Conditions: Leukemia, Acute Myeloid (AML)
Keywords: ASP2215 Relapsed Acute Myeloid Leukemia FLT3 Mutation gilteritinib Refractory Acute Myeloid Leukemia Acute Myeloid Leukemia (AML) XOSPATA®
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 371
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who were refractory to or had relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and determined the efficacy of ASP2215 therapy as assessed by the rate of complete remission and complete remission with partial hematological recovery (CR/CRh) in these participants. This study also determined the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Detailed description:
Participants considered an adult according to local regulations at the time of signing informed consent participated in this study. Participants were randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen was pre-selected for each participant; options included low-dose cytarabine (LoDAC), azacitidine, mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC), or fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) with idarubicin (FLAG-IDA). The randomization was stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles. After treatment discontinuation, participants had a pre-hematopoietic stem cell transplant (HSCT)/end-of-treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-up for safety, in which a telephone contact with the participant was sufficient unless any assessment had to be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up was done every 3 months up to 3 years from the participant's end-of-treatment visit.

Arms:
arm 1: Participants received 120 mg dose (3 tablets of 40 mg) orally once a day in continuous 28-day cycles, at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants met one of the treatment discontinuation criteria. arm 2: Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m\^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m\^2 daily by IV for 5 days, etoposide 100 mg/m\^2 daily by IV for 5 days and cytarabine 1000 mg/m\^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m\^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m\^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m\^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m\^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.

Interventions: intervention 1: gilteritinib intervention 2: LoDAC (Low Dose Cytarabine) intervention 3: Azacitidine intervention 4: MEC (Mitoxantrone, Etoposide, Cytarabine) intervention 5: FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)
Intervention descriptions: intervention 1: tablet, oral intervention 2: subcutaneous (SC) or intravenous (IV) injection intervention 3: SC or IV injection intervention 4: IV injection intervention 5: SC (G-CSF) and IV (Fludarabine, Cytarabine, Idarubicin) injection

Protocol document:
Prot_002.pdf: 
Sponsor: APGD 
ISN/Protocol 2215-CL-0301 
EudraCT 2015-000140-42  
 
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07 Dec 2020 
Astellas 
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Version 9.2 Incorporating Nonsubstantial Amendment 4 
A 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-0301 
Version 9.2 
Incorporating Nonsubstantial Amendment 4 [See Attachment 1] 
07 December 2020 
IND 117548 
EudraCT 2015-000140-42 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
Protocol History:  
Version 1.0 [24Mar2015] 
Version 2.0 Incorporating Substantial Amendment 1 [22Jun2015] 
Version 2.1 [JP] Incorporating Country-specific Non-Substantial Amendment 1 [06Aug2015] 
Version 3.0 Incorporating Substantial Amendment 2 [13Aug2015] 
Version 3.0 [JP] Incorporating Substantial Amendment 2 [13Aug2015] 
Version 4.0 [KR] Incorporating Country-specific Substantial Amendment 3 [08Oct2015] 
Version 5.0 Incorporating Substantial Amendment 4 [09Dec2015] 
Version 5.0 [KR] Incorporating Substantial Amendment 4 [09Dec2015] 
Version 5.0 [JP] Incorporating Substantial Amendment 4 [09Dec2015] 
Version 6.0 [KR] Incorporating Substantial Amendment 5 [31Mar2016] 
Version 7.0 [FR] Incorporating Country-specific Substantial Amendment 6 [22Jun2016] 
Version 8.0 Incorporating Substantial Amendment 7 [08Aug2016] 
Version 8.1 Incorporating Non-substantial Amendment 2 [27Sep2016] 
Version 9.0 Incorporating Substantial Amendment 8 [20Sep2017] 
Version 9.0 [KR] Incorporating Country-specific Substantial Amendment 8 [20Sep2017] 
Version 9.0 [FR] Incorporating Country-specific Substantial Amendment 8 [20Sep2017] 
Version 9.1 [JP] Incorporating Country-specific Non-Substantial Amendment 3 [16 May 2018] 
 
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: APGD 
ISN/Protocol 2215-CL-0301 
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Table of Contents 
I. 
SIGNATURES ······················································································ 8 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 12 
IV. 
SYNOPSIS ·························································································· 16 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 30 
1 
INTRODUCTION ················································································· 39 
1.1 
Background ···················································································· 39 
1.2 
Nonclinical and Clinical Data ······························································· 40 
1.2.1 
Nonclinical Data ········································································· 40 
1.2.2 
Clinical Data ············································································· 42 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 43 
1.3.1 
ASP2215·················································································· 43 
1.3.2 
Comparative Chemotherapy Regimens ··············································· 46 
1.4 
Risk-Benefit Assessment ····································································· 46 
2 
STUDY OBJECTIVES, DESIGN AND ENDPOINTS ····································· 47 
2.1 
Study Objectives ·············································································· 47 
2.1.1 
Primary Objectives ······································································ 47 
2.1.2 
Secondary Objectives ··································································· 47 
2.1.3 
Exploratory Objectives ································································· 47 
2.2 
Study Design and Dose Rationale ··························································· 48 
2.2.1 
Study Design ············································································· 48 
2.2.2 
Dose Rationale ··········································································· 50 
2.3 
Endpoints ······················································································· 50 
2.3.1 
Co-Primary Endpoints ·································································· 50 
2.3.2 
Secondary Endpoints ···································································· 50 
2.3.3 
Exploratory Endpoints ·································································· 51 
2.3.4 
Safety Endpoints ········································································· 51 
2.3.5 
Pharmacokinetics ········································································ 51 
3 
STUDY POPULATION ·········································································· 51 
3.1 
Selection of Study Population ······························································· 51 
3.2 
Inclusion Criteria ·············································································· 51 
3.3 
Exclusion Criteria ············································································· 53 


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4 
TREATMENT(S) ·················································································· 55 
4.1 
Identification of Investigational Products ·················································· 55 
4.1.1 
ASP2215·················································································· 55 
4.1.2 
Comparative Drug(s) ···································································· 55 
4.2 
Packaging and Labeling ······································································ 56 
4.3 
Study Drug Handling ········································································· 56 
4.4 
Blinding ························································································ 57 
4.5 
Assignment and Allocation ·································································· 58 
5 
TREATMENTS AND EVALUATION ························································ 58 
5.1 
Dosing and Administration of Study Drugs and Other Medications ···················· 58 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 58 
5.1.2 
Interruption, Reduction or Escalation in Dose of the Study Drug ················· 59 
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ·················································································· 61 
5.1.4 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation ······ 62 
5.1.5 
Treatment Compliance ·································································· 62 
5.2 
Demographics and Baseline Characteristics ··············································· 63 
5.2.1 
Demographics ············································································ 63 
5.2.2 
Medical History ·········································································· 63 
5.2.3 
Diagnosis of the Target Disease, Severity and Duration of Disease ·············· 63 
5.2.4 
FLT3 Mutation Status ··································································· 63 
5.2.5 
Performance Status ······································································ 64 
5.3 
Efficacy Assessment ·········································································· 64 
5.3.1 
Response Definitions ··································································· 64 
5.3.2 
Survival Time, Duration and Other Efficacy Endpoints ···························· 66 
5.3.3 
Bone Marrow Aspiration and/or Biopsy ·············································· 67 
5.3.4 
Survival Status and Subsequent Antileukemic Treatments and Their 
Outcomes ················································································· 67 
5.4 
Safety Assessment ············································································ 68 
5.4.1 
Vital Signs ················································································ 68 
5.4.2 
Adverse Events ·········································································· 68 
5.4.3 
Laboratory Assessments ································································ 69 
5.4.4 
Physical Examination ··································································· 69 
5.4.5 
Electrocardiogram ······································································· 70 


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5.4.6 
Chest X-ray or Computed Tomography Scan ········································ 71 
5.4.7 
Multigated Acquisition Scan or Echocardiogram ··································· 71 
5.4.8 
Ophthalmologic Exam ·································································· 71 
5.5 
Adverse Events and Other Safety Aspects ················································· 71 
5.5.1 
Definition of Adverse Events ·························································· 71 
5.5.2 
Definition of Serious Adverse Events················································· 72 
5.5.3 
Criteria for Causal Relationship to the Study Drug ································· 73 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 73 
5.5.5 
Reporting of Serious Adverse Events ················································· 74 
5.5.6 
Follow-up of Adverse Events ·························································· 75 
5.5.7 
Monitoring of Common Serious Adverse Events ··································· 76 
5.5.8 
Procedure in Case of Pregnancy ······················································· 76 
5.5.9 
Emergency Procedures and Management of Overdose ····························· 77 
5.5.10 
Supply of New Information Affecting the Conduct of the Study ·················· 77 
5.5.11 
Deviations from the Protocol and Other Actions Taken to Avoid 
Life-threatening Risks to Subjects (Japan Only) ···································· 77 
5.6 
Test Drug Concentration ····································································· 78 
5.6.1 
Pharmacokinetics ········································································ 78 
5.7 
Other Measurements, Assessments or Methods ··········································· 78 
5.7.1 
Patient Reported Outcome Measures ················································· 78 
5.7.2 
Resource Utilization ···································································· 79 
5.7.3 
Exploratory Biomarker Analysis ······················································ 79 
5.7.4 
Whole Blood and Buccal Sample for Future Pharmacogenomics Analysis 
(Retrospective Pharmacogenomics Analysis) (Optional) ··························· 80 
5.8 
Total Amount of Blood ······································································· 80 
6 
DISCONTINUATION ············································································ 81 
6.1 
Discontinuation of Individual Subject(s) ··················································· 81 
6.1.1 
Discontinuation Criteria from Treatment for Individual Subjects ················· 81 
6.1.2 
Discontinuation Criteria from the Posttreatment Period for Individual 
Subjects ··················································································· 82 
6.2 
Discontinuation of the Site ··································································· 82 
6.3 
Discontinuation of the Study································································· 82 
7 
STATISTICAL METHODOLOGY ··························································· 82 
7.1 
Sample Size ···················································································· 83 
7.2 
Analysis Sets ··················································································· 84 


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7.2.1 
Intention To Treatment Set ····························································· 85 
7.2.2 
Response Analysis Set ·································································· 85 
7.2.3 
Full Analysis Set ········································································ 85 
7.2.4 
Per Protocol Set ·········································································· 85 
7.2.5 
Modified Response Analysis Set ······················································ 85 
7.2.6 
Safety Analysis Set ······································································ 85 
7.2.7 
Pharmacokinetic Analysis Set ························································· 85 
7.3 
Demographics and Other Baseline Characteristics ········································ 86 
7.3.1 
Demographics ············································································ 86 
7.3.2 
Medical History ·········································································· 86 
7.3.3 
Disease History ·········································································· 86 
7.3.4 
Previous and Concomitant Medications ·············································· 86 
7.3.5 
Subject Disposition ······································································ 86 
7.3.6 
Drug Exposure ··········································································· 86 
7.4 
Analysis of Efficacy ·········································································· 86 
7.4.1 
Analysis of Co-Primary Endpoints ···················································· 87 
7.4.2 
Analysis of Secondary Endpoints ····················································· 88 
7.4.3 
Analysis of Exploratory Endpoints ···················································· 89 
7.4.4 
Subgroup Analysis ······································································ 89 
7.5 
Analysis of Safety ············································································· 89 
7.5.1 
Adverse Events ·········································································· 90 
7.5.2 
Laboratory Assessments ································································ 90 
7.5.3 
Vital Signs ················································································ 90 
7.5.4 
Physical Examination ··································································· 90 
7.5.5 
Electrocardiograms ······································································ 90 
7.5.6 
Ophthalmologic Assessment ··························································· 91 
7.5.7 
Eastern Cooperative Oncology Group Performance Scores ························ 91 
7.6 
Analysis of Pharmacokinetics ······························································· 91 
7.7 
Protocol Deviations ··········································································· 91 
7.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 91 
7.9 
Handling of Missing Data, Outliers, Visit Windows and Other Information ·········· 93 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 94 
8.1 
Procedure for Clinical Study Quality Control ············································· 94 
8.1.1 
Data Collection ·········································································· 94 


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8.1.2 
Specification of Source Documents ··················································· 94 
8.1.3 
Clinical Study Monitoring ······························································ 95 
8.1.4 
Direct Access to Source Data/Documents ············································ 95 
8.1.5 
Data Management ······································································· 95 
8.1.6 
Protocol Deviations ····································································· 95 
8.1.7 
End of Trial in All Participating Countries ··········································· 96 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 96 
8.2.1 
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities ················································································ 96 
8.2.2 
Ethical Conduct of the Study ··························································· 97 
8.2.3 
Informed Consent of Subjects ························································· 97 
8.2.4 
Subject Confidentiality ································································· 98 
8.3 
Administrative Matters ······································································· 98 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 98 
8.3.2 
Documents and Records Related to the Clinical Study ····························· 99 
8.3.3 
Protocol Amendment and/or Revision ·············································· 101 
8.3.4 
Insurance of Subjects and Others ···················································· 101 
8.3.5 
Signatory Investigator for Clinical Study Report ·································· 102 
9 
QUALITY ASSURANCE ······································································ 102 
10 
STUDY ORGANIZATION ···································································· 102 
10.1 
Independent Data Monitoring Committee ················································ 102 
10.2 
Other Study Organization ·································································· 102 
11 
REFERENCES ·················································································· 103 
12 
APPENDICES ··················································································· 106 
12.1 
List of Excluded and Cautionary Concomitant Medications ··························· 106 
12.2 
Liver Safety Monitoring and Assessment ················································ 111 
12.3 
Laboratory Tests ············································································ 114 
12.4 
Common Serious Adverse Events ························································· 116 
12.5 
Retrospective PGx Sub-study (Optional) ················································· 118 
12.6 
Definitions of Line of Therapy and Tools to Determine Study Eligibility ··········· 120 
12.7 
Clinical Study Continuity ·································································· 121 
13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 4 ·························· 127 
12.7 
Clinical Study Continuity ·································································· 135 


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14 
SPONSOR’S SIGNATURES ·································································· 141 
 
List of Tables 
Table 1 
Schedule of Assessments for ASP2215 Arm ·············································· 31 
Table 2 
Schedule of Assessments for Chemotherapy Arm ········································ 34 
Table 3 
Posttreatment Schedule of Assessments ···················································· 37 
Table 4 
Test Drug (ASP2215 Tablets 40 mg) ······················································· 55 
Table 5 
Comparator Drug Products Supplied by the Sponsor ····································· 56 
Table 6 
Guidelines for ASP2215 Dose Interruption or Reduction Event ························ 60 
Table 7 
Guidelines for ASP2215 Dose Escalation Event ·········································· 61 
Table 8 
ECOG Performance Status ··································································· 64 
Table 9 
Summary of Timing, Sample Size and Decision Guidance at the Planned 
Analyses ························································································ 93 
Table 10 
Schedule of Assessments for ASP2215 Arm ············································ 123 
 


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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 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the 
end of this document.   


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2. INVESTIGATOR’S SIGNATURE 
A 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-0301 
Version 9.2 / Incorporating Nonsubstantial Amendment 4 
07 Dec 2020 
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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Specific to Japan: 
Contact Information for the Sponsor 
Corporate Name: Astellas Pharma Inc. 
Location: 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
Phone No.: 03-3244-1097 
Fax: 03-3243-5737 
Sponsor’s Personnel: 
 
Contact Numbers during Nonbusiness Hours and for Emergency:  
Phone No.: 
 
 
 
Contact Information for the Contract Research Organization (CRO) 
Corporate name: PPD-SNBL K.K. 
Location: St Luke’s Tower 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo 
Phone No.:  06-4560-6826   
Fax: 03-5565-3312 
CRO’s personnel: 
 
Contact Numbers during Nonbusiness Hours and for Emergency:  
Phone No.:  
 
PPD
PPD
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 corrected relative to baseline 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
APGD 
Astellas Pharma Global Development, Inc. 
AST 
Aspartate aminotransferase 
AUST 
Astellas United States Technologies 
AXL 
AXL tyrosine kinase 
BCRP 
Breast cancer resistance protein 
BFI 
Brief Fatigue Inventory 
Ca2+ 
Calcium 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete remission 
CR/CRh 
Complete remission and complete remission with partial hematological recovery 
CRc 
Composite complete remission 
CRF 
Case report form 
CRh 
Complete remission with partial hematologic recovery 
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 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFS 
Event-free survival 
EQ-5D-5L 
EuroQol Group-5 Dimension-5 Level Instrument 


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Abbreviations 
Description of Abbreviations 
FACIT-Dys-SF 
Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms 
FACT-Leu 
Functional Assessment of Cancer Therapy-Leukemia 
FAS 
Full Analysis Set 
FLAG-IDA 
Fludarabine, cytarabine and granulocyte colony-stimulating factor with idarubicin 
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 Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
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 
LA-CRF 
Liver Abnormality-Case Report Form 
LFS 
Leukemia-free survival 
LFT 
Liver function tests 
LLN 
Lower limit of normal 
LoDAC 
Low-dose cytarabine 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LVEF 
Left ventricular ejection fraction 
MATE1 
Multidrug and toxin extrusion protein 1 
MDS 
Myelodysplastic syndrome 
MEC 
Mitoxantrone, etoposide and intermediate-dose cytarabine 
mRAS 
Modified Response Analysis Set 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NDA 
New Drug Application 


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Abbreviations 
Description of Abbreviations 
NE 
Not evaluable 
NOAEL 
No observed adverse effect level 
NR 
No response 
NYHA 
New York Heart Association 
OATP 
Organic anion transporting polypeptide 
OS 
Overall survival 
PD 
Protocol deviation 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenomics 
PH 
Proportional hazards 
PIA 
Plasma inhibitory assay 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic Analysis Set 
PPS 
Per Protocol Set 
PR 
Partial remission 
PRES 
Posterior reversible encephalopathy syndrome 
PRO 
Patient reported outcome 
PT 
Preferred term 
QTc 
Corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RAS 
Response analysis set 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TK 
Tyrosine kinase 
TKD 
Tyrosine kinase domain 
TLFs 
Tables, listings and figures 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
VOD 
Veno-occlusive disease 
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, pharmacogenomics). 
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. 
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. 
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. 
Screening 
A process of active consideration of potential subjects for enrollment in a trial. 
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. 
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: 
07 December 2020/Version 9.2 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
Protocol Number: 
2215-CL-0301 
Name of Study Drug:  
ASP2215 
Phase of Development:  
Phase 3 
Specific to Japan: 
Phase of Development:  
Phase 3 
In case that ASP2215 is approved for marketing with the indication of relapsed or refractory acute 
myeloid leukemia with FLT3 mutation, the study will continue as “Phase 4 post-marketing study” in 
accordance with Good Post-marketing Study Practice after the next day of marketing authorization. In 
this case, “Study” in the protocol is read as “Post-marketing study.” 
Title of Study: 
A 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 August 2015 to December 2021 (including long-term follow-up period) 
Study Objective(s): 
The primary objectives are 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. 
• 
Determine the efficacy of ASP2215 therapy as assessed by the rate of complete remission and 
complete remission with partial hematological recovery (CR/CRh) in subjects with FLT3 mutated 
AML who are refractory to or have relapsed after first-line AML therapy. 
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 
• 
complete remission with partial hematologic recovery (CRh) rate 
• 
composite complete remission (CRc) rate 
• 
transfusion conversion rate; transfusion maintenance rate 
• 
transplantation rate 
• 
patient reported fatigue (Brief Fatigue Inventory [BFI]) 
• 
adverse events (AEs), safety labs, vital signs, ophthalmologic exams, electrocardiograms (ECGs) 
and Eastern Cooperative Oncology Group (ECOG) performance scores 
• 
Evaluation of ASP2215 (and metabolites as appropriate) plasma concentration and population 
pharmacokinetics 


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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 
o mechanisms of acquired resistance 
• 
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 140 centers  
North America, Europe, Asia and rest of the world 
Study Population: 
FLT3-mutated subjects with relapsed or refractory AML after first-line therapy. 
Number of Subjects to be Enrolled/Randomized:  
369 subjects will be randomized 
Study Design Overview:  
This is a 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 sixty nine subjects will be randomized in a 2:1 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 low-dose cytarabine (LoDAC), azacitidine, mitoxantrone, etoposide and 
intermediate-dose cytarabine (MEC) or fludarabine, cytarabine and granulocyte colony-stimulating 
factor with idarubicin (FLAG-IDA). 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 of the 
protocol. 
For subjects taking ASP2215, LoDAC, or azacitidine, treatment should continue until the subject 
meets a treatment discontinuation criterion. 
Subjects receiving MEC or FLAG-IDA 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 marrow cellularity is between 5% and 20%, the investigator should make the 
decision whether a subject should receive another treatment cycle or be observed for recovery. If bone 
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  


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investigator’s discretion. Subject 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 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 the 
OS endpoint. 
After treatment discontinuation, subjects will have a pre-HSCT/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 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 as follows: every 3 months for up to 3 years from 
the subject’s end of treatment visit.  
Two interim analyses by an Independent Data Monitoring Committee (IDMC) will be conducted. The 
first interim analysis is planned when approximately 141 subjects are randomized into the ASP2215 
arm and at least 112 days (4 treatment cycles) post first dose or randomization (for subjects who 
received no study drug). The first interim analysis will be performed to evaluate the efficacy endpoint 
of CR/CRh rate and the study conduct will not be impacted by the result of the CR/CRh rate.  
The second interim analysis will be performed when approximately 50% of the planned total number 
of deaths (death events = 129 of planned 258 death events) by any cause have occurred. . The second 
interim 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 second interim analysis demonstrates a more favorable outcome for ASP2215 based on OS, 
enrollment to the study may be stopped. 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 the assigned study treatment if one or more of the following 
conditions have been met: 
• 
until the subject has met a treatment discontinuation criterion as outlined in Section 6  
• 
after ≥ 3 years of study drug treatment have been completed for all subjects*  
*At that point, subject(s) can be transitioned to commercial supply once ASP2215 achieves marketing 
authorization, commercial availability and applicable reimbursement in the country of residence. Once 
a subject(s) transition to commercial supply, the subject(s) will be discontinued from the study. 


