraftment as demonstrated by absolute neutrophil count 
(ANC) ≥ 500/mm3 and platelets ≥ 20000/mm3 without transfusions 
● 
Subject does not have ≥ grade 2 acute graft-versus-host disease (GVHD) 
● 
Subject is in CRc 
For subjects resuming treatment, subjects will follow the procedures listed under subsequent 
cycles day 1 in the Schedule of Assessments. Subjects who do not resume ASP2215 will be 
followed for primary endpoint. 
After treatment discontinuation, subjects will have an end of treatment visit within 7 days 
after treatment discontinuation, followed by a 30-day follow-up, in which a telephone contact 
with the subject is sufficient unless any assessment must be repeated for resolution of 
treatment-related AEs. After which the subjects will enter the long-term follow-up period for 
collection of patient reported outcome (PRO) using EQ-5D-5L, subsequent AML treatment, 
remission status and survival (cause of death and date of death). The long-term follow-up will 
be every 3 months, for up to 3 years from the subject’s end of treatment visit until the 
implementation and reconsent of the current protocol version 7.0, at which time they will 
discontinue from the study. 
A formal interim analysis by an Independent Data Monitoring Committee (IDMC) will be 
done when approximately 50% of deaths by any cause have occurred. This analysis will be 
utilized to determine whether the study should be terminated earlier than planned if ASP2215 
has more favorable or harmful outcome than the salvage chemotherapy group. If the interim 
analysis demonstrates a more favorable outcome for ASP2215, enrollment to the study may 
be stopped in advance. If it demonstrates a harmful outcome, the enrollment will be stopped. 
However, any subject continuing to derive clinical benefit from ASP2215 as assessed by the 
investigator will be allowed to continue treatment until they meet a discontinuation criterion 
as outlined in [Section 6 Discontinuation] or upon marketing authorization, commercial 
availability and applicable reimbursement of ASP2215 in the country of residence. 

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Subjects will be managed per the local institution’s standard of care for safety and efficacy 
assessments while on study treatment after subjects reconsents under this protocol version 
7.0. No data (including PK assessments) will be collected in the eCRFs after subjects’ 
reconsent under this protocol version 7.0. Only SAEs, as defined in [Section 5.5.2 Definition 
of Serious Adverse Events], will be collected and reported to Astellas Pharma Inc. Product 
Safety & Pharmacovigilance. SAE data will be reported in the safety database. SAE 
collection will continue until 30 days after the last dose of study treatment. Once subjects 
receiving study treatment meet the study discontinuation criteria or upon marketing 
authorization, commercial availability and applicable reimbursement of ASP2215 in the 
country of residence, subjects will be discontinued from the study.  
Subjects in long-term follow-up who are no longer receiving study treatment will be followed 
every 3 months for up to 3 years until implementation and reconsent of the current protocol 
version 7.0, at which time they will discontinue from the study. 
The detailed assessments and procedures are presented in [Appendix 12.8] 
The interim analysis of the study demonstrated a positive outcome and hence the Crossover 
Extension (COE) as outlined in [Section 12.7 Crossover Extension] was implemented. 
2.2.2 
Dose Rationale 
2.2.2.1 ASP2215 
In the first-in-human phase 1/2 clinical Study [2215-CL-0101], relapsed/refractory AML 
subjects were treated with ASP2215 at doses ranging from 20 to 450 mg administered once 
daily. The primary objectives for this study were to determine the safety and pharmacokinetics 
of ASP2215 following single and repeat dosing. In addition, preliminary efficacy as assessed 
by response rates was evaluated. 
Clinical safety data indicated an MTD of 300 mg. Clinical efficacy data supports doses of 
120 mg and greater to ensure efficacy in FLT3-mutation positive subjects. PIA has shown 
substantial reduction of phospho-FLT3, with > 90% inhibition at doses of 80 mg or greater. 
Although, none of the dose levels within the expansion cohort have reached the threshold to 
stop enrollment (> 20% DLT with posterior probability of 80%), 120 mg and 200 mg doses 
especially had low DLT rates. However, CK and AST elevations correlating with increasing 
dose and increasing exposure were observed. Overall, 120 mg provides a good balance of 
ensuring effective drug levels for virtually all subjects with a low incidence of safety 
concerns, while still preserving the 200 mg dose available for dose escalation. 
2.2.2.2 Comparator Chemotherapy Regimens 
Doses of chemotherapy regimens were taken from representative publications as listed in 
[Section 5.1.1.2 Comparative Drugs]. Doses used in randomized trials were chosen where 
available. 

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2.3 
Endpoints 
2.3.1 
Primary Endpoint 
● 
OS 
2.3.2 
Secondary Endpoints 
Key Secondary Efficacy Endpoints 
● 
EFS 
● 
CR 
Secondary Efficacy Endpoints 
● 
LFS 
● 
Duration of remission 
● 
CRc (CR + CRi + CRp)  
● 
Transplantation  
● 
BFI 
2.3.3 
Exploratory Endpoints 
● 
Pharmacogenomics (PGx) 
● 
FLT3 gene mutation status 
o mutation types and frequency 
o relationship to efficacy and safety 
● 
Exploratory (predictive) biomarkers of ASP2215 activity 
● 
Resource utilization, including hospitalization, blood transfusion, antibiotic iv infusions, 
medication for AEs and opioid usage  
● 
FACIT-Dys-SF 
● 
FACT-Leu and dizziness and mouth sore items 
● 
EQ-5D-5L 
2.3.4 
Safety Endpoints 
● 
AEs 
● 
Serum chemistry, hematology, coagulation and urinalysis 
● 
Vital signs 
● 
ECGs 
● 
ECOG performance scores 
2.3.5 
Pharmacokinetics 
● 
ASP2215 concentration in blood 
● 
Pharmacokinetic parameters of ASP2215 in Chinese population 

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3 
STUDY POPULATION 
3.1 
Selection of Study Population 
FLT3-mutated subjects with relapsed or refractory AML after first-line therapy will be selected 
for this study. Rescreening is allowed, with a limit of 2 rescreenings for any potential subject. 
Screening assessments (central FLT3) completed within 28 days prior to first dose do not need 
to be repeated. 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written Informed Consent and privacy language as per national regulations must be 
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject is considered an adult according to local regulation (e.g., age ≥ 18 years old in 
China) at the time of signing informed consent. 
3. Subject has a diagnosis of primary AML or AML secondary to MDS according to World 
Health Organization (WHO) classification [Swerdlow et al, 2008] as determined by 
pathology review at the treating institution. 
4. Subject is refractory to or relapsed after first-line AML therapy (with or without HSCT) 
(see definition of line of therapy in Appendix 12.6). 
● 
Refractory to first-line AML therapy is defined as: 
a. Subject did not achieve CR/CRi/CRp under initial therapy. A subject eligible 
for standard therapy must receive at least 1 cycle of an anthracycline containing 
induction block in standard dose for the selected induction regimen. A subject 
not eligible for standard therapy must have received at least 1 complete block 
of induction therapy seen as the optimum choice of therapy to induce remission 
for this subject as per investigator’s assessment. 
● 
Untreated first hematologic relapse is defined as: 
a. Subject must have achieved a CR/CRi/CRp (criteria as defined by [Cheson et 
al, 2003], see [Section 5.3 Efficacy Assessment]) with first-line treatment and 
has hematologic relapse. 
5. Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by 
the central lab. In the investigator’s opinion, a subject with rapidly proliferative disease 
and unable to wait for the central lab results can be enrolled based on a local test 
performed after completion of the last interventional treatment. Subjects can be enrolled 
from a local test result if they have any of the following FLT3 mutations: FLT3-ITD, 
FLT3-TKD/D835 or FLT3-TKD/I836. 
6. Subject has an ECOG performance status ≤ 2. 

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7. Subject is eligible for preselected salvage chemotherapy according to investigator 
assessment. 
8. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
● 
Serum AST and ALT ≤ 2.5 x upper limit of normal (ULN) 
● 
Serum total bilirubin (TBL) ≤ 1.5 x ULN 
● 
Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of 
> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation. 
9. Subject is suitable for oral administration of study drug. 
10. Female subject must either: 
● 
Be of non-childbearing potential: 
● Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or 
● Documented as surgically sterile (at least 1 month prior to screening) 
● 
Or, if of childbearing potential, 
● Agree not to try to become pregnant during the study and for 60 days after the 
final study drug administration 
● And have a negative serum or urine pregnancy test at screening 
● And, if heterosexually active, agree to consistently use highly effective 
contraception per locally accepted standards in addition to a barrier method 
starting at screening and throughout the study period and for 60 days after the 
final study drug administration. 
11. Female subject must agree not to breastfeed at screening and throughout the study period 
and for 60 days after the final study drug administration. 
12. Female subject must not donate ova starting at screening and throughout the study period 
and for 60 days after the final study drug administration. 
13. Male subject and their female partners who are of childbearing potential must be using 
highly effective contraception per locally accepted standards in addition to a barrier 
method starting at screening and continue throughout the study period and for 120 days 
after the final study drug administration. 
14. Male subject must not donate sperm starting at screening and throughout the study period 
and for 120 days after the final study drug administration 
15. Subject agrees not to participate in another interventional study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed. 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. Subject was diagnosed as acute promyelocytic leukemia. 
2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 

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3. Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS). 
4. Subject is in second or later hematologic relapse or has received salvage therapy for 
refractory disease. 
5. Subject has clinically active central nervous system leukemia. 
6. Subject has been diagnosed with another malignancy, unless disease-free for at least 
5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study 
if definitive treatment for the condition has been completed. Subjects with organ-confined 
prostate cancer with no evidence of recurrent or progressive disease are eligible if 
hormonal therapy has been initiated or the malignancy has been surgically removed or 
treated with definitive radiotherapy. 
7. Subject has received prior treatment with ASP2215 or other FLT3 inhibitors (with the 
exception of sorafenib and midostaurin used in first-line therapy regimen as part of 
induction, consolidation and/or maintenance). 
8. Subject has clinically significant abnormality of coagulation profile, such as disseminated 
intravascular coagulation. 
9. Subject has had major surgery within 4 weeks prior to the first study dose. 
10. Subject has radiation therapy within 4 weeks prior to the first study dose. 
11. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or 
subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a 
screening echocardiogram (ECHO) performed within 1 month prior to study entry results 
in a left ventricular ejection fraction (LVEF) that is ≥ 45%. 
12. Subject with mean of triplicate QTcF > 450 ms at Screening based on central reading.  
13. Subject with Long QT Syndrome at Screening. 
14. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below 
lower limit of normal [LLN]). 
15. Subject requires treatment with concomitant drugs that are strong inducers of CYP3A. 
16. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of 
P-gp with the exception of drugs that are considered absolutely essential for the care of the 
subject. 
17. Subject requires treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR 
receptors or sigma nonspecific receptor with the exception of drugs that are considered 
absolutely essential for the care of the subject. 
18. Subject has an active uncontrolled infection. 
19. Subject is known to have human immunodeficiency virus infection. 
20. Subject has active hepatitis B or C or other active hepatic disorder. 

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21. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
22. Subject has active clinically significant GVHD or is on treatment with systemic 
corticosteroids for GVHD. 
23. Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or 
FLT3-TKD/I836 
Waivers to the exclusion criteria will NOT be allowed. 
4 
TREATMENT(S) 
4.1 
Identification of Investigational Products 
4.1.1 
ASP2215 
ASP2215 tablets containing 40 mg of active ingredient. The tablets are contained within the 
high-density polyethylene bottle. 
The study centers will be provided bottles of ASP2215 each containing 30 tablets. The study 
site personnel will fill out the label to indicate the dispensing date, subject's ASP2215 dose 
and the corresponding number of tablets that need to be taken each day. The ASP2215 40 mg 
tablet product information is listed in [Table 7].  
Table 7 
Test Drug (ASP2215 Tablets 40 mg) 
Test Drug 
ASP2215 Tablets 40 mg 
Code name 
ASP2215 
Active ingredient 
Chemical name: C29H44N8O3•1/2 C4H4O4 
Composition and 
dosage form 
One tablet contains 40 mg of ASP2215 in free form. 
ASP2215 Tablets are round light-yellow film-coated tablets. 
Lot No. 
Described in separately prepared “Study Drug Handling Procedures” 
Storage 
ASP2215 should be stored according to labeled storage conditions and 
should not be stored above the temperature specified on the ASP2215 label. 
Store in original container. 
 
4.1.2 
Comparative Drug(s) 
The specific regimen will be preselected by the investigator prior to randomization of each 
subject [Table 8]. All regimens will be administered per institutional guidelines for 
chemotherapy product preparation and administration. All cycles will be 28 days. 
The comparative chemotherapy regimen will be supplied by the responsible site pharmacy of 
each investigational site or by the Sponsor if applicable. Sites are permitted to use generic 
chemotherapy drug that is approved by the respective regulatory authority. 
Refer to the approved package insert, summary of product characteristics or local product 
information for comparative chemotherapy drug product information and storage condition 
supplied by the manufacturers. 

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In the situation when comparator chemotherapy products are supplied by the Sponsor, 
comparator chemotherapy products used in this study will be packaged by the manufacturer, 
but labeled under the responsibility of Astellas Pharma Global Development, Inc. (APGD) 
and Astellas Pharma Inc. (API) in accordance with the packaging vendor qualified by API 
QA Standard Operating Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and 
applicable local laws/regulations. 
Table 8 
Comparator Drug Products Supplied by the Sponsor 
Comparator Chemotherapy Drug 
Drug Product (Example) 
LoDAC 
Low-dose cytarabine  
Cytarabine 20 mg/mL (100 mg/5 mL) Solution for Injection/ 
concentrate for Solution for Infusion 
Cytarabine 100 mg/mL (100 mg/1 mL) Solution for Injection/ 
concentrate for Solution for Infusion 
(For China) Cytarabine 0.1 g powder for Solution for Injection or 
Infusion + 1 ampoule diluent (5 mL) 
Cytarabine 0.1 g powder for Solution for Injection or Infusion 
MEC Induction Chemotherapy 
Cytarabine intermediate dose 
Cytarabine 100 mg/mL  (5 g/50 mL) Concentrate for Solution for 
Infusion 
(For China) Cytarabine 0.5g powder for Solution for Injection or 
Infusion + 1 ampoule diluent (10 mL) 
Cytarabine Hydrochloride 0.1g powder for Solution for Injection 
or Infusion 
Mitoxantrone 
Mitoxantrone 20 mg/10 mL (2 mg/mL) Concentrate for Solution 
for Infusion 
(For China) Mitoxantrone 5 mg/5 mL Concentrate for Solution for 
Injection 
Etoposide  
Etoposide 20 mg/mL (100 mg/5 mL) Concentrate for Solution for 
Infusion 
(For China) Etoposide 20 mg/mL (0.1 g/5 mL) Concentrate for 
Solution for Infusion 
FLAG Induction Chemotherapy 
High-dose cytarabine  
Cytarabine 100 mg/mL (5 g/50 mL) Concentrate for Solution for 
Infusion 
(For China) Cytarabine 0.5g powder for solution for Injection or 
Infusion + 1 ampoule diluent (10 mL) 
Cytarabine Hydrochloride 0.1g powder for Solution for Injection 
or Infusion 
G-CSF 
Filgrastim 30 million U/0.5 mL Solution for Injection or Solution 
for Infusion 
(For China) Lenograstim 34 million IU/mL, powder and solvent 
for Solution for Injection/Infusion   
Fludarabine 
Fludarabine Phosphate 25 mg/mL (50 mg/2 mL) Concentrate for 
Solution for Injection or Infusion 
(For China) Fludarabine Phosphate 50 mg/vial Powder for 
Injection after dilution 
FLAG: fludarabine, cytarabine and granulocyte colony-stimulating factor; G-CSF: granulocyte colony-
stimulating factor; LoDAC: low-dose cytarabine; MEC: mitoxantrone, etoposide and intermediate-dose 
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4.2 
Packaging and Labeling 
ASP2215 used in this study will be prepared, packaged and labeled under the responsibility 
of an authorized person at API Quality Assurance (QA)-API Technology in accordance with 
SOPs, GMP guidelines, ICH GCP guidelines and applicable local laws/regulations. 
Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations which identifies the contents as investigational drug. 
In the situation when comparative drug(s) are supplied by the Sponsor, comparative drugs 
used in this study will be labeled under the responsibility of API Technology in accordance 
with the packaging vendor qualified by API QA SOPs, GMP guidelines, ICH GCP guidelines 
and applicable local laws/regulations. 
4.3 
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator or designee and 
● 
that such deliveries are recorded, 
● 
that study drug is handled and stored according to labeled storage conditions, 
● 
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and 
● 
that any unused study drug is returned to the Sponsor or standard procedures for the 
alternative disposition of unused study drug are followed. 
Drug inventory and accountability records for the study drugs will be kept by the investigator 
or designee. Study drug accountability throughout the study must be documented and 
reconciled. The following guidelines are therefore pertinent: 
● 
The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol. 
● 
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs. 
● 
A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject. 
● 
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility. 
● 
The site must return unused study drug including ASP2215 and comparative chemo-
therapy drugs supplied by Sponsor back to the Sponsor or designee at the end of the 
study or upon expiration. 