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Inclusion/Exclusion Criteria: 
Inclusion: 
Subject is eligible for the study if all of the following apply: 
1. 
Institutional Review Board-/Independent Ethics Committee-approved written Informed Consent 
and privacy language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act Authorization for United States sites) 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 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) 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 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. 
9. 
Subject is suitable for oral administration of study drug. 
10. Female subject must either: 
• Be of non-childbearing potential: 
o Postmenopausal (defined as at least 1 year without any menses) prior to screening, or 
o Documented as surgically sterile (at least 1 month prior to screening) 
• Or, if of childbearing potential, 


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o Agree not to try to become pregnant during the study and for 180 days after the final 
study drug administration 
o And have a negative urine pregnancy test at screening 
o 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 180 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 
180 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. 
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.  


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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 that is ≥ 45%. 
12. Subjects with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening 
based on central reading.  
13. Subjects with Long QT Syndrome at Screening. 
14. Subjects 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 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. 
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. 
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 salvage chemotherapy 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.  


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Azacitidine [Itzykson et al, 2015] 
• 
75 mg/m2 azacitidine will be administered daily by SC or IV injection for 7 days.  Follow 
Institution’s guidelines if dose reduction is needed after cycle 1. 
MEC Induction Chemotherapy [Levis et al, 2011] 
• 
Mitoxantrone 8 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-IDA Induction Chemotherapy [Parker et al, 1997; Paul et al, 2014] 
• 
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). 
• 
Idarubicin 10 mg/m2 per day will be administered by IV for 3 days (days 2 through 4). 
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 interventional study while on treatment is prohibited. 
Duration of Treatment:  
For subjects taking ASP2215, LoDAC or azacitidine, treatment should continue until the subject 
meets a treatment discontinuation criterion. 
Subjects receiving MEC or FLAG-IDA 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 marrow cellularity is between 5% and 20%, the investigator should make the 
decision whether a subject should receive another treatment cycle or be observed for recovery. If bone 
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 if one or more of the following 
criteria have been met:  
• 
until the subject has met a treatment discontinuation criterion as outlined in Section 6 and 
below 
• 
after ≥ 3 years of study drug treatment have been completed for all subjects*  
*At that point, subject(s) can be transitioned to commercial supply once ASP2215 achieves marketing 
authorization, commercial availability and applicable reimbursement in the country of residence. Once 
a subject(s) transitions to commercial supply, the subject(s) will be discontinued from the study. 
 
Discontinuation 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-IDA and has NR or progressive disease following cycle 1. 
• Subject is receiving LoDAC, azacitidine 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.  
The subject will be discontinued from the posttreatment 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. 
• Death. 


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Endpoints for Evaluation: 
Co-Primary Efficacy Endpoints: 
• OS 
• CR/CRh rate 
Key Secondary Efficacy Endpoints: 
• EFS 
• CR rate 
Secondary Efficacy Endpoints: 
• LFS 
• Duration of remission 
• CRh rate 
• CRc (CR + CRi + CRp) rate 
• Transfusion conversion rate; transfusion maintenance rate 
• Transplantation rate  
• BFI 
Exploratory Endpoints: 
• PGx 
• FLT3 gene mutation status 
o mutation types and frequency 
o relationship to efficacy and safety 
o mechanisms of acquired resistance 
• 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 
• Ophthalmologic assessments 
• ECGs 
• ECOG performance scores 
Pharmacokinetics 
• ASP2215 (and metabolites as appropriate) concentration in blood 


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Statistical Methods: 
Sample Size Justification: 
This is a group sequential design based co-primary endpoint of OS using the O’Brien-Fleming 
boundaries (non-binding) as implemented by Lan-DeMets alpha/beta spending method (East®).   
The overall 0.025 one-sided type I error rate is allocated by 0.0005 and 0.0245 (0.001 and 0.049 for 
two-sided type I error rate) for the two co-primary efficacy endpoints of CR/CRh and OS, 
respectively. The type I error (alpha) in the first interim analysis will not be recycled in the second 
interim analysis and final analysis. 
The first interim analysis is planned when approximately 141 subjects are randomized into 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for 
subjects who received no study drug). The second interim analysis is planned when 
approximately 129 death events have occurred and the final analysis is planned when 
approximately 258 death events have occurred. After the completion of the final (primary) analysis 
when approximately 258 death events have occurred, additional data summary for subjects is planned 
when ≥ 3 years of study drug treatment have been completed.  
OS:  
Approximately 369 subjects (the planned sample size with 10% dropout rate) will be randomized in a 
2:1 ratio to receive ASP2215 or salvage chemotherapy (246 subjects in the ASP2215 treatment arm 
and 123 subjects in the salvage chemotherapy arm). The planned 258 death events will provide about 
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 1-sided 0.0245 significance level. 
CR/CRh rate:  
The first interim analysis will be conducted only to evaluate the co-primary endpoint of CR/CRh in 
ASP2215 arm only. One hundred and forty-one subjects randomized to ASP2215 arm (211 subjects in 
total: 141 in the ASP2215 arm and 70 in the salvage chemotherapy arm) with a minimum follow-up 
of 4 treatment cycles are considered to achieve a maximum width of 15.78% for the two-sided 95% 
exact confidence interval (CI) when the CR/CRh is expected to be in the 5% to 30% range as 
summarized in the table below. A sample size of 141 subjects provides 80% power to exclude a 
CR/CRh rate of 12% using the two-sided 95% exact CI when the CR/CRh rate of ASP2215 is 
assumed to be 21%. 
Observed CR/CRh with Exact 95% CI (N=141 in ASP2215 arm) 
Observed CR/CRh (n and %) 
Exact 95% CI 
43 (30.50%) 
(23.03%, 38.80%) 
36 (25.53%) 
(18.57%, 33.55%) 
29 (20.57%) 
(14.23%, 28.18%) 
28 (19.86%) 
(13.62%, 27.41%) 
27 (19.15%) 
(13.01%, 26.62%) 
26 (18.44%) 
(12.41%, 25.84%) 
25 (17.73%) 
(11.82%, 25.05%) 
24 (17.02%) 
(11.22%, 24.26%) 
23 (16.31%) 
(10.63%, 23.46%) 
22 (15.60%) 
(10.04%, 22.66%) 
15 (10.64%) 
(6.08%, 16.94%) 
8 (5.67%) 
(2.48%, 10.87%) 
 
 


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EFS and CR rate:  
The planned sample size with 258 EFS events will provide about 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 at the overall 1-sided 0.0245 significance 
level. 
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-IDA or MEC) 
• 
Low intensity chemotherapy (LoDAC or azacitidine) 
Primary Efficacy Analysis: 
OS: 
The co-primary efficacy endpoint of OS will be analyzed using the stratified log-rank test with strata 
to control for response to first-line AML therapy and preselected salvage chemotherapy on the 
Intention to Treatment (ITT) Analysis Set. The ITT is defined as all randomized subjects and the 
analysis is based on the randomized treatment.  
The hypothesis testing on the primary analysis of OS will be performed to test the null hypothesis that 
OS in the ASP2215 arm is worse than or equal to OS in the salvage chemotherapy arm versus the 
alternative hypothesis that OS in the ASP2215 arm is better than OS in the salvage chemotherapy 
arm. 
The sensitivity analysis for the primary efficacy endpoint of OS will be performed as follows: 
• 
Same analysis as primary analysis, but on Full Analysis Set (FAS), which included all 
randomized subjects who are FLT3 mutated subjects based on central test; 
• 
Same analysis as primary analysis, but on PPS, which include all subjects in ITT and do not have 
any major PDs; 
• 
Stratified Cox proportional hazard model with strata to control for response to first-line AML 
therapy and preselected salvage chemotherapy on ITT;  
• 
Same analysis as primary analysis on ITT, but censoring the subjects who undergo HSCT at the 
time of HSCT; 
• 
To account for the possible confounding effect due to subsequent anti-leukemia therapies, a 
sensitivity analysis of OS that censors subjects at the time of initiation of new therapy will be 
performed and an OS analysis that treats initiation of new therapy as a time-dependent binary 
covariate will also be conducted.  
• 
Additional sensitivity analysis may be performed to compare the survival curves when the 
proportional hazards (PH) assumption is plausible.   


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CR/CRh rate: 
The two-sided 95% exact confidence interval of CR/CRh rate will be calculated for approximately 
141 subjects who are randomized into ASP2215 arm and at least 112 days (4 treatment cycles) post 
first dose or randomization (for subjects who received no study drug), i.e., 2215 subjects in response 
analysis set (RAS). The lower limit will be used to compare with the benchmark of CR/CRh rate of 
12%.  
Sensitivity analyses will be performed to assess the robustness of the CR/CRh rate based on: 
• 
Same population as for the primary analysis, but only include subjects in modified response 
analysis set (mRAS);  
• 
Same population as for the primary analysis, but only include subjects who took at least one dose 
of ASP2215; 
• 
Same population as for the primary analysis, but only include subjects who had at least one post-
baseline bone marrow assessment; 
• 
Same population as for the primary analysis, but evaluate the CR/CRh by cycle 4, which is 
defined as the number of subjects who achieve CR/CRh by cycle 4 divided by the number of 
subjects in the analysis population.  
• 
Same population as for the primary analysis, but evaluate the CR/CRh prior to HSCT, which is 
defined as the number of subjects who achieve CR/CRh prior to HSCT divided by the number of 
subjects in the analysis population.     
Key Secondary Efficacy Analysis: 
EFS: 
The key secondary efficacy endpoint of EFS will be analyzed using the stratified log-rank test 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 0.0245 significance level, the hypothesis testing 
on EFS will be performed only if the null hypothesis on the primary analysis of OS is rejected at its 
corresponding significance level at the second interim analysis and final analysis.  
The sensitivity analysis for the key secondary efficacy endpoint of EFS will be performed as follows: 
• 
Same analysis as primary analysis, but on FAS, which includes all randomized subjects who are 
FLT3 mutated subjects based on central test; 
• 
Same analysis as primary analysis, but on PPS, which includes all subjects in ITT and do not 
have any major PDs; 
• 
Stratified Cox proportional hazard model with strata to control for response to first-line AML 
therapy and preselected salvage chemotherapy on ITT;  
• 
EFS will be defined similarly as in Section 5.3.2.2, however the date of the first new anti-
leukemia therapy after end of study treatment or the last treatment evaluation (when new anti-
leukemia therapy date is not available) will be used as the event date of treatment failure; 
• 
EFS will be defined similarly as in Section 5.3.2.2, however subjects who discontinued the 
treatment due to “Lost to follow up” will also be considered as an EFS event and the subjects 
will be censored at the date of “Lost to follow up”. 


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CR rate: 
The key secondary efficacy endpoint of CR rate will be tested 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 0.0245 significance level, the hypothesis 
testing on CR rate will be performed only if the null hypothesis on EFS is rejected at its 
corresponding significance level at the second interim analysis and final analysis.  
Sensitivity analyses for CR rate will be performed as follows: 
• 
CMH test on subjects in ITT and received at least one dose of study treatment 
• 
CMH test on subjects in ITT with at least one post-baseline bone marrow assessment 
• 
Un-stratified Fisher’s exact test on subjects in ITT 
Secondary Efficacy Analyses: 
The statistical analyses on secondary efficacy endpoints include: 
• 
Stratified log-rank test on duration of remission and LFS 
• 
CMH method on the CRc rate and transplantation rate 
• Transfusion conversion rate and transfusion maintenance rate will be summarized by descriptive 
statistics 
• 
Analysis of covariance (ANCOVA) 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 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, 
ophthalmologic assessments 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. 
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. 
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 ANCOVA model will be used for 
resource utilization counts (hospital stays, duration of medications, blood transfusions, antibiotic iv 
infusions, medication for AEs and opioid medication). 
ANCOVA model will be used to analyze the change in the FACIT-Dys-SF domain scores from 
baseline to post-baseline visits. 
ANCOVA 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. 
ANCOVA model will be used for the change from baseline of EQ-5D-5L visual analogue scale 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 benchmark data 
or the salvage chemotherapy group while the study is ongoing, two interim analyses are planned. 
First Interim Analysis 
The first interim analysis is planned when approximately 141 subjects are randomized into the 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for subjects 
who received no study drug). At the first interim analysis, only the co-primary endpoint of CR/CRh 
rate will be evaluated in the ASP2215 arm only. The descriptive statistics including two-sided 95% 
exact CI of CR/CRh rate will be provided to IDMC. The historical control of the CR/CRh rate is 
considered to be 12%. The IDMC will evaluate the CR/CRh rate and inform the Sponsor if the lower 
limit is higher than the historical control or not. The study conduct will not be impacted by the first 
interim analysis result. 
A nominal 1-sided p-value 0.0005 (i.e., 2-sided p-value 0.001), which is arbitrarily selected, will be 
spent to acknowledge the single-arm CR/CRh rate evaluation at the first interim analysis and will not 
be recycled in the second interim analysis and final analysis. No formal hypothesis testing will be 
conducted for CR/CRh rate for the study, only the descriptive statistics including 2-sided 95% exact 
CI of CR/CRh rate will be provided to IDMC at the first interim. The hypothesis testing for the 
primary and secondary endpoints of OS, EFS and CR rate at the secondary interim analysis and final 
analysis are well controlled at an overall 1-sided type I error rate 0.0245 based on a sequential testing 
procedure. 
Second Interim Analysis 
The second interim analysis will be performed when approximately 50% of the total planned death 
events (death events = 129) have occurred in the study. OS will be tested at 1-sided 0.00147/0.38674 
significant level for efficacy/futility according to the O’Brien-Fleming type alpha/beta spending 
function.  
The IDMC may recommend terminating the trial for favorable or unfavorable results at the second 
interim analysis based on OS endpoint. In the case of favorable results (i.e., the 1-sided P-value is less 
than 0.00147), the IDMC may recommend terminating the trial for success. In the case of unfavorable 
results (i.e., the 1-sided P-value is greater than 0.38674), the IDMC may recommend terminating the 
trial for futility. 
 




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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 
 
Xp 
 
 
 
 
 
 
 
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)o 
X 
 
 
 
 
 
 
 
 
12-lead ECGe 
Xg 
X 
 
Xs 
Xs 
X 
X 
 
X 
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)f 
Xg 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Testt 
X 
 
 
 
 
 
 
 
Xt 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
 
MUGA or ECHOh 
X 
 
 
 
 
 
 
 
 
Ophthalmologic Assessmenti 
X 
 
 
 
 
 
X 
 
X 
FLT3 Mutation Statusj (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xk 
 
 
 
 
 
Xk 
 
Xk 
AE/SAE Assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
PK (whole blood samples for plasma PK) 
 
Xl 
 
Xl 
 
Xl 
Xl 
 
Xl 
PGxm 
 
X 
 
 
 
 
 
 
 
Patient Reported Outcome Toolsq, r 
 
Xa 
 
Xq 
 
Xq 
X 
Xq 
X 
EQ-5D-5Lr 
 
Xa 
 
 
 
 
X 
 
X 
Resource Utilization 
 
Xa 
 
 
 
 
X 
 
X 
IRT Transaction Requiredp 
X 
X 
 
 
 
 
X 
 
X 
ASP2215 Dosing at the Clinicn 
 
X 
X 
X 
 
X 
X 
X 
X 
Footnotes appear on next page 


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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-IDA: fludarabine, cytarabine and granulocyte colony-stimulating factor with 
idarubicin; 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.  
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 read. 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. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy during the screening period, day 1 (± 7 days) of cycle 2, day 1 (± 7 days) of 
every 2 cycles thereafter, and when clinically indicated.  In symptomatic subjects, the ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields 
performed by Humphrey method and optical coherence tomography. 
j. 
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. 
k. 
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. 
Footnotes continued on next page 


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l. 
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 (within1 hour 
before drug administration).  See Section 7.6.   
m. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomic study. 
n. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
o. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
p. 
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. 
q. 
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). 
r. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
s. 
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. 
t. 
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 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 
 
Xp 
 
 
 
 
 
 
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)o 
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 Tests 
X 
 
 
 
 
 
 
Xs 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
MUGA or ECHOh 
X 
 
 
 
 
 
 
 
Ophthalmologic Assessment 
Xi 
 
 
 
 
Xi 
 
Xi 
FLT3 Mutation Statusj (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xk 
 
 
 
Xk 
Xk 
 
Xk 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
PGxl 
 
X 
 
 
 
 
 
 
Patient Reported Outcome Toolsq, r 
 
Xa 
 
Xq 
Xq 
X 
Xq 
X 
EQ-5D-5Lr 
 
Xa 
 
 
 
X 
 
X 
Resource Utilization 
 
Xa 
 
 
 
X 
 
X 
IRT Transaction Requiredp 
X 
X 
 
 
 
X 
 
X 
LoDAC or Azacitidine Dosing  
 
See Footnotem 
MEC or FLAG-IDA Dosing 
 
See Footnoten 
 
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-IDA: fludarabine, cytarabine and granulocyte colony-stimulating factor with 
idarubicin; 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. 
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 read.  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. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy during the screening period, day 1 (± 7 days) of cycle 2, day 1 (± 7 days) of 
every  
2 cycles thereafter, and when clinically indicated. In symptomatic subjects, the ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields 
performed by Humphrey method and optical coherence tomography. 
j. 
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 lab. 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. 
k. 
For MEC and FLAG-IDA, 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 a second cycle. For LoDAC or azacitidine, bone marrow samples are required during screening, and at cycle 2 day 1 
and at 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 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. 
l. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomic study. 
m. 
LoDAC or azacitidine dosing may continue past cycle 2. 
n. 
Additional clinic visits are allowed per institutional guidelines for subjects receiving MEC (days 1 through 5) or FLAG-IDA (days 1 through 6). MEC and FLAG-IDA are 
administered for up to 2 cycles depending on response and safety assessments as described in Section 5.1. 
o. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
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p. 
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. 
q. 
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). 
r. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
s. 
For subjects receiving LoDAC or azacitidine, thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
 
 
 


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Table 3 
Posttreatment Schedule of Assessments 
Activity 
Pre-HSCT Visit / 
End of Treatment Visita 
30-Day 
Follow-up (+ 7 days Post 
Pre-HSCT Visit/Post End of 
Treatment Visit) 
Long-term Follow-up  
(+/- 7 days)h 
Physical Examination 
Xb 
 
 
Vital Signs 
Xb 
 
 
ECOG Performance 
Xb 
 
 
Concomitant Medications 
Xl 
 
 
Pregnancy Test for Woman of Childbearing Potential 
X 
 
 
12-lead ECG 
X 
 
 
Ophthalmologic Assessmentj  
X 
 
 
Clinical Laboratory Tests (chemistry, hematology, coagulation ) 
Xb 
 
 
Thyroid Function Tests 
X 
 
 
Bone Marrow Aspiration and/or Biopsy  
Xc 
 
 
FLT3 Mutationsd (bone marrow or whole blood) 
X 
 
 
Patient Reported Outcome Toolsi, k 
X 
 
 
EQ-5D-5Lk 
X 
X 
X 
Resource Utilization 
X 
 
 
AE/SAE Assessment 
X 
Xe,f 
Xg 
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. 
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. 
d. 
FLT3 mutation analysis will be performed on the bone marrow samples collected post study treatment. 
Footnotes continued on next page 


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e. 
For subjects who plan to proceed to HSCT and resume ASP2215 treatment after HSCT, AE collection will continue until the start of the HSCT conditioning regimen and AE 
collection will resume upon the resumption of ASP2215 treatment until 30 days after the last dose of study drug.  For subjects who do not plan to resume ASP2215 treatment 
after HSCT, AE collection will continue until the start of the HSCT conditioning regimen or 30 days after the last dose of study drug, whichever comes first.  However, the 
following AE/SAEs will continue to be collected until 30 days after the last dose of study drug, regardless of the time of the HSCT conditioning regimen: 
• 
Any study drug related AE that is ongoing will be followed until resolved 
• 
Any SAE that is deemed to be related to study drug by the investigator 
• 
Any event of veno-occlusive disease (VOD) of the liver, cardiac failure, Grade 3 or higher QT prolongation, rhabdomyolysis, drug-induced liver injury, or posterior reversible 
encephalopathy syndrome (PRES) 
• 
Adverse events leading to death 
f. 
Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
g. Only SAE data that is related to ASP2215 will be collected. 
h. Telephone contact every 3 months. Ad hoc contact will be required during interim analysis. 
i. 
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. 
j. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy, at the preHSCT/end of treatment (± 7 days). In symptomatic subjects, the 
ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields and optical coherence tomography. 
k. If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
l. 
Concomitant medications should be collected for reported AE/SAEs through 30 days post dose for subjects who have discontinued.  For subjects who undergo HSCT, 
concomitant medications should be collected for reported AE/SAEs through start of conditioning treatment or 30 days post dose, whichever comes first. 
 
 


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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].  In a recent international randomized phase III study of 
elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid 
leukemia, the CR rate in the control arm was only 12% [Roboz et al, 2014].  In this study, the 
treatment options available in the control arm (physician’s choice) reflect contemporary 
clinical practice, rather than a strict selection of only patients that are eligible for intensive 
salvage regimens.  As a result, this control arm should more appropriately represent what can 
be expected in standard clinical practice. 


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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 
[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 
nonclinical 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 with idarubicin [FLAG-IDA]) and less-aggressive (low-dose 
cytarabine [LoDAC] and azacitidine) regimens are included in the study. 
1.2 
Nonclinical and Clinical Data 
1.2.1 
Nonclinical 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. 


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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.   
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 substrates (see Section 1.2.2.1).  
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. 


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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. 
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 
In Study 2215-CL-0101, as of 02 Feb 2015, 154 subjects were evaluable for response. The 
response assessments were done based on central laboratory evaluation of samples 
supplemented with local results when the central results were not available (derived response). 
Based on the derived response at end of treatment in the 154 subjects (both FLT3-mutation 
positive and negative) who received at least 1 dose of ASP2215, 41 (26.6%) subjects achieved 
composite complete remission (CRc), and the best overall response rate  
(CRc + partial remission [PR]) was 35.7%. 
Nearly all subjects that achieved a derived response of PR or CRc at the end of treatment were 
FLT3-mutation positive. Based on the derived response in the 98 FLT3-mutation positive 
subjects at the end of treatment, 36 (36.7%) subjects achieved CRc, and the best overall 
response rate was 49.0%. Five (5.1%) subjects achieved CR, 3 (3.1%) subjects achieved 
complete remission with incomplete platelet recovery (CRp), 28 (28.6%) subjects achieved 


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complete remission with incomplete hematologic recovery (CRi) and 12 (12.2%) subjects 
achieved PR. 
CRc rates for 80, 120 and 200 mg dose groups were 41.7%, 48.6% and 45.8% respectively. 
Among the 77 FLT3-mutation positive subjects in the 80 mg, 120 mg, 200 mg, 300 mg and 
450 mg dose groups, 34 (44.2%) had achieved CRc as the derived response at the end of 
treatment and the overall response rate was 55.8%. Four (5.2%) subjects achieved CR, 
3 (3.9%) subjects achieved CRp, 27 (35.1%) subjects achieved CRi and 9 (11.7%) subjects 
achieved PR. 
Based on the derived response in the 47 FLT3-mutation negative subjects at the end of 
treatment, 2 (4.3%) subjects achieved CRc, and the best overall response rate (CRc + PR) 
was 8.5%. Two (4.3%) subjects each achieved CRi and PR. 
1.3 
Summary of Key Safety Information for Study Drugs 
1.3.1 
ASP2215 
The nonclinical and clinical studies which are referred to in this section are described in more 
detail in the ASP2215 Investigator’s Brochure [2015]. 
1.3.1.1 ASP2215 Nonclinical Data 
ASP2215 showed a concentration-dependent suppression effect on the human ether-a-go-go 
related gene current in HEK293 cells at concentrations of 3 × 10-6, 1 × 10-5 and 
3 × 10-5 mol/L with compensated suppression rates of 18.1%, 32.8% and 70.7%, respectively; 
no suppression was observed at 1 × 10-6 mol/L. The IC50 was 1.6 × 10-5 mol/L. 
ASP2215 showed no effects on the central nervous system in rats at 10 mg/kg.  At 30 mg/kg 
and higher, decreased urination was noted.  In addition, at 100 mg/kg, decreased defecation 
was noted.  The changes in urination and defecation were resolved in the recovery period. 
ASP2215 did not show any effect on the cardiovascular or respiratory system in dogs up to 
100 mg/kg or on the central nervous system at 1 mg/kg. At 3 mg/kg and higher, the following 
signs were noted: retching at 3 mg/kg, vomiting and positive fecal occult blood at 10 mg/kg 
and higher, a decrease in the blood calcium (Ca2+) concentration at 30 mg/kg and salivation 
and an increase followed by a decrease in the blood Ca2+ concentration at 100 mg/kg. All of 
the findings recovered. 
In the single oral dose toxicity study in rats, the approximate lethal dose level was 300 mg/kg 
for males and females. The major change was a gastrointestinal hemorrhagic disorder at 
100 and 300 mg/kg. Reversibility of the changes noted in the surviving animals was seen.  
No definitive single oral dose toxicity study in dogs was conducted.  In the 4-week toxicity 
study in dogs, a dose of 1000 mg/kg per day caused deaths and moribund sacrifices on day 2.  
The cause of death and moribundity was considered to be deterioration of general condition 
caused by gastrointestinal hemorrhage. 
In the 1-week oral repeated dose toxicity study in rats, interstitial pneumonia in the lung and 
vacuolar change in the rod-cone layer of the retina were observed in a male at 30 mg/kg per 


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day.  In the 13-week oral repeated dose toxicity study in rats, deaths occurred at 20 mg/kg per 
day in both sexes. Target organ toxicity was identified in the gastrointestinal tract, immune 
system, hematopoietic system, eye, lung, kidney and liver. The no observed adverse effect 
level (NOAEL) was lower than 2.5 mg/kg per day for males and females. The changes noted 
during the dosing period recovered or tended to recover during the 4-week recovery period.  
In the 4-week oral repeated dose study in dogs, mortality occurred at 10 mg/kg per day or 
more. Target organ toxicity was identified in the gastrointestinal tract, immune system, 
hematopoietic system, eye, kidney and liver. The NOAEL was 1 mg/kg per day for males and 
females. Reversibility of most of the test article related changes was indicated by the end of 
the 4-week recovery period. In the 13-week oral repeated dose study in dogs, mortality 
occurred at 5 mg/kg per day. Target organ toxicity was identified in the lung, lacrimal gland, 
urinary bladder, epithelial tissue, gastrointestinal tract, immune system, hematopoietic 
system, eye, kidney and liver. The NOAEL was 1 mg/kg per day for males and females.  
Reversibility of most of the test article-related changes was indicated by the end of the 
4-week recovery period. 
ASP2215 did not induce gene mutation in the definitive in vitro reversion test in bacteria.  
Similarly, ASP2215 did not induce chromosomal aberrations in the definitive in vitro 
chromosomal aberration test in mammalian cells. The definitive in vivo micronucleus test 
showed that ASP2215 has a potential to induce micronuclei in mice. Based on the results of 
the battery of genotoxicity studies above, it was concluded that ASP2215 has a potential to 
induce genotoxicity in vivo. 
ASP2215 showed teratogenic potential and embryo-fetal deaths in the embryo-fetal 
development study in rats. The NOAEL of ASP2215 for dams and embryo-fetal development 
was 10 mg/kg per day. 
ASP2215 showed no potential to induce phototoxicity to cultured mammalian cells. 
1.3.1.2 ASP2215 Clinical Data 
As of February 2016, 447 subjects (300 AML patients; 131 healthy subjects and 16 subjects 
with mild or moderate hepatic impairment) have been enrolled in phase 1 studies.  Study 
2215-CL-0101 is a first-in-human phase 1/2 open-label, dose-escalation study initiated in 
October, 2013, and as of 31 Oct 2015, 262 subjects had been enrolled.  Of the subjects in that 
study who received ASP2215, 245 (97.2%) developed at least 1 treatment -emergent adverse 
event (TEAE) during the study.  Overall, the most frequently reported TEAEs (occurring in 
at least 10% of subjects) included febrile neutropenia (38.5%), diarrhea (33.7%), anemia 
(29.0%), fatigue (28.2%), aspartate aminotransferase (AST) increased (23.0%), edema 
peripheral (22.6%), pyrexia and dyspnea (21.8% each), constipation and cough (18.7% each), 
epistaxis (17.9%), nausea (17.5%), dizziness (17.1%), hypotension and alanine 
aminotransferase (ALT) increased (16.7% each), vomiting (15.9%), hypokalemia (15.1%), 
hypocalcemia (14.7%), platelet count decreased (13.5%), blood creatinine increased (13.1%), 
hyponatremia and AML (12.7% each), pneumonia (12.3%), sepsis (11.9%), fall (11.5%), 
thrombocytopenia, hypomagnesemia, and arthralgia (11.1% each), headache and blood 
alkaline phosphatase (ALP) increased (10.7% each), and hypoxia (10.3%).  A total of 


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183 (72.6%) subjects experienced at least 1 TEAE considered by the investigator to be 
possibly or probably related to study drug.  Common drug-related TEAEs (occurring in at 
least 5% of subjects) included diarrhea (16.3%), fatigue (13.1%), increased AST (11.9%), 
anemia (9.1%), constipation, increased ALT and peripheral edema (8.3% each), decreased 
platelet count and nausea (7.5% each), thrombocytopenia and vomiting (6.7% each), 
increased creatine phosphokinase, dizziness and dysgeusia (6.3% each) and increased 
transaminases (6.0%). 
A total of 198 (78.6%) of the subjects developed at least 1 serious TEAE. The most 
commonly reported serious TEAEs (occurring in at least 5% of subjects) included febrile 
neutropenia (30.6%), AML (12.7%), sepsis (11.9%), pneumonia (9.5%), 
renal failure acute (8.3%), pyrexia (6.7%) and bacteremia (5.2%).  Of the serious TEAEs, 
69 (27.4%) subjects had serious TEAEs that were considered by the investigators to be 
related to ASP2215.  Drug-related serious TEAEs that occurred in 2 or more subjects 
included febrile neutropenia (2.4%); renal failure acute, gastrointestinal hemorrhage and 
increased AST (1.6% each); blood bilirubin increased, blood creatine phosphokinase 
increased, hypotension (1.2% each); nausea, liver function test abnormal, pyrexia, sepsis, 
increased ALT, muscular weakness, transaminases increased, small intestinal obstruction, 
hypoxia, posterior reversible encephalopathy syndrome (PRES) and vomiting (0.8% each). 
Eighty-seven (34.5%) subjects experienced a TEAE that resulted in death: AML in 32 (12.7%) 
subjects; multi-organ failure in 7 (2.8%) subjects; respiratory failure in 6 (2.4%) subjects; 
sepsis and septic shock in 4 (1.6%) subjects each, pneumonia, cardiac arrest and intracranial 
hemorrhage in 3 (1.2%) subjects each; disease progression and renal failure in 2 (0.8%) 
subjects each; anemia, neutropenia, peripheral edema, bronchopulmonary aspergillosis, 
enterococcal infection, lung infection, pyoderma, staphylococcal bacteremia, staphylococcal 
sepsis, malignant neoplasm progression, cerebral ischemia, loss of consciousness, acute 
respiratory failure, hypoxia, pulmonary embolism, colitis, ventricular fibrillation, ventricular 
tachycardia, neutropenic colitis, bacteremia, cellulitis, diabetic ketoacidosis, sudden death and 
hemoptysis each in 1 (0.4%) subject. 
A preliminary analysis of the relationship between ASP2215 plasma concentration and 
Fridericia-corrected QT interval (QTcF) change from baseline (ΔQTcF) was performed on data 
from the 2215-CL-0101 study (data cutoff 31 Oct 2015). This assessment included 1359 
observations from 199 subjects.  A model-averaging approach was used to develop a robust 
model to describe and predict the ASP2215 concentration-ΔQTcF relationship. A 
concentration-related increase in ΔQTcF was observed and the mean ΔQTcF at the mean 
steady-state Cmax was predicted to be less than the 10 msec threshold considered clinically 
significant. Additionally, less than 5% of Relapsed/Refractory AML subjects had a maximum 
post-baseline QTcF interval > 500 msec. These data indicate clinically-relevant QTc 
prolongation is not anticipated.  
An exposure-related increase in circulating creatine kinase (CK) concentration relative to 
baseline was also observed in Relapse/Refractory AML subjects enrolled in Study 
2215-CL-0101. Almost all CK elevations were grade 1 and grade 2, however, Common 


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Terminology Criteria for Adverse Events (CTCAE) Grade 3 and 4 adverse events (AEs) 
related to elevated CK occurred in higher ASP2215 dose groups. Similarly, a significant 
correlation between ASP2215 concentration and aspartate aminotransferase change from 
baseline (ΔAST) was also observed. However, the incidence of ≥ Grade 3 events related to 
elevated AST was < 3% (data cutoff 31 Oct 2015). 
As of 31 Oct 2015, 23 subjects experienced a dose limiting toxicity (DLT). All DLTs occurred 
in the dose expansion cohort, with the exception of 2 subjects in the 450 mg dose escalation 
cohort that experienced grade 3 increased AST and grade 3 diarrhea. No further subjects will 
be enrolled in the 450 mg dose group. None of the doses below 450 mg met the criteria for 
pausing enrollment. The maximum tolerated dose (MTD) in Study 2215-CL-0101 is 
considered 300 mg. 
Expected adverse drug reactions for ASP2215 include (by preferred term) diarrhea, peripheral 
edema, increased blood creatine phosphokinase, increased ALT, increased AST and myopathy. 
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. 
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.   


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2 
STUDY OBJECTIVES, DESIGN AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objectives  
The primary objectives are 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. 
● 
Determine the efficacy of ASP2215 therapy as assessed by the rate of complete 
remission and complete remission with partial hematological recovery (CR/CRh) in 
subjects with FLT3-mutated AML who are refractory to or have relapsed after first-line 
AML therapy.  
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 
● 
CRh rate 
● 
CRc rate 
● 
Transfusion conversion rate; transfusion maintenance rate 
● 
Transplantation rate 
● 
Patient reported fatigue (Brief Fatigue Inventory [BFI]) 
● 
AEs, safety labs, vital signs, ophthalmologic exams, electrocardiograms (ECGs) and 
Eastern Cooperative Oncology Group (ECOG) performance scores 
● 
Evaluation of ASP2215 (and metabolites as appropriate) plasma concentration and 
population pharmacokinetics  
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 
o mechanisms of acquired resistance 


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● 
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) 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is a 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 140 centers in 
North America, Europe, Asia and rest of the world will participate in this study. 
Three hundred sixty nine subjects will be randomized. The randomization of the 369 subjects 
will be in a 2:1 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, azacitidine, MEC or FLAG-IDA. 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 of the protocol. 
For subjects taking ASP2215, LoDAC or azacitidine, treatment should continue until the 
subject meets a treatment discontinuation criterion. 
Subjects receiving MEC or FLAG-IDA 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 marrow 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 bone 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] 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 


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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 the OS endpoint. 
After treatment discontinuation, subjects will have a pre-HSCT/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 as follows: every 3 months for up to 3 years from the subject’s end of treatment visit. 
Two interim analyses by an Independent Data Monitoring Committee (IDMC) will be 
conducted. The first interim analysis is planned when approximately 141 subjects are 
randomized into the ASP2215 arm and at least 112 days (4 treatment cycles) post first dose 
or randomization (for subjects who received no study drug). The first interim analysis will be 
performed to evaluate the efficacy endpoint of CR/CRh and the study conduct will not be 
impacted by the result of the CR/CRh rate. 
The second interim analysis will be performed when approximately 50% of the planned total 
number of deaths (death event = 129 of planned 258 death events) by any cause have 
occurred. The second interim 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 second interim analysis demonstrates a more 
favorable outcome for ASP2215 based on OS, enrollment to the study may be stopped. 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 the assigned study treatment if one or more of the following conditions 
have been met: 
● 
until the subject has met a treatment discontinuation criterion as outlined in Section 6;  
● 
after ≥ 3 years of study drug treatment have been completed for all subjects* 
*At that point, subject(s) can be transitioned to commercial supply once ASP2215 achieves marketing 
authorization, commercial availability and applicable reimbursement in the country of residence. Once a 
subject(s) transitions to commercial supply, the subject(s) will be discontinued from the study. 


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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.  Doses used in randomized trials were chosen where available. 
2.3 
Endpoints 
2.3.1 
Co-Primary Endpoints 
● OS 
● CR/CRh rate 
2.3.2 
Secondary Endpoints 
Key Secondary Efficacy Endpoints 
● EFS 
● CR rate 
Secondary Efficacy Endpoints 
● LFS 
● Duration of remission 
● CRh rate 
● CRc (CR + CRi + CRp) rate 
● Transfusion conversion rate; transfusion maintenance rate 
● Transplantation rate 
● BFI 


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2.3.3 
Exploratory Endpoints 
● PGx 
● FLT3 gene mutation status 
o mutation types and frequency 
o relationship to efficacy and safety 
o mechanisms of acquired resistance 
● 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 
● Ophthalmologic assessments 
● ECGs 
● ECOG performance scores 
2.3.5 
Pharmacokinetics 
● ASP2215 (and metabolites as appropriate) concentration in blood 
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, ophthalmology examination) 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 (e.g., Health 
Insurance Portability and Accountability Act [HIPAA] Authorization for United States 
sites) 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 at the time of signing 
informed consent. 


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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 (as defined by [Cheson et al, 
2003], see Section 5.3) 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. 
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: 
o Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or 
o Documented as surgically sterile (at least 1 month prior to screening) 
● Or, if of childbearing potential, 
o Agree not to try to become pregnant during the study and for 180 days after the 
final study drug administration 
o And have a negative urine pregnancy test at screening 


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o 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 180 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 180 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 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). 
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). 


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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. 
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.  


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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 4].   
Table 4 
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 5]. 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 (e.g., FDA, 
European Commission or each country regulatory agency). 
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. 
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)-Astellas United States Technologies (AUST) in accordance with APGD-AUST 
Standard Operating Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and 
applicable local laws/regulations.  


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Table 5 
Comparator Drug Products Supplied by the Sponsor 
Comparator Chemotherapy Drug 
Drug Product 
LoDAC 
Low-dose cytarabine  
Cytarabine 20 mg/mL Injection Solution 100 mg/5mL 
Azacitidine 
Azacitidine 
Azacitidine 25 mg/mL Powder for Suspension for Injection 
MEC Induction Chemotherapy 
Cytarabine intermediate dose 
Cytarabine 100 mg/mL Solution for Injection or Infusion 
Mitoxantrone 
Mitoxantrone 2 mg/mL Concentrate for Solution for Infusion 
Etoposide  
Etoposide 20 mg/mL Concentrate for Solution for Infusion 
FLAG-IDA Induction Chemotherapy 
High-dose cytarabine  
Cytarabine 100 mg/mL Solution for Injection or Infusion 
G-CSF filgrastim 
Filgrastim 30 MU (0.3 mg/mL) Solution for Injection 
Idarubicin 
Idarubicin 10 mg Powder for Solution for Injection 
Fludarabine 
Fludarabine Phosphate 25 mg/mL Concentrate for Solution 
for Injection or Infusion 
FLAG-IDA: fludarabine, cytarabine and granulocyte colony-stimulating factor with idarubicin; G-CSF: 
granulocyte colony-stimulating factor; LoDAC: low-dose cytarabine; MEC: mitoxantrone, etoposide and 
intermediate-dose cytarabine 
4.2 
Packaging and Labeling 
ASP2215 used in this study will be prepared, packaged and labeled under the responsibility 
of qualified staff at APGD-AUST or Sponsor’s designee in accordance with APGD-AUST or 
Sponsor’s designee 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. 
A qualified person of Astellas Pharma Europe B.V. or Sponsor’s designee will perform the 
final release of the medication according to Directive 2003/94/EC annex 13. 
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 APGD-AUST in accordance 
with APGD-AUST 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, 


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● 
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. 
Specific to Japan 
In Japan, the head of the study site or the study drug storage manager should take 
accountability of the study drugs as follows: 
● 
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written by the Sponsor. 
● 
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study site, the use by each subject and the return to the 
Sponsor or alternative disposal of unused study drugs. These records should include 
dates, quantities, batch/serial numbers, expiration dates (if applicable) and the unique 
code numbers assigned to the study drugs and subjects. 
● 
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol and 
reconcile all the study drugs supplied from the Sponsor. 
4.4 
Blinding 
This section is not applicable as this is an open-label study. 


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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. 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. 
Azacitidine [Itzykson et al, 2015] 
● 75 mg/m2 azacitidine will be administered daily by SC or IV injection for 7 days.  
 Follow Institution’s guidelines if dose reduction is needed after cycle 1. 
MEC Induction Chemotherapy [Levis et al, 2011] 
● Mitoxantrone 8 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-IDA Induction Chemotherapy [Parker et al, 1997; Paul et al, 2014] 
● 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). 
● Idarubicin 10 mg/m2 per day will be administered by IV for 3 days (days 2 through 4). 
Subjects receiving LoDAC or azacitidine treatment should continue until the subject meets a 
treatment discontinuation criterion. 
Subjects receiving MEC or FLAG-IDA 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 marrow 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 bone 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 6]. 
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 6]. 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 6]. 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. 
Any subjects that have been off treatment for more than 14 days other than for HSCT can only 
resume treatment after discussion with the medical monitor. 
If the ASP2215 dose has been reduced, the ASP2215 dose will not be re-escalated. 


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Table 6 
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 1day 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). 
Retinopathy 
Grade 2 
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 3/4 
Treatment will be discontinued. 
Nonhematological Events 
Grade 3 toxicity at 
least possibly 
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 
related to ASP2215 
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 
 


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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 7]. 
Table 7 
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 Nonmedication Therapy) 
All medications and concomitant treatments administered from 28 days prior to cycle 1 day 1 
must be recorded in the Case Report Form (CRF). Concomitant medications should be 
collected for reported AE/serious adverse events (SAEs) through 30 days post dose for subjects 
who have discontinued.  For subjects who undergo HSCT, concomitant medications should be 
collected for reported AE/SAEs through start of conditioning treatment or 30 days post dose, 
whichever comes first. 
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 the 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. 


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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.   
5.1.4 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation 
Subjects in ASP2215 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.). 


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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).  
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 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. 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. 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. 


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5.2.5 
Performance Status 
The ECOG Scale [Oken et al, 1982] will be used to assess performance status [Table 8]. 
Table 8 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all predisease 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 at a post-baseline visit, 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 at a post-baseline visit, 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 at a post-baseline visit, 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 
For subjects to be classified as being in CRc at a post-baseline visit, they must either achieve 
CR, CRp or CRi at the visit.  


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5.3.1.5 Complete Remission with Partial Hematologic Recovery 
At a post baseline visit, subjects will be classified as CRh if they have marrow blasts < 5%, 
partial hematologic recovery ANC ≥ 0.5 x 109/L and platelets ≥ 50 x 109/L, no evidence of 
extramedullary leukemia and cannot be classified as CR. 
5.3.1.6 Partial Remission 
For subjects to be classified as being in PR at a post-baseline visit, 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%. A value of less or equal than 5% blasts is also considered a PR if Auer rods are present. 
5.3.1.7 Not Evaluable/No Response 
In the situation where no bone marrow assessments are performed or myeloblast value is 
missing, blast value from peripheral blood is missing or ≤ 2%, and extramedullary leukemia 
is missing or not done, the response will be classified as not evaluable (NE). In any case 
response cannot be categorized as CR, CRp, CRi, PR or NE, it will be categorized as NR. 
5.3.1.8 Relapse 
Relapse after CR, CRh, 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. 
5.3.1.9 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-baseline. 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. 
5.3.1.10 Complete Remission Rate  
CR rate is defined as the number of subjects who achieve the best response of CR divided by 
the number of subjects in the analysis population. 
5.3.1.11  Composite Complete Remission Rate 
CRc rate is defined as the number of subjects who achieve the best response of CRc (CR, 
CRp or CRi) divided by the number of subjects in the analysis population. 