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4.4 
Blinding 
This section is not applicable as this is an open-label study. 
4.5 
Assignment and Allocation 
Randomization and study drug assignment will be performed via Interactive Response 
Technology (IRT). Prior to the initiation of the study treatment, the site staff will contact the 
IRT in order to determine the randomly assigned treatment. Specific procedures for 
randomization through the IRT are contained in the study procedures manual. 
5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drugs and Other Medications 
5.1.1 
Dose/Dose Regimen and Administration Period 
5.1.1.1 ASP2215 
ASP2215 is an oral tablet that subjects will take once daily without food in continuous 28-day 
cycles. Subjects will be instructed to take the daily 120 mg dose with water as close to the 
same time each morning as possible. ASP2215 can be taken at least 2 hours after or 1 hour 
before food. ASP2215 will be self-administered at home when subjects are not scheduled for 
clinic visits. For the subjects in the PK cohort, study drug should be taken in the clinic on 
Day 1 and Day 15. If a subject forgets to take a dose in the morning and within 6 hours of the 
planned dosing time, they should be instructed to take their dose. If the subject forgets to take 
their daily dose and more than 6 hours has passed the planned dosing time, they should be 
instructed to wait for the next morning to dose. If vomiting occurs after dosing, the subject 
should not receive another dose, but just wait until the next morning to dose. 
ASP2215 will be given daily in continuous 28-day cycles. For subjects taking ASP2215 
treatment should continue until the subject meets a treatment discontinuation criterion. 
5.1.1.2 Comparative Drugs 
All regimens will be administered as 28-day cycles and per institutional guidelines for 
chemotherapy product preparation / administration. Options for comparative salvage 
chemotherapies are limited to the following (all dose levels as defined below must be 
followed): 
LoDAC [Burnett & Knapper, 2007] 
● 
20 mg cytarabine will be administered twice daily by SC or IV injection for 10 days. 
MEC Induction Chemotherapy [Amadori et al, 1991] 
● 
Mitoxantrone 6 mg/m2 per day will be administered by IV for 5 days (days 1 through 5). 
● 
Etoposide 100 mg/m2 per day will be administered by IV for 5 days (days 1 through 5). 
● 
Cytarabine 1000 mg/m2 per day will be administered by IV for 5 days (days 1 through 5). 

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FLAG Induction Chemotherapy [Montillo et al, 1998] 
● 
Granulocyte colony-stimulating factor (G-CSF) 300 µg/m2 per day will be administered 
by SC/IV for 5 days (days 1 through 5). Additional G-CSF by SC/IV is recommended 7 
days after completing chemotherapy until ANC > 0.5 x 109/L. 
● 
Fludarabine 30 mg/m2 per day will be administered by IV for 5 days (days 2 through 6). 
● 
Cytarabine 2000 mg/m2 per day will be administered by IV for 5 days (days 2 through 6). 
Subjects receiving LoDAC treatment should continue until the subject meets a treatment 
discontinuation criterion. 
Subjects receiving MEC or FLAG will receive 1 cycle of therapy and will be assessed for 
response on or after day 15, per institutional guidelines. If the bone marrow cellularity is 20% 
or greater with at least a 50% reduction in blasts, the subject may receive a second cycle of 
the same chemotherapy. If bone cellularity is between 5% and 20%, the investigator should 
make the decision whether the subject should receive another treatment cycle or be observed 
for recovery. If marrow cellularity is 5% or less, the subject will be observed for recovery. 
Subjects achieving CR, CRi or CRp may receive a second cycle of chemotherapy at the 
investigator’s discretion. Subjects with NR or progressive disease following cycle 1 will 
discontinue study treatment. 
5.1.2 
Interruption, Reduction or Escalation in Dose of the Study Drug 
Guidelines for ASP2215 dose interruption and reduction are provided in [Table 9]. 
The ASP2215 dose may be initially reduced to 80 mg per day. The ASP2215 dose can be 
further reduced to 40 mg per day if the subject has already experienced clinical benefit. Note 
that dose reductions should occur in a step-wise manner. Dose reduction can occur during the 
treatment cycle based on the dose reduction guideline in [Table 9]. No further dose reductions 
are allowed. (i.e., if a subject is receiving ASP2215 40 mg and further dose reduction is 
required, study treatment will be discontinued).  
Additionally, if the investigator deems it necessary to ensure subject safety, dosing may be 
interrupted or reduced for reasons other than those provided in [Table 9]. In the unusual 
circumstance that dosing is interrupted or reduced for reasons not specified in the tables, the 
investigator should promptly inform the study medical monitor or his/her designee. 
Under the protocol version 7.0, any subjects that have been off treatment for more than 14 days 
for any reasons other than for HSCT cannot resume the treatment. 
If the ASP2215 dose has been reduced, the ASP2215 dose will not be re-escalated. 

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Table 9 
Guidelines for ASP2215 Dose Interruption or Reduction Event 
ASP2215 Dosing Instructions 
Event 
Action 
QTc prolongation 
QTcF > 500 ms 
If the mean of the triplicate QTcF is > 500 ms at any time point (by 
either value on ECG tracing printout or central reading), then 
triplicate ECGs will be repeated (within 2 hours if based on value on 
ECG tracing printout and as soon as possible if based on central 
reading). If the repeat ECG confirms a mean of the triplicate QTcF 
> 500 ms, dosing of ASP2215 will be interrupted for up to 14 days. 
While ASP2215 may be interrupted temporarily based on value on 
ECG tracing printout, the central reading should be used for final 
treatment decisions. Cardiology consult will be obtained as medically 
indicated. If QTcF resolves to ≤ 480 ms (grade 1 or less) by central 
reading within 14 days, the subject may resume dosing at the reduced 
dose. 
QTcF cycle 1 day 8 
increase > 30 ms 
If the mean of the triplicate QTcF from cycle 1 day 1 to cycle 1 day 8 
has increased > 30 ms based on central read ECG without any other 
etiology, a confirmatory ECG will be performed on day 9. If the 
cycle 1 day 9 central read ECG is confirmatory, a dose reduction 
should be considered. QTcF values based on central reading from 
triplicate ECGs should be used for this determination (i.e., day 8 
mean QTcF from triplicate ECGs at predose minus the day 1 mean 
QTcF from triplicate ECGs at predose). 
Non-hematological Events 
Grade 3 related to 
ASP2215  
Dosing will be interrupted for up to 14 days. 
If the AE resolves to ≤ grade 1 within 14 days, the subject may 
resume dosing at the reduced dose. 
Grade 4 toxicity at least 
possibly due to study drug 
Treatment will be discontinued. 
Myelosuppression 
CRp or CRi 
Dose may be reduced without interruption if the following criteria 
are met: 
-Subject has received a minimum of 2 cycles of ASP2215, 
-Platelets < 25 x 109/L and/or ANC ≤ 0.5 x 109/L, 
-Marrow blasts < 5%, 
-No evidence of extramedullary disease, 
Further dose reduction is permitted if dosing 1 full cycle at the 
reduced dose has not resulted in the desired hematologic recovery. 
AE: adverse event; ANC: absolute neutrophil count; CRi: complete remission with incomplete hematologic 
recovery; CRp: complete remission with incomplete platelet recovery; ECG: electrocardiogram; QTcF: 
Fridericia-corrected QT interval 
Subjects who do not achieve a CRc may dose escalate to 200 mg per day. Dose escalation can 
occur during the treatment cycle based on bone marrow and hematology results. No further 
dose escalation is allowed. Guidelines for ASP2215 dose escalation are provided in [Table 10]. 

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Table 10 
Guidelines for ASP2215 Dose Escalation Event 
ASP2215 Dosing Instructions 
Event 
Action 
No CRc (CR, CRp or CRi) after cycle 
1 
Subjects on 120 mg dose level can escalate to 200 mg 
dose level. 
CR: complete remission; CRc: composite complete remission; CRi: complete remission with incomplete 
hematologic recovery; CRp: complete remission with incomplete platelet recovery 
5.1.3 
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy) 
All medications and concomitant treatments (except for the medications for the purpose other 
than treatment for disease or event such as contrast agent, laboratory examination, etc.) 
administered from 28 days prior to cycle 1 day 1 must be recorded in the electronic Case 
Report Form (eCRF).  
5.1.3.1 ASP2215 Group Only 
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. 
Treatment with concomitant drugs that are strong inhibitors or inducers of P-gp and 
concomitant drugs that target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor are 
to be avoided with the exception of drugs that are considered absolutely essential for the care 
of the subject. Treatment with concomitant drugs that are strong inhibitors of CYP3A should 
be avoided with the exception of antibiotics, antifungals and antivirals that are used as 
standard of care to prevent or treat infections. If CYP3A inhibitors are used concomitantly, 
subjects should be monitored for AEs. 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are known to 
prolong QT or QTc intervals. 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are substrates 
of BCRP, since the transporter has been shown to be inhibited by ASP2215 in in vitro studies. 
Common CYP3A inhibitors, CYP3A inducers, drugs targeting the serotonin receptor, P-gp 
inhibitors or inducers, and drugs known to prolong QT or QTc intervals are listed in 
[Appendix 12.1]. The investigator should consult individual labels for all drugs that the 
subject is taking to evaluate if they fall into any of above named categories. For concomitant 
drugs that have the potential to prolong QT or QTc intervals, a cardiology consult should be 
obtained as medically indicated.  
5.1.3.2 ASP2215 Group and Chemotherapy Group 
Any other treatments of AML (including but not limited to chemotherapy, radiotherapy, 
surgery, immunotherapy or cellular therapy) are prohibited during therapy with the exception 
of hydroxyurea daily for up to 2 weeks to keep the absolute blast count below 50 x 109/L and 
prophylactic intrathecal chemotherapy, cranial radiation, and donor lymphocyte infusion as 
part of the HSCT treatment plan. Participating in another interventional study while on 
treatment is prohibited. 

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5.1.4 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation 
Subjects in ASP2215 group and COE group who have donor identified and achieve a 
response allowing them to undergo HSCT per each institution’s assessment can undergo 
HSCT without leaving the study. However, ASP2215 should be stopped and a preHSCT visit 
should be performed prior to starting the conditioning regimen for HSCT. ASP2215 can be 
resumed after stem cell transplantation if the following conditions are met: 
● 
Subject is between 30 - 90 days post HSCT 
● 
Subject has had successful engraftment as demonstrated by ANC ≥ 500/mm3 and platelets 
≥ 20000/mm3 without transfusions 
● 
Subject does not have ≥ grade 2 acute GVHD 
● 
Subject is in CRc 
For subjects resuming treatment, subjects will follow the procedures listed under subsequent 
cycles day 1 in the Schedule of Assessments. 
5.1.5 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with study drug. 
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period. Compliance will be verified by the accounting of study drug at each monthly visit after 
baseline. When study drug is administered at the research facility, it will be administered under 
the supervision of study personnel. 
Compliance of ASP2215 will be monitored by the accounting of unused medication returned 
by the subject at visits. Compliance will be documented. 
The dose and schedule of ASP2215 and comparative chemotherapy administered to each 
subject will be recorded. Reasons for dose delay, reduction or omission will also be recorded 
when applicable. 
Treatment compliance should be monitored closely and deviations in compliance should be 
reported to the Sponsor except in cases where directed by protocol or principal investigator 
(e.g., account for dose interruptions, adjustments, etc.). 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be collected for all subjects and will include age, sex, race and 
ethnicity. 
5.2.2 
Medical History 
Medical history includes all significant medical conditions other than AML that have 
resolved prior to informed consent. Conditions that are ongoing at the time of consent will be 
collected as baseline condition on the Medical History Electronic Case Report Form (eCRF). 

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Details that will be collected include the onset date and recovery date and CTCAE grade, if 
applicable for ongoing conditions. 
5.2.3 
Diagnosis of the Target Disease, Severity and Duration of Disease 
AML diagnosis and studies related to AML subtype classification will be collected and will 
include date and method of diagnosis, bone marrow evaluations, histopathology, cytogenetics, 
immunophenotyping and cytochemistry, FLT3 mutation status performed using institutional 
assay, lumbar puncture results if performed (red blood cell [RBC], white blood cell [WBC] and 
differential, cytospin results) and related genetic syndromes. Dates for diagnostic procedures 
will be collected. 
Prior HSCT and AML therapy including induction, consolidation and maintenance 
chemotherapy will be collected. Response to HSCT and AML therapy as well as the duration 
of the response will also be collected. 
5.2.4 
FLT3 Mutation Status 
FLT3 mutation status will be analyzed by a Sponsor designated central laboratory or contracted 
3 clinical sites in China using bone marrow aspirate samples. If bone marrow sample is 
unavailable (e.g., dry tap), the whole blood sample taken at the screening visit will be used. 
Subjects will be screened from the central lab. If the central result is negative, FLT3 testing can 
be repeated during the screening period. Bone marrow sample before the informed consent date 
may be used for screening if the patient has already performed bone marrow assessment within 
14 days prior to the planned Cycle 1 Day 1, and the sample should be stored at 2˚C to 8˚C and 
can be started testing within 7 days after sample collection. All subjects including those with 
rapidly proliferative disease must have screening sample sent to central lab. If institutional 
FLT3 assay is available, then the institutional results will be recorded and can be used for 
randomization only if, in the investigator’s opinion, subject has rapidly proliferative disease 
and cannot wait for the central lab results. The institutional FLT3 test must have been 
performed after completion of subject’s last interventional treatment. For randomization only, 
institutional FLT3 result prior to informed consent can be used if it has been performed after 
completion of subject’s last interventional treatment. However, central testing will still be 
performed. Subjects can remain on assigned treatment if the randomization is based on the 
local test, but central lab result is discordant. 
Bone marrow/blood sampling, processing, storage and shipment instructions will be provided 
in the Lab Manual. Refer to the Lab Manual for more detailed information. 
5.2.5 
Performance Status 
The ECOG Scale [Oken et al, 1982] will be used to assess performance status [Table 11]. 

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Table 11 
ECOG Performance Status 
Grade Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
ECOG: Eastern Cooperative Oncology Group 
5.3 
Efficacy Assessment 
5.3.1 
Response Definitions 
Response to treatment will be defined per modified criteria [Cheson et al, 2003] as outlined 
below. 
5.3.1.1 Complete Remission 
For subjects to be classified as being in CR, they must have bone marrow regenerating 
normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an 
ANC > 1 x 109/L and platelet count ≥ 100 x 109/L and normal marrow differential with 
< 5% blasts, and they will be RBC and platelet transfusion independent (defined as 1 week 
without RBC transfusion and 1 week without platelet transfusion). There should be no 
evidence of extramedullary leukemia. 
5.3.1.2 Complete Remission with Incomplete Platelet Recovery 
For subjects to be classified as being in CRp, they must achieve CR except for incomplete 
platelet recovery (< 100 x 109/L). 
5.3.1.3 Complete Remission with Incomplete Hematologic Recovery 
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for 
incomplete hematological recovery with residual neutropenia < 1 x 109/L with or without 
complete platelet recovery. RBC and platelet transfusion independence is not required. 
5.3.1.4 Composite Complete Remission Rate 
Defined as the remission rate of all CR, CRp and CRi (i.e., CR + CRp + CRi). 
5.3.1.5 Partial Remission 
For subjects to be classified as being in PR, they must have bone marrow regenerating 
normal hematopoietic cells with evidence of peripheral recovery with no (or only a few 
regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts 
in the bone marrow aspirate with the total marrow blasts between 5% and 25%. 

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5.3.1.6 Relapse 
Relapse after CR, CRp or CRi is defined as a reappearance of leukemic blasts in the peripheral 
blood or ≥ 5% blasts in the bone marrow aspirate not attributable to any other cause or 
reappearance or new appearance of extramedullary leukemia. 
Relapse after PR is similarly defined with reappearance of significant numbers of peripheral 
blasts and an increase in the percentage of blasts in the bone marrow aspirate to > 25% not 
attributable to any other cause or reappearance or new appearance of extramedullary 
leukemia. 
5.3.1.7 Best Response 
Best response is defined as the best measured response to treatment for all visits (in the order 
of CR, CRp, CRi, PR, NR and NE) post-treatment. Subjects with best responses of CR, CRp, 
CRi or PR will be considered responders. Subjects who do not achieve at least a best 
response of PR will be considered nonresponders. 
5.3.2 
Survival Time, Duration and Other Efficacy Endpoints 
5.3.2.1 Overall Survival 
OS is defined as the time from the date of randomization until the date of death from any 
cause. For a subject who is not known to have died by the end of study follow-up, OS is 
censored at the date of last contact. 
Date of last contact is defined as the death date or the latest of the following dates: treatment 
discontinuation date, last dosing administration date, last disease assessment date or the last 
follow-up date on which the subject was known to be alive. 
5.3.2.2 Event-free Survival 
EFS is defined as the time from the date of randomization until the date of documented 
relapse (including relapse after CR, CRp and CRi), treatment failure, death, reported off-
treatment relapse or new AML therapy start (excluding subsequent HSCT) whichever occurs 
first, including the long-term follow-up data. Treatment failure is defined as subject who ends 
treatment without having a previous response. For a subject who is not known to have EFS 
events, EFS is censored at the date of last relapse-free disease assessment or subsequent 
HSCT date (whichever is later). Subject is not censored at on-study HSCT. 
5.3.2.3 Leukemia-free Survival 
LFS is defined as the time from the date of first CRc until the date of documented relapse or 
death for subjects who achieve CRc. For a subject who is not known to have relapsed or died, 
LFS is censored on the date of last relapse-free disease assessment date. 
5.3.2.4 Duration of Remission 
Duration of Remission 
This includes duration of CRc, duration of CR, duration of CRi, duration of CRp and duration 
of response (CRc + PR). 