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5.3.1.12 Complete Remission with Partial Hematologic Recovery Rate 
CRh is defined as the number of subjects who achieve CRh at any of the post-baseline visits 
and do not have best response of CR divided by the number of subjects in the analysis 
population. 
5.3.1.13 Complete Remission and Complete Remission with Partial Hematologic 
Recovery Rate 
CR/CRh is defined as the number of subjects who achieve either CR or CRh at any of the 
post-baseline visits divided by the number of subjects in the analysis population.  
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 the latest date the subject is known to be alive by the cutoff date. 
5.3.2.2 Event-free Survival 
EFS is defined as the time from the date of randomization until the date of documented 
relapse (excluding relapse after PR), treatment failure or death, whichever occurs first. If a 
subject experiences relapse or death, the subject is defined as having EFS event related to 
either “relapse” or “death”, and the event date is the date of relapse or death. If a subject fails 
to achieve any of the response of CR, CRp, CRi or PR during the treatment period, the 
subject is defined as having EFS event related to treatment failure, and the event date is the 
randomization date. For a subject who is not known to have had a relapse or treatment failure 
or death event, EFS is censored at the date of last relapse-free disease assessment.  Subject is 
not censored at 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 
Duration of remission includes duration of CRc, duration of CR/CRh, duration of CRh, 
duration of CR, duration of CRi, duration of CRp and duration of response (CRc + PR). 
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 


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date. Other subjects who do not relapse on study are considered nonevents and censored at 
the last relapse-free disease assessment date. 
Duration of CR/CRh, CRh, CR, CRp, CRi 
Duration of CR/CRh, CRh, 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. 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-IDA 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 or 
azacitidine groups, bone marrow samples are required during screening and at cycle 2 day 1 
and at 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 
ethylenediaminetetraacetic acid 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. 
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. 


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The first survival status will occur at the 30 day follow-up post pre-HSCT/end of treatment 
visit 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 for up to 3 years after end of treatment visit. Data may be supplemented by site 
records when available at the time of the contact (e.g., treatment records, outcomes). Follow-
up will continue until the final database lock, which is estimated to be up to 3 years of 
follow-up. 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 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. 
5.4 
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.  


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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. 
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 
For subjects who plan to proceed to HSCT and resume ASP2215 treatment after HSCT, AE 
collection will continue until the start of the HSCT conditioning regimen and AE collection 
will resume upon the resumption of ASP2215 treatment until 30 days after the last dose of 
study drug.  For subjects who do not plan to resume ASP2215 treatment after HSCT, AE 
collection will continue until the start of the HSCT conditioning regimen or 30 days after the 
last dose of study drug, whichever comes first. However, the following AE/SAEs will 
continue to be collected until 30 days after the last dose of study drug, regardless of the time 
of the HSCT conditioning regimen: 
● Any study drug related AE that is ongoing will be followed until resolved 
● Any SAE that is deemed to be related to study drug by the investigator 
● Any event of veno-occlusive disease (VOD) of the liver, cardiac failure, Grade 3 or 
higher QT prolongation, rhabdomyolysis, drug-induced liver injury or PRES 
● AEs leading to death 
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 


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(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. 
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]. 
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]. 
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. 


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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%). 
5.4.8 
Ophthalmologic Exam 
Ophthalmologic examinations will be conducted during the screening period, day 1 
(± 7 days) of cycle 2, day 1 (± 7 days) of every 2 cycles thereafter, at the preHSCT/end of 
treatment (± 7 days) and when clinically indicated. The following tests and exams are 
required at every visit: 
● Visual Acuity: best-corrected visual acuity as per ETDRS or Snellen charts or other 
visual acuity chart testing reported as Logarithm of the Minimum Angle of Resolution 
(logMAR) scores (For the visual acuity testing using a near card at bedside, the results 
must indicate the vision was tested with a near card.)  
● Ophthalmoscopy (A dilated ophthalmoscopy can be performed at bedside.) 
In symptomatic subjects, the ophthalmologic assessment should also include slit lamp 
biomicroscopy, visual fields performed by Humphrey method and optical coherence 
tomography. 
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. 


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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 
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) 


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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 “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested. 
5.5.3 
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). 
5.5.4 
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 
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 


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5.5.5 
Reporting of Serious Adverse Events 
SAE collection will begin from time of informed consent through 30 days after last dose of 
study medication. During the long-term follow-up period, only SAE data for the event that is 
related to ASP2215 will be collected. Progressive Disease should not be reported as an 
AE/SAE unless the disease progression is the cause of death. 
In the case of a SAE, the investigator must contact the Sponsor by telephone, email or fax 
immediately (within 24 hours of awareness). 
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor/delegated Contract Research 
Organization (CRO) by email or fax immediately (within 24 hours of awareness). If the 
faxing of an SAE Worksheet is not possible or is not possible within 24 hours, the local drug 
safety contact should be informed by phone. 
Specific to Japan: In Japan, in the case of a SAE, the investigator or sub-investigator must 
report to the head of the study site and must contact the Sponsor by telephone or fax 
immediately (within 24 hours of awareness). 
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the Regulatory Authorities to 
the Sponsor by fax immediately (within 24 hours of awareness) and to the head of the 
hospital. If the faxing of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not possible or 
is not possible within 24 hours, the Sponsor should be informed by phone. 
For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please fax or 
email the SAE Worksheet to: 
Astellas Pharma Global Development 
Pharmacovigilance 
North American Fax: 888-396-3750 
(North America Alternate Fax: 847-317-1241) 
International Fax: +44-800-471-5263 
Email: safety-us@astellas.com 
Specific to Japan:  
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE Worksheet to: 
PPD-SNBL K.K. 
FAX 03-5565-3312 
or 
Astellas Pharma Inc.-Japan 
Japan/Asia Clinical Development I 
Fax: 03-3243-5737 


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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., IND Safety 
Reports, CIOMS-I) to the regulatory agencies (e.g., FDA, EMA) per current local 
regulations, and will 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 (e.g., EU, (e)CTD, FDA) 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. 
5.5.6 
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. 


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5.5.7 
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 5.5.5 Reporting of Serious Adverse Events].  
5.5.8 
Procedure in Case of Pregnancy 
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 120 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 
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 are 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.  


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5.5.9 
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.   
5.5.10 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. 
Specific to Japan: 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Enforcement Regulations of the Act on 
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics, in 
compliance with Article 80-2 Paragraph 6 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, the Sponsor should inform all the 
investigators involved in the clinical study, the head of the study site and the regulatory 
authorities of such information. The head of the study site who receives such information 
will decide whether the clinical study should be continued after hearing the opinions of 
the IRB. The investigator will supply the new information to the subjects, in compliance 
with [Section 8.2.3.2 Supply of New and Important Information Influencing the 
Subject’s Consent and Revision of Written Information]. 
● In addition to the above item (1), when the head of the study site receives the 
revisions of the Investigator’s Brochure, protocol or written information, 
information on the matters covering the quality of the study drug, efficacy and 
safety, information necessary for conducting the clinical study properly or 
documents to be examined by the IRB should be sent to the IRB. 
5.5.11 Deviations from the Protocol and Other Actions Taken to Avoid 
Life-threatening Risks to Subjects (Japan Only) 
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects. When the investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the investigator should take the following actions. 
● 
Describe the contents of the deviation or amendment and the reasons for it in a written 
notice and immediately send the document stating the deviation or amendment and the 
reasons to the Sponsor and the head of the study site.  Keep a copy of the notice. 


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● 
Consult with the Sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor. 
5.6 
Test Drug Concentration 
5.6.1 
Pharmacokinetics 
Plasma concentrations of ASP2215 will be evaluated as outlined in Schedule of Assessments.  
For each sample, 2 mL of blood will be collected and processed. 
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. 
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 
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 


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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. 
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 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 


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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 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. 
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-0301), 
● 
Subject number and 
● 
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 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 90 mL. 


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The maximum amount of blood collected for study specific assessments in cycle 2 is 
approximately 35 mL. 
The maximum amount of blood collected for study specific assessments in cycle 3 and 
beyond is approximately 20 mL per cycle. 
6 
DISCONTINUATION 
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. 
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 if one or more of the following 
conditions have been met: 
● 
until the subject has met a treatment discontinuation criterion as outlined in 
Section 6.1.1;  
● 
after ≥ 3 years of study drug treatment have been completed for all subjects* 
*At that point, subject(s) can be transitioned to commercial supply once ASP2215 achieves 
marketing authorization, commercial availability and applicable reimbursement in the 
country of residence. Once a subject(s) transition to commercial supply, the subject(s) will be 
discontinued from the study. 
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. 


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● 
Subject is receiving MEC or FLAG-IDA and has NR or progressive disease following 
cycle 1. 
● 
Subject is receiving LoDAC, azacitidine 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. 
● 
Death. 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor (in Japan: and the head of the study site). 
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 of APGD-United 
States.  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. 


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7.1 
Sample Size 
This is a group sequential design based on co-primary endpoint of OS using the O’Brien-
Fleming boundaries (non-binding) as implemented by Lan-DeMets alpha/beta spending 
method (East®) [Lan & DeMets, 1983].  
The overall 0.025 one-sided type I error rate is allocated by 0.0005 and 0.0245 (0.001 and 
0.049 for two-sided type I error rate) for the two co-primary efficacy endpoints of CR/CRh 
and OS, respectively. The type I error (alpha) in the first interim analysis will not be recycled 
in the second interim analysis and final analysis. 
The first interim analysis is planned when approximately 141 subjects are randomized into 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for 
subjects who received no study drug). The second interim analysis is planned when 
approximately 129 death events have occurred and the final analysis is planned when 
approximately 258 death events have occurred. After the completion of the final (primary) 
analysis when approximately 258 death events have occurred, additional data summary for 
subjects is planned when ≥ 3 years of study drug treatment have been completed.   
OS:  
Approximately 369 subjects (the planned sample size with 10% dropout rate) will be 
randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy (246 subjects in the 
ASP2215 treatment arm and 123 subjects in the salvage chemotherapy arm). The planned 
258 death events will provide about 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 1-sided 0.0245 significance 
level. 
CR/CRh rate:  
The first interim analysis will be conducted only to evaluate the co-primary endpoint of 
CR/CRh. One hundred and forty-one subjects randomized to ASP2215 arm (211 subjects in 
total: 141 in the ASP2215 arm and 70 in the salvage chemotherapy arm) with a minimum 
follow-up of 4 treatment cycles are considered to achieve a maximum width of 15.78% for 
the two-sided 95% exact confidence interval (CI) when the CR/CRh is expected to be in the 
5% to 30% range as summarized in below table. A sample size of 141 subjects provides 80% 
power to exclude a CR/CRh rate of 12% using the two-sided 95% exact CI when the CR/CRh 
rate of ASP2215 is assumed to be 21%. 


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Observed CR/CRh with Exact 95% CI 
(N = 141 in ASP2215 arm) 
Observed CR/CRh (n and %) 
Exact 95% CI 
43 (30.50%) 
(23.03%, 38.80%) 
36 (25.53%) 
(18.57%, 33.55%) 
29 (20.57%) 
(14.23%, 28.18%) 
28 (19.86%) 
(13.62%, 27.41%) 
27 (19.15%) 
(13.01%, 26.62%) 
26 (18.44%) 
(12.41%, 25.84%) 
25 (17.73%) 
(11.82%, 25.05%) 
24 (17.02%) 
(11.22%, 24.26%) 
23 (16.31%) 
(10.63%, 23.46%) 
22 (15.60%) 
(10.04%, 22.66%) 
15 (10.64%) 
(6.08%, 16.94%) 
8 (5.67%) 
(2.48%, 10.87%) 
EFS and CR rate:  
The planned sample size with 258 EFS events will provide about 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 at 
the overall 1-sided 0.0245 significance level. 
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-IDA, MEC) 
● 
Low intensity chemotherapy (LoDAC or azacitidine) 
7.2 
Analysis Sets 
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. 


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7.2.1 
Intention To Treatment Set 
The Intention to Treatment Set (ITT) will consist of all subjects who are randomized and will 
be used for primary efficacy analysis. The subjects will be analyzed based on the randomized 
treatments. 
7.2.2 
Response Analysis Set 
The Response Analysis Set (RAS) consists of subjects who are at least 112 days post first 
dose or randomization (for subjects who received no study drug). The subjects will be 
analyzed based on the randomized treatments.  
The RAS will be used only at the interim analyses and will be used for primary analyses of 
response related efficacy data.  
7.2.3 
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 sensitivity analysis. The 
subjects will be analyzed based on the randomized treatments. 
7.2.4 
Per Protocol Set 
The Per Protocol Set (PPS) will consist of the subset of the FAS who do not meet criteria for 
PPS exclusion. These criteria are to capture relevant nonadherence to the protocol and will be 
defined in the SAP. The sensitivity analysis for the primary and key secondary efficacy 
endpoints will be performed on PPS.  Select demographic and baseline characteristics may 
also be summarized for the PPS. 
7.2.5 
Modified Response Analysis Set 
The modified Response Analysis Set (mRAS) will consist of the subset of the RAS who do 
not meet the criteria for mRAS exclusion. These criteria are to capture relevant nonadherence 
to the protocol and other factors may impact the response assessment and will be defined in 
the SAP. The sensitivity analysis for the primary endpoint of CR/CRh rate will be performed 
on mRAS.   
7.2.6 
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. 
7.2.7 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF for which at least 
1 plasma concentration data is available and for whom the time of dosing on the day of 
sampling is 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 


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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, CR/CRh rate, EFS, CR rate, CRc rate, CRh rate, duration of remission, transfusion 
conversion rate, transfusion maintenance rate, 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 Co-Primary Endpoints 
OS: 
The co-primary efficacy endpoint of OS will be analyzed using the stratified log-rank test with 
strata to control for response to first-line AML therapy and preselected salvage chemotherapy 
on the Intention to Treatment (ITT) Analysis Set. The ITT is defined as all subjects who are 
randomized and the analysis is based on the randomized treatment. 
The hypothesis testing on the primary analysis of OS will be performed to test the null 
hypothesis that OS in the ASP2215 arm is worse than or equal to OS in the salvage 
chemotherapy arm.  
The sensitivity analysis for the primary efficacy endpoint of OS will be performed as follows: 
● 
Same analysis as primary analysis, but on FAS, which included all randomized subjects 
who are FLT3 mutated subjects based on central test; 
● 
Same analysis as primary analysis, but on PPS, which include all subjects in ITT and do 
not have any major PDs; 
● 
Stratified Cox proportional hazard model with strata to control for response to first-line 
AML therapy and preselected salvage chemotherapy on ITT;  
● 
Same analysis as primary analysis on ITT, but censoring the subjects who undergo 
HSCT at the time of HSCT; 
● 
To account for the possible confounding effect due to subsequent anti-leukemia 
therapies, a sensitivity analysis of OS that censors subjects at the time of initiation of 
new therapy will be performed and an OS analysis that treats initiation of new therapy as 
a time-dependent binary covariate will also be conducted. 
● 
Additional sensitivity analysis may be performed to compare the survival curves when 
the proportional hazards (PH) assumption is plausible.   
CR/CRh: 
The two-sided 95% exact confidence interval of CR/CRh rate will be calculated for 
approximately 141 subjects who are randomized into ASP2215 arm and at least 112 days 
(4 treatment cycles) post first dose or randomization (for subjects who received no study 
drug), i.e., 2215 subjects in RAS. The lower limit will be used to compare with the 
benchmark of CR/CRh rate of 12%.  
Sensitivity analyses will be performed to assess the robustness of the CR/CRh rate based on: 
● 
Same population as for the primary analysis, but only include subjects in mRAS; 
● 
Same population as for the primary analysis, but only include subjects who took at least 
one dose of ASP2215; 
● 
Same population as for the primary analysis, but only include subjects who had at least 
one post-baseline bone marrow assessment; 


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● 
Same population as for the primary analysis, but evaluate the CR/CRh by cycle 4, which 
is defined as the number of subjects who achieve CR/CRh by cycle 4 divided by the 
number of subjects in the analysis population. 
● 
Same population as for the primary analysis, but evaluate the CR/CRh prior to HSCT, 
which is defined as the number of subjects who achieve CR/CRh prior to HSCT divided 
by the number of subjects in the analysis population. 
7.4.2 
Analysis of Secondary Endpoints 
7.4.2.1 Key Secondary Efficacy Analysis 
EFS: 
The key secondary efficacy endpoint of EFS will be analyzed using the stratified log-rank 
test 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 0.0245 significance 
level, the hypothesis testing on EFS will be performed only if the null hypothesis on the 
primary analysis of OS is rejected at its corresponding significance level for the second 
interim analysis and final analysis.  
The sensitivity analysis for the key secondary efficacy endpoint of EFS will be performed as 
follows:  
● 
Same analysis as primary analysis, but on FAS, which includes all randomized subjects 
who are FLT3 mutated subjects based on central test; 
● 
Same analysis as primary analysis, but on PPS, which includes all subjects in ITT and do 
not have any major PDs; 
● 
Stratified Cox proportional hazard model with strata to control for response to first-line 
AML therapy and preselected salvage chemotherapy on ITT;  
● 
EFS will be defined similarly as in Section 5.3.2.2, however the date of the first new 
anti-leukemia therapy after end of study treatment or the last treatment evaluation (when 
new anti-leukemia therapy date is not available) will be used as the event date of 
treatment failure; 
● 
EFS will be defined similarly as in Section 5.3.2.2, however subjects who discontinued 
the treatment due to “Lost to follow up” will also be considered as an EFS event and the 
subjects will be censored at the date of “Lost to follow up”. 
CR rate: 
The key secondary efficacy endpoint of CR rate will be tested 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 
0.0245 significance level, the hypothesis testing on CR rate will be performed only if the null 
hypothesis on EFS is rejected at its corresponding significance level for second interim 
analysis and final analysis.   


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Sensitivity analysis for CR rate will be performed as follows: 
● 
CMH test on subjects in ITT and received at least one dose of study treatment 
● 
CMH test on subjects in ITT with at least one post-baseline bone marrow assessment 
● 
Un-stratified Fisher’s exact test on subjects in ITT 
7.4.2.2 Secondary Efficacy Analyses 
The statistical analyses on secondary efficacy endpoints include: 
● 
Stratified log-rank test on duration of remission and LFS 
● 
CMH method on the CRc rate and transplantation rate 
● 
Transfusion conversion rate and transfusion maintenance rate will be summarized by 
descriptive statistics 
● 
Analysis of covariance (ANCOVA) model to analyze the change in the BFI global 
fatigue score (average of all 9 items) 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 ANCOVA model 
will be used for resource utilization counts (hospital stays, duration of medications, blood 
transfusions, antibiotic iv infusions, medication for AEs and opioid medication). 
ANCOVA model will be used to analyze the change in the FACIT-Dys-SF domain scores 
from baseline to post-baseline visits. 
ANCOVA 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. 
ANCOVA 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, race, region, 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, 
ophthalmologic assessments and ECOG.  Descriptive statistics will be used to summarize 
safety data. All safety data will be performed on the SAF. 


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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 to 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. 
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. 
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. 


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7.5.6 
Ophthalmologic Assessment 
Ophthalmologic variables will be summarized by treatment group at each visit for each eye. 
7.5.7 
Eastern Cooperative Oncology Group Performance Scores 
ECOG performance scores will be summarized by treatment group and visit. 
7.6 
Analysis of Pharmacokinetics 
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 
benchmark data or the salvage chemotherapy group while the study is ongoing, two interim 
analyses are planned. 
First Interim Analysis 
The first interim analysis is planned when approximately 141 subjects are randomized into 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for 
subjects who received no study drug). At the first interim analysis, only the co-primary 
endpoint of CR/CRh rate will be evaluated in the ASP2215 arm only. The descriptive 
statistics including two-sided 95% exact CI of CR/CRh rate will be provided to IDMC. The 
historical control of the CR/CRh rate is considered to be 12%. The IDMC will evaluate the 
CR/CRh rate and inform the Sponsor if the lower limit is higher than the historical control or 
not. The study conduct will not be impacted by the first interim analysis result. 
A nominal 1-sided p-value 0.0005 (i.e., 2-sided p-value 0.001), which is arbitrarily selected, 
will be spent to acknowledge the single-arm CR/CRh rate evaluation at the first interim 


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analysis, and will not be recycled in the second interim analysis and final analysis. No formal 
hypothesis testing will be conducted for CR/CRh rate for the study, only the descriptive 
statistics including 2-sided 95% exact CI of CR/CRh rate will be provided to IDMC at the 
first interim. The hypothesis testing for the primary and secondary endpoints of OS, EFS and 
CR rate at the secondary interim analysis and final analysis are well controlled at an overall 
1-sided type I error rate 0.0245 based on a sequential testing procedure. 
Second Interim Analysis 
The second interim analysis will be performed when approximately 50% of the total planned 
death events (death events = 129) have occurred in the study. OS will be tested at 1-sided 
0.00147/0.38674 significant level for efficacy/futility according to the O’Brien-Fleming type 
alpha/beta spending function.  
The IDMC may recommend terminating the trial for favorable or unfavorable results at the 
second interim analysis based on OS endpoint. In the case of favorable results (i.e., the 
1-sided P-value is less than 0.00147), the IDMC may recommend terminating the trial for 
success. In the case of unfavorable results (i.e., the 1-sided P-value is greater than 0.38674), 
the IDMC may recommend terminating the trial for futility. 
EFS will be tested when the null hypothesis of OS is rejected at the second interim. CR rate 
will be tested when the null hypotheses of both OS and EFS are rejected at the second interim. 
Their significance levels at the second interim and final interim will be based on Pocock/ 
O’Brien-Fleming alpha/beta spending function. See Table 9 below for details about the 
significance levels at each interim and final analyses for each co-primary and secondary 
endpoints. 
Details for the interim analyses, 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 the available data.  
If the study is not stopped after the second interim analysis, a final analysis based on OS will 
occur after 100% of the total planned death events (death events = 258) have been observed. 
The 1-sided significance level for the final analysis is 0.02402 for OS.  
 


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Table 9 
Summary of Timing, Sample Size and Decision Guidance at the Planned 
Analyses 
Analysis 
Criteria for 
Conduct of 
Analysis 
(Projected 
timing) 
Endpoint/ 
Analysis Set 
Efficacy Boundary* 
Futility Boundary* 
P-value 
(1-sided) 
at the 
Boundary 
Approx. 
Observed 
HR at 
Boundary 
P-value  
(1-sided)  
at the 
Boundary 
Approx. 
Observed 
HR at 
Boundary 
IA1: 
CR/CRh rate 
When 141 
subjects are 
randomized 
into ASP2215 
arm and at 
least 112 days 
(4 treatment 
cycles) post 
first dose or 
randomization 
(for subjects 
who received 
no study drug) 
CR/CRh 
rate/ASP221 
5 subjects in 
RAS 
NA 
(0.0005 
nominal) 
NA 
NA 
NA 
IA 2: 
OS; EFS when 
null hypothesis 
of OS is rejected; 
CR rate when 
null hypotheses 
of both EFS and 
OS are rejected 
Approx. 129 
OS events are 
observed 
OS/ITT 
0.00147 
0.57 
0.38674 
0.95 
EFS/ITT 
0.01519 
0.67 
0.30218 
0.91 
CR rate/ITT 
0.01519 
NA 
0.30218 
NA 
Final: 
OS; EFS when 
null hypothesis 
OS is rejected; 
CR rate when 
null hypotheses 
of both EFS and 
OS are rejected 
Approx. 258 
OS events are 
observed  
OS/ITT 
0.02402 
0.77 
NA 
NA 
EFS/ITT 
0.01357 
0.75 
NA 
NA 
CR rate/ITT 
0.01357 
NA 
NA 
NA 
CR: complete remission; CR/CRh: complete remission and complete remission with partial hematological 
recovery; EFS: event-free survival; HR: hazard ratio; ITT: intention to treatment set; NA: not applicable; OS: 
overall survival; RAS: response analysis set . 
*: P-value at both efficacy and futility boundaries(except the first interim) are based on 50% information 
fraction for OS, EFS and CR rate, and need update based on observed information fraction at the second interim 
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.  


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8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
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. 
For screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
Subject diaries and 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 diary and 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) 


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● 
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 
(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 Global 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. 


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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.   
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. 


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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. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies or for Astellas Pharma Europe 
B.V./Astellas Pharma Europe Ltd.-sponsored studies within 1 year after last subject out or 
termination of the study. 
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. 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
● 
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. 
● 
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 


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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., 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 
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. 
Specifc to Japan: After agreement between investigator(s) and Sponsor, the manuscript can 
be submitted for publication.   


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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 
● 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO (Specific to Japan) 
● 
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 and dated FDA form 1572, if conducted under a United States IND 
● 
Signed Investigator's Statement in this protocol and eCRF 
● 
Current Curricula Vitae of all investigators 
● 
List of subinvestigators and collaborators 
● 
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY) 
● 
Instruction and decision of the head of the study site (Specific to Japan) 
● 
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 (for United States sites, 2 years 
after approval of the New Drug Application (NDA) or discontinuation of the IND). 
The following paragraph does not apply to Japan. 
The Sponsor will notify the site/investigator if the NDA/MAA/J-NDA is approved or if the 
IND/IMPD/CHIKEN TODOKE is discontinued. The investigator agrees to obtain the 
Sponsor's agreement prior to disposal, moving, or 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. 


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The following paragraphs are applicable to investigational sites in Japan: 
The records to be retained at the study sites are the ones listed as essential documents in GCP.  
These records shall be retained by the head of the study site or the record keeper designated 
by the head until notice issued by the Sponsor on completion of the retention period is 
received. These documents are also subject to direct access and should be provided upon 
request from the Sponsor or regulatory authorities. 
The head of the study site will retain the essential documents that should be stored at the study 
site in an appropriate manner according to the rules of the study site concerned until the date 
defined in points 1 or 2 below, whichever comes later. 
● 
Approval date of marketing of the test drug (if development of the drug is stopped, until 
3 years after the decision to discontinue development is notified) 
Until 3 years after discontinuation or termination of the study. 
The following are the major documents to be retained at the study site, wherever applicable. 
● 
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. 
● 
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 
subinvestigators, list of signatures and print of seals (copy), and case report forms 
(copy), etc. 
● 
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. 


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● 
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.  
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). In 
Japan, it is followed by the approval of the head of the study site. 
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. 
Specific to Japan: 
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study site, the Sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the study-
related injury is provided by the following procedures: 
● 
If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and other necessary measures. The Sponsor should be 
notified of the injury. 
● 
When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the Sponsor. Both parties should work together towards 
compensation settlement. 
● 
The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract. 


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● 
The Sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above. 
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 
The IDMC will be responsible for the review of subject safety, enrollment rates and event 
(death) rates during the second interim analysis when approximately 50% of the planned 
death events have occurred in the study. The IDMC may recommend terminating the trial for 
favorable or unfavorable results at the interim analysis. Additionally, during the first interim 
analysis, the IDMC will inform the Sponsor if the lower boundary of 95% CI of CR/CRh rate 
in ASP2215 arm is higher than benchmark rate or not. 
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 
Specific to sites in Japan:  The Japan site contact list is kept as a separate attachment to the 
protocol. 


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11 
REFERENCES 
American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 2014. 
ASP2215 Investigator’s Brochure, 2015. 
Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, et al. Axl, a 
prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of 
leukemia cells with bone marrow stroma. Blood. 2013;122:2443-52. 
Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, et al. Impact of FLT3 internal tandem 
duplication on the outcome of related and unrelated hematopoietic transplantation for adult 
acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol.  
2012;30:735-41. 
Burnett AK, Knapper S. Targeting treatment in AML. Hematology Am Soc Hematol Educ Program. 
2007:429-34. 
Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality 
of life in leukemia: the Functional Assessment of Cancer Therapy--Leukemia (FACT-Leu) 
questionnaire. Value Health. 2012;15:1051-8. 
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. 
Itzykson R, Thépot S, Berthon C, Delaunay J, Bouscary D, Cluzeau T, et al. Azacitidine for the 
treatment of relapsed and refractory AML in older patients. Leuk Res. 2015;39:124-30. 
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. 
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. 
Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, 
signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 
2008;100:35-83. 


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Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 
1999;85:1186-96. 
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. 
Park IK, Mishra A, Chandler J, Whitman SP, Marcucci G, Caligiuri MA. Inhibition of the receptor 
tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute 
myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 
2013;121:2064-73. 
Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, et al. Fludarabine, 
cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic 
syndromes and acute myeloid leukaemia. Br J Haematol. 1997;99:939-44. 
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. 
Paul M, Ram R, Kugler E, Farbman L, Peck A, Leibovici L, et al. Subcutaneous versus intravenous 
granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato-
oncological patients: randomized controlled trial. Am J Hematol. 2014; 89(3):243–248. 
Roboz GJ, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, et al. International 
randomized phase III study of elacytarabine versus investigator choice in patients with 
relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014 Jun 20;32(18):1919-26. 
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 
(SAKK). Leukemia. 1999;13:1352-8. 
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 
other novel agents. Hematology Am Soc Hematol Educ Program. 2005:143-50. 
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. 


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Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem 
duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. 
Leukemia. 2005;19:1345-9. 
Yap GY, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89:1363-72. 
 


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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) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf 


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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 
 
 


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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.  
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 
Source:  Yap GY, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89:1363-72. 
 


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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, 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.  


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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 
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: 
● 
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) 
● 
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 
3 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 count 
Chemistry 
10 mL into serum tube 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Glomerular filtration rate 
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 
Table continued on next page 
Footnotes


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Panel/ Assessment 
Matrix/Collecting Tube 
Parameters to be Analyzed 
Coagulation Profile 
(PT/INR, aPTT, D-
dimer, fibrinogen)  
2.5 mL into sodium citrate 
tube 
INR 
PT 
aPTT 
Fibrinogen (Screening Only) 
D-dimer (Screening Only) 
Urinalysis 
Dipstick 
Color 
Appearance 
Specific Gravity 
pH 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
Protein 
Urobilinogen 
Bone Marrow 
Aspirate 3 mL EDTA, 2 -
 3 bedside smear slides 
and/or biopsy (or peripheral 
blood in the event of a dry 
tap) 
Blast Count and Cell Countsa 
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 Event]. 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 5.5.5 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. 


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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 
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 
1 line of therapy. HSCT by itself and hydroxyurea are not considered to be lines of therapy.  


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12.7 
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).    
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 on Table 1 and Table 2 unless the site 
principal investigator (PI) 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 to 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 and 
Table 2 is expected, where plausible, in the case of a crisis. The alternate measures as noted 
in Table 10 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 and Table 2.  
 


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Table 10 
Schedule of Assessments for ASP2215 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 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
TREATMENTS 
ASP2215 Dosing at the Clinica 
Courier service directly to patient 
X 
X 
X 
X 
X 
X 
X 
SAFETY ASSESSMENTS 
Physical Examinationb
The exam can be done at a local clinic 
and the results submitted to PI. 
Xc 
X 
X 
X 
X 
X 
X 
Vital Signs 
Can be performed at a local clinic per 
SOC and results submitted to PI for 
evaluation 
Xc 
X 
X 
X 
X 
X 
X 
ECOG Performance 
ECOG status can be done by phone 
contact at each visit. 
Xc 
X 
X 
X 
X 
12-lead ECGd
ECG testing can be completed at local 
clinic 
X 
Xe 
Xe 
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 Medications 
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 
Footnotes


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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 
Thyroid Function Testf 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
 
 
 
 
 
 
 
Xf 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation, urinalysis)g 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
Xc 
Xc 
Xc 
 
Xc 
Xc 
Xc 
Xc 
Pregnancy Test for Woman of Childbearing 
Potential 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
X 
 
 
 
 
X 
 
X 
Bone Marrow Aspiration and/or Biopsy 
Perform BM biopsy in a local facility 
acceptable if results can be made 
available to investigative site 
 
 
 
 
Xh 
Xh 
 
Xh 
Ophthalmologic Assessmenti 
None since the assessment cannot be 
performed at local clinic  
 
 
 
 
 
Xi 
 
Xi 
SAMPLING 
PK (whole blood samples for plasma PK) 
Astellas Medical Monitor to assess. 
Not allowed at an alternate clinical due 
to special sample handling 
Xj 
 
Xj 
 
Xj 
Xj 
 
Xj 
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-IDA: fludarabine, cytarabine and granulocyte colony-stimulating factor with 
idarubicin; 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; PI: principal investigator; PK: pharmacokinetic; PT: 
prothrombin time; SAE: serious adverse event. 
Footnotes continued on next page 


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a. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
b. 
Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
c. 
Obtained predose. 
d. 
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. 
e. 
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. 
f. 
Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.).   
g. 
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. 
h. 
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. 
i. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy during the screening period, day 1 (± 7 days) of cycle 2, day 1 (± 7 days) of every 
2 cycles thereafter, and when clinically indicated.  In symptomatic subjects, the ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields performed 
by Humphrey method and optical coherence tomography. 
j. 
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 (within1 hour before 
drug administration).  See Section 7.6.   
 
 


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INVESTIGATIONAL MEDICINAL PRODUCT 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 shipments of IMP 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 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 4 
I.  The purpose of this amendment is: 
Nonsubstantial Changes 
1. Extension of Planned Study Period and Related Safety Analysis 
DESCRIPTION OF CHANGE: 
This modification and clarification impacts the planned study period and the treatment 
discontinuation of individual subject(s) as well as the statistical analysis. 
The end of the planned study period is extended from March 2020 to December 2021 to 
allow subject(s) to remain on study drug treatment before they can transition to commercial 
supply. 
The individual subjects discontinuation from the study is clarified further based on 
commercial supply once ASP2215 has achieved marketing authorization, commercial 
availability, and applicable reimbursement in the country of residence after completing 
≥ 3 years of the study drug treatment. 
The long-term safety analysis is added for subjects completing ≥ 3 years of study drug 
treatment. 
Section 2.2.1 (Study Design), Section 6.1 (Discontinuation of Individual Subjects) and 
Section 7.1 (Sample Size) are updated to reflect the changes accordingly. 
 
RATIONALE: 
Extending the planned study period will allow subject(s) to be transitioned to commercial 
supply once ASP2215 achieves marketing authorization, commercial availability and 
applicable reimbursement in the country of residence as well as demonstrate safety for 
long-term treatment with ASP2215. 
 
2. Add Appendix for Clinical Study Continuity 
DESCRIPTION OF CHANGE: 
A Clinical Study Continuity appendix is added to the protocol. The appendix contains 
procedures for continuity of care during a crisis. An alternative schedule of assessments is 
provided. 
 
RATIONALE: 
This appendix is assed to provide acceptable alternate methods to assess safety and efficacy 
parameters in the event the clinical study is interrupted at the country, state, site or 
participant level during any crisis (e.g., natural disaster or pandemic). 
 
3. Minor Administrative-type Changes 
DESCRIPTION OF CHANGE:  
Include minor administrative-type changes, e.g., typos, format, numbering, consistency 


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throughout the protocol, and update of study personnel.   
 
RATIONALE: 
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures. 
 








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Phone No.:  03 5565 3311 (Main), 03 6821 0943 (Dial in) 06-4560-6826  
Fax: 03-5565-3312 
CRO’s personnel:  
  
Contact Numbers during Nonbusiness Hours and for Emergency:  
Phone No.:   
 
 
)  
 
IV Synopsis, Planned Study Period 
WAS: 
From August 2015 to March 2020 (including long-term follow-up period) 
 
IS AMENDED TO: 
From August 2015 to March 2020 December 2021 (including long-term follow-up period) 
 
IV Synopsis, Study Design Overview and 2 Study Objectives, Design and Endpoints 
2.2.1 Study Design 
WAS: 
After treatment discontinuation, subjects will have a pre-HSCT/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 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.  
The second interim analysis will be performed when approximately 50% of the planned total 
number of deaths (death events = 129 of planned 258 death events) by any cause have 
occurred. . The second interim 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 second interim analysis demonstrates a 
more favorable outcome for ASP2215 based on OS, enrollment to the study may be stopped. 
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 or upon marketing authorization and commercial availability and reimbursement of 
ASP2215 in the country of residence. 
 
IS AMENDED TO: 
After treatment discontinuation, subjects will have a pre-HSCT/end of treatment visit within 
7 days after treatment discontinuation, followed by a 30-day follow-up, in which a telephone 
PPD
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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 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 as follows: every 3 months, for up to 3 years from the subject’s end of treatment visit.  
The second interim analysis will be performed when approximately 50% of the planned total 
number of deaths (death events = 129 of planned 258 death events) by any cause have 
occurred. . The second interim 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 second interim analysis demonstrates a 
more favorable outcome for ASP2215 based on OS, enrollment to the study may be stopped. 
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 the assigned study treatment if one or more of the following 
conditions have been met: 
• 
until they the subject has meet met a treatment discontinuation criterion as outlined 
in Section 6 or upon marketing authorization and commercial availability and reimbursement 
of ASP2215 in the country of residence upon 3 years from the last subject’s end of treatment 
visit for 2215 arm subjects. 
• 
after ≥ 3 years of study drug treatment have been completed for all subjects*  
*At that point, subject(s) can be transitioned to commercial supply once ASP2215 
achieves marketing authorization, commercial availability and applicable 
reimbursement in the country of residence. Once a subject(s) transitions to commercial 
supply, the subject(s) will be discontinued from the study. 
 
IV Synopsis 
Duration of Treatment 
WAS: 
For subjects taking ASP2215, LoDAC or azacitidine, treatment should continue. 
 
IS AMENDED TO: 
For subjects taking ASP2215, LoDAC or azacitidine, treatment should continue until the 
subject meets a treatment discontinuation criterion. 
 
5 Treatments and Evaluation 
5.8 Total Amount of Blood 
DELETED: 
Discontinuation 
Subjects will be eligible to continue receiving treatment in this study until they meet a 
discontinuation criterion as outlined in [Section 6] or upon marketing authorization and 


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commercial availability of ASP2215 in the country of residence. 
 
IV Synopsis, Statistical Methods and 7 Statistical Methodology 
7.1 Sample Size 
WAS: 
The first interim analysis is planned when approximately 141 subjects are randomized into 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for 
subjects who received no study drug). The second interim analysis is planned when 
approximately 129 death events have occurred and the final analysis is planned when 
approximately 258 death events have occurred.   
 
IS AMENDED TO: 
The first interim analysis is planned when approximately 141 subjects are randomized into 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for 
subjects who received no study drug). The second interim analysis is planned when 
approximately 129 death events have occurred and the final analysis is planned when 
approximately 258 death events have occurred. After the completion of the final (primary) 
analysis when approximately 258 death events have occurred, additional data summary 
for subjects is planned when ≥ 3 years of study drug treatment have been completed. 
 
6 Discontinuation 
6.1 Discontinuation of Individual Subject(s) 
WAS: 
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 of ASP2215 in the country of residence. 
 
IS AMENDED TO: 
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 of ASP2215 
in the country of residence if one or more of the following conditions have been met: 
• 
until the subject has met a treatment discontinuation criterion as outlined Section 6.1.1  
• 
after ≥ 3 years of study drug treatment have been completed for all subjects* 
*At that point, subject(s) can be transitioned to commercial supply once ASP2215 achieves 
marketing authorization, commercial availability and applicable reimbursement in the country 
of residence. Once a subject(s) transition to commercial supply, the subject(s) will be 
discontinued from the study. 
 
12 Appendices 
12.7 Clinical Study Continuity 
ADDED: 


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12.7 
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).    
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 on Table 1 and Table 2 unless the 
site PI 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 


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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 to avoid placing a burden on the participant with respect to travel. 
• 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 
and Table 2 is expected, where plausible, in the case of a crisis. The alternate measures 
as noted in Table 11 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 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 and Table 2.  
INVESTIGATIONAL MEDICINAL PRODUCT 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 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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12 Appendices 
12.7 Clinical Study Continuity 
ADDED: 
Table 1 
Schedule of Assessments for ASP2215 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 9 
Day 15 
± 1 
Day 1 
± 2 
Day 15 
± 1 
Day 1 
± 2 
TREATMENTS 
ASP2215 Dosing at the Clinica 
Courier service directly to patient 
X 
X 
X 
 
X 
X 
X 
X 
SAFETY ASSESSMENTS 
Physical Examinationb 
The exam can be done at a local 
clinic and the results submitted to 
PI. 
Xc 
X 
X 
 
X 
X 
X 
X 
Vital Signs 
Can be performed  at a local clinic 
per SOC and results submitted to 
PI for evaluation 
Xc 
X 
X 
 
X 
X 
X 
X 
ECOG Performance 
ECOG status can be done by phone 
contact at each visit. 
Xc 
 
 
 
X 
X 
X 
X 
12-lead ECGd 
ECG testing can be completed at 
local clinic 
X 
 
Xe 
Xe 
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 Medications 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits.   
Please refer to protocol schedule of 
assessments. 
X 
X 
X 
 
X 
X 
X 
X 
LABORATORY TESTS 


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Thyroid Function Testf 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
 
 
 
 
 
 
 
Xf 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation, urinalysis)g 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
Xc 
Xc 
Xc 
 
Xc 
Xc 
Xc 
Xc 
Pregnancy Test for Woman of 
Childbearing Potential 
Visit collection of samples at local 
facility acceptable if results can be 
made available to investigative site 
X 
 
 
 
 
X 
 
X 
Bone Marrow Aspiration and/or 
Biopsy 
Perform BM biopsy in a local 
facility acceptable if results can be 
made available to investigative site 
 
 
 
 
Xh 
Xh 
 
Xh 
Ophthalmologic Assessmenti 
None since the assessment cannot 
be performed at local clinic  
 
 
 
 
 
Xi 
 
Xi 
SAMPLING 
PK (whole blood samples for plasma 
PK) 
Astellas Medical Monitor to assess. 
Not allowed at an alternate clinical 
due to special sample handling 
Xj 
 
Xj 
 
Xj 
Xj 
 
Xj 
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-IDA: fludarabine, cytarabine and granulocyte colony-stimulating 
factor with idarubicin; 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; PI: 
principal investigator; PK: pharmacokinetic; PT: prothrombin time; SAE: serious adverse event. 
Footnotes continued on next page 
a.     ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
b.     Height measurement performed only at screening. Weight measurement should be performed at screening and day 1 of each cycle. 
c.     Obtained predose. 
d.     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. 


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e.    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. 
f.     Thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.).   
g.    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. 
h.     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. 
i.     Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy during the screening period, day 1 (± 7 days) of cycle 2, day 1 (± 7 days) of 
every 2 cycles thereafter, and when clinically indicated.  In symptomatic subjects, the ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields 
performed by Humphrey method and optical coherence tomography. 
j.     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 (within1 hour 
before drug administration).  See Section 7.6.   
 
 


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III.  Non-Substantial Amendment Rationale: 
Rationale for Nonsubstantial Designation 
This is a nonsubstantial amendment in that there is an increase in the duration of the trial in 
which exposure to treatment with the study drug is not extended, the definition of the end of 
the trial is unchanged and patient monitoring activities are unchanged. 
 


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14 
SPONSOR’S SIGNATURES  
 
Astellas Signatories 
(Electronic signatures are attached at the end of the document.) 
 