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Duration of CRc 
Duration of CRc is defined as the time from the date of first CRc until the date of 
documented relapse for subjects who achieve CRc. Subjects who die without report of 
relapse are considered nonevents and censored at their last relapse-free disease assessment 
date. Subjects who undergo an allogeneic HSCT will be considered nonevents and censored 
at the time of HSCT. Other subjects who do not relapse on study are considered nonevents 
and censored at the last relapse-free disease assessment date. 
Duration of CR, CRp, CRi 
Duration of CR, CRp, CRi is defined similarly as duration of CRc. 
Duration of Response 
Duration of response is defined as the time from the date of either first CRc or PR until the 
date of documented relapse of any type for subjects who achieve CRc or PR. Subjects who 
die without report of relapse are considered nonevents and censored at their last relapse-free 
disease assessment date. Subjects who undergo an allogeneic HSCT will be considered 
nonevents and censored at the time of HSCT. Other subjects who do not relapse on study are 
considered nonevents and censored at the last relapse-free assessment date. 
5.3.2.5 Transplantation Rate 
Transplantation rate is defined as the percentage of subjects undergoing HSCT during the 
study period. 
5.3.3 
Bone Marrow Aspiration and/or Biopsy 
For ASP2215 group, bone marrow samples are required during screening, cycle 2 day 1 and 
cycle 3 day 1. For subjects who do not achieve a CRc (CR, CRp or CRi), the bone marrow 
assessments will be repeated at day 1 of every 2 subsequent cycles. For subjects who achieve 
a CRc (CR, CRp or CRi), bone marrow sampling will be repeated on 1 month after the date 
of remission and every 3 subsequent cycles or if there is suspicion of relapse in the whole 
blood.  
For the MEC and FLAG groups, bone marrow samples are required during screening and at 
cycle 2 day 1. Also, an additional bone marrow sample is required at cycle 1 day 15 or later, 
per institutional guidelines, to assess the need for second cycle. For the LoDAC group, bone 
marrow samples are required during screening and at cycle 2 day 1 and cycle 3 day 1. 
Subjects who do not achieve a CRc (CR, CRp or CRi), the bone marrow assessments will be 
repeated at day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or 
CRi), bone marrow sampling will be repeated on 1 month after the date of remission and 
every 3 subsequent cycles or if there is suspicion of relapse in the whole blood.  
Bone marrow samples are also required at the pre-HSCT visit /end of treatment visit and as 
clinically indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional 
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marrow aspirate is required, and bone marrow biopsy is preferred. In case of inadequate 
aspirate, bone marrow biopsy is required. 
Bone marrow assessment for blasts counts and cell counts and flow cytometry will be 
conducted at local lab. 
5.3.4 
Survival Status and Subsequent Antileukemic Treatments and Their Outcomes 
Information on survival status, subsequent antileukemic treatments and outcomes will be 
collected for all subjects. 
The first survival status will occur at the 30-day follow-up where telephone contact with the 
subject is sufficient unless any assessment must be repeated for resolution of 
treatment-related AEs. After the 30-day follow-up, the subject or caregiver will continue to 
be contacted via telephone by site personnel for follow-up every 3 months up to 3 years after 
end of treatment visit or subject’s reconsent under this protocol version 7.0, whichever comes 
first. Data may be supplemented by site records when available at the time of the contact 
(e.g., treatment records, outcomes). Additional contacts may be made to support key analyses 
(e.g., interim analysis or analyses by the Independent Data Monitoring Committee). 
Reasonable effort should be made to contact any subjects lost to follow-up during the course 
of the study in order to complete study-related assessments and retrieve any outstanding data 
and study drug. Following unsuccessful telephone contact, an effort to contact the subject by 
mail using a method that provides proof of receipt should be attempted. Contact via an 
alternate, preapproved contact is permissible if the subject is not reachable. Such efforts 
should be documented in the source documents. 
If a subject death occurs during the serious adverse event (SAE) reporting period or if the 
death occurs after the SAE reporting period, but is determined by the investigator to be 
possibly related to study drug, then the associated AE with outcome of death will also be 
reported on the CRF and SAE form. If a subject death does not meet the criteria of an SAE, 
then death and antileukemic treatment and outcome up through the date of death should be 
collected and entered in CRF. 
5.3.5 
Pharmacokinetics Assessment 
Blood sampling for pharmacokinetic analysis in approximately 20 Chinese subjects (10 male 
and 10 female subjects) enrolled in the PK cohort will be done at the following time points; 
    Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour after dosing of study drug 
    Cycle 1 Day 8: predose 
    Cycle 1 Day 15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours after dosing of study drug 
    Day 1 of each subsequent Cycle: predose 
Blood sampling for pharmacokinetic analysis in subjects other than PK Cohort will be done 
at the following time points; 

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Cycle 1 Day 1: predose, Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, Day 1 predose of 
each subsequent Cycle 
Acceptable time ranges for blood sampling for measurement of plasma concentrations are as 
follows (The time of administration on Day 1 is defined as “0” minutes):  
Predose 
Scheduled date, Within 1 hour before dosing 
Day1/Day 15: 0.5 hour post-dose 
Scheduled date, scheduled time ± 5 minutes 
Day 1/Day 15: 1, 2, 3, 4, 6, 10 hours post-
dose 
Scheduled date, scheduled time ± 10 minutes 
Day 2/Day 16: 24 hours post-dose 
Scheduled date, scheduled time ± 20 minutes 
After the subject reconsents under this protocol version 7.0, no PK assessments will be 
performed. 
5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Vital signs, including systolic and diastolic blood pressures (mm Hg), radial pulse rate 
(beats/minute) and temperature will be obtained and recorded at the times specified in the 
Schedule of Assessments. All vital sign measures will be obtained with the subject in the 
sitting or supine position. 
If clinically significant vital sign changes from baseline (pretreatment) are noted, the changes 
will be documented as AEs on the AE page of the CRF. Clinical significance will be defined 
as a variation in vital signs, which has medical relevance that could result in an alteration in 
medical care. The investigator will continue to monitor the subject until the parameter returns 
to ≤ grade 1 or to the baseline (pretreatment) value or until the investigator determines that 
follow up is no longer medically necessary. 
5.4.2 
Adverse Events 
AE collection will begin from time of informed consent and continue through the 30-day 
follow-up visit. AEs will be documented at each clinic visit, but can be collected at any time.  
Any AE that meets the definition of a SAE will also be reported on a separate form to the 
Sponsor. See [Section 5.5 Adverse Events and Other Safety Aspects] for information 
regarding AE collection and data handling. See [Appendix 12.8 Continuation of Study 
Treatment with ASP2215] for information regarding SAE collection while subjects are 
receiving study drug treatment with ASP2215 until they meet discontinuation criteria or 
applicable reimbursement becomes available in the country of residence. 
5.4.2.1 Adverse Events of Possible Hepatic Origin 
See [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function tests (LFTs) (e.g., AST, 
ALT, TBL, etc.) or is suspected to be due to hepatic dysfunction. 

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Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored. 
5.4.2.2 Adverse Events during Hematopoietic Stem Cell Transplant 
AE collection will continue during HSCT for subjects who plan to resume ASP2215 
treatment after HSCT. 
5.4.3 
Laboratory Assessments 
[Appendix 12.3] contains the laboratory tests that will be performed centrally during the 
conduct of the study. Refer to the Schedule of Assessments for study visit collection dates. 
Subjects may be screened and randomized from local labs only. However, samples must also 
be submitted for central read. Labs can be repeated during the screening period. Additional 
laboratory tests should be performed according to institutional standard of care. Local testing 
of hematology and bone marrow aspirate and/or biopsy at screening and day 1 of each cycle 
will be reported in the eCRF. Clinical significance of out-of-range laboratory findings is to be 
determined and documented by the investigator or delegated sub-investigator who is a 
qualified physician. 
5.4.4 
Physical Examination 
Standard, full physical examinations will be performed to assess general appearance, skin, 
eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 
neurologic status, mental status and lymphatic systems. Genitourinary and rectal system 
exams are to be performed only if clinically indicated. Physical examinations will be 
conducted at visits as outlined in the Schedule of Assessments. Each physical examination 
will include the observation and review of body system, weight at screening and on day 1 of 
each cycle, height is only required at screening. If clinically significant worsening of findings 
from predose (day 1) is noted at any study visit, the changes will be documented as AEs on 
the AE page of the CRF. Clinical significance is defined as any variation in physical findings, 
which has medical relevance that could result in an alteration in medical care. The 
investigator will continue to monitor the subject until the parameter returns to ≤ grade 1 or to 
the baseline (pretreatment) condition or until the investigator determines that follow up is no 
longer medically necessary. 
5.4.5 
Electrocardiogram 
ECGs will be conducted at visits as outlined in the Schedule of Assessments. Screening ECG 
is required. ECG can be repeated during the screening period. ECG assessment will be 
evaluated at screening, predose of cycle 1 day 1, cycle 1 day 8, cycle 1 day 15, day 1 of each 
subsequent cycle and pre-HSCT/end of treatment visit. Predose assessments should be taken 
within 1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate 
(3 separate ECGs 10 minutes resting prior to first ECG and at least 5 minutes apart per time 
point) and transmitted electronically for central reading. The mean QTcF of the triplicate 
ECG tracings based on central reading will be used for final treatment decisions and AE 
reporting.  

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A cycle 1 day 8 ECG will be taken and the central read results will be provided to the site 
24 hours after receipt of the tracing. A confirmatory ECG should be performed on cycle 1 
day 9 if the mean QTcF from cycle 1 day 1 to cycle 1 day 8 has increased > 30 ms with no 
other known etiology, based on the central read ECG. On cycle 1 day 8, it is recommended 
that the ECG is taken as early as possible in the morning and transmitted immediately. In 
addition, it is recommended that the cycle 1 day 9 visit is scheduled later in the day in order 
to allow for receipt and assessment of the cycle 1 day 8 central read ECG. This also allows 
for a subject to be contacted if the cycle 1 day 9 ECG is no longer required. If the cycle 1 day 
9 ECG is still required, the central read ECG will be received on day 10, in which the 
investigator should assess if the ASP2215 dose modification should occur as per the dose 
interruption or reduction guideline in [Section 5.1.2 Interruption, Reduction or Escalation in 
Dose of the Study Drug]. 
If the mean of the triplicate QTcF is > 500 ms at any time point (by either value on ECG 
tracing printout or central reading), then triplicate ECGs will be repeated (within 2 hours if 
based on value on ECG tracing printout and as soon as possible if based on central reading). 
If QTcF > 500 ms is confirmed, then the investigator will interrupt and reduce ASP2215 per 
the interruption or reduction guidelines in [Section 5.1.2 Interruption, Reduction or 
Escalation in Dose of the Study Drug]. 
ECGs should be obtained after the subject has rested quietly and is awake in a fully supine 
position (or semi-recumbent, if supine not tolerated) for 10 minutes before the first ECG from 
a triplicate. Whenever a study procedure coincides with the scheduled timepoint for an ECG 
triplicate, the study activities will ideally be undertaken in a fixed sequence: ECG triplicate 
first, vital signs (blood pressure and heart rate) second and any type of blood draw as the last 
assessment. This order of events can be changed if required in order to accommodate 
pharmacokinetic time points and is not mandatory. 
<PK cohort> 
In addition to above, a cycle 1 day 15 ECG will be taken predose and 4 hours post dose. 
5.4.6 
Chest X-ray or Computed Tomography Scan 
Chest X-ray or computed tomography (CT) scan is to be performed at screening. A chest X-ray 
(or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of 
screening. 
5.4.7 
Multigated Acquisition Scan or Echocardiogram 
Multigated acquisition scans or ECHO (as per standard of care) are to be performed at 
screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless 
multigated acquisition scans or ECHO performed either within 1 month prior revealed 
LVEF ≥ 45%). 

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5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the eCRF accordingly. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets 1 of the 
following criteria: 
● 
Induces clinical signs or symptoms. 
● 
Requires active intervention. 
● 
Requires interruption or discontinuation of study medication. 
● 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
5.5.2 
Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes: 
● 
Results in death 
● 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death) 
● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
● 
Results in congenital anomaly or birth defect 
● 
Requires in-subject hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
● 
Other medically important events 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These events, including those that may result in disability/incapacity, should also 

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usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse. 
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator and background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to: 
● 
Overdose of the medicinal product(s) 
● 
Suspected abuse/misuse of the medicinal product(s) 
● 
Inadvertent or accidental exposure to the medicinal product(s) 
● 
Medication error involving the medicinal product(s) (with or without subject exposure to 
the Sponsor medicinal product, e.g., name confusion) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE. For example, admission for treatment of a preexisting condition 
not associated with the development of a new AE or with a worsening of the preexisting 
condition such as transfusion for preexisting anemia, leukopenia, or thrombocytopenia. 
All of the events of interest noted above should be recorded on the eCRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and the SAE worksheet. 
The Sponsor has a list of events that they classify as “important medical” or “always serious” 
events. If an AE is reported that is considered to be an event per this classification as 
“important medical” or “always serious”, additional information on the event may be 
requested and they may be reported as SAE in the CSR. 
5.5.3 
Special Situations 
Special Situations observed in association with the study drug(s) (e.g., test drug, comparator, 
or background therapy) administered to the subject as part of the study are collected as 
described in the table below. These Special Situations are not considered adverse events but 
can be associated with or result in an AE. An AE that may be associated with or result from a 
Special Situation is to be assessed separately from the Special Situation and captured in the 
eCRF or electronic data source. If the AE meets the definition of serious, these SAEs are to 
be collected via the SAE/Special Situation worksheet together with the details of the 
associated Special Situation and reported as described in [Section 5.5.6 Reporting of Serious 
Adverse Events]. 
Special Situation 
Collected 
SAE/Special 
Situation 
worksheet 
eCRF  Protocol 
Deviation [see 
Section 8.1.6] 
Lack of Efficacy  
 
X 
 
Uses outside what is stated in the 
protocol (“off label use”) 
 
 
X 
Medication error  
 
 
X 

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Special Situation 
Collected 
SAE/Special 
Situation 
worksheet 
eCRF  Protocol 
Deviation [see 
Section 8.1.6] 
Overdose of the medicinal product(s) 
[see Section 5.5.10 Emergency 
Procedures and Management of 
Overdose]  
 
 
X 
Suspected misuse/abuse of the 
investigational medicinal product(s) 
X 
 
X 
Occupational exposure (e.g. of site staff) 
to the investigational medicinal 
product(s)  
X 
 
 
Suspected Drug-Drug interaction  
 
X 
 
Suspected Transmission of Infectious 
Agents   
X 
 
 
5.5.4 
Criteria for Causal Relationship to the Study Drug 
AEs that fall under either "Possible" or "Probable" should be defined as "AE whose 
relationship to the study drugs could not be ruled out". 
Causal 
Relationship to 
the Study Drug 
Criteria for Causal Relationship 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable and/or in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by 
concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent 
disease or other drugs or chemicals and which follows a clinically reasonable 
response on readministration (rechallenge) or withdrawal (dechallenge). 
5.5.5 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute (NCI)-CTCAE guidelines (version 4.03). The items that are not stipulated in the 
NCI-CTCAE version 4.03 will be assessed according to the criteria below and entered into 
the eCRF. 
Grade 
Assessment Standard 
1-Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations noted; 
intervention not indicated 
2-Moderate 
Local or noninvasive intervention indicated 

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Grade 
Assessment Standard 
3-Severe 
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization 
4-Life 
Threatening 
Life threatening consequences, urgent intervention indicated 
5-Death 
Death related to adverse event 
5.5.6 
Reporting of Serious Adverse Events 
SAE collection will begin from the time of informed consent through the 30 days follow-up 
visit until the implementation and reconsent of protocol version 7.0. After subjects reconsent 
under the protocol version 7.0, SAE collection will continue through 30 days after the last 
dose of study treatment. During the long-term follow-up period, only SAE data for the event 
that is related to ASP2215 will be collected. In the case of a SAE, the investigator must 
contact the Sponsor by telephone or fax immediately (within 24 hours of awareness). 
The investigator should complete and submit an SAE/Special Situation Worksheet containing 
all information that is required by the Regulatory Authorities to the Sponsor/delegated 
Contract Research Organization (CRO) by email immediately (within 24 hours of 
awareness). If the email of an SAE/Special Situation Worksheet is not possible or is not 
possible within 24 hours, the local drug safety contact should be informed by phone. 
For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please email 
the SAE/Special Situation Worksheet to: 
IQVIA Lifecycle Safety Department 
IQVIA RDS East Asia Pte. Ltd. 
Email address: QLS_ASP2215@iqvia.com 
For more information, please refer to the SAE/Special Situation worksheet completion 
guideline.  
If there are any questions or if clarification is needed regarding the SAE, please contact the 
Sponsor's medical monitor/expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
Follow-up information for the event should be sent promptly (within 7 days) of the initial 
notification. 
Full details of the SAE should be recorded on the medical records and on the eCRF.  
The following minimum information is required: 
● 
International study number/study number, 
● 
Subject number, sex and age, 
● 
The date of report, 
● 
A description of the SAE (event, seriousness of the event) and 
● 
Causal relationship to the study drug. 
The Sponsor or Sponsor's designee will submit expedited safety reports (e.g., Investigational 
New Drug (IND) Safety Reports, CIOMS-I) to the regulatory agencies as required and will 

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inform the investigators of such regulatory reports as required. Investigators must submit 
safety reports as required by their IRB/local IEC within timelines set by regional regulations 
where required. Documentation of the submission to and receipt by the IRB/local IEC of 
expedited safety reports should be retained by the site. 
The Sponsor/delegated CRO will notify all investigators responsible for ongoing clinical 
studies with the study drug of all SAEs which require submission per local requirements 
IRB/IEC/head of the study site. 
The heads of the study sites/investigators should provide written documentation of IRB/IEC 
notification for each report to the Sponsor. 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor. 
You may contact the Sponsor's medical monitor/expert for any other problem related to the 
safety, welfare or rights of the subject. 
5.5.7 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the AE progresses to an “SAE” or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor.  
Please refer to [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed 
instructions on drug induced liver injury. 
5.5.8 
Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in [Appendix 12.4 Common 
Serious Adverse Events] for your reference. The list does NOT change your reporting 
obligations or prevent the need to report an AE meeting the definition of an SAE as detailed 
above. The purpose of this list is to alert you that some events reported as SAEs may not 
require expedited reporting to the regulatory authorities based on the classification of 
“common serious adverse events” as specified in [Appendix 12.4 Common Serious Adverse 
Events]. The Sponsor will monitor these events throughout the course of the study for any 
change in frequency. Any changes to this list will be communicated to the participating 
investigational sites. Investigators must report individual occurrences of these events as 
stated in [Section 5.5.6 Reporting of Serious Adverse Events]. 
5.5.9 
Procedure in Case of Pregnancy 
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 90 days from the discontinuation of dosing, the investigator should report the 
information to the Sponsor/delegated CRO as if it is an SAE. The expected date of delivery or 

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expected date of the end of the pregnancy, last menstruation, estimated conception date, 
pregnancy result and neonatal data etc., should be included in this information. 
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor. 
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below. 
● 
"Spontaneous abortion" includes miscarriage, abortion and missed abortion 
● 
Death of an infant within 1 month after birth should be reported as an SAE regardless of its 
relationship with the study drug 
● 
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by the 
investigator 
● 
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth 
● 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination 
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator. The investigator will report the pregnancy to 
the Sponsor as an SAE. 
5.5.10 Emergency Procedures and Management of Overdose 
In the event of suspected ASP2215 overdose, the subject should receive supportive care and 
monitoring. The medical monitor/expert should be contacted as applicable. 
In the event of suspected overdose of salvage chemotherapy, please refer to the approved 
Package Insert, Summary of Product Characteristics or local product information supplied by 
the manufacturer for each agent. 
5.5.11 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
5.5.12 Urgent Safety Measures 
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities (CA), IRB/IEC, where applicable, in order to protect 
participants from any immediate hazard to their health and/or safety. Either the investigator 

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or the sponsor can initiate a USM. The cause of a USM can be safety-, product- or 
procedure-related.  
5.5.13 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the study physician within 
24 hours of awareness. Full details of the potential USM are to be recorded in the 
participant’s medical records. The sponsor may request additional information related to the 
event to support their evaluation.  
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the participants. These actions may include but are not limited to a 
change in study procedures or study treatment, halting further enrollment in the study, or 
stopping the study in its entirety. The sponsor or sponsor's designee will notify the relevant 
competent authorities and concerned ethics committee within the timelines required per 
current local regulations, and will inform the investigators, as required. When required, 
investigators must notify their IRB/IEC within timelines set by regional regulations. 
5.6 
Test Drug Concentration 
5.6.1 
Pharmacokinetics 
Plasma concentrations of ASP2215 will be evaluated as outlined in Schedule of Assessments, 
and Schedule of Assessments for PK cohort. For each sample, 2 mL of blood will be collected 
and processed. Plasma concentration of ASP2215 metabolite may be also evaluated for each 
sample. 
Plasma samples may also be used for metabolite profiling of ASP2215. The reports for the 
metabolite profiling and identification will not be incorporated to the Clinical Study Report 
(CSR). 
Blood sampling, processing, storage and shipment instructions will be provided in the Lab 
Manual. Samples will be shipped to and analyzed by a Sponsor designated analytical 
laboratory. Please refer to the Lab Manual for more detailed information on this topic. 
After the subject reconsents under this protocol version 7.0, no PK assessments will be 
performed. 
5.7 
Other Measurements, Assessments or Methods 
5.7.1 
Patient Reported Outcome Measures 
BFI, EQ-5D-5L, FACIT-Dys-SF, FACT-Leu and dizziness and mouth sore items will be 
assessed during the study period to report subjects experience of symptoms/treatment and 
quality of life. 
5.7.1.1 Brief Fatigue Inventory 
The BFI [Mendoza et al, 1999] was developed to assess the severity of fatigue and the impact 
of fatigue on daily functioning in patients with fatigue due to cancer and cancer treatment.  
The BFI short form has 9 items and a 24-hour recall. A global fatigue score is computed by 

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averaging the 9 items. The BFI will be administered at site visits directly to the subjects via 
an electronic PRO device. The BFI will be administered at cycle 1 day 1 predose, cycle 1 day 
8 (± 1 day), day 15 (± 1 day), cycle 2 day 1 (± 2 days), day 15 (± 1 day) and all subsequent 
cycles day 1 (± 2 days) as well as preHSCT/end of treatment visit. If possible, patient 
reported outcome measures should be performed prior to any other assessments on that visit 
day. 
5.7.1.2 EuroQol Group-5 Dimension-5 Level Instrument 
The EQ-5D-5L is a self-reported questionnaire. The EQ-5D-5L is being used as a measure of 
respondents' health related quality of life. The EQ-5D-5L consists of the EuroQol Group-5 
Dimension descriptive system and the EuroQol Group visual analogue scale (VAS). The 
EuroQol Group-5 Dimension descriptive system comprises of 5 dimensions of health: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems. The VAS records the respondent's self-rated health status on a graduated (0 - 100) 
scale, where the endpoints are labeled ‘best imaginable health state’ and ‘worst imaginable 
health state’ with higher scores for higher health related quality of life. It will be administered 
at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days) 
as well as preHSCT/end of treatment visit and the 30-day follow-up, if a visit is required. If 
possible, patient reported outcome measures should be performed prior to any other 
assessments on that visit day. During 30-day follow-up and long-term follow up, subjects 
will be contacted by site personnel via telephone to provide responses to the questionnaire. 
5.7.1.3 Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms 
The FACIT-Dys-SF [Choi et al, 2011] was developed to assess dyspnea severity and related 
functional limitations. It has a 7-day recall period and 20 items. The FACIT-Dys-SF is scored 
with 2 domains: dyspnea and function limitations. This instrument will be administered at 
site visits directly to the subjects via an electronic PRO device. It will be administered at 
cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days) as 
well as preHSCT/end of treatment visit. If possible, patient reported outcome measures 
should be performed prior to any other assessments on that visit day. 
5.7.1.4 Functional Assessment of Cancer Therapy-Leukemia 
The FACT-Leu [Cella et al, 2012] is designed to measure leukemia-specific signs, symptoms 
and the impact of AML on patients. The 44-item scale has global and domain scores 
including physical well-being, social/ family well-being, emotional well-being, functional 
well-being and additional leukemia-specific concerns. The FACT-Leu contains most of the 
common patient reported impacts of AML. The FACT-Leu has a 7-day recall period. The 
FACT-Leu will be administered at site visits directly to the subjects via an electronic PRO 
device. It will be administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all 
subsequent cycles day 1 (± 2 days) as well as preHSCT/end of treatment visit. If possible, 
patient reported outcome measures should be performed prior to any other assessments on 
that visit day. 

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5.7.1.5 Dizziness and Mouth Sores Items 
Two additional questionnaires evaluating commonly reported impacts on AML on patients, 
dizziness and mouth sores, will be administered to subjects. These 2 questionnaires will be 
administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles 
day 1 (± 2 days) as well as preHSCT/end of treatment visit. If possible, patient reported 
outcome measures should be performed prior to any other assessments on that visit day. 
5.7.2 
Resource Utilization 
Resource utilization in this study population will include hospitalization, blood transfusion, 
antibiotic iv infusions, medication for AEs and opioid usage. 
5.7.3 
Exploratory Biomarker Analysis 
FLT3 mutation status will be assessed from bone marrow samples taken at the screening visit 
and may be assessed from pre-HSCT visit/EOT visit. Additional genetic biomarkers related 
to AML and ASP2215 activity may be analyzed. All biomarker samples collected will be 
stored for a period of up to 15 years following study database hard lock. If there is no 
requirement for analysis, the whole blood sample will be destroyed after the planned storage 
period. If bone marrow sample is unavailable (e.g., dry tap), the whole blood samples taken 
at the screening visit and end of study will be used. 
The FLT3 mutation assay is an investigational use only companion diagnostic that is being 
used to determine a subject’s FLT3 mutation status. The manufacturer of the assay or the 
contracted clinical sites with the manufacturer in China will analyze the samples collected 
from this study and utilize it to seek regulatory approval of the FLT3 mutation assay 
companion diagnostic that will be used with ASP2215. 
Bone marrow/blood sampling, processing, storage and shipment instructions will be provided 
in the Lab Manual. Samples will be shipped to and analyzed by a Sponsor designated 
analytical laboratory. Please refer to the Lab Manual for more detailed information on this 
topic. 
Specific to China: 
All biomarker samples collected will be stored until all clinical study database hard lock. 
5.7.4 
Whole Blood and Buccal Sample for Future Pharmacogenomics Analysis 
(Retrospective Pharmacogenomics Analysis) (Optional) 
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety issues. After randomization (see 
Schedule of Assessments), a whole blood and buccal swab sample for possible retrospective 
PGx analysis will be collected for subjects who provide separate consent. 
Samples will be shipped to a Sponsor designated banking CRO. Labels should uniquely 
identify each sample and contain at least: 
● 
Protocol number [2215-CL-0303], 
● 
Subject number and 

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● 
Purpose and biological matrix (i.e., “biobanking”, “whole blood”). 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual. 
See [Appendix 12.5 Retrospective PGx Sub-study (Optional)] for further details on the 
banking procedures. 
5.8 
Total Amount of Blood 
The total amount of blood collected for study assessments for each subject will vary depending 
on how long they stay on treatment. 
At any time during the study, if any laboratory abnormalities are found for a subject for 
disease assessment, institutional monitoring for donor chimerism and GVHD assessment, or 
if laboratory results are needed before central laboratory results are available, additional 
blood may be drawn for local laboratory testing. 
Additional blood beyond standard monitoring that will be drawn for this study will include 
draws for eligibility assessment, hematology, chemistry, coagulation and pregnancy test at 
specific study defined time points, pharmacokinetics and bioanalytical sampling. 
The maximum amount of blood collected for study specific assessments during the screening 
and cycle 1 period is approximately 60 mL. For subjects in PK cohort, the maximum amount 
of blood collected for study specific assessment during the screening and cycle 1 period is 
approximately 90 mL. 
The maximum amount of blood collected for study specific assessments in cycle 2 is 
approximately 20 mL. 
The maximum amount of blood collected for study specific assessments in cycle 3 and 
beyond is approximately 15 mL per cycle. 
Specific to China: 
PGx Sub-study (Optional) is not conducted in China. 
6 
DISCONTINUATION 
Subjects will be eligible to continue receiving treatment in this study until they meet a 
discontinuation criterion or upon marketing authorization, commercial availability and 
applicable reimbursement of ASP2215 in the country of residence. 
6.1 
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued for any reason. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it. 

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If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
Subjects will be eligible to continue receiving treatment in this study until they meet a 
discontinuation criterion as outlined below or upon marketing authorization and commercial 
availability and applicable reimbursement of ASP2215 in the country of residence. 
6.1.1 
Discontinuation Criteria from Treatment for Individual Subjects 
● 
Subject declines further study participation (i.e., withdrawal of consent). 
● 
Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment. 
● 
Subject is found to have significantly deviated from any 1 of the inclusion or exclusion 
criteria after enrollment (subjects having clinical benefit may be kept in the study after 
discussion with the medical monitor). 
● 
Subject develops an intolerable or unacceptable toxicity. 
● 
Subject receives any antileukemic therapy other than the assigned treatment, with the 
exceptions of hydroxyurea for up to 2 weeks, prophylactic intrathecal chemotherapy or 
cranial irradiation, and donor lymphocyte infusion as part of the HSCT treatment plan. 
● 
Investigator/sub-investigator determines that the continuation of the study treatment will 
be detrimental to the subject. 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Subject is receiving MEC or FLAG and has NR or progressive disease following cycle 1. 
● 
Subject is receiving LoDAC or ASP2215 and has progressive disease or no response and 
the subject, in the opinion of the investigator, is no longer deriving clinical benefit. 
● 
Subject is in comparator group (chemotherapy) and goes on for HSCT. 
● 
Female subject becomes pregnant.  
● 
Death. 
6.1.2 
Discontinuation Criteria from the Posttreatment Period for Individual Subjects 
● 
Subject declines further study participation (i.e., withdraws consent). 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
More than 3 years has passed from the subject’s end of treatment visit.   
● 
The implementation and reconsent of protocol version 7.0. 
● 
Death. 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor. 

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6.3 
Discontinuation of the Study 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination. 
7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the responsible biostatistician. A Statistical 
Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures (TLFs) to be produced. The SAP will be 
finalized before the database soft lock at the latest. Any changes from the analyses planned in 
SAP will be justified in the CSR. 
Prior to database lock, a Final Review of Data and TLFs Meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database lock. 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints and 
frequency and percentage for categorical endpoints. 
7.1 
Sample Size 
This is a group sequential design using the O’Brien-Fleming boundaries as implemented by 
Lan-DeMets alpha spending method (East®). One interim analysis and 1 final analysis are 
planned. The interim and final analyses will be performed after the prespecified number of 
death events. All statistical tests of treatment effects will be conducted at the 2-sided 
0.05 level of significance. 
Approximately 318 subjects (the planned sample size with 10% dropout rate) will be 
randomized in a 1:1 ratio to receive ASP2215 or salvage chemotherapy (159 subjects in the 
ASP2215 treatment arm and 159 subjects in the salvage chemotherapy arm). The planned 
230 events during the study will provide 90% power to detect a difference in OS between the 
ASP2215 arm with 7.7 months median survival time and salvage chemotherapy arm with 
5 months median survival time (hazard ratio = 0.65) at the overall 2-sided 0.05 significance 
level. 
The planned sample size with 250 EFS events will provide 90% power to detect the difference 
in EFS (6 months median EFS for ASP2215 arm and 3.9 months for salvage chemotherapy arm 
with hazard ratio = 0.65) and > 90% power to detect a difference in CR rate between ASP2215 
with 25% CR rate and the salvage chemotherapy with 10% CR rate. 

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Randomization will be stratified by response to first-line AML therapy and preselected salvage 
chemotherapy: 
Response to first-line therapy: 
● 
Relapse within 6 months after allogeneic HSCT 
● 
Relapse after 6 months after allogeneic HSCT 
● 
Primary refractory without HSCT 
● 
Relapse within 6 months after CRc and no HSCT 
● 
Relapse after 6 months after CRc and no HSCT 
Preselected chemotherapy: 
● 
High intensity chemotherapy (FLAG, MEC) 
● 
Low intensity chemotherapy (LoDAC) 
Approximately 20 Chinese subjects (10 male and 10 female subjects) will be allocated to the 
PK cohort. This sample size is calculated based on the following considerations: 
● 
“The Technical Guidelines for Clinical Pharmacokinetics Research of Chemical Drugs” 
in China (March 2005) require 8 to 12 subjects of each gender in each dose group. 
● 
To account for several subjects dropping out from the study and to ensure at least 16 
evaluable subjects in the ASP2215 arm, approximately 20 subjects will be enrolled. 
7.2 
Analysis Set 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
7.2.1 
Intention to Treatment Set 
The Intention to Treatment Set (ITT) will consist of all subjects who are randomized. The 
subjects will be analyzed based on the randomized treatments. 
7.2.2 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects who are randomized with FLT3 
mutation based on the central test and will be used for efficacy analysis. The subjects will be 
analyzed based on the randomized treatments. 
7.2.3 
Safety Analysis Set 
For the statistical summary of the safety data, the Safety Analysis Set (SAF) will be used. 
The SAF consists of all subjects who took at least 1 dose of study treatment (ASP2215 or 
salvage chemotherapy) and will be used for safety analyses. The subjects will be analyzed 
based on the actual treatment received. 
7.2.4 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least 
1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling is 

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known. Additional subjects may be excluded from the PKAS at the discretion of the 
Pharmacokineticist. Any formal definitions for exclusion of subjects or time-points from the 
PKAS will be documented in the Classification Specifications and determined the 
Classification Meeting. 
7.3 
Demographics and Other Baseline Characteristics 
7.3.1 
Demographics 
Demographics and other baseline characteristics will be summarized by treatment group. 
Descriptive statistics will include number of subjects, mean, standard deviation, minimum, 
median and maximum for continuous endpoints and frequency and percentage for categorical 
endpoints. 
7.3.2 
Medical History 
A detailed medical history for each subject will be obtained during screening period and will 
be summarized by treatment group. 
7.3.3 
Disease History 
Each subject’s complete cancer history will be listed. The number and percentage of subjects 
will be used to summarize the AML subtype, FLT3 mutation status. 
7.3.4 
Previous and Concomitant Medications 
The frequency of concomitant medications (prescription, over-the-counter and nutritional 
supplements) will be summarized by treatment group and preferred term (PT) for SAF. 
Medications will be coded using the WHO drug dictionary. Medications will be counted by 
the number of subjects who took each medication. A subject taking the same medication 
multiple times will only be counted once for that medication. Medications will be presented 
in decreasing order of frequency based on the total number of subjects who took each 
medication. 
7.3.5 
Subject Disposition 
The number and percentage of all subjects during the study will be reported per treatment 
group, study drug administration, subject completion, premature discontinuation and major 
protocol violations. 
7.3.6 
Drug Exposure 
Drug exposure including duration of exposure, cumulative dose, average daily dose, dose 
intensity and relative dose intensity will be summarized by treatment group. The number and 
proportion of subjects with dose reduction, dose escalation and dose interruption will be 
tabulated. Details of the calculation will be provided in SAP. 
7.4 
Analysis of Efficacy 
OS, EFS, CR rate, CRc rate, duration of remission, LFS and transplantation rate will be 
summarized using descriptive statistics. The survival curve and median for time-to-event 