TA Oncology 
 
Statistics Biostatistics 
  
CPED (GCPL) 
 
Medical Affairs, Japan 
Operational Excellence 
 
PPD
PPD
PPD
PPD

SAP_003.pdf: 
Sponsor: Astellas Pharma Global Development, Inc. 
SAP Final Version 4.0 
ISN/Protocol 2215-CL-0301 
31-May-2022 
Astellas 
Page 1 of 73 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Final Version 4.0, dated 31-MAY-2022 
 
A 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-0301 
 
IND number: 117,548 
 
 
 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
 
1 Astellas Way 
Northbrook, IL 60062 
 
 
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: Astellas Pharma Global Development, Inc. 
SAP Final Version 4.0 
ISN/Protocol 2215-CL-0301 
31-May-2022 
Astellas 
Page 2 of 73 
Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 5 
1 
INTRODUCTION ································
································
··················
 9 
2 
FLOW CHART AND VISIT SCHEDULE ································
···················
 10 
3 
STUDY OBJECTIVES AND DESIGN ································
························
 19 
3.1 
Study Objectives ································
································
··············
 19 
3.1.1 
Primary Objectives ································
································
······  19 
3.1.2 
Secondary Objectives ································
································
···  19 
3.1.3 
Exploratory Objectives: ································
································
· 20 
3.2 
Study Design ································
································
···················
 20 
3.2.1 
Study Design ································
································
·············
 20 
3.3 
Randomization ································
································
·················
 22 
4 
SAMPLE SIZE································
································
·····················
 22 
5 
ANALYSIS SETS ································
································
·················
 24 
5.1 
Intention to Treatment Set (ITT) ································
····························
 24 
5.2 
Full Analysis Set (FAS) ································
································
······  24 
5.3 
Safety Analysis Set (SAF) ································
································
···  24 
5.4 
Pharmacokinetics Analysis Set (PKAS) ································
····················
 24 
6 
ANALYSIS VARIABLES ································
································
·······  25 
6.1 
Efficacy Endpoints ································
································
············
 25 
6.1.1 
Co-Primary Efficacy Endpoint of OS (Second Interim and Final only) ··········
 25 
6.1.2 
Co-Primary Efficacy Endpoint of CR/CRh Rate (First Interim only) ·············
 25 
6.1.3 
Secondary Efficacy Endpoints ································
·························
 26 
6.1.4 
Exploratory Endpoints ································
································
··  31 
6.1.5 
Other Efficacy Variables ································
·······························
 32 
6.2 
Safety Variables ································
································
···············
 33 
6.3 
Pharmacokinetics Variables································
································
··  34 
6.4 
Other Variables ································
································
················
 34 
7 
STATISTICAL METHODOLOGY ································
···························
 37 
7.1 
General Considerations ································
································
·······  37 
7.2 
Study Population ································
································
··············
 37 
7.2.1 
Disposition of Subjects ································
································
· 37 


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7.2.2 
Protocol Deviations ································
································
·····  38 
7.2.3 
Demographic and Other Baseline Characteristics ································
···  38 
7.2.4 
Previous and Concomitant Medications ································
··············
 39 
7.2.5 
Previous and Concomitant Transfusions ································
·············
 39 
7.2.6 
Prior AML Chemotherapy ································
·····························
 39 
7.2.7 
Non-Medication Therapy ································
·······························
 40 
7.2.8 
Clinical/Diagnostic Procedures ································
························
 40 
7.2.9 
Subsequent AML Therapy ································
·····························
 40 
7.3 
Study Drugs ································
································
····················
 40 
7.3.1 
Exposure ································
································
··················
 40 
7.4 
Analysis of Efficacy ································
································
··········
 41 
7.4.1 
Analysis of Co-Primary Endpoint of OS (Second Interim and Final only) ·······  42 
7.4.2 
Analysis of Co-Primary Endpoint of CR/CRh Rate (First Interim only) ·········  44 
7.4.3 
Analysis of Secondary Endpoints ································
·····················
 45 
7.4.4 
Analysis of Exploratory Endpoints ································
····················
 48 
7.4.5 
Analysis of Other Variables ································
····························
 49 
7.4.6 
Analysis of CR/CRh rate, Duration of CR/CRh and Time to first and best 
CR/CRh at Final Analysis ································
······························
 49 
7.5 
Analysis of Safety ································
································
·············
 50 
7.5.1 
Adverse Events ································
································
··········
 50 
7.5.2 
Clinical Laboratory Evaluation ································
························
 52 
7.5.3 
Vital Signs ································
································
················
 53 
7.5.4 
Electrocardiograms (ECGs) ································
····························
 54 
7.5.5 
Pregnancies ································
································
···············
 54 
7.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores ·············
 54 
7.5.7 
Ophthalmologic Assessment ································
···························
 54 
7.6 
Analysis of PK ································
································
·················
 54 
7.7 
Analysis of PD ································
································
·················
 55 
7.8 
Subgroups of Interest ································
································
·········  55 
7.9 
Other Analyses ································
································
················
 57 
7.9.1 
PK-PD Analysis ································
································
·········  57 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 57 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········  58 
7.11.1 
Missing Data ································
································
·············
 58 


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7.11.2 
Outliers ································
································
···················
 60 
7.11.3 
Visit Windows ································
································
···········
 60 
7.11.4 
Pooling Strata ································
································
············
 60 
7.11.5 
Blinding································
································
···················
 61 
8 
DOCUMENT REVISION HISTORY ································
·························
 62 
9 
REFERENCES ································
································
····················
 68 
10 
APPENDICES ································
································
·····················
 69 
10.1 
Appendix 1: Approvers ································
································
·······  69 
10.2 
Appendix 2: Blinding Process ································
·······························
 70 
10.3 
Appendix 3: Search Strategy for Adverse Events of Interest ····························
 71 
10.4 
Appendix 4: Japan Specific Analysis ································
·······················
 73 
10.4.1 
Introduction ································
································
··············
 73 
10.4.2 
Region Specific Analyses of Japan ································
····················
 73 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
APGD 
Astellas Pharma Global Development 
aPTT 
Activated Partial Thromboplastin Time 
ASCM 
Analysis Set Classification Meeting  
ASP2215 
Astellas Compound code for 2215 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical classification system 
BFI 
Brief Fatigue Inventory 
BQL 
Blow Quantification Limit 
CI 
Confidence Intervals 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Remission 
CRc 
Composite Complete Remission 
CRh 
Complete Remission with partial hematological recovery 
CRi 
Complete Remission with incomplete hematological recovery 
CRp 
Complete Remission with incomplete platelet recovery 
CRF 
Case Report Form 
CS 
Classification Specifications 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
EFS 
Event-Free Survival 
EQ-5D-5L 
EuroQol Group-5 Dimension-5 Level Instrument 
FAB 
French-American-British  
FACIT-Dys-SF 
Functional Assessment of Chronic Illness Therapy–Dyspnea-Short Forms 


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Abbreviations 
Description of abbreviations 
FACT-Leu 
Functional Assessment of Cancer Therapy-Leukemia 
FAS 
Full Analysis Set 
FLAG-IDA 
Fludarabine, cytarabine and granulocyte colony-stimulating factor with 
idarubicin 
FLT3 
FMS-like TyrosineKkinase 
GD 
Global Development 
GVHD 
Graft-versus-host disease 
H 
High 
HSCT 
Hematopoietic Stem Cell Transplant 
IAP 
Interim Analysis Plan 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug 
INR 
International Normalization Ratio 
IRT 
Interactive Response Technology 
ISN 
International Study Number 
ITD 
Internal Tandem Duplication 
ITT 
Intention to Treatment Set 
IU/L 
International units/liter 
IV 
Intravenous 
L 
Low 
LFS 
Leukemia-Free Survival 
MEC 
Mitoxantrone, etoposide and intermediate-dose cytarabine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
Min 
Minute 
mL 
Milliliter 
mmHg 
millimeters of mercury 
MMRM 
Mixed-Effect Model Repeated Measure 
mRAS 
Modified Response Analysis Set 
msec 
milliseconds 
MUGA 
Multigated acquisition scan 
N 
Number 
N 
Normal 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NR 
No Response 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PD 
Protocol Deviation 
PGx 
Pharmacogenetics 


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Abbreviations 
Description of abbreviations 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic Analysis Set 
PPS 
Per Protocol Set 
PR 
Partial Remission 
PRO 
Patient reported outcome 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QD 
quaque die, a Latin phrase meaning “every day” 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s factor 
RAS 
Response Analysis Set 
RBC 
Red Blood Cell 
RR 
Interval between 2 consecutive r waves on an ECG 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TKD 
Tyrosine kinase domain 
TLF 
Tables, Listings and Figures 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 


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List of Key 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. 
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. 
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. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
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. 
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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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.  
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, interim analysis, or accumulation of substantial amount of data in an open-label 
study to ensure lack of bias. For operational efficiency an earlier time is usually targeted and 
wherever possible, the SAP should be developed in parallel with protocol finalization. For 
Phase 2-4 studies the SAP should be developed and approved before First Subject In (FSI). If 
the expected interval between FSI and soft-lock is less than 12 weeks, then the SAP should 
be approved by 12 weeks prior to the planned date of soft-lock.  If needed, revisions to the 
approved SAP may be made prior to database hard lock. Revisions will be version controlled. 
This statistical analysis is coordinated by the responsible biostatistician of GD-US. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR). 
SAP version 3.0 dated 27 SEP 2018 has described the final analysis of primary, secondary, 
and exploratory efficacy endpoints with the data cutoff date of 17 SEP 2018. There will be no 
efficacy analysis performed for the end-of-study report. The End of Study analysis will be 
performed on safety data only and COVID-19 related data will be listed. 
 




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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 
 
Xp 
 
 
 
 
 
 
 
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)o 
X 
 
 
 
 
 
 
 
 
12-lead ECGe 
Xg 
X 
 
Xs 
Xs 
X 
X 
 
X 
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)f 
Xg 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Thyroid Function Testt 
X 
 
 
 
 
 
 
 
Xt 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
 
MUGA or ECHOh 
X 
 
 
 
 
 
 
 
 
Ophthalmologic Assessmenti 
X 
 
 
 
 
 
X 
 
X 
FLT3 Mutation Statusj (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xk 
 
 
 
 
 
Xk 
 
Xk 
AE/SAE Assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
PK (whole blood samples for plasma PK) 
 
Xl 
 
Xl 
 
Xl 
Xl 
 
Xl 
PGxm 
 
X 
 
 
 
 
 
 
 
Patient Reported Outcome Toolsq, r 
 
Xa 
 
Xq 
 
Xq 
X 
Xq 
X 
EQ-5D 5Lr 
 
Xa 
 
 
 
 
X 
 
X 
Resource Utilization 
 
Xa 
 
 
 
 
X 
 
X 
IRT Transaction Requiredp 
X 
X 
 
 
 
 
X 
 
X 
ASP2215 Dosing at the Clinicn 
 
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;  
FLT3: FMS-like tyrosine kinase; ICF: Informed Consent Form; INR: international normalization ratio; IRT: interactive response technology; 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 read. 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. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy during the screening period, day 1 (± 7 days) of cycle 2, day 1 (± 7 days) of every 
2 cycles thereafter, and when clinically indicated.  In symptomatic subjects, the ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields performed 
by Humphrey method and optical coherence tomography. 
j. 
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. 
k. 
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. 
l. 
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 (1 hour before drug 
administration).  See Section 7.6 of the protocol. 
m. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomic study. 
n. 
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic. 
Footnotes continued on next page 


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o. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
p. 
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. 
q. 
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 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).    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). 
r. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
s. 
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 of the protocol. 
t. 
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 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 
 
Xp 
 
 
 
 
 
 
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)o 
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 Tests 
X 
 
 
 
 
 
 
Xs 
Coagulation Profile (PT/INR, D-dimer, fibrinogen) 
X 
 
 
 
 
 
 
 
MUGA or ECHOh 
X 
 
 
 
 
 
 
 
Ophthalmologic Assessment 
Xi 
 
 
 
 
Xi 
 
Xi 
FLT3 Mutation Statusj (bone marrow aspirate or whole blood) 
X 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or Biopsy 
Xk 
 
 
 
Xk 
Xk 
 
Xk 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
PGxl 
 
X 
 
 
 
 
 
 
Patient Reported Outcome Toolsq, r 
 
Xa 
 
Xq 
Xq 
X 
Xq 
X 
EQ-5D 5Lr 
 
Xa 
 
 
 
X 
 
X 
Resource Utilization 
 
Xa 
 
 
 
X 
 
X 
IRT Transaction Requiredp 
X 
X 
 
 
 
X 
 
X 
LoDAC or Azacitidine Dosing  
 
See Footnote m 
MEC or FLAG-IDA Dosing 
 
See Footnoten 
 
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-IDA: fludarabine, cytarabine and granulocyte colony-stimulating factor with 
idarubicin; 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 of the protocol. 
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 read. 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. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy during the screening period, day 1 (± 7 days) of cycle 2, day 1 (± 7 days) of every 
2 cycles thereafter, and when clinically indicated.  In symptomatic subjects, the ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields performed 
by Humphrey method and optical coherence tomography. 
j. 
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 lab.  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. 
k. 
For MEC and FLAG-IDA, bone marrow samples are required during screening and 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 a second cycle. For LoDAC or azacitidine, bone marrow samples are required during screening, and at cycle 2 day 1 and at 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 at 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 end of treatment visit and as clinically indicated.  If bone marrow aspirate is unobtainable (e.g., dry tap), an 
additional EDTA tube of peripheral 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. 
l. 
Whole blood and buccal swab collected at day 1 for optional pharmacogenomic study. 
m. 
LoDAC or azacitidine dosing may continue past cycle 2. 
n. 
Additional clinic visits are allowed per institutional guideline for subjects receiving MEC (days 1 through 5) or FLAG-IDA (days 1 through 6).  MEC and FLAG-IDA are 
administered for up to 2 cycles depending on response and safety assessments as described in Section 5.1 of the protocol. 
o. 
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of screening. 
p. 
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. 
Footnotes continued on next page. 
 


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q. 
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 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).  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). 
r. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
s. 
For subjects receiving LoDAC or azacitidine, thyroid function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 


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Table 3 
Post-treatment Schedule of Assessments 
Activity 
Pre-HSCT Visit/ 
End of Treatment Visita 
30-Day 
Follow-up (+ 7 days Post Pre-HSCT 
Visit/Post End of Treatment Visit) 
Long-term Follow-up  
(+/- 7 days)h 
Physical Examination 
Xb 
 
 
Vital Signs 
Xb 
 
 
ECOG Performance 
Xb 
 
 
Concomitant Medications 
Xl 
 
 
Pregnancy Test for Woman of Childbearing Potential 
X 
 
 
12-lead ECG 
X 
 
 
Ophthalmologic Assessmentj  
X 
 
 
Clinical Laboratory Tests (chemistry, hematology, coagulation) 
Xb 
 
 
Thyroid Function Tests 
X 
 
 
Bone Marrow Aspiration and/or Biopsy  
Xc 
 
 
FLT3 Mutationsd (bone marrow or whole blood) 
X 
 
 
Patient Reported Outcome Toolsi,k 
X 
 
 
EQ-5D-5Lk 
X 
X 
X 
Resource Utilization 
X 
 
 
AE/SAE Assessment 
X 
Xe,f 
Xg 
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. 
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. 
d. 
FLT3 mutation analysis will be performed on the bone marrow samples collected post study treatment. 
Footnotes continued on next page 


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e. 
For subjects who plan to proceed to HSCT and resume ASP2215 treatment after HSCT, AE collection will continue until the start of the HSCT conditioning regimen and AE 
collection will resume upon the resumption of ASP2215 treatment until 30 days after the last dose of study drug.  For subjects who do not plan to resume ASP2215 treatment after 
HSCT, AE collection will continue until the start of the HSCT conditioning regimen or 30 days after the last dose of study drug, whichever comes first. However, the following 
AE/SAEs will continue to be collected until 30 days after the last dose of study drug, regardless of the time of the HSCT conditioning regimen:  
• 
Any study drug related AE that is ongoing will be followed until resolved 
• 
Any SAE that is deemed to be related to study drug by the investigator 
• 
Any event of veno-occlusive disease (VOD) of the liver, cardiac failure, Grade 3 or higher QT prolongation, rhabdomyolysis, drug-induced liver injury, or PRES 
• 
Adverse events leading to death 
f. 
Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
g. 
Only SAE data that is related to ASP2215 will be collected. 
h. 
Telephone contact every 3 months. Ad hoc contact will be required during interim analysis. 
i. 
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 BFI will be administered at pre-HSCT/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 pre-HSCT/end of treatment visit. 
j. 
Ophthalmologic assessment to be performed by visual acuity measurement and ophthalmoscopy, at the Pre-HSCT/end of treatment (+/- 7 days). In symptomatic subjects, the 
ophthalmologic assessment should also include slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT).  
k. 
If possible, patient reported outcome measures should be performed prior to any other assessments on that visit day. 
l. 
Concomitant medications should be collected for reported AE/SAEs through 30 days post dose for subjects who have discontinued.  For subjects who undergo HSCT, 
concomitant medications should be collected for reported AE/SAEs through start of conditioning treatment or 30 days post dose, whichever comes first. 
 


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3 
STUDY OBJECTIVES AND DESIGN 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
The primary objectives are 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. 
● Determine the efficacy of ASP2215 therapy as assessed by the rate of complete 
remission and complete remission with partial hematological recovery (CR/CRh) in 
subjects with FLT3 mutated AML who are refractory to or have relapsed after 
first-line AML therapy. 
3.1.2 
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 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 
● Complete remission with partial hematologic recovery (CRh) rate 
● Composite complete remission (CRc=CR+CRp+CRi) rate 
● Transfusion conversion rate; Transfusion maintenance rate 
● Transplantation rate 
● Patient reported fatigue (Brief Fatigue Inventory [BFI]) 
● Adverse events (AEs), safety labs, vital signs, ophthalmologic exams, 
electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) 
performance scores 
● Evaluation of ASP2215 (and metabolites as appropriate) plasma concentration and 
population pharmacokinetics (PK) 


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3.1.3 
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 
o mechanisms of acquired resistance 
● Exploratory (predictive) biomarkers of ASP2215 activity 
● Resource utilization in this study population including hospitalization, blood 
transfusion, antibiotic intravenous 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 Dimention-5 Level Instrument (EQ-5D-5L) 
3.2 
Study Design 
3.2.1 
Study Design 
This is a 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 140 centers in 
North America, Europe, Asia and rest of the world will participate in this study. 
Three hundred sixty nine subjects will be randomized.  The randomization of the 
369 subjects will be in a 2:1 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, azacitidine, MEC or FLAG-IDA.  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 of the protocol. 
For subjects taking ASP2215, LoDAC or azacitidine, treatment should continue until the 
subject meets a treatment discontinuation criterion. 
Subjects receiving MEC or FLAG-IDA 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 


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20% or greater with at least a 50% reduction in blasts, the subject may receive a second cycle 
of the same chemotherapy.  If bone marrow 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 bone 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 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 - 60 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 OS endpoint. 
After treatment discontinuation, subjects will have a pre-HSCT/end of treatment visit within 
7 days after treatment discontinuation, followed by a 30-day follow-up visit 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. 
Two interim analyses by an Independent Data Monitoring Committee (IDMC) will be 
conducted. The first interim analysis is planned when approximately 141 subjects are 
randomized into ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or 
randomization (for subjects who received no study drug). The first interim analysis will be 
performed to evaluate the efficacy endpoint of CR/CRh rate and the study conduct will not be 
impacted by the result of the CR/CRh rate.  
The second interim analysis will be performed when approximately 50% of the planned total 
number of deaths (death events =129 of planned 258 death events) by any cause have 
occurred. The second interim analysis will be utilized to determine whether the study should 
be terminated earlier than planned if ASP2215 has more favorable or harmful outcome than 


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the salvage chemotherapy group. Details of the interim analyses are described in 
Section 7.10. 
The End of Study analysis will be performed on safety data only. 
3.3 
Randomization 
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.  
Subjects will be randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. 
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-IDA, MEC) 
● 
Low intensity chemotherapy (LoDAC or azacitidine) 
4 
SAMPLE SIZE 
This is a group sequential design based on co-primary endpoint of OS using the 
O’Brien-Fleming boundaries (non-binding) as implemented by Lan-DeMets alpha/beta 
spending method (East®).  
The overall 0.025 one-sided type I error rate is allocated by 0.0005 and 0.0245 
(corresponding to 0.001 and 0.049 for two-sided type I error rates) for the two co-primary 
efficacy endpoints of CR/CRh and OS, respectively. The type I error (alpha) in the first 
interim analysis is a nominal alpha which is arbitrarily selected for acknowledgement of the 
CR/CRh rate evaluation at the first interim and will not be recycled in the second interim 
analysis and final analysis. 
Two interim analyses and one final analysis are planned. The first interim analysis is planned 
when approximately 141 subjects are randomized into ASP2215 arm and at least 112 days 
(4 treatment cycles) post first dose or randomization (for subjects who received no study 
drug). The second interim analysis is planned when approximately 129 death events have 
occurred and the final analysis is planned when approximately 258 death events have 
occurred.   


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OS:  
Approximately 369 subjects (the planned sample size with 10% dropout rate) will be 
randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy (246 subjects in the 
ASP2215 treatment arm and 123 subjects in the salvage chemotherapy arm).  The planned 
258 death events will provide about 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 one-sided 
0.0245 significance level. 
CR/CRh rate:  
The co-primary endpoint of CR/CRh rate will be evaluated only at the first interim analysis. 
One hundred and forty one subjects randomized to ASP2215 arm (211 subjects in total: 
141 in the ASP2215 arm and 70 in the salvage chemotherapy arm) with a minimum 
follow-up of 4 treatment cycles are considered to achieve a maximum width of 15.78% for 
the two-sided 95% exact confidence interval (CI) when the CR/CRh is expected to be in the 
5% to 30% range as summarized in the following table. A sample size of 141 subjects 
provides 80% power to exclude a CR/CRh rate of 12% using the two-sided 95% exact CI 
when the CR/CRh rate of ASP2215 is assumed to be 21%.  
Table 1: Observed CR/CRh with Exact 95% CI (N=141 in ASP2215 arm) 
Observed CR/CRh (n and %) 
95% Exact CI 
43 (30.50%) 
(23.03%, 38.80%) 
36 (25.53%) 
(18.57%, 33.55%) 
29 (20.57%) 
(14.23%, 28.18%) 
28 (19.86%) 
(13.62%, 27.41%) 
27 (19.15%) 
(13.01%, 26.62%) 
26 (18.44%) 
(12.41%, 25.84%) 
25 (17.73%) 
(11.82%, 25.05%) 
24 (17.02%) 
(11.22%, 24.26%) 
23 (16.31%) 
(10.63%, 23.46%) 
22 (15.60%) 
(10.04%, 22.66%) 
15 (10.64%) 
( 6.08%, 16.94%) 
8 ( 5.67%) 
( 2.48%, 10.87%) 
 
EFS and CR rate: 
The planned sample size with 258 EFS events will provide about 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) at the overall 1-sided 0.0245 significance level.  


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5 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
Safety Analysis Set (SAF) will be used for the analyses of safety variables. Pharmacokinetic 
Analysis Set (PKAS) will be used for pharmacokinetic analyses. The data from all 
randomized subjects will be included in the data listings. 
The ITT, SAF and PKAS analysis sets will be used for the final end-of-study report. 
5.1 
Intention to Treatment Set (ITT) 
The Intention to Treatment Set (ITT) consists of all subjects who are randomized. The 
subjects will be analyzed based on the randomized treatments. 
The ITT will be used for primary analyses of efficacy data. Selected demographic and 
baseline characteristics, patient reported outcomes and resource utilization. 
5.2 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) consists of all randomized subjects with FLT3 mutation based 
on central test. The subjects will be analyzed based on the randomized treatments.  
The selection of subjects for the FAS will be confirmed in the Analysis Set Classification 
Meeting (ASCM). 
The FAS will be used for sensitivity analyses of efficacy data Selected demographic and 
baseline characteristics will be summarized for the FAS. 
5.3 
Safety Analysis Set (SAF) 
The Safety Analysis Set (SAF) consists of all subjects who received at least one dose of study 
treatment (ASP2215 or salvage chemotherapy). The subjects will be analyzed based on the 
actual treatment received.  
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety variables.  
5.4 
Pharmacokinetics Analysis Set (PKAS) 
The Pharmacokinetics Analysis Set (PKAS) consists of the subset of the SAF who received 
at least one dose of ASP2215 for whom at least 1 plasma concentration datum is available 
and both the date and time of dosing on the day of PK sampling and the date and time of 
sampling are 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. 
The PKAS is used for all tables and graphical summaries of the PK data.  