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variables will be estimated using the Kaplan-Meier method and will be reported along with 
the corresponding 95% CI. 
7.4.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint of OS will be analyzed using the stratified Cox proportional 
hazard model with strata to control for response to first-line AML therapy and preselected 
salvage chemotherapy on the ITT. The ITT is defined as all randomized subjects. 
The hypothesis testing on the primary analysis will be performed at overall 2-sided 
0.05 significance level to test the null hypothesis that OS is equal between the 2 treatment 
arms versus the alternative hypothesis that OS is different between the ASP2215 arm versus 
the salvage chemotherapy arm.  
The sensitivity analysis for the primary efficacy endpoint will be performed on the FAS, 
which includes all randomized subjects who are FLT3-mutated subjects based on the central 
test. The sensitivity analysis for OS with censoring at the time of HSCT for subjects who 
undergo HSCT will be conducted on the ITT. If the FLT3-mutated subjects constitute less 
than 90% of the total number of randomized subjects, the difference in the primary efficacy 
endpoint will be evaluated between FLT3-mutated subjects and FLT wild type subjects per 
central lab test. 
7.4.2 
Analysis of Secondary Endpoints 
7.4.2.1 Key Secondary Efficacy Analysis 
The key secondary efficacy endpoint of EFS will be analyzed using the stratified Cox 
proportional hazard model with strata to control for response to first-line AML therapy and 
preselected salvage chemotherapy on the ITT. To maintain the overall Type I error rate at the 
0.05 significance level, the hypothesis testing on EFS will be performed only if the null 
hypothesis on the primary analysis is rejected at the overall 2-sided 0.05 significance level. 
The key secondary efficacy endpoint of CR rate will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test to control for response to first-line AML therapy and preselected 
salvage chemotherapy on the ITT. To maintain the overall Type I error rate at the 
0.05 significance level, the hypothesis testing on CR rate will be performed only if the null 
hypothesis on EFS is rejected at the overall 2-sided 0.05 significance level. 
The sensitivity analysis for the key secondary efficacy endpoints will be performed on the 
FAS, which included all randomized subjects who are FLT3-mutated subjects based on the 
central test. Additional sensitivity analysis will be performed to evaluate the impact on the 
analysis of EFS due to any missing data/assessments and any loss to follow-up or 
discontinuation of assessments of EFS not due to an event. 
7.4.2.2 Secondary Efficacy Analyses 
The statistical analyses on secondary efficacy endpoints include: 
● 
Stratified Cox proportional hazard model on duration of remission and LFS 
● 
CMH method on the CRc rate and transplantation rate 

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● 
ANOVA model to analyze the change in the BFI global fatigue score (average of all 
9 items) from baseline to post-baseline visits. 
7.4.3 
Analysis of Exploratory Endpoints 
An exploratory analysis of FLT3 mutation status and clinical efficacy will be conducted. 
FLT3 mutation status, including subgroups of FLT3 ITD mutation, D835/I836 TKD 
mutations and allelic ratio, will be analyzed. Additional biomarkers related to AML and 
ASP2215 activity may be analyzed. 
CMH method will be used for resource utilization status (hospitalization, blood transfusion, 
antibiotic iv infusions, medication for AEs and opioid medication); and ANOVA model will 
be used for resource utilization counts (hospital stays, duration of medications, blood 
transfusions, antibiotic iv infusions, medication for AEs and opioid medication). 
ANOVA model will be used to analyze the change in the FACIT-Dys-SF domain scores from 
baseline to post-baseline visits. 
ANOVA model will be used to evaluate change from baseline to post-baseline visits for the 
global and domain scores, individual items and item clusters of the FACT-Leu. The same 
analytic approach will be used for the dizziness and mouth sore items. 
ANOVA model will be used for the change from baseline of EQ-5D-5L VAS and shift table 
for the 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/ 
depression) baseline to post-baseline visits. 
7.4.4 
Subgroup Analysis 
Subgroup analysis will be performed on primary and key secondary efficacy endpoints for 
age (< 65 vs ≥ 65 years), gender, ECOG performance scores, region (China vs ex-China), 
response to first-line therapy, and preselected salvage chemotherapy. 
7.5 
Analysis of Safety 
The safety evaluation will be based mainly on AEs, clinical laboratory, vital signs, ECG and 
ECOG. Descriptive statistics will be used to summarize safety data. All safety data will be 
performed on the SAF. 
7.5.1 
Adverse Events 
All AEs recorded on treatment including within 30 days from the last study treatment will be 
summarized. AEs will be categorized by SOC and PT using MedDRA and will be graded 
according to the NCI-CTCAE version 4.03. 
The number and percent of subjects experiencing 1 or more AE(s) will be summarized by 
treatment group, SOC and PT. The number and percentage of subjects with at least 1 grade 3 
or higher AE will be summarized by treatment group, SOC and PT. 
Distribution of the maximum severity (grade) and treatment-related AEs will be summarized 
by treatment group, SOC and PT. Distribution of SAEs, discontinuations due to AE and 
deaths on study will be presented for each treatment group. 

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Additional summary tables will be generated for the following population subsets: subjects 
with SAEs including deaths, subjects who discontinue due to AEs and investigator-attributed 
relationship to study drug for AEs and SAEs. 
All summaries of AEs will include only treatment-emergent events unless otherwise stated.  
Listings of AEs, SAEs, deaths and withdrawals due to AEs will be presented. 
AEs and SAEs reported during HSCT while off ASP2215 as well as before resumption of 
ASP2215 will be summarized and listed separately. 
SAE information may be added to update patient narratives for subjects who continue to 
receive study treatment with ASP2215 upon reconsent until they meet discontinuation criteria 
or applicable reimbursement becomes available in the country of residence. 
7.5.2 
Laboratory Assessments 
Clinical laboratory evaluations (including hematology, serum chemistry and coagulation) and 
their changes from baseline will be summarized by treatment using descriptive statistics. 
Clinically significant abnormalities in laboratory values will be presented for each treatment. 
Shift tables will present shift from baseline to worst grade for selected variables using the NCI-
CTCAE grade and lab reference range indicator. Frequency of subjects with laboratory values 
outside normal range will be generated in addition to tabulation of worst toxicity grade. 
7.5.3 
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time. 
7.5.4 
Physical Examination 
Physical examination will be listed by treatment group. All clinically significant abnormal 
findings will be recorded as medical history or AEs and graded using NCI-CTCAE guidelines. 
7.5.5 
Electrocardiograms 
The 12-lead ECG results will be summarized by treatment group and time point. Overall 
ECG interpretation will be summarized for each time point. A shift analysis table showing 
shifts from baseline in overall ECG (normal, abnormal) will be provided. ECG parameters 
and their change from baseline will be summarized by treatment group using descriptive 
statistics. 
7.5.6 
ECOG Performance Scores 
ECOG performance scores will be summarized by treatment group and visit. 
7.6 
Analysis of Pharmacokinetics 
7.6.1 
Estimation of Pharmacokinetic Parameters 
PK Analysis in Chinese subjects (PK cohort) 
Plasma concentrations and PK parameters will be summarized using descriptive statistics, 
including number of subjects, mean, standard deviation, minimum, median, maximum, and 

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coefficient of variation (CV) of the mean. Time-course of drug concentrations will be plotted 
as appropriate. 
Subjects with sufficient PK samples will have PK parameter estimates for ASP2215 
including calculation of AUC24, Cmax, Ctrough and tmax using standard non-compartmental 
analysis (NCA). 
PK Analysis in subjects other than PK cohort 
Based on pharmacokinetic data obtained within this study, a separate population 
pharmacokinetic analysis will be performed. Data from this study may be pooled with other 
studies for analysis. The prospective details of this analysis will be specified in a separate 
population pharmacokinetic analysis plan. 
7.7 
Protocol Deviations 
PDs as defined in [Section 8.1.6 Protocol Deviations] will be summarized for all randomized 
subjects by treatment group and total as well as by site. A data listing will be provided by site 
and subject.  
The PD criteria will be uniquely identified in the summary table and listing. The unique 
identifiers will be as follows: 
PD1-Entered into the study even though they did not satisfy entry criteria, 
PD2-Developed withdrawal criteria during the study and was not withdrawn, 
PD3-Received wrong treatment or incorrect dose, 
PD4-Received excluded concomitant treatment. 
7.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
To evaluate whether ASP2215 is particularly beneficial or harmful compared to the salvage 
chemotherapy group while the study is ongoing, a formal interim analysis is planned when 
approximately 50% of the planned death events have occurred in the study. A group 
sequential design using the O’Brien-Fleming type alpha-spending function [Lan & DeMets, 
1983] will be used to control the overall 2-sided 0.05 significance level (East®). The IDMC 
may recommend terminating the trial for favorable or unfavorable results at the interim 
analysis. In the case of favorable results, the 2-sided significance levels for superiority are 
0.0031 for the interim analysis and 0.0490 for the final analysis. If the estimated hazard ratio 
(HR) is less than 1 and the 2-sided P value of the interim analysis is less than 0.0031, the 
IDMC may recommend terminating the trial for success. In the case of unfavorable results in 
the interim analysis, the 2-sided significance level for futility (nonbinding) is 0.8458. If the 
estimated HR is greater than 1 and the 2-sided P value of the interim analysis is greater than 
0.8458 or the estimated HR is greater than 1, the IDMC may recommend terminating the trial 
for futility. The decision rules based on P value and estimated HR at the formal interim 
analysis are as follows.  

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Decision Rules based on P Value and HR obtained at Interim Analysis 
● 
HR < 1 
o P value < 0.0031 
 
: Termination due to success 
o 0.0031 ≤ P value ≤ 0.8458 
: Continuation of study 
o P value > 0.8458 
 
: Termination due to futility 
● 
HR ≥ 1 
o Termination due to futility 
Details for the interim analysis, monitoring subject safety, enrollment rates and event (death) 
rates will be contained in the Interim Analysis Plan (IAP) and IDMC Charter. 
Recommendations regarding study conduct will be made by the IDMC based on their 
assessment of these rates. If the study is not stopped after the interim analysis, a final analysis 
will occur after 100% of events have been observed. 
7.9 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses by visit will be outlined in the SAP. 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
The relevant study data will be collected in English, and will be translated from English to 
Chinese by sponsor/CRO if required. 
The investigator or site designee will enter data collected using an Electronic Data Capture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within 
10 days after the subject visit. 
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents.  
These documents should be appropriately maintained by the site. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 
Laboratory tests are performed at central laboratory. Laboratory data will be transferred 
electronically to the Sponsor or designee at predefined intervals during the study. The 
laboratory will provide the Sponsor or designee with a complete and clean copy of the data. 
ECG results are performed at a central ECG reading laboratory. Central ECG read data will 
be transferred electronically to the Sponsor or designee at predefined intervals during the 
study. The central ECG laboratory will provide the Sponsor or designee with a complete and 
clean copy of the data. 

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For screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
Subject questionnaires will be completed by the subject on an electronic device.  The 
information completed by the subject on the electronic device will be automatically uploaded 
into a central website. The investigator or site designee should review the diaries and 
questionnaire data on the website for correct completion while the subject is at the site.  The 
questionnaire data will be transferred electronically to Sponsor or designee at predefined 
intervals during the study. The vendor will provide Sponsor or designee with a complete and 
clean copy of the data. 
8.1.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject. 
The following information should be included in the source medical records: 
● 
Demographic data (age, sex, race, ethnicity, height and body weight) 
● 
Inclusion and exclusion criteria details 
● 
Participation in study and original signed and dated informed consent forms (ICFs) 
● 
Visit dates 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data, if applicable (as specified in the protocol) 
● 
AEs and concomitant medication  
● 
Results of relevant examinations (e.g., ECG charts, X-ray films etc.) 
● 
Laboratory printouts (if applicable) 
● 
Dispensing and return of study drug details 
● 
Reason for premature discontinuation (if applicable) 
● 
Randomization number (if applicable) 
8.1.3 
Clinical Study Monitoring 
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures. 
8.1.4 
Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents 

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(refer to [Section 8.1.2 Specification of Source Documents]) when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access. 
8.1.5 
Data Management 
Data Management will be coordinated by the Japan-Asia Data Science department of the 
Sponsor in accordance with the SOPs for data management. All study specific processes and 
definitions will be documented by Data Management. eCRF completion will be described in 
the eCRF instructions. Coding of medical terms and medications will be performed using 
MedDRA and WHO Drug Dictionary respectively. 
8.1.6 
Protocol Deviations 
A PD is generally an unplanned excursion from the protocol that is not implemented or 
intended as a systematic change. The investigator is responsible for ensuring the study is 
conducted in accordance with the procedures and evaluations described in this protocol and 
must protect the rights, safety and welfare of subjects. The investigator should not implement 
any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial subjects. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
● 
Entered into the study even though they did not satisfy entry criteria 
● 
Developed withdrawal criteria during the study and not withdrawn 
● 
Received wrong treatment or incorrect dose 
● 
Received excluded concomitant treatment 
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and/or 
efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately. 
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File. 
NOTE: Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as applicable. 

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8.1.7 
End of Trial in All Participating Countries 
The end of trial in all participating countries is defined as the last subject’s last visit. 
8.2 
Ethics and Protection of Subject Confidentiality 
8.2.1 
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities 
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) and any other necessary documents be reviewed 
by an IEC/IRB. The IEC/IRB will review the ethical, scientific and medical appropriateness 
of the study before it is conducted. IEC/IRB approval of the protocol, informed consent and 
subject information and/or advertising, as relevant, will be obtained prior to the authorization 
of drug shipment to a study site. 
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP. 
Any SAE that meet reporting criteria, as dictated by local regulations, will be reported to both 
responsible Ethics Committees and Regulatory Agencies, as required. During the conduct of 
the study, the investigator should promptly provide written reports (e.g., ICH Expedited 
Reports and any additional reports required by local regulations) to the IEC/IRB of any 
changes that affect the conduct of the study and/or increase the risk to subjects. Written 
documentation of the submission to the IEC/IRB should also be provided to Sponsor. 
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. 
8.2.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3 
Informed Consent of Subjects 
8.2.3.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative and answer all questions regarding this study. Prior to 
any study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed ICF will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must also be made in the 
subject’s dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy. 

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8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not. 
2. The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must reconsent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF. A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record. An entry must be made in the subject’s records documenting the 
reconsent process. 
8.2.4 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being. 
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study. 
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., Health Insurance Portability and 
Accountability Act [HIPAA]). 
8.3 
Administrative Matters 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 

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of the study only. It is understood by the investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the drug 
and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study. 
Publication of the study results is discussed in the Clinical Study Agreement. 
8.3.2 
Documents and Records Related to the Clinical Study 
The Sponsor will provide the investigator and/or institution with the following: 
• 
Study protocol (and amendments, where applicable) 
• 
Investigator’s Brochure (and amendments, where applicable) 
• 
eCRFs 
• 
Study drug with all necessary documentation 
• 
Study contract 
In order to start the study, the investigator and/or study site is required to provide the following 
documentation to the Sponsor: 
• 
Financial disclosure in compliance with federal regulation 21CFR Part 54 
• 
Signed Investigator's Statement in this protocol and eCRF 
• 
Current Curricula Vitae of all investigators 
• 
List of sub-investigators and collaborators 
• 
IRB approval of the protocol, protocol amendments (if applicable) including a membership 
list with names and qualification (COPY) 
• 
Study contract 
• 
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee) 
At the end of the study, the Sponsor is responsible for the collection of: 
• 
Study related documentation, 
• 
Unused study drug, if applicable 
The investigator will archive all study data (e.g., Subject Identification Code List, source data, 
eCRFs and Investigator's File) and relevant correspondence. These documents are to be kept on 
file for the appropriate term determined by local regulation. The Sponsor will notify the 
site/investigator if the New Drug Application (NDA)/Marketing Authorization 
Application/IMPD.  
The investigator agrees to obtain the Sponsor's agreement prior to disposal, moving or 

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transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the eCRFs supplied 
for each subject. 
The following are the major documents to be retained at the study site, wherever applicable. 
1. Source documents (clinical data, documents, and records for preparing the eCRF), 
hospital records, medical records, test records, memoranda, subject diary or check lists 
for evaluation, administration records, data recorded by automatic measuring 
instruments, reproductions or transcripts verified as precise copies, microfiche, negative 
films, microfilms/magnetic media, x-ray films, subject files and study-related records 
kept at either a pharmacy, a laboratory, or medical technical office, as well as subject 
registration forms, laboratory test slips including central measurement, worksheets 
specified by the Sponsor, records of clinical coordinators, and records related to the 
clinical study selected from those verified in other departments or hospitals. 
2. Contracts, written ICFs, written information, and other documents or their copies 
prepared by the study personnel. A letter of request for clinical study (including a request 
for continuation/amendment), letter of request for review, notice of clinical study 
contract, clinical study contract, notification of discontinuation or completion of clinical 
study, written information for informed consent (including revisions), signed and dated 
written informed consent (including revisions), Curricula Vitae of investigators, list of 
sub-investigators, list of signatures and print of seals (copy), and case report forms 
(copy), etc. 
3. The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical study, documents obtained from the IRB related to the adequacy of 
conducting a clinical study whose period exceeds 1 year or the adequacy of continuously 
conducting the clinical study from which information on adverse drug reactions is 
obtained, and other documents obtained. An agreed-upon protocol (including revisions), 
Investigator's Brochure (including revisions), operational procedures for the investigator, 
materials and information supplied by the Sponsor (e.g., AE report), matters reported by 
the investigator (revisions of the protocol, AE reports, etc.), the list of names of the IRB 
members, materials for IRB review, IRB review records, and the review result report of 
the IRB, etc. 
4. Records of control for study drugs and other duties related to the clinical study.  
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and the prescriptions for 
concomitant medications. 
8.3.3 
Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments.  

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Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority and the IRB/IEC (if applicable). 
Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations. 
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor. 
8.3.4 
Insurance of Subjects and Others 
The Sponsor has covered this study by means of an insurance of the study according to national 
requirements. The name and address of the relevant insurance company, the certificate of 
insurance, the policy number and the sum insured are provided in the Investigator's File. 
8.3.5 
Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and European Union Directive 2001/83/EC requires that a 
final study report which forms part of a Marketing Authorization Application be signed by 
the representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator(s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock. 
9 
QUALITY ASSURANCE 
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s). 
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, CRFs and source documents. Direct access to these documents will be required 
by the auditors. 
10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) 
The IDMC will be responsible for the review of subject safety, enrollment rates and event 
(death) rates during interim analysis when approximately 50% of the planned death events 

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have occurred in the study. The IDMC may recommend terminating the trial for favorable or 
unfavorable results at the interim analysis. 
Members of the IDMC will be independent from the Sponsor and also will not participate as 
investigators in the trial. Additional details regarding responsibilities and membership 
requirements will be included in the IDMC Charter. 
10.2 
Other Study Organization 
Not applicable. 

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11 
REFERENCES 
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American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 2014. 
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prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of 
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Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, et al. Impact of FLT3 internal tandem 
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Burnett AK, Knapper S. Targeting treatment in AML. Hematology Am Soc Hematol Educ Program. 
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Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality 
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Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642-9. 
Chevallier P, Labopin M, Turlure P, Prebet T, Pigneux A, Hunault M, et al. A new Leukemia 
Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia 
patients: a GOELAMS study. Leukemia. 2011;25:939-44. 
Choi SW, Victorson DE, Yount S, Anton S, Cella D. Development of a conceptual framework and 
calibrated item banks to measure patient-reported dyspnea severity and related functional 
limitations. Value Health. 2011;14:291-306. 
Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal 
tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large 
cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776-84. 
Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, et al. Receptor tyrosine kinase AXL is 
induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute 
myeloid leukemia. Cancer Lett. 2008;268:314-24. 
Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert Opin Ther Targets. 2015;19:37-54. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659-63. 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A More Accurate Method To Estimate 
Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation. Annals of 
Internal Medicine. 1999;130:461-470. 
Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of 
salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first 
relapse. Blood. 2011;117:3294-301. 

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Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, 
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Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
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Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment 
of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-109. 
Moreno I, Martín G, Bolufer P, Barragán E, Rueda E, Román J, et al. Incidence and prognostic value 
of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. 
Haematologica. 2003;88:19-24. 
O'Donnell MR, Abboud CN, Altman J, Appelbaum FR, Arber DA, Attar E, et al. Acute myeloid 
leukemia. J Natl Compr Canc Netw. 2012;10:984-1021. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55. 
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tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute 
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Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of 
integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079-89. 
Rochlitz C, Lohri A, Bacchi M, Schmidt M, Nagel S, Fopp M, et al. Axl expression is associated with 
adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia 
(AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research 
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Schlenk RF, Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol. 2009;16:98-104. 
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. editors. WHO classification of 
tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: IARC Press. 2008. 
Tallman MS. New strategies for the treatment of acute myeloid leukemia including antibodies and 
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Tiesmeier J, Müller-Tidow C, Westermann A, Czwalinna A, Hoffmann M, Krauter J, et al. Evolution 
of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and 
response to salvage therapy. Leuk Res. 2004;28:1069-74. 
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of 
D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 
2001;97:2434-9. 
Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem 
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12 
APPENDICES 
12.1 
List of Excluded and Cautionary Concomitant Medications 
The following list describes medications and foods that are common strong inhibitors of 
CYP3A. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A. If there are concerns or 
questions about concomitant use of any drugs listed below, discussion with the co-chairs and 
protocol officer is strongly encouraged. 
Strong CYP3A Inhibitors 
Drug Type 
Generic Drug Name 
Human Immunodeficiency Virus Protease 
Inhibitors 
Indinavir 
Nelfinavir 
Lopinavir 
Ritonavir 
Saquinavir 
Food/Juice 
Grapefruit juice 
Others 
Boceprevir 
Telaprevir 
Clarithromycin 
Telithromycin 
Conivaptan 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Nefazodone  
CYP: cytochrome P450 
Source: Table 4 in FDA Draft Guidance for Industry - Drug Interaction Studies - Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf 
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. The 
following lists describe medications and foods which are common strong inducers of 
CYP3A.  This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to induce CYP3A. 
Strong CYP3A Inducers 
Drug Type 
Generic Drug Name 
Antiepileptic, Anticonvulsant 
carbamazepine 
phenytoin 
Antibiotic 
rifampicin 
Food/Juice Supplement 
St. John’s wort 
CYP: cytochrome P450 
Source: Table 4 in FDA Draft Guidance for Industry - Drug Interaction Studies - Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
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The following lists describe medications which target serotonin receptors. This list should not 
be considered all inclusive. Consult individual drug labels for specific information on 
whether a compound targets serotonin receptors. 
Drugs Targeting Serotonin Receptor 
Drug Type 
Generic Drug Name 
Affinity or Function to 5HT2BR 
eletriptan hydrobromide 
Affinity or Function to 5HT1R 
almotriptan malate  
aripiprazole  
avitriptan  
buspirone hydrochloride  
dihydroergotamine mesylate 
droperidol  
eletriptan hydrobromide  
ergoloid mesylates  
ergonovine maleate  
ergotamine tartrate  
frovatriptan succinate  
haloperidol  
haloperidol decanoate 
lesopitron  
methylergonovine maleate  
methylergotamine  
methysergide maleate  
naratriptan hydrochloride  
pizotifen  
quetiapine fumarate  
rizatriptan benzoate  
sumatriptan succinate  
tegaserod maleate  
thioridazine  
thioridazine hydrochloride  
ziprasidone hydrochloride  
ziprasidone mesylate  
zolmitriptan  
zotepine 
5HT1R: 5-hydroxytryptamine receptor 1; 5HT2BR: 5-hydroxytryptamine receptor 2B 
The following lists describe medications and foods which are common inhibitors or inducers 
of P-gp. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit or induce P-gp. 

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P-gp Inhibitors or Inducers 
Transporter  
Gene 
Inhibitor 
Inducer 
P-gp 
ABCB1 
amiodarone 
azithromycin 
captopril 
carvedilol 
clarithromycin 
conivaptan 
cyclosporine 
diltiazem 
dronedarone 
erythromycin 
felodipine 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
quercetin 
quinidine 
ranolazine 
verapamil 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St John’s wort 
tipranavir/ritonavir 
P-gp: P-glycoprotein 
Source: Table 12 in http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664 htm#major 
No list of drugs that target sigma nonspecific receptor is provided. Please consult individual 
drug labels for specific information on whether a compound targets sigma nonspecific 
receptors. 

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Drugs that may Prolong QT or QTc 
The following list describes drugs that are known to prolong QT or QTc. This list should not 
be considered all inclusive. Consult individual drug labels for specific information on 
whether a compound is known to prolong QT or QTc. 
Drug Type 
Generic Drug Name 
Class IA antiarrhythmics 
Quinidine 
Procainamide 
Disopyramide 
Class IC antiarrhythmics 
Flecainide  
Propafenone  
Moricizine 
Class III antiarrhythmics  
Amiodarone 
Sotalol 
Bretylium 
Ibutilide 
Dofetilide 
Antipsychotics 
Thioridazine 
Mesoridazine 
Chlorpromazine 
Prochlorperazine 
Trifluoperazine 
Fluphenazine 
Perphenazine 
Pimozide 
Risperidone 
Ziprasadone 
Lithium 
Haloperidol 
Tricyclic/tetracyclic antidepressants  
Amitriptyline 
Desipramine 
Doxepin 
Dosulepin hydrochloride 
Imipramine 
Maprotiline 
Selective serotonin and norepinephrine 
reuptake inhibitors (SSNRIs) antidepressants  
Venlafaxine 
Macrolide antibiotics 
Azithromycin 
Erythromycin 
Clarithromycin 
Dirithromycin 
Roxithromycin 
Tulathromycin 
Fluoroquinolone antibiotics 
Moxifloxacin 
Gatifloxacin 
Table continued on next page 

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Drug Type 
Generic Drug Name 
Azole antifungals  
Ketoconazole 
Fluconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Antimalarials 
Amodiaquine 
Atovaquone 
Chloroquine 
Doxycycline 
Halofantrine 
Mefloquine  
Proguanil 
Primaquine 
Pyrimethamine 
Quinine 
Sulphadoxine 
Antiprotozoals 
Pentamidine 
Antiemetics 
Droperidol 
Dolasetron 
Granisetron 
Ondansetron 
Antiestrogens 
Tamoxifen 
Immunosuppressants 
Tacrolimus 
 
Precaution is advised in the use of ASP2215 with concomitant drugs that are substrates of 
P-gp (e.g., digoxin, dabigatran etexilate), BCRP (e.g., mitoxantrone, rosuvastatin), and OCT1 
(e.g., metformin) since these transporters have been shown to be inhibited by ASP2215 in in 
vitro studies. 

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12.2 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 × ULN (to > 5 × ULN in subjects with liver metastases) or 
TBL > 2 × ULN, should undergo detailed testing for liver enzymes (including at least ALT, 
AST, alkaline phosphatase [ALP] and TBL). Testing should be repeated within 48 - 72 hours of 
notification of the test results. For studies for which a central laboratory is used, alerts will be 
generated by the central lab regarding moderate and severe liver abnormality to inform the 
investigator, study monitor and study team. Subjects should be asked if they have any 
symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
  
ALT or AST 
 
TBL 
Moderate 
> 3 x ULN (in subjects without liver 
metastases), > 5 x ULN (in subjects with 
liver metastases) 
or 
> 2 x ULN 
 
 
 
 
Severe† 
> 3 x ULN 
and 
> 2 x ULN 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases) 
● 
ALT or AST > 3 × ULN and International normalization ratio (INR) > 1.5 (If INR 
testing is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality-Case Report 
Form (LA-CRF) or appropriate document. Subjects with confirmed abnormal liver function 
testing should be followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2 - 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 

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Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ‘AEs’ on the AE page of eCRF. Illnesses 
and conditions such as hypotensive events and decompensated cardiac disease that may 
lead to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is 
seen in obese hyperlipoproteinemic and/or diabetic subjects and may be associated with 
fluctuating aminotransferase levels. The investigator should ensure that the medical 
history form captures any illness that predates study enrollment that may be relevant in 
assessing hepatic function. 
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the eCRF. Information on alcohol, other substance use and diet 
should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including: 
o acute viral hepatitis (A, B, C, D, E or other infectious agents) 
o ultrasound or other imaging to assess biliary tract disease 
o other laboratory tests including INR, direct bilirubin 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Discontinuation 
In the absence of an explanation for increased LFTs, such as viral hepatitis, preexisting or 
acute liver disease, presence of liver metastases or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases) 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN and TBL > 2 × ULN (in subjects with liver metastases) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued. 

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† Hy’s Law Definition: drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% - 50% 
mortality (or transplant). The 2 “requirements” for Hy’s Law are the following: 
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in transaminase elevations higher than 3 × ULN (2 × ULN elevations are too 
common in treated and untreated subjects to be discriminating) 
2. Cases of increased TBL (at least 2 × ULN) with concurrent transaminase elevations at 
least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
ALP) or Gilbert’s syndrome 
Source: Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15:241-3. 
Reference 
FDA. Guidance for industry-drug-induced liver injury: premarketing clinical evaluation. 2009. 

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12.3 
Laboratory Tests 
Panel/ 
Assessment 
Matrix/Collecting Tube 
Parameters to be Analyzed 
Hematology 
2 mL into EDTA tube 
White Blood Cell Counta 
White Blood Cell Differentiala 
Red Blood Cell Count 
Hemoglobina 
Hematocrita  
Mean Corpuscular Volume 
Platelet Counta 
Mean Corpuscular Hemoglobin Concentration 
Mean Corpuscular Hemoglobin 
Blast counta 
Chemistrya 
7.5 mL into serum tube 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Uric acidb 
Glucose 
Calcium 
Phosphate 
Magnesium 
Albumin 
Total Protein 
Alkaline Phosphatase 
Lactate Dehydrogenase 
Creatine Phosphokinase 
Aldolase 
Triglycerides 
Total Cholesterol 
Phospholipid 
Globulin 
Liver Function Tests including: 
Total Bilirubin 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Thyroid Function Tests including 
TSH 
Free T4 
Pregnancy Test 
1 mL serum and/or urinec 
Human Chorionic Gonadotropin 
Coagulation 
Profile (PT/INR, 
D-dimer, 
fibrinogen)  
1.8 mL into sodium citrate 
tube 
INR 
PT 
aPTT 
Fibrinogen (Screening Only) 
D-dimer (Screening Only) 
Table continued on next page 

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Panel/ 
Assessment 
Matrix/Collecting Tube 
Parameters to be Analyzed 
Urinalysis 
Dipstick 
Color 
Appearance 
Specific Gravity 
pH 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
Protein 
Urobilinogen 
Bone Marrow 
Aspirate around 3 mL, 
2 - 3 bedside smear slides 
and/or biopsy (or peripheral 
blood in the event of a dry tap) 
(Local Test) 
Blast Count and Cell Counts 
Flow Cytometry for Blasts 
Bone Marrow 
Aspirate and/or 
Blood 
Aspirate 0.25 mL – 0.75 mL 
in sodium heparin   
Blood 1 mL – 3 mL in sodium 
heparin 
FLT3 Mutation Status 
PK 
2 mL into dipotassium EDTA 
ASP2215 
PGx 
3 mL into dipotassium EDTA 
tube and a buccal swab sample 
Pharmacogenomics analysis 
aPTT: activated partial thromboplastin time; eCRF: Electronic Case Report Form;  
EDTA: ethylenediaminetetraacetic acid; FLT3: FMS-like tyrosine kinase; INR: international normalization ratio; 
PK: pharmacokinetics; PT: prothrombin time; T4: thyroxin; TSH: thyroid stimulating hormone. 
a. In addition to the central read of these values, available local results will also be entered into the eCRF. 
b. On days 1, 4, 8 and 15 in cycle 1. 
c. Refer to Schedule of Assessments. 

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12.4 
Common Serious Adverse Events 
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the 
need to report an AE meeting the definition of an SAE as detailed in [Section 5.5.2 
Definition of Serious Adverse Events]. The purpose of this list is to alert you that some 
events reported as SAEs may not require expedited reporting to the regulatory authorities based 
on the classification of “common serious adverse events.” You are required to follow the 
requirements detailed in [Section 5.5.6 Reporting of Serious Adverse Events]. 
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicates they occur more 
frequently with study drug, an expedited IND safety report may be submitted to the FDA. 
Serious Adverse Events Caused by AML 
Grades Usually 
Observed with AML 
Hematologic AE 
Anemia 
0 - 4 
Bone marrow hypocellular 
0 - 4 
CD4 lymphocytes decreased 
0 - 4 
Disseminated intravascular coagulation 
0 - 3 
Leukocytosis 
0 - 4 
Lymphocyte count decreased 
0 - 4 
Lymphocyte count increased 
0 - 4 
Neutropenia 
0 - 4 
Neutrophil count decreased 
0 - 4 
Platelet count decreased 
0 - 4 
Purpura 
0 - 3 
Thrombocytopenia 
0 - 4 
White blood cell decreased 
0 - 4 
Infection-related AE 
Bacterial infection (regardless of organ-system involved or specific 
bacterial cause) 
0 - 3 
Chills 
0 - 3 
Cough 
0 - 3 
Febrile neutropenia (without infection) 
0 - 4 
Fever 
0 - 5 
Flu-like symptoms 
0 - 3 
Fungal infections (regardless of organ-system involved or fungal cause) 
0 - 3 
Mucositis 
0 - 4 
Periodontal disease 
0 - 3 
Pneumonia 
0 - 5 
Sepsis/septicemia/bacteremia (all causes) 
0 - 5 
Sinusitis 
0 - 4 
Sore throat 
0 - 3 
Table continued on next page 

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Serious Adverse Events Caused by AML 
Grades Usually 
Observed with AML 
Psychiatric and Nervous System Related AE 
Anxiety 
0 - 2 
Cognitive disturbance 
0 - 3 
Confusion 
0 - 5 
Depressed level of consciousness 
0 - 5 
Depression 
0 - 3 
Libido decreased 
0 - 2 
Meningismus 
0 - 5 
Seizure 
0 - 5 
Somnolence 
0 - 5 
Syncope 
3 
Other AE 
Activated partial thromboplastin time prolonged 
0 - 2 
Alanine aminotransferase increased 
0 - 2 
Alkaline phosphatase increased 
0 - 2 
Anorexia 
0 - 2 
Aspartate aminotransferase increased 
0 - 2 
Blood bilirubin increased 
0 - 2 
Bone and/or joint pain 
0 - 2 
Bruising 
0 - 2  
Bleeding/hemorrhage 
0 - 5 
Diarrhea 
0 - 2 
Dyspnea 
0 - 5 
Fatigue 
0 - 3 
Flushing 
0 - 2 
Gamma-glutamyltransferase increased 
0 - 1 
GVHD-acute and chronic 
0 - 2 
Hypertrophied gums 
0 - 1 
Hyperuricemia 
0 - 1 
Hypokalemia 
0 - 2 
Hypotension 
0 - 2 
Hypoxia 
0 - 3 
INR increased 
0 - 1 
Lactate dehydrogenase increased 
0 - 2 
Malaise 
0 - 2 
Multi-organ failure 
0 - 5 
Nausea 
0 - 2 
Oral dysesthesia 
0 - 2 
Petechiae 
0 - 2 
Pruritus 
0 - 3 
Skin and subcutaneous tissue disorders 
0 - 3 
Transient ischemic attacks 
0 - 2 
Tumor lysis syndrome 
3 - 5 
Vasculitis 
0 - 5 
Vomiting 
0 - 2 
Weight loss 
0 - 2 
AE: adverse event; AML: acute myeloid leukemia; GVHD: graft-versus-host disease; INR: International 
normalization ratio 

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12.5 
Retrospective PGx Sub-Study (Optional) 
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment options 
are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies, the 
relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may be better 
understood. As many diseases may be influenced by 1 or more genetic variations, PGx research 
may identify which genes are involved in determining the way a subject may or may not 
respond to a drug. 
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to AML subjects’ clinical response, pharmacokinetics and toxicity/safety concerns in relation 
to ASP2215 treatment. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity. 
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study may participate in this PGx sub-study. 
As part of this sub-study, subjects must provide written consent prior to providing any blood 
samples that may be used at a later time for genetic analysis. 
For subjects study, subjects who have consented to participate in this study may participate in 
this PGx sub-study. As part of this sub-study, subjects must provide separate written consent 
prior to providing any blood samples that may be used at a later time for genetic analysis. 
SAMPLE COLLECTION AND STORAGE 
Subjects who consent to participate in this sub-study will provide a 3 mL whole blood sample 
and a buccal swab per Astellas’ instructions. Each sample will be identified by the unique 
subject number (first code). Samples will be shipped frozen to a designated banking CRO 
either directly from site or via a central laboratory as directed by Astellas. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s kinetics, 
efficacy and/or safety. 
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 

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destroyed after the planned storage period. The subject has the right to withdraw consent at any 
time. When a subject’s withdraw notification is received, the PGx sample will be destroyed.  
The results of any PGx analysis conducted on a sample prior to its withdrawal will be retained 
at Astellas indefinitely. 
INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained from 
the PGx analysis will be the property of Astellas. 
 