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6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
There will be no efficacy analysis performed for the end of study report. Summaries of the 
primary, secondary, and exploratory efficacy results are available in the primary CSR dated 
24 JAN 2019 for the data with cutoff date 17 SEP 2018. 
6.1.1 
Co-Primary Efficacy Endpoint of OS (Second Interim and Final only) 
Overall survival (OS) is one of the co-primary efficacy endpoints. OS will be evaluated at the 
second interim and final analysis. No formal evaluation on OS will be conducted at the first 
interim. OS is defined as the time from the date of randomization until the date of death from 
any cause (death date – randomization date + 1).  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 – randomization date + 1). 
The date of last contact is the latest date that the subject is known to be alive by the cutoff 
date. The last contact date will be derived for subjects alive at the analysis cutoff date.  
Subjects with last contact date beyond the analysis cutoff date will be censored at the analysis 
cutoff date. 
As a sensitivity analysis, OS will be defined similarly as the above primary analysis, 
however, subjects who undergo an HSCT will be censored at the time of HSCT (HSCT date 
– randomization date +1).  
In addition, as another sensitivity analysis, OS will be defined similarly as the above primary 
analysis, however, subjects who initiate any new anti-leukemia therapy will be censored at 
the time of first new anti-leukemia therapy (first new anti-leukemia therapy date – 
randomization date +1). 
During second interim analysis and final analysis, only death events occurring on or prior to 
the cutoff date are counted as OS events. Subjects with death date after the cutoff date will be 
censored at the cutoff date. 
6.1.2 
Co-Primary Efficacy Endpoint of CR/CRh Rate (First Interim only) 
The co-primary efficacy endpoint of CR/CRh rate will be evaluated only at the first interim 
analysis. Complete remission and complete remission with partial hematologic recovery 
(CR/CRh) rate is defined as the number of subjects who achieve either CR or CRh (as 
defined in Section 6.1.3.3) at any of the post-baseline visit divided by the number of subjects 
in the analysis population. 
As a sensitivity analysis, CR/CRh rate by cycle 4 will be defined as the number of subjects 
who achieve CR/CRh by the end of 4 cycles treatment divided by the number of subjects in 
the analysis population. As another sensitivity analysis, CR/CRh rate prior to HSCT will be 
defined as the number of subjects who achieve CR/CRh prior to HSCT divided by the 
number of subjects in the analysis population. 


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6.1.3 
Secondary Efficacy Endpoints 
6.1.3.1 Key Secondary Efficacy Endpoints 
● Event-free survival (EFS)  
EFS is defined as the time from the date of randomization until the date of documented 
relapse (excluding relapse after PR), treatment failure or death from any cause within 
30 days after the last dose of study drug, whichever occurs first [earliest of (relapse date, 
treatment failure date, death date) – randomization date + 1].  
If a subject experiences relapse or death within 30 days after the last dose of study drug, 
the subject is defined as having EFS event related to either “relapse” or “death”, and the 
event date is the date of relapse or death. 
If a subject discontinues the treatment and fails to achieve any of the response of CR, 
CRp or CRi during the treatment period (subject with best response of PR or NR), the 
subject is defined as having EFS event related to treatment failure, and the event date is 
the randomization date. Subjects that discontinue the treatment with post-treatment 
disease assessment and best response of NE will be censored. 
For a subject who is not known to have relapsed or treatment failure or death, EFS is 
censored at the date of last relapse-free disease assessment (last relapse-free disease 
assessment date – randomization date +1). Subject is not censored at HSCT. For subjects 
who are censored, last relapse-free disease assessment date refers to the subject’s last 
disease assessment date. Subject without post-treatment disease assessment or without 
study treatment will be censored at randomization date. 
EFS will be tested at the second interim and final analysis only when OS is rejected. No 
formal evaluation on EFS will be conducted at the first interim. During second interim 
analysis and final analysis, only death, relapse, treatment failure occurring on or prior to 
the cutoff date are counted as EFS events. Subjects without these events before cutoff 
date will be censored at the last relapse-free disease assessment date post-baseline on or 
before the cutoff date. 
Disease assessment date refers to the date of central bone marrow aspiration or biopsy 
assessment. In the event that central bone marrow assessment is not performed or bone 
marrow is not adequate, local bone marrow assessment date will be used. If no aspirate or 
biopsy is available and subject is evaluated based on blast count from peripheral blood 
the date the peripheral blood sample is drawn will be used. If none of the above is 
available and subject is evaluated based on the presence of extramedullary leukemia, the 
assessment date of extramedullary leukemia will be used. 
The following sensitivity analyses for EFS will be conducted: 
- 
EFS will be defined similarly as the above primary analysis, however the date of the 
first new anti-leukemia therapy or the last treatment evaluation (when new anti-
leukemia therapy date is not available), will be used as the event date of treatment 
failure. 


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- 
Sensitivity analysis of EFS will be performed to evaluate the impact of loss to follow-
up on EFS. EFS will be defined similarly as the above primary analysis, however, 
subjects who discontinue the treatment due to “Lost to follow up” will also be 
considered as an EFS event (See Section 7.4.3.1 for details of “Lost to follow up” 
event), and the event date is withdrawal date or last evaluation date as collected on 
end of treatment, end of 30-day follow up, and end of long-term follow up CRF page 
whichever occurs first.  
- 
EFS will be defined similarly as the above primary analysis with the following 
differences: 
• Subjects who discontinue the treatment and achieve best response of NR only will 
be defined as treatment failure and the event date is the randomization date 
• Subjects who discontinue the treatment and achieve best response of CR, CRp, 
CRi or PR and experience relapse will be defined as relapse and the event date is 
the date of first NR after CR, CRp, CRi or PR. 
- 
EFS will be defined similarly as the above primary analysis, however, subjects who 
discontinue the treatment with post-treatment disease assessment and achieve best 
response of PR, NR or NE will be defined as treatment failure and the event date is the 
randomization date.  
● Complete remission (CR) rate  
CR rate is defined as the number of subjects who achieve the best response of CR divided 
by the number of subjects in the analysis population. As a sensitivity analysis, CR rate 
prior to HSCT will be defined as the number of subjects who achieve CR prior to HSCT 
divided by the number of subjects in the analysis population. 
CR rate will be tested at the second interim and final analysis only when both OS and 
EFS are rejected. No formal evaluation on CR rate will be conducted at the first interim.  
6.1.3.2 Other Secondary Efficacy Endpoints 
● Leukemia-free survival (LFS) 
LFS is defined as the time from the date of first CRc until the date of documented relapse 
(excluding relapse from PR) or death for subjects who achieve CRc (relapse date or death 
date – first CRc disease assessment date + 1). 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 
(last relapse-free disease assessment date – first CRc disease assessment date + 1). 
● Complete Remission with Partial Hematologic Recovery (CRh) Rate 
CRh rate is defined as the number of subjects who achieve CRh at any of the post-
baseline visits and do not have best response of CR divided by the number of subjects in 
the analysis population. 
● Composite Complete Remission (CRc) Rate 


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CRc rate is defined as the number of subjects who achieve the best response of CRc (CR, 
CRp or CRi) divided by the number of subjects in the analysis population. 
● Duration of remission 
Duration of remission includes duration of CRc (DCRc), duration of CR/CRh 
(DCRCRh), duration of CRh (DCRh), duration of CR (DCR), and duration of response 
(DR) (i.e., CRc + PR). 
Duration of CRc is defined as the time from the date of first CRc until the date of first 
documented relapse for subjects who achieve CRc (relapse date – first CRc disease 
assessment date + 1). Subjects who die without report of relapse are considered 
non-events and censored at their last relapse-free disease assessment date (last 
relapse-free disease assessment date – first CRc disease assessment date + 1). Other 
subjects who do not relapse on study are considered non-events and censored at the last 
relapse-free disease assessment date. 
Duration of CR/CRh is defined similarly as duration of CRc for subjects who achieve 
either CR or CRh. For subjects who achieve both CR and CRh, the first date will be used 
as the starting date of the duration. 
As a sensitivity analysis, Duration of CR/CRh will be defined similarly as the above, 
however deaths without report of relapse are considered as events. 
Duration of CRh is defined similarly as duration of CRc for subjects who achieve CRh. 
Duration of CR is defined similarly as duration of CRc for subjects who achieve CR.  
Duration of response is defined as the time from the date of either first CRc or PR until 
the date of documented relapse (i.e., the date of first NR after CRc or PR) for subjects 
who achieve CRc or PR (relapse date – first CRc or PR disease assessment date + 1). 
Subjects who die without report of relapse are considered non-events and censored at 
their last relapse-free disease assessment date (last relapse-free disease assessment date – 
first CRc or PR disease assessment date + 1). Other subjects who do not relapse on study 
are considered non-events and censored at the last response relapse-free disease 
assessment date. 
● 
Transfusion conversion rate and transfusion maintenance rate 
Transfusion conversion rate and transfusion maintenance rate will only be defined for 
subjects in ASP2215 arm. 
For the purpose of defining transfusion conversion rate and transfusion maintenance rate, 
transfusion status (independent vs. dependent) at baseline period and post-baseline period 
are defined in the following for subjects who took at least one dose of study drug: 
Baseline transfusion status: 
o Baseline period is defined as the period from 28 days prior to the first dose to 
28 days post first dose. For subjects who are on treatment <28 days, baseline 
period is from 28 days prior to the first dose until the end of treatment.   


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o Subjects are classified as baseline transfusion independent if there is no RBC or 
platelet transfusions within the baseline period; otherwise, the subject is baseline 
transfusion dependent.  
Post-baseline transfusion status (only defined for ASP2215 arm): 
o Post-baseline period is defined as the period from 29 days post first dose until last 
dose.  
o For subjects who are on treatment >=84 days, subjects are classified post-baseline 
transfusion independent if there is one consecutive 56 days without any RBC or 
platelet transfusion within post-baseline period. 
o For subjects who are on treatment >28 days but <84 days, if there is no RBC or 
platelet transfusion within post-baseline period, post-baseline transfusion status is 
not evaluable.  
o For subjects who are on treatment <=28 days, post-baseline transfusion status is 
not evaluable.  
o Otherwise, the subject is considered post-baseline transfusion dependent.     
Both transfusion conversion rate and maintenance rate are defined for subjects who has 
evaluable post-baseline transfusion status. 
Transfusion conversion rate is defined as the number of subjects who were transfusion 
dependent at baseline period but become transfusion independent at post-baseline period 
divided by the total number of subjects who were transfusion dependent at baseline 
period.  
Transfusion maintenance rate is defined as the number of subjects who were transfusion 
independent at baseline period and still maintain transfusion independent at post-baseline 
period divided by the total number of subjects who were transfusion independent at 
baseline period. 
As a sensitivity analysis, transfusion conversion rate and transfusion maintenance rate 
will be defined alternatively by considering all subjects who had not-evaluable post-
baseline transfusion status as transfusion dependent. 
● Transplantation rate 
Transplantation rate is defined as the percentage of subjects undergoing HSCT during the 
study period. 
● 
Brief fatigue inventory (BFI) 
BFI 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 averaging 
the scores of the 9 items. Other BFI scores will be derived per PRO SAP. 


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6.1.3.3 Response Definition 
Response to treatment will be defined per modified Cheson criteria [2003] as outlined below. 
Response will be derived using myeloblast counts from centrally evaluated bone marrow 
aspirate if it’s adequate. In case of non-adequacy, myeloblast counts from centrally evaluated 
bone marrow biopsy will be used. If neither central bone marrow aspirate nor biopsy is 
available, myeloblast counts will be imputed with locally evaluated bone marrow aspirate, if 
not available, locally evaluated bone marrow biopsy assessments. Centrally evaluated 
hematology results including ANC, platelet count and blast count in peripheral blood will be 
used in response derivation. Missing central hematology results will be imputed with local 
hematology results as collected on the eCRF.  
Response will be derived for all post-baseline visits on or after 21 days from first dosing date.  
● Complete Remission (CR) 
For subjects to be classified as being in CR at a post-baseline visit, they must have bone 
marrow regenerating normal hematopoietic cells and achieve a morphologic 
leukemia-free state and must have an absolute neutrophil count (ANC) ≥1 x 109/L and 
platelet count ≥ 100 x 109/L, and normal marrow differential with < 5% blasts, and they 
will be red blood cell (RBC) and platelet transfusion independent (defined as 1 weeks 
without RBC transfusion and 1 week without platelet transfusion). There must be no 
presence of Auer rods. There should be no evidence of extramedullary leukemia. The 
blast counts in peripheral blood must be ≤ 2%.  
● Complete Remission with Incomplete Platelet Recovery (CRp) 
For subjects to be classified as being in CRp at a post-baseline visit, they must achieve 
CR except for incomplete platelet recovery (< 100  109/L). 
● Complete Remission with Incomplete Hematological Recovery (CRi) 
For subjects to be classified as being in CRi at a post-baseline visit, they must fulfill all 
the criteria for CR except for incomplete hematological recovery with residual 
neutropenia < 1  109/L with or without complete platelet recovery. RBC and platelet 
transfusion independence is not required. 
● Composite Complete Remission (CRc) 
For subjects to be classified as being in CRc at a post-baseline visit, they must either 
achieve CR, CRp or CRi at the visit. 
● Complete Remission with Partial Hematologic Recovery (CRh) 
At a post baseline visit, subjects will be classified as CRh if they have marrow blasts < 
5%, partial hematologic recovery ANC >= 0.5 x 109/L and platelets >= 50 x 109/L, no 
evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in 
peripheral blood must be ≤ 2% 
● Partial Remission (PR) 


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For subjects to be classified as being in PR at a post-baseline visit, 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%. A value of less or equal than 5% blasts is also considered a PR if 
Auer rods are present. There should be no evidence of extramedullary leukemia. 
● Not Evaluable (NE)/No Response (NR) 
In the situation where no bone marrow assessments are performed or myeloblast value is 
missing, blast value from peripheral blood is missing or <=2%, and extramedullary 
leukemia is missing or not present, the response will be classified as not evaluable (NE). 
In any case response cannot be categorized as CR, CRp, CRi, PR or NE, it will be 
categorized as NR 
● Relapse 
Relapse after CR, CRh, CRp or CRi is defined as a reappearance of leukemic blasts in the 
peripheral blood (> 2%) 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. 
● 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-baseline. Subjects who achieve the best 
responses of CR, CRp, CRi, or PR will be classified as responders. Subjects who do not 
achieve at least a best response of PR will be classified as non-responders. 
6.1.4 
Exploratory Endpoints 
● Pharmacogenomics 
● FLT3 gene mutation status 
o mutation types (FLT3-ITD mutation and D835/I836 TKD mutation) and frequency 
o relationship to efficacy and safety  
o mechanisms of acquired resistance 
● Exploratory (predictive) biomarkers of ASP2215 activity 
● Resource utilization, including hospitalization, blood transfusion, antibiotic intravenous 
infusions, medication for AEs and opioid usage  
● Functional Assessment of Chronic Illness Therapy-Dyspnea-Short Forms (FACIT-Dys-
SF) 


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The FACIT-Dys-SF 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.   
● Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)  
The FACT-Leu 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 some of the most 
common patient reported signs, symptoms, and impacts of AML. The FACT-Leu has a 
7-day recall period. 
● Dizziness and mouth sore items 
● EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L) 
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 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. 
6.1.5 
Other Efficacy Variables 
● CRp rate, CRi rate, PR rate – Defined similarly as CR rate. 
● Best response rate – Defined as the number of subjects who achieve the best response of 
CR or CRp or CRi or PR divided by the number of subjects in the analysis population.  
● Time to remission 
Time to remission includes time to CRc (TTCRc), time to CR (TTCR), time to first 
CR/CRh (TTFCRCRH), time to best CR/CRh (TTBCRCRH) and time to response 
(TTR). 
Time to CRc is defined as the time from the date of randomization until the date of first 
CRc (first CRc disease assessment date – randomization date +1). TTCRc will only be 
evaluated for subjects who achieved CRc. 
Time to CR is defined similarly as time to CRc for subjects who achieve CR. 
Time to first CR/CRh is defined similarly as time to CRc for subjects who achieved either 
CR or CRh. For subjects who achieve both CR and CRh, the first CR date or CRh date, 
whichever occurs first, will be used.  


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Time to best CR/CRh is defined similarly as time to CRc for subjects who achieved either 
CR or CRh. For subjects who achieve both CR and CRh, the first CR date will be used. 
Time to response is defined as the time from the date of randomization until the date of 
either first CRc or PR (first CRc or PR disease assessment date – randomization date +1). 
TTR will only be evaluated for subjects who achieved CRc or PR.  
6.2 
Safety Variables 
Safety will be assessed by evaluation of the following variables:  
● Treatment-emergent adverse events (TEAEs; frequency, severity, CTCAE grade, 
seriousness, and relationship to study drug) 
o TEAE is defined as an adverse event observed after starting administration of the 
study treatment (ASP2215 or salvage chemotherapy). If the adverse event occurs on 
Day 1 and the onset check box is marked “Onset after first dose of study drug” or the 
onset check box is left blank, then the adverse event will be considered treatment 
emergent. If the adverse event occurs on Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, then the adverse event will not be considered 
treatment emergent. If a subject experiences an event both during the pre-
investigational period and during the investigational period, the event will be 
considered as TEAE only if it has worsened in severity (i.e. it is reported with a new 
start date). All adverse events collected that begin within 30 days after taking the last 
dose of study drug will also be counted as TEAE, except for subjects that undergo 
HSCT without leaving the study and plan to resume ASP2215 treatment after HSCT. 
For these subjects, TEAE is defined as adverse events observed after starting 
administration of the study treatment until the last dose before pre-HSCT visit plus 
30 days, and adverse events that begin after resumption of ASP2215 and within 
30 days after the last dose of ASP2215 will also be counted as TEAE. Any AEs with 
onset dates completely missing will be considered TEAEs in summaries. AEs with 
partially missing onset dates will be assumed TEAEs unless the available portion of 
the date indicates that the onset was strictly before start of study medication or 
30 days after the last study treatment. Missing or partial AE onset date will be 
imputed per Section 7.11.1. 
o A drug-related TEAE is defined as any TEAE with at least possible relationship 
(possibly or probably related) to study treatment as assessed by the investigator or 
with missing assessment of the causal relationship 
● Serious adverse events (SAEs) include adverse events that are flagged as serious by the 
investigator on eCRF, or upgraded by the Sponsor based on review of the Sponsor’s list 
of Always Serious term.  
● Adverse events of special safety interest (AESI) are defined in the Safety Review Plan for 
ASP2215 (as specific in Section 10.3, Appendix 3).  
● Clinical laboratory variables (hematology, biochemistry including liver function test and 
thyroid function test)  


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● Vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) 
● 12-lead electrocardiogram (ECG) 
● Ophthalmologic assessment (visual acuity measurement) 
● ECOG performance scores  
6.3 
Pharmacokinetics Variables 
Plasma concentration data of ASP2215 will be used in pharmacokinetic analysis.  
6.4 
Other Variables 
● 
Duration of exposure  
Duration of exposure to each component of a study drug will be calculated in days, using 
the following formula: 
Last date of exposure – First dose date + 1 – (on-study HSCT period for subjects 
undergo on-study HSCT) 
For ASP2215, last date of exposure = last dose date of ASP2215 
For chemotherapy, last date of exposure = (initial dose date of the last cycle + 28 – 1) 
or death date if death occur within last cycle 
When the start or stop date is missing, then the exposure will be treated as missing. 
Duration of exposure for a chemotherapy regimen, i.e. MEC and FLG-IDA, will be the 
maximum (duration of exposure of all treatment components).  
When the last date of exposure is beyond cutoff date, the cutoff date will be used as the 
last date of exposure. 
● 
Number of dosing days 
Number of days with non-zero dosing. 
● 
Number of cycles 
Number of cycles for each component of study drug refers to total number of cycles with 
non-zero dosing in the cycle. 
Number of cycles for a chemotherapy regimen refers to total number of cycles with non-
zero dosing of any treatment component in the cycle. 
● 
Cumulative dose (dose unit) 
Cumulative dose will be calculated using the following formula for each type of study 
drug:  
o ASP2215: Sum of [(stop date – start date + 1) * dose captured on dosing CRF] 
across all records 
o LoDAC: Sum of (number of dose taken * 20mg) across all records and all cycles. 
If number of dose take is “unknown”, it will be treated as missing. 
o Azacitidine: Sum of (number of dose taken * actual delivered dose captured on 
dosing CRF) across all records and all cycles. If number of dose taken is 
“unknown”, it will be treated as missing. 