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12.6 
Definitions of Line of Therapy and Tools to Determine Study 
Eligibility 
Schematic representation of AML treatment and eligible path for study participation after 
treatment with 1 line of therapy. 
 
Below are examples of the treatment paths that would qualify the patient to participate in the 
study: 
● 
First induction → Refractory  
● 
First induction → Refractory → Second Induction*→ Refractory 
● 
First induction → Refractory → Second Induction*→ Remission→ Relapse 
(*can include different treatment from first induction) 
● 
First induction → Remission → Consolidation/Maintenance with HSCT→ Relapse 
● 
First induction → Consolidation/Maintenance without HSCT → Relapse 
Please note: Induction with consolidation/maintenance followed by HSCT is considered as 
one line of therapy. HSCT by itself and hydroxyurea are not considered to be lines of 
therapy. 
12.7 
Crossover Extension 
The Crossover Extension (COE) was implemented. With the exception of those procedures 
and processes indicated below, this extension study will be performed using the same general 
approach of ASP2215 arm as described in the protocol. Refer to the main protocol for any 
study details not contained in the supplemental COE appendix. 
12.7.1 Rationale and design for COE portion of the study  
The study planned interim analysis demonstrated superior OS outcome for the ASP2215 arm 
compared to the Salvage chemotherapy arm. The IDMC concluded that the primary endpoint 
of OS crossed the predefined efficacy stopping boundary and recommended that the study 
should stop for efficacy. According to IDMC’s recommendation, the sponsor determined that 
no further screening/enrollment is required. In addition, COE is implemented to allow active 

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salvage chemotherapy arm subjects and salvage chemotherapy arm subjects in follow to 
receive ASP2215 treatment on the study based on the investigators’ discretion. 
All eligible subjects must be evaluated and meet the eligibility criteria for COE. 
Subjects on active salvage chemotherapy arm who are participating in COE, will have an end 
of treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-
up, in which a telephone contact with the subject is sufficient unless any assessment must be 
repeated for resolution of treatment-related AEs. 
Day 1 of the COE will occur after COE informed consent form is signed and eligibility is 
confirmed.  
In COE portion of the study, subjects will receive treatment with ASP2215 over continuous 
28-day cycles. Subjects taking ASP2215 should continue until the subject meets a treatment 
discontinuation criterion. The subjects will have an end of treatment visit within 7 days after 
treatment discontinuation, followed by a 30-day follow-up, in which a telephone contact with 
the subject is sufficient unless any assessment must be repeated for resolution of treatment-
related AEs. Dose interruption and reduction due to adverse events related to ASP2215 must 
be followed [Table 9]. 
Study procedures during the COE will be limited to safety data collection including AE/SAE 
collection/assessment, clinical laboratory, ECGs, physical exams, vital signs and concomitant 
treatment as detailed in the schedule of assessment [Table 4 and Table 6]. 
12.7.2 Inclusion Criteria 
Subject is eligible for the COE if they meet the following criteria when the subject is 
evaluated for eligibility to participate in the COE portion of the study: 
1. Institutional Review Board (IRB) -/Independent Ethics Committee (IEC) -approved 
written Informed Consent and privacy language as per national regulations must be 
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject has received study treatment of either LoDAC, MEC or FLAG and has no 
response or progressive disease.  
3. Subject has not received other antileukemic therapy after EoT (hydroxyurea is allowed 
for the control of peripheral leukemic blasts in patients with leukocytosis). 
4. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
● 
Serum AST and ALT ≤ 2.5 x upper limit of normal (ULN) 
● 
Serum total bilirubin ≤ 1.5 x ULN 
● 
Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of 
> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation 
[Levey et al, 1999]. 
● 
Serum potassium ≥ lower limit of normal (LLN) (Repletion of potassium levels prior 
to C1D1 of COE is allowed). 
● 
Serum magnesium ≥ LLN (Repletion of magnesium levels prior to C1D1 of COE is 
allowed). 

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5. Subject has an ECOG performance status ≤ 2. 
6. Female subject must either: 
● 
Be of non-childbearing potential: 
● 
Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or 
● 
Documented as surgically sterile (at least 1 month prior to screening) 
● 
Or, if of childbearing potential,  
● 
Agree not to try to become pregnant during the study and for 60 days after the 
final study drug administration 
● 
And have a negative serum or urine pregnancy test at screening 
● 
And, if heterosexually active, agree to consistently use highly effective 
contraception per locally accepted standards in addition to barrier method 
starting at screening and throughout the study period and for 60 days after the 
final study drug administration. 
7. Female subject must agree not to breastfeed at screening and throughout the study period 
and for 60 days after the final study drug administration. 
8. Female subject must not donate ova starting at screening and throughout the study period 
and for 60 days after the final study drug administration. 
9. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception per locally accepted standards in addition to a 
barrier method starting at screening and continue throughout the study period and for 
120 days after the final study drug administration. 
10. Male subject must not donate sperm starting at screening and throughout the study period 
and for 120 days after the final study drug administration. 
11. Subject agrees not to participate in another interventional study while on treatment. 
Waivers to the COE inclusion criteria will NOT be allowed. 
12.7.3 Exclusion Criteria 
Subject will be excluded from participation in the COE if any of the following apply when 
the subject is evaluated for eligibility to participate in the COE portion of the study: 
1. Subject has been diagnosed with another malignancy, unless disease-free for at least 
5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study 
if definitive treatment for the condition has been completed. Subjects with organ-
confined prostate cancer with no evidence of recurrent or progressive disease are eligible 
if hormonal therapy has been initiated or the malignancy has been surgically removed or 
treated with definitive radiotherapy. 
2. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or 
subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a 
screening echocardiogram performed within 1 month prior to study entry results in a left 
ventricular ejection fraction (LVEF) that is ≥ 45%. 

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3. Subjects with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at 
COE Screening based on central reading.  
4. Subject has clinically active central nervous system leukemia. 
5. Subject has clinically significant abnormality of coagulation profile, such as 
disseminated intravascular coagulation. 
6. Subject has had major surgery within 4 weeks prior to the first study dose. 
7. Subject has radiation therapy within 4 weeks prior to the first study dose.  
8. Subject with Long QT Syndrome at Screening. 
9. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below 
lower limit of normal [LLN]). 
10. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 
11. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers 
of P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely 
essential for the care of the subject. 
12. Subject requires treatment with concomitant drugs that target serotonin 5-
hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) 
or sigma nonspecific receptor with the exception of drugs that are considered absolutely 
essential for the care of the subject. 
13. Subject has an active uncontrolled infection. 
14. Subject is known to have human immunodeficiency virus infection. 
15. Subject has active hepatitis B or C or other active hepatic disorder. 
16. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
Waivers to the COE exclusion criteria will NOT be allowed. 
12.7.4 Treatment of COE 
Subjects participating in COE will receive the following treatment during each 28-day cycle: 
 
ASP2215 orally once daily 120 mg /day from day 1 to 28 of the 28-day cycles.  
Dosing guidance for ASP2215 outlined [Section 5.1 Dosing and Administration of Study 
Drugs and Other Medications] should be followed. 
12.7.5 Schedule and Assessments 
Salvage chemotherapy arm subjects meeting criteria as indicated in [Section 12.7.2 Inclusion 
Criteria and 12.7.3 Exclusion Criteria] will sign informed consent prior to initiation of any 
COE C1D1 procedures. The COE subjects will follow Treatment Schedule of Assessments 
for Crossover Extension [Table 4] and the Post treatment Schedule of Assessments for 
Crossover Extension [Table 6].  

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12.7.6 Previous and Concomitant Treatment (Medication and Non-medication 
Therapy) 
All medications and concomitant treatments (except for the medications for the purpose other 
than treatment for disease or event such as contrast agent, laboratory examination, etc.) 
administered from 28 days prior to cycle 1 day 1 must be recorded in the electronic Case 
Report Form (eCRF). If EoT of salvage chemotherapy arm was performed within 28 days 
prior to C1D1 of the COE, only the medication after EoT of salvage chemotherapy arm and 
prior to C1D1 should be recorded. 
COE receiving ASP2215 group: 
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. 
Treatment with concomitant drugs that are strong inhibitors or inducers of P-gp and 
concomitant drugs that target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor are 
to be avoided with the exception of drugs that are considered absolutely essential for the care 
of the subject. Treatment with concomitant drugs that are strong inhibitors of CYP3A should 
be avoided with the exception of antibiotics, antifungals and antivirals that are used as 
standard of care to prevent or treat infections. If CYP3A inhibitors are used concomitantly, 
subjects should be monitored for AEs. 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are known to 
prolong QT or QTc intervals. 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are substrates 
of BCRP, since the transporter has been shown to be inhibited by ASP2215 in in vitro studies. 
Common CYP3A inhibitors, CYP3A inducers, drugs targeting the serotonin receptor, P-gp 
inhibitors or inducers, and drugs known to prolong QT or QTc intervals are listed in 
[Appendix 12.1]. The investigator should consult individual labels for all drugs that the 
subject is taking to evaluate if they fall into any of above named categories. For concomitant 
drugs that have the potential to prolong QT or QTc intervals, a cardiology consult should be 
obtained as medically indicated.  
12.7.7 Duration of Treatment and Discontinuation Criteria 
Subjects will be eligible to continue receiving treatment in this study until they meet a 
discontinuation criterion as outlined below or upon marketing authorization commercial 
availability and applicable reimbursement of ASP2215 in the country of residence. Once a 
subject(s) transitions to commercial supply, the subject(s) will be discontinued from the 
study. 
Discontinuation Criteria from Treatment for Individual Subjects: 
● 
Subject declines further study participation (i.e. withdrawal of consent). 
● 
Subject is noncompliant with the protocol based on the investigator or medical 
monitor assessment. 

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● 
Subject is found to have significantly deviated from any 1 of the inclusion or 
exclusion criteria after enrollment (subjects having clinical benefit may be kept in the 
study after discussion with the medical monitor). 
● 
Subject develops an intolerable or unacceptable toxicity. 
● 
Subject receives any antileukemic therapy other than the assigned treatment, with the 
exceptions of hydroxyurea up to 2 weeks, prophylactic intrathecal chemotherapy or 
cranial irradiation, and donor lymphocyte infusion as part of the HSCT treatment 
plan. 
● 
Investigator/sub-investigator determines that the continuation of the study treatment 
will be detrimental to the subject. 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Subject is receiving ASP2215 and has progressive disease or NR and the subject, in 
the opinion of the investigator, is no longer deriving clinical benefit. 
● 
Female subject becomes pregnant. 
● 
Death. 
12.7.8 Statistical Methods 
Since the cross-over choice of chemotherapy patients were introduced as a result of the 
interim analysis of the efficacy, the main statistical analysis of efficacy and safety should be 
conducted on the data up to the implementation of this choice to maintain the integrity of the 
study conclusion. 
All eligible salvage chemotherapy arm subjects who cross to COE ASP2215 treatment will 
be summarized separately to support the safety conclusion for the ASP2215. More details 
will be included in the SAP. 
12.8 
Continuation of Study Treatment with ASP2215 
Subjects can continue to receive study treatment with ASP2215 upon reconsent under this 
protocol version 7.0 until subjects meet discontinuation criteria or applicable reimbursement 
becomes available in the country of residence. ASP2215 will be supplied every 3 months via 
IRT as applicable to the subjects until subjects’ transition to the commercial product or meet 
discontinuation criteria. IRT notification is required when subjects discontinue from study 
treatment. Subjects will be managed per the local institution’s standard of care for safety and 
efficacy assessments while on study treatment after subjects reconsent under this protocol 
version 7.0. Subjects will follow the Schedule of Assessments in [Table 12]. No data 
(including PK assessment) will be collected in the eCRFs after subjects reconsent under this 
protocol version 7.0. Only SAEs, as defined in [Section 5.5.2 Definition of Serious Adverse 
Events], will be collected and reported as outlined in [Section 5.5.6 Reporting of Serious 
Adverse Events]. Once subjects transition to commercial supply or meet the study 
discontinuation criteria, subjects will be discontinued from the study, and no further follow-
up will be performed.  

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Table 12 
Continuation of Study Treatment with ASP2215 Schedule of Assessments 
Activity 
Reconsent 
Every 3 Months for Subjects Who 
Reconsent to Receive ASP2215 
End of 
Treatment 
Reconsent (Signed ICF) 
X 
 
 
SAE Assessment 
 
Xa 
X 
IRT Transaction Required  
 
X 
Xb 
Local Standard of Care 
 
X 
X 
ICF: Informed Consent Form; IRT: interactive response technology; SAE: serious adverse event   
a. 
All SAEs will be collected and reported as outlined in [Section 5.5.6 Reporting of Serious Adverse Events] 
until subjects meet discontinuation criteria or applicable reimbursement becomes available in the country 
of residence. After subjects reconsent under this protocol version 7.0, SAEs collection will continue until 
30 days after the last dose of study treatment. Subjects who complete treatment with a SAE for which 
relationship to ASP2215 is plausibly related should be followed until the event stabilizes or returns to 
baseline. 
b. 
IRT notification is required when subjects discontinue from study treatment. 
Discontinuation Criteria for Subjects who Reconsent Under This Protocol Version 7.0 
Subjects will continue to receive study treatment with ASP2215 until 1 of the following 
occurs: 
● 
Subject develops an intolerable or unacceptable toxicity 
● 
Subject receives any antileukemic therapy other than the assigned treatment 
● 
Pregnancy 
● 
Subject undergoes HSCT 
● 
Investigator/sub-investigator determines that the continuation of the study treatment will 
be detrimental to the subject. 
● 
Subject declines further study participation (i.e., withdrawal of consent) 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Death 
● 
Sponsor elects to discontinue the study. 
● 
ASP2215 reimbursement becomes available in the country of residence.  
The subject will be considered to have completed the study on their last date of ASP2215 
therapy. No follow-up visits are required after the end of treatment. The subjects who 
complete treatment with an AE or SAE for which the relationship to ASP2215 is plausibly 
related should be followed until the event stabilizes or returns to baseline. 
12.9 
Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).   
Alternate methods cannot be implemented for screening and enrolling/randomizing a 
participant in the study. Screening and randomization procedures have to be performed in 

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compliance to the study protocol. This section only applies to a participant who has been 
randomized in the study and entered in COE part of the study.  
Since the chemotherapy dosing must be given in the investigative site, all the required 
assessment can be completed in investigative site in compliance to the study protocol during 
the dosing period. No alternative methods are applicable for this period. 
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated Schedule of Assessments [Table 1, Table 2, Table 3, Table 4, Table 5 
and Table 6] unless the investigator discusses the need with the Astellas Medical Monitor to 
implement the alternate measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent, which explicitly informs them of the nature of 
and rationale for these changes, and gain their agreement to continue participation in the 
study prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the PI or designee will obtain oral agreement from the 
subject followed by written documentation as soon as is feasible. A separate addendum to the 
study informed consent will be provided to document the participant’s consent of the 
changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
● 
Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible. 
● 
Site facilities have been closed for clinical study conduct. 
● 
Site has been restricted to treating patients with conditions outside of the scope of the 
study. 
● 
Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel. 
● 
Participant(s) have temporarily relocated from the current study site to an alternate study 
site avoid placing a burden on the participant with respect to travel. 