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o Each component of MEC and FLAG-IDA: Sum of (actual delivered dose captured 
on dosing CRF) across the days when study drug was administered. If answer to 
“entire infusion administered” is No, actual delivered dose will be treated as 
missing. 
● 
Average daily dose (dose unit/days) 
 
Cumulative dose (dose unit) 
-------------------------------------- 
Number of dosing days (days)  
 
● 
Dose intensity  
Dose intensity will be calculated in mg/day for ASP2215 as: 
Cumulative dose (mg) 
------------------------------------  
Duration of exposure (days)  
 
Dose intensity will be calculated in dose unit/cycle for chemotherapy as: 
Cumulative dose (dose unit) 
------------------------------------ x 28 (days/cycle) 
Duration of exposure (days)  
 
● 
Relative dose intensity 
Relative dose intensity for ASP2215 will be calculated as: 
Dose intensity (mg/day) 
----------------------------------------- x 100% 
120 (mg/day) 
 
Relative dose intensity for each component of chemotherapy will be calculated as: 
Dose intensity (dose unit/cycle) 
----------------------------------------- x 100% 
Planned dose intensity (dose unit/cycle) 
Where planned dose intensity (dose unit/cycle) will be calculated based on protocol 
specified dose: 
o LoDAC: 40 mg/day * 10 days/cycle 
o Azacitidine: 75 mg/m2/day * BSA * 7 days/cycle 
o MEC 
Mitoxantrone: 8 mg/m2/day * BSA * 5 days/cycle 
Etoposide: 100 mg/m2/day * BSA * 5 days/cycle 
Cytarabine: 1000 mg/m2/day * BSA * 5 days/cycle 
o FLAG-IDA 


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G-CSF: 300 μg/m2/day * BSA * 5 days/cycle 
Fludarabine: 30 mg/m2/day * BSA * 5 days/cycle 
Cytarabine: 2000 mg/m2/day * BSA * 5 days/cycle 
Idarubicin: 10 mg/m2/day * BSA* 3 days/cycle 
Average of BSA for all dosed cycles will be used in the calculation of planned dose 
intensity. 
● 
Relative dose intensity for a chemotherapy regimen will be the average of relative dose 
intensity of all treatment components.  
● 
Duration of AML 
Duration of AML will be calculated in days using the following formula: 
(Randomization date – date of initial diagnosis of AML) + 1 
Partial date of initial diagnosis of AML will be imputed per Section 7.11.1. 
● 
Previous and concomitant medication 
Previous medication is defined as medication with at least one dose taken before the date 
of the first dose of study drug (exclusive).  
Concomitant medication is defined as medication with at least one dose taken between 
the date of first dose (inclusive) and the date of last dose (inclusive) of study drug. 
For subjects that undergo HSCT without leaving the study and plan to resume ASP2215 
treatment after HSCT, concomitant medication is defined as medication with at least one 
dose taken between the date of first dose (inclusive) and the date of last dose (inclusive) 
before pre-HSCT visit, or between resumption of ASP2215 (inclusive) and the date of 
last dose (inclusive). 
● 
Prior Use of FLT3 inhibitor 
Prior Use of FLT3 inhibitor is defined as “Yes” if subjects received prior AML therapy 
of Midostaurin, Sorafenib or Quizartinib. 
● 
Previous and concomitant transfusion 
Previous transfusion is defined as transfusion received before the date of first dose of 
study drug, i.e. transfusion completed before the date of first dose (exclusive). 
Concomitant transfusion is defined as transfusion received between the date of first dose 
(inclusive) and the date of last dose (inclusive) of study drug. 
For subjects that undergo HSCT without leaving the study and plan to resume ASP2215 
treatment after HSCT, concomitant transfusion is defined as transfusion received 
between the date of first dose (inclusive) and the date of last dose (inclusive) before pre-
HSCT visit, or between resumption of ASP2215 (inclusive) and the date of last dose 
(inclusive). 


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7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be specified in the relevant section. In 
addition, for plasma concentrations, the coefficient of variation and the geometric mean will 
also be calculated. Frequencies and percentages will be displayed for categorical data. 
Percentages by categories will be based on the number of subjects with no missing data, i.e., 
will add up to 100%.  
Summaries based on ITT (e.g., disposition) will be presented by randomized treatment group, 
unless specifically stated otherwise. Safety analysis and other summaries based on SAF will 
be presented by actual treatment received. Pharmacokinetic summaries based on PKAS will 
be presented by actual treatment received. For subjects with dose increase/decrease, actual 
treatment refers to the initial dose received before dose change.   
All statistical comparisons will be made using two-sided tests at the α=0.05 significance level 
unless specifically stated otherwise.  All null hypotheses will be of no treatment difference, 
all alternative hypotheses will be two-sided, unless specifically stated otherwise. 
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
or higher on Statistical Computing Environment. Specifications for table, figure, and data 
listing formats can be found in the TLF specifications for this study. 
Baseline is defined as the last available measurement prior to the first dose of study drug. 
Unless otherwise specified, all summaries will be presented by treatment groups.  
For the definition of subgroups of interest please refer to Section 7.8.  
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be presented: 
● 
Number and percentage of subjects with informed consent, re-screening, discontinued 
before randomization, randomized (overall only); 
● 
Number and percentage of subjects randomized in each analysis set, by treatment group 
and overall; 
● 
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation for randomized subjects, by treatment group;  
● 
Number and percentage of subjects completed the 30-day follow-up evaluation, by 
30-day follow-up status for randomized subjects and by treatment group;  
● 
Number and percentage of subjects completed the long term follow-up evaluation, by 
long term follow-up status for randomized subjects and by treatment group. 


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7.2.2 
Protocol Deviations 
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all randomized subjects. The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall, by treatment group and total as 
well as by study site. Subjects deviating from a criterion more than once will be counted once 
for the corresponding criterion. Any subjects who have more than one protocol deviation will 
be counted once in the overall summary. A data listing will be provided by site and subject. 
The protocol deviation 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. 
The visit-based assessments affected by COVID-19 pandemic such as the assessments 
performed out of window, performed at alternative location or virtual assessment due to 
COVID-19 will be provided in data listings by site and subject.  
The non-visit-based assessments affected by COVID-19 pandemic such as treatment 
discontinuation, adverse event, dose changes due to COVID-19 will be provided in data 
listings by site and subject.  
7.2.3 
Demographic and Other Baseline Characteristics 
The demographics and other baseline characteristics were reported in the primary CSR dated 
24 JAN 2019 for the data with cutoff date of 17 SEP 2018. Those will not be summarized for 
the end of study report. 
Demographic and other baseline characteristics will be summarized by descriptive statistics. 
Number and percentage of subjects allocated to treatment in each country and site will be 
presented by treatment group.  
Descriptive statistics for age, weight, body surface area (BSA) and height at study entry will 
be presented by treatment group. Frequency tabulations for sex, ethnicity, age group (defined 
in Section 7.8), race, region, baseline central FLT3 status, baseline ECOG, prior use of FLT3 
inhibitor and cytogenetic risk status will be presented by treatment group.  
Frequency tabulations for AML disease history including AML subtype as classified by 
World Health Organization (WHO) classification and French-American-British (FAB) 
classification, risk status, antecedent hematological disorder, central nervous system 
leukemia, rapidly progressing disease, local FLT3 mutation status, local FLT3-ITD mutation 
status, local FLT3 point mutation status will be presented by treatment group. 
Medical history other than AML and conditions existing at Baseline will be coded in 
MedDRA and summarized by System Organ Class (SOC) and Preferred Term (PT) as well as 


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by PT alone, by treatment group. Baseline conditions are defined as those ongoing at the time 
of informed consent or arise following the time of informed consent and before the first dose 
of study drug. For ongoing medical conditions, Common Terminology Criteria for Adverse 
Events (CTCAE) grade will be provided in listing. 
Frequency tabulations for prior transplant including number of prior transplant, graft type, 
donor relatedness, match type and outcome of transplant will be presented by treatment 
group. 
Results from lumbar puncture, baseline extramedullary leukemia and MUGA scan, if 
performed, will be provided in listing. 
7.2.4 
Previous and Concomitant Medications 
The prior medications were reported in the primary CSR dated 24 JAN 2019 for the data with 
cutoff date of 17 SEP 2018. Only concomitant medications will be summarized for the end of 
study report. 
Previous medications are coded with World Health Organization – Drug Dictionary 
(WHO-DD), and will be summarized by therapeutic subgroup (Anatomical Therapeutic 
Chemical [ATC] 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO 
name by treatment group. 
As with previous medication, concomitant medication will be summarized for each treatment 
group by therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and 
preferred WHO name for the SAF. Subjects taking the same medication multiple times will 
be counted once per medication and investigational period. A medication which can be 
classified into several chemical and/or therapeutic subgroups is presented in all chemical and 
therapeutic subgroups. 
Concomitant medication will also be summarized by treatment group and PT and presented 
in decreasing order of frequency based on the total number of subjects took each medication.  
7.2.5 
Previous and Concomitant Transfusions 
The prior transfusions were reported in the primary CSR dated 24 JAN 2019 for the data with 
cutoff date of 17 SEP 2018. Only concomitant transfusions will be summarized for the end of 
study report. 
Frequency tabulations of subjects received transfusions and blood product will be presented 
for previous transfusion and concomitant transfusion by treatment group Descriptive statistics 
will be presented for number of transfusion unit received per subject for each type of blood 
product. 
7.2.6 
Prior AML Chemotherapy 
The prior AML chemotherapy was reported in the primary CSR dated 24 JAN 2019 for the 
data with cutoff date of 17 SEP 2018. This data will not be summarized for the end of study 
report. 


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Frequency tabulations of subjects with prior AML chemotherapy, response to first line 
therapy, regimen, type of treatment, prior use of FLT3 inhibitor, and best response to prior 
AML therapy will be presented by treatment group. Descriptive statistics will be presented 
for duration of response to prior AML therapy.  
7.2.7 
Non-Medication Therapy 
Frequency tabulations of subjects with non-medication therapy and reason for use will be 
presented by treatment group. Number of non-medication therapy received per subject will 
be summarized using descriptive statistics. 
7.2.8 
Clinical/Diagnostic Procedures 
Frequency tabulations of subjects with clinical/diagnostic procedures and reason for use will 
be presented by treatment group. Number of clinical/diagnostic procedures received per 
subject will be summarized using descriptive statistics. 
7.2.9 
Subsequent AML Therapy 
Frequency tabulations of subjects with subsequent AML therapy, regimens, relapse prior to 
subsequent AML therapy, reason of starting subsequent AML therapy, and response to 
subsequent AML treatment will be presented by treatment group. Descriptive statistics will 
be presented for duration of subsequent AML therapy.  
7.3 
Study Drugs 
7.3.1 
Exposure 
The following information on drug exposure will be presented for each treatment regimen for 
the SAF: 
● 
Descriptive statistics for cumulative amount of the drug subject was exposed to, number 
of dosing days, number of dosing cycles, average daily dose, dose intensity, and relative 
dose intensity; and 
● 
Number and percent of subject with dose increases, decreases or interruptions. 
Duration of exposure will be summarized in two ways. 
● 
Descriptive statistics will be presented by treatment regimen. 
● 
Exposure time will be categorized according to the following categories by treatment 
regimen: 
o less than or equal to 5 days 
o at least 6 days, less than 28 days  
o at least 28 days, less than 84 days  
o at least 84 days, less than 168 days 
o 168 days or more 
o Unknown. 
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment regimen for the SAF. 


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Listing of subjects with dose reduction and dose escalation will also be provided. 
7.4 
Analysis of Efficacy 
There will be no efficacy analysis performed for the end of study report. 
The significance levels at each interim and final analyses for each co-primary and secondary 
endpoints are specified in Table 4 below: 


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Table 4 
Summary of Timing, Sample Size and Decision Guidance at the Planned 
Analyses 
Analysis 
Criteria for 
conduct of 
analysis 
(Projected timing) 
Endpoint/
Analysis 
Set 
Efficacy Boundary* 
Futility Boundary* 
p-value 
(1-sided) 
at the 
Boundary 
Approx. 
Observed 
HR at 
Boundary 
p-value 
(1-sided) 
at the 
Boundary 
Approx. 
Observed 
HR at 
Boundary 
First Interim 
Analysis: 
CR/CRh rate 
When 141 subjects 
are randomized 
into ASP2215 arm 
and at least 112 
days (4 treatment 
cycles) post first 
dose or 
randomization (for 
subjects who 
received no study 
drug) 
CR/CRh 
rate /2215 
subjects in 
RAS 
NA 
(0.0005 
nominal) 
NA 
NA 
NA 
Second Interim 
Analysis: 
OS; EFS when 
null hypothesis 
of OS is 
rejected; CR 
rate when null 
hypotheses of 
both EFS and 
OS are rejected 
Approx. 129 OS 
events were 
observed 
OS/ITT 
0.00147 
0.57 
0.38674 
0.95 
EFS/ITT 
0.01519 
0.67 
0.30218 
0.91 
CR 
rate/ITT 
0.01519 
NA 
0.30218 
NA 
Final Analysis: 
OS; EFS when 
null hypothesis 
of OS is 
rejected; CR 
rate when null 
hypotheses of 
both EFS and 
OS are rejected 
Approx. 258 OS 
events were 
observed  
OS/ITT 
0.02402 
0.77 
NA 
NA 
EFS/ITT 
0.01357 
0.75 
NA 
NA 
CR 
rate/ITT 
0.01357 
NA 
NA 
NA 
*: P-value at both efficacy and futility boundaries (except the first interim) are based on 50% information 
fraction for OS, EFS and CR rate, and need update based on actual observed number of events at the second 
interim and final analysis. 
 
7.4.1 
Analysis of Co-Primary Endpoint of OS (Second Interim and Final only) 
The co-primary efficacy endpoint of OS will be analyzed on ITT for primary analysis. In 
order to compare the OS between ASP2215 and the salvage chemotherapy, the null 
hypothesis will be constructed: 
● H01: OS in ASP2215 is worse or equal to the OS in salvage chemotherapy 
The accompanying alternative hypothesis is: 
● H11: OS in ASP2215 is better than the OS in salvage chemotherapy 


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The co-primary endpoint of the OS will be tested only at second interim and final analyses. 
The one-sided p-value for the above hypothesis test will be performed using the stratified 
log-rank test (primary test) with strata (per IRT) to control for response to first-line AML 
therapy and preselected salvage chemotherapy.  
The SAS code to implement stratified log-rank will be similar to that shown below: 
PROC LIFETEST; 
 
TIME time * status (1); 
 
STRATA stratification variables/group=treatment; 
RUN; 
The hazard ratio of the treatment effect along with 95% confidence interval will be calculated 
by the stratified Cox proportional hazard model. The same stratification factors will be 
applied to both the stratified log-rank test and the stratified Cox proportional hazard model. 
The same Cox proportional hazard model will be included as a sensitivity analysis for testing 
H01.   
The SAS code to calculate the hazard ratio of the treatment effect along with 95% confidence 
interval will be similar to that shown below: 
PROC PHREG; 
MODEL time * status (1) = treatment/RL; 
STRATA stratification variables; 
 RUN; 
Stratification variables will include response to first-line AML therapy and preselected 
salvage chemotherapy. 
Kaplan-Meier survival plots will be used to describe the OS in each treatment group. Median 
OS and 95% confidence interval, survival rates at 6, 12, 24 and 36 months and 95% 
confidence interval will be estimated from the Kaplan-Meier curve using the SAS code 
similar to that shown below: 
PROC LIFETEST DATA=XX TIMELIST=(XX XX XX); 
 
TIME time * status (1); 
 
STRATA treatment; 
RUN; 
Where TIMELIST option contains timepoint of interest to estimate survival rate. 
Sensitivity analyses for OS include: 
● 
The same analysis as primary analysis but on FAS 
● 
The same analysis as primary analysis but on PPS 


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● 
Stratified Cox proportional hazard model with strata to control for response to first-
line AML therapy and preselected salvage chemotherapy on ITT  
● 
The same analysis as primary analysis but with OS censoring at HSCT as defined in 
Section 6.1.1 
● 
The same analysis as primary analysis but with OS censoring at first new anti-
leukemia therapy as defined in Section 6.1.1 
● 
Stratified Cox proportional hazard model with strata to control for response to first-
line AML therapy and preselected salvage chemotherapy and initiation of new anti-
leukemia therapy as a time-dependent binary covariate on ITT 
● 
Additional sensitivity analysis will be performed using a new test for equality of two 
survival functions based on weighted differences of Kaplan–Meier curves with 
estimation of difference of Restricted Mean Survival Time (RMST) and its 95% CI 
(Uno et.al, 2015) by a pre-specified cutoff time at 18 months. The 18-month time-
point was determined to ensure that reasonable number of patients were still at risk at 
the cutoff.  
● 
The same analysis as primary analysis will be performed by dose adjustment for 
subjects whose dose was increased (200 mg dose), decreased (80 mg dose) or 
remained at 120 mg in ASP2215 arm. 
7.4.2 
Analysis of Co-Primary Endpoint of CR/CRh Rate (First Interim only) 
The co-primary efficacy endpoint of CR/CRh rate will be evaluated at the first interim 
analysis only. The two-sided 95% exact confidence interval of CR/CRh rate will be 
calculated for approximately 141 subjects who are randomized into ASP2215 arm and at 
least 112 days (4 treatment cycles) post first dose or randomization (for subjects who 
received no study drug), i.e., 2215 subjects in RAS. The lower limit will be used to compare 
with the benchmark of CR/CRh rate of 12%. 
CR/CRh rate along with the two-sided 95% exact confidence interval based on binomial 
distribution will be calculated using SAS code similar to that shown below: 
PROC FREQ; 
 
TABLES outcome/BIONOMIAL (EXACT); 
RUN; 
The sensitivity analysis for CR/CRh rate will be performed to assess the robustness of the 
CR/CRh rate as follows: 
● 
The same analysis as primary analysis but only including subjects in mRAS 
● 
The same analysis as primary analysis but only including subjects who took at least 
one dose of ASP2215 
● 
The same analysis as primary analysis but only including subjects who had at least 
one post baseline bone marrow assessment 
● 
Apply the same analysis method used for primary analysis to evaluate CR/CRh rate 
by cycle 4 (as defined in Section 6.1.2) 


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● 
Apply the same analysis method used for primary analysis to evaluate CR/CRh rate 
prior to HSCT (as defined in Section 6.1.2) 
7.4.3 
Analysis of Secondary Endpoints 
7.4.3.1 Key Secondary Efficacy Analysis 
The key secondary efficacy endpoint of EFS will be analyzed in the same manner as the 
co-primary endpoint of OS.  In order to compare the EFS between ASP2215 and the salvage 
chemotherapy, the null hypothesis will be constructed:   
● H02: EFS in ASP2215 is worse or equal to EFS in salvage chemotherapy 
The accompanying alternative hypothesis is: 
● H12: EFS in ASP2215 is better than EFS in salvage chemotherapy 
To maintain the overall 1-sided Type I error rate at the 0.0245 significance level, the key 
secondary efficacy endpoint of EFS will be tested only at second interim and final analyses 
and only if the null hypothesis on OS (H01) is rejected. The test significance levels of EFS 
endpoint at the second interim and final analyses are specified in Table 4.  
The one-sided p-value for the above hypothesis test will be performed using the stratified 
log-rank test with strata (per IRT) to control for response to first-line AML therapy and 
preselected salvage chemotherapy.  
The hazard ratio of the treatment effect along with 95% confidence interval will be calculated 
using stratified Cox proportional hazard model. The same stratification factors will be 
applied to both the stratified log-rank test and the stratified Cox proportional hazard model. 
The same Cox proportional hazard model will be included as a sensitivity analysis for testing 
H03.   
Kaplan-Meier survival plots will be used to describe the EFS in each treatment group. 
Median EFS and 95% confidence interval, EFS rates at 6, 12, 24 and 36 months and 95% 
confidence interval will be estimated from the Kaplan-Meier curve. The number and 
percentage of EFS event (relapse, death or treatment failure) and censoring will be 
summarized for each treatment group.  
The sensitivity analyses for the key secondary efficacy endpoints of EFS include: 
● The same analysis as primary analysis but on FAS 
● The same analysis as primary analysis but on PPS 
● Stratified Cox proportional hazard model with strata to control for response to first-
line AML therapy and preselected salvage chemotherapy on ITT  
● The same analysis as primary analysis but with the date of the first new anti-leukemia 
therapy after the end of study treatment or the last treatment evaluation date (when the 
date of new anti-leukemia is not available) will be used as the event date of treatment 
failure as defined in Section 6.1.3.1  
● The same analysis as primary analysis but with “Lost to follow up” also considered as 
an EFS event as defined in Section 6.1.3.1. “Lost to follow up” event includes 


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subjects who discontinued either study treatment or study follow up (including 30 day 
and long term follow up) due to either “LOST TO FOLLOW-UP” or 
“WITHDRAWAL BY SUBJECT”. For subjects who discontinued the study 
treatment due to “WITHDRAWAL BY SUBJECT”, only those who revoked the 
authorization to follow up will be included. 
● The same analysis as primary but consider the subjects who discontinued the 
treatment and only achieved best response of NR as treatment failure as defined in 
Section 6.1.3.1. 
● The same analysis as primary but consider the subjects who discontinued the 
treatment with post-treatment disease assessment and achieved best response of PR, 
NR or NE as treatment failure as defined in Section 6.1.3.1.  
• The same analysis as primary but consider using long term follow up data of Death 
and new AML therapies. The new AML therapies captured on CRF page will only be 
considered as event when the patient did not relapse per derived response. 
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 (Per IRT) on ITT. In order to compare the CR rate 
between ASP2215 and the salvage chemotherapy, the null hypothesis will be constructed: 
● H03: CR rate in ASP2215 arm is lower than or equal to the CR rate in salvage 
chemotherapy arm 
The accompanying alternative hypothesis is: 
● H13: CR rate in ASP2215 arm is higher than in salvage chemotherapy  
To maintain the overall 1-sided Type I error rate at the 0.0245 significance level, the key 
secondary efficacy endpoint of CR rate will be tested only at second interim and final 
analyses and only if the null hypothesis on OS (H01) and EFS (H02) are rejected 
hierarchically. The test significance levels of CR rate endpoint at the second interim and final 
analyses are specified in Table 4.  
The treatment difference along with 95% confidence interval will be calculated using Mantel-
Haenszel estimate. 
The SAS code to implement the above test will be similar to that shown below: 
PROC FREQ; 
 
TABLES stratification variables * response * treatment/cmh; 
RUN; 
CR rate along with the two-sided 95% exact confidence interval based on binomial 
distribution will be calculated for each treatment group using SAS code similar to that shown 
below: 
PROC FREQ; 


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TABLES outcome/BIONOMIAL (EXACT); 
 
BY treatment; 
RUN; 
The sensitivity analysis for CR rate will be performed as following: 
● 
The same analysis as primary analysis but on FAS 
● 
The same analysis as primary analysis but on PPS 
● 
The same analysis as primary analysis but only including subjects who received at 
least one dose of study treatment 
● 
The same analysis as primary analysis but only including subjects who had at least 
one post baseline bone marrow assessment 
● 
Apply the same analysis method used for primary analysis to evaluate CR rate prior to 
HSCT (as defined in Section 6.1.3.1) 
● 
Un-stratified Fisher’s exact test on ITT 
● 
The same analysis as primary analysis for CR rate will be performed by dose 
adjustment in ASP2215 arm. 
 
7.4.3.2 Other Secondary Efficacy Analysis 
At the first interim analysis, Duration of CR/CRh (DCRCRh) will be summarized 
descriptively by median, corresponding 95% confidence interval and range as estimated from 
the Kaplan-Meier curve. DCRCRh will be analyzed for subjects who achieved either CR or 
CRh in the same analysis set of CR/CRh rate. Duration of CRh (DCRh) will also be 
summarized similarly as duration of CR/CRh but for subjects who achieved CRh only. 
Transfusion status (independent vs. dependent) at