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● 
Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel. 
● 
Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety. 
Adherence to the original protocol as reflected in the Schedule of Assessment [Table 1, 
Table 2, Table 3, Table 4, Table 5 and Table 6] is expected, where plausible, in the case of a 
crisis. The alternate measures as noted in [Table 13, Table 14 and Table 15] below are only 
permissible in the event of a crisis, and after discussing the need with the Astellas Medical 
Monitor to implement the alternate measures.  This is to allow for continuity of receiving 
investigational medicinal product (IMP) and maintaining critical safety and efficacy 
assessments for patients participating in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding time point(s). 
All other assessments should be completed as outlined in [Table 1, Table 2, Table 3, Table 4, 
Table 5 and Table 6]. 
 

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Table 13 
Alternative Schedule of Assessments in Response to a Crisis:  
Schedule of Assessments for ASP2215 Arm and ASP2215 Arm in PK cohort 
Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
TREATMENTS 
ASP2215 Dosing at the Clinicj 
Courier service directly to patient 
X 
X 
X 
 
X 
X 
X 
X 
ASSESSMENTS 
Physical Examinationb 
The exam can be done at a local clinic 
and the results submitted to PI. 
Xa 
X 
X 
 
X 
X 
X 
X 
Vital Signs 
Can be performed at a local clinic per 
SOC and results submitted to PI for 
evaluation 
Xa 
X 
X 
 
X 
X 
X 
X 
ECOG Performance 
ECOG status can be done by phone 
contact at each visit. 
Xa 
 
 
 
X 
X 
X 
X 
12-lead ECGe 
ECG testing can be completed at local 
clinic and the results submitted to PI. 
X 
 
Xm 
Xm 
X 
X 
 
X 
AE/SAE Assessment 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits. Please 
refer to protocol schedule of 
assessments.   
X 
X 
X 
 
X 
X 
X 
X 
Prior and Concomitant Medicationsc 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits.   
Please refer to protocol schedule of 
assessments. 
X 
X 
X 
 
X 
X 
X 
X 
Patient Reported Outcome Toolsk, l 
Since validated scripts for phone 
contacts are not available, data need to 
be entered at the hospital. 
Xa 
 
Xk 
 
Xk 
X 
Xk 
X 
Table continued on next page 

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Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
EQ-5D-5Ll 
Phone Script is available for EQ-5D-
5L, hence can be collected via phone 
script. 
Xa 
 
 
 
 
X 
 
X 
Resource Utilization 
Virtual/Telemedicine Visits allowed 
for non-dosing visits. 
In addition, if any resource utilization 
is done at local facility, that 
information should be requested to 
made available to investigative site. 
Xa 
 
 
 
 
X 
 
X 
LABORATORY TESTS 
Pregnancy Test for Woman of Childbearing 
Potentiald 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
X 
 
 
 
 
X 
 
X 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation)f 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Testn 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
 
 
 
 
 
 
 
Xn 
Bone Marrow Aspiration and/or Biopsy 
Perform BM biopsy in a local facility 
acceptable if results can be made 
available to investigative site 
 
 
 
 
 
Xg 
 
Xg 
SAMPLING 
PK (whole blood samples for plasma PK) 
Astellas Medical Monitor to assess. 
Not allowed at an alternate clinical due 
to special sample handling 
Xh 
 
Xh 
 
Xh 
Xh 
 
Xh 
PGxi 
Not allowed at an alternate clinical due 
to special sample handling 
X 
 
 
 
 
 
 
 
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with incomplete hematologic recovery; CRp: complete remission with 
incomplete platelet recovery; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EDTA: ethylenediaminetetraacetic acid; EQ-5D-5L: EuroQol Group-
5 Dimension-5 Level Instrument; INR: international normalization ratio; PGx: pharmacogenomics; PK: pharmacokinetic; PT: prothrombin time; SAE: serious adverse event 

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a. 
Obtained predose. 
b. 
Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
c. 
Includes medications taken within 28 days prior to cycle 1 day 1. 
d. 
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
e. 
ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 8, cycle 1 day 15 and day 1 of each subsequent cycle. Predose assessments should be taken within 
1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 5 minutes apart per time 
point) and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for final treatment decisions and AE 
reporting. If the mean of the triplicate QTcF is > 500 ms at any time point (by either value on ECG tracing printout or central reading), then triplicate ECGs will be repeated 
(within 2 hours if based on value on ECG tracing printout and as soon as possible if based on central reading). If the repeat ECG confirms a mean of the triplicate QTcF > 500 ms, 
dosing of ASP2215 will be interrupted for up to 14 days. While ASP2215 may be interrupted temporarily based on value on ECG tracing printout, the central reading should be 
used for final treatment decisions. Cardiology consult will be obtained as medically indicated. If QTcF resolves to ≤ 480 ms (grade 1 or less) by central reading within 14 days, 
the subject may resume dosing at the reduced dose. 
f. 
Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard of care. 
g. 
Bone marrow samples are required at cycle 2 day 1 and cycle 3 day 1. For subjects who do not achieve a CRc (CR, CRp or CRi), the bone marrow assessments will be repeated at 
day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), bone marrow sampling will be repeated on 1 month after the date of remission and every 
3 subsequent cycles, or if there is suspicion of relapse in the whole blood. Bone marrow samples are also required at the pre-HSCT visit /end of treatment visit and as clinically 
indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of whole blood should be collected instead. Bone marrow aspirate is required, and 
bone marrow biopsy is preferred. In case of inadequate aspirate, bone marrow biopsy is required. Bone marrow assessment for blasts counts and cell counts and flow cytometry 
will be conducted at local lab.  
h. 
PK samples for ASP2215 will be collected on cycle 1 day 1 predose, cycle 1 day 8 predose, and at cycle 1 day 15 and day 1 predose of each subsequent cycle (within 1 hour 
before drug administration). See [Section 7.6 Analysis of Pharmacokinetics]. 
i. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomics study. Optional pharmacogenomics study is not conducted in China. 
j. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
k. 
Includes Brief Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness 
and mouth sores items. The Brief Fatigue Inventory will be administered at cycle 1 day 1 predose, cycle 1 day 8 (± 1 day), day 15 (± 1 day), cycle 2 day 1 (± 2 days), 
day 15 (± 1 day) and all subsequent cycles day 1 (± 2 days). Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer 
Therapy-Leukemia and dizziness and mouth sores items will be administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days). 
l. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
m. 
A cycle 1 day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on cycle 
1 day 9 if the mean QTcF from cycle 1 day 1 to cycle 1 day 8 has increased > 30 ms with no other known etiology, based on the central read ECG. On cycle 1 day 8, it is 
recommended that the ECG is taken as early as possible in the morning and transmitted immediately. In addition, it is recommended that the cycle 1 day 9 visit is scheduled later 
in the day in order to allow for receipt and assessment of the cycle 1 day 8 central read ECG.  This also allows for a subject to be contacted if the cycle 1 day 9 ECG is no longer 
required. If the cycle 1 day 9 ECG is still required, the result of the central read ECG will be received on cycle 1 day 10, in which the investigator should assess if the ASP2215 
dose modification should occur as per the dose interruption or reduction guideline in [Section 5.1.2 Interruption, Reduction or Escalation in Dose of the Study Drug]. 
n. 
Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.) 

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Table 14 
Alternative Schedule of Assessments in Response to a Crisis:  
Schedule of Assessments for Chemotherapy Arm 
Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
TREATMENTS 
LoDAC Dosing  
LoDAC dosing must be given in the 
investigative site and all the required 
assessment can be completed in 
investigative site during the dosing 
period.  No alternative methods are 
applicable for this period. 
See Footnotei 
MEC or FLAG Dosing 
MEC or FLAG dosing must be given 
in the investigative site and all the 
required assessment can be completed 
in investigative site during the dosing 
period.  No alternative methods are 
applicable for this period. 
See Footnotej 
 
ASSESSMENTS 
Physical Examinationb 
The exam can be done at a local clinic 
and the results submitted to PI. 
Xa 
X 
X 
X 
X 
X 
X 
Vital Signs 
Can be performed at a local clinic per 
SOC and results submitted to PI for 
evaluation 
Xa 
X 
X 
X 
X 
X 
X 
ECOG Performance 
ECOG status can be done by phone 
contact at each visit. 
Xa 
 
 
X 
X 
X 
X 
Table continued on next page 

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Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
12-lead ECGe 
ECG testing can be completed at local 
clinic and the results submitted to PI. 
X 
 
 
X 
X 
 
X 
AE/SAE Assessment 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits. Please 
refer to protocol schedule of 
assessments.   
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medicationsc 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits.   
Please refer to protocol schedule of 
assessments. 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcome Toolsk,l  
Since validated scripts for phone 
contacts are not available, data need to 
be entered at the hospital. 
Xa 
 
Xk 
Xk 
X 
Xk 
X 
EQ-5D-5Ll 
Phone Script is available for EQ-5D-
5L, hence can be collected via phone 
script. 
Xa 
 
 
 
X 
 
X 
Resource Utilization 
Virtual/Telemedicine Visits allowed 
for non-dosing visits. 
In addition, if any resource utilization 
is done at local facility, that 
information should be requested to 
made available to investigative site. 
Xa 
 
 
 
X 
 
X 
Table continued on next page 

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Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
LABORATORY TESTS 
Pregnancy Test for Woman of Childbearing 
Potentiald 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
X 
 
 
 
X 
 
X 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation)f 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
Xa 
Xa 
X 
X 
Xa 
X 
Xa 
Thyroid Function Testm 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
 
 
 
 
 
 
Xm 
Bone Marrow Aspiration and/or Biopsy 
Perform BM biopsy in a local facility 
acceptable if results can be made 
available to investigative site 
 
 
 
Xg 
Xg 
 
Xg 
SAMPLING 
PGxh 
Not allowed at an alternate clinical due 
to special sample handling 
X 
 
 
 
 
 
 
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with incomplete hematologic recovery; CRp: complete remission with 
incomplete platelet recovery; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EDTA: ethylenediaminetetraacetic acid; EQ-5D-5L: 
EuroQol Group-5 Dimension-5 Level Instrument; FLAG: fludarabine, cytarabine and granulocyte colony-stimulating factor; INR: international normalization ratio; LoDAC: low-dose 
cytarabine; MEC: mitoxantrone, etoposide and intermediate-dose cytarabine; PGx: pharmacogenomics; PT: prothrombin time; SAE: serious adverse event 
a. 
Obtained predose. 
b. 
Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
c. 
Includes medications taken within 28 days prior to cycle 1 day 1. 
d. 
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
Footnotes continued on next page 

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e. 
ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 15 and day 1 each subsequent cycle. Predose assessments should be taken within 1 hour before drug 
administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and transmitted 
electronically for central reading. See [Section 7.5.5 Electrocardiograms]. 
f. 
Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard of care. 
g. 
For MEC and FLAG, bone marrow samples are required at cycle 2 day1. Also, an additional bone marrow sample is required at cycle 1 day 15 or later, per institutional 
guidelines, to assess the need for a second cycle. For LoDAC, bone marrow samples are required at cycle 2 day 1 and at cycle 3 day1. For subjects who do not achieve a CRc 
(CR, CRp or CRi), the bone marrow assessments will be repeated at day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), bone marrow 
sampling will be repeated at 1 month after the date of remission and at every 3 subsequent cycles or if there is suspicion of relapse in the whole blood. Bone marrow samples are 
also required at the end of treatment visit and as clinically indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of whole blood should be 
collected instead. Bone marrow aspirate is required, and bone marrow biopsy is preferred. In case of inadequate aspirate, bone marrow biopsy is required. Bone marrow 
assessment for blasts counts and cell counts and flow cytometry will be conducted at local lab.  
h. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomics study. Optional pharmacogenomics study is not conducted in China. 
i. 
LoDAC dosing may continue past cycle 2. 
j. 
Additional clinic visits are allowed per institutional guidelines for subjects receiving MEC (days 1 through 5) or FLAG (days 1 through 6). MEC and FLAG are administered for 
up to 2 cycles depending on response and safety assessments as described in [Section 5.1 Dosing and Administration of Study Drugs and Other Medications]. 
k. 
Includes Brief Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer Therapy-Leukemia and dizziness 
and mouth sores items. The Brief Fatigue Inventory will be administered at cycle 1 day 1 predose, cycle 1 day 8 (± 1 day), day 15 (± 1 day), cycle 2 day 1 (± 2 days), 
day 15 (± 1 day) and all subsequent cycles day 1 (± 2 days). Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms, Functional Assessment of Cancer 
Therapy-Leukemia and dizziness and mouth sores items will be administered at cycle 1 day 1 predose, cycle 2 day 1 (± 2 days) and all subsequent cycles day 1 (± 2 days). 
l. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
m. 
For subjects receiving LoDAC, thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
 

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Table 15 
Alternative Schedule of Assessments in Response to a Crisis:  
Schedule of Assessments for Crossover Extension 
Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
TREATMENTS 
ASP2215 Dosing at the Clinich 
Courier service directly to patient 
X 
X 
X 
 
X 
X 
X 
X 
ASSESSMENTS 
Physical Examinationb 
The exam can be done at a local clinic 
and the results submitted to PI. 
Xa 
X 
X 
 
X 
X 
X 
X 
Vital Signs 
Can be performed at a local clinic per 
SOC and results submitted to PI for 
evaluation 
Xa 
X 
X 
 
X 
X 
X 
X 
ECOG Performance 
ECOG status can be done by phone 
contact at each visit. 
Xa 
 
 
 
X 
X 
X 
X 
12-lead ECGe 
ECG testing can be completed at local 
clinic and the results submitted to PI. 
Xg 
 
Xi 
Xi 
X 
X 
 
X 
AE/SAE Assessment 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits. Please 
refer to protocol schedule of 
assessments.   
X 
X 
X 
 
X 
X 
X 
X 
Prior and Concomitant Medicationsc 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits.   
Please refer to protocol schedule of 
assessments. 
X 
X 
X 
 
X 
X 
X 
X 
Table continued on next page 

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Critical Assessments 
Alternate Approach(es) 
Critical Timepoints 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Cycle Day 
 
Day 1 
Day 4 
± 1 
Day 8 
± 1 
Day 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
LABORATORY TESTS 
Pregnancy Test for Woman of Childbearing 
Potentiald 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
X 
 
 
 
 
X 
 
X 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation, urinalysis)f 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
Xa,g 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Testj 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
 
 
 
 
 
 
 
X 
AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; IRT: interactive response technology; SAE: serious adverse event 
a. Obtained predose. 
b. Weight measurement should be performed at day 1 of each cycle. 
c. Includes medications taken within 28 days prior to C1D1. If EoT was performed within 28 days prior to C1D1, only includes medication after EoT of salvage chemotherapy arm 
and prior to C1D1. 
d. Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
72 hours prior to the start of study treatment. 
e. ECG assessment will be evaluated at predose of cycle 1 day 1, cycle 1 day 8, cycle 1 day 15 and day 1 of each subsequent cycle. Predose assessments should be taken within 
1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs 10 minutes resting prior to first ECG and at least 5 minutes apart per time 
point) and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for final treatment decisions and AE 
reporting. If the mean of the triplicate QTcF is > 500 ms at any time point (by either value on ECG tracing printout or central reading), then triplicate ECGs will be repeated 
(within 2 hours if based on value on ECG tracing printout and as soon as possible if based on central reading). If the repeat ECG confirms a mean of the triplicate QTcF > 500 ms, 
dosing of ASP2215 will be interrupted for up to 14 days. While ASP2215 may be interrupted temporarily based on value on ECG tracing printout, the central reading should be 
used for final treatment decisions. Cardiology consult will be obtained as medically indicated. If QTcF resolves to ≤ 480 ms (grade 1 or less) by central reading within 14 days, 
the subject may resume dosing at the reduced dose. 
f. 
Uric acid will be tested on days 1, 4, 8, and 15 in cycle 1. Additional laboratory tests should be performed according to institutional standard of care. 
g. Subjects may be enrolled from local labs only. However, samples must also be submitted for central lab.  
h. ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 

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i. 
A cycle 1 day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on cycle 
1 day 9 if the mean QTcF from cycle 1 day 1 to cycle 1 day 8 has increased > 30 ms with no other known etiology, based on the central read ECG. On cycle 1 day 8, it is 
recommended that the ECG is taken as early as possible in the morning and transmitted immediately. In addition, it is recommended that the cycle 1 day 9 visit is scheduled later 
in the day in order to allow for receipt and assessment of the cycle 1 day 8 central read ECG.  This also allows for a subject to be contacted if the cycle 1 day 9 ECG is no longer 
required. If the cycle 1 day 9 ECG is still required, the result of the central read ECG will be received on cycle 1 day 10, in which the investigator should assess if the ASP2215 
dose modification should occur as per the dose interruption or reduction guideline in [Section 5.1.2 Interruption, Reduction or Escalation in Dose of the Study Drug]. 
j. 
Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
 

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IMP SUPPLY  
If any of the conditions outlined above in the Participants Procedures Assessment are met, 
one or all of the following mitigating strategies will be employed, as needed, to ensure 
continuity of IMP supply to the participants:   
● 
Increase stock of IMP on site to reduce number of shipments required, if site 
space will allow.  
● 
Direct-to-Participant (DTP) shipments of IMP (only for ASP2215) from the site 
to the participant’s home.  
DATA COLLECTION REQUIREMENTS  
Additional data may be collected in order to indicate how participation in the study may have 
been affected by a crisis and to accommodate data collection resulting from alternate 
measures implemented to manage the conduct of the study and participant safety.   
● 
Critical assessments for safety and efficacy based on study endpoints to be 
identified as missing or altered (performed virtually, at alternative locations, out 
of window, or other modifications) due to the crisis. 
 
 

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13 
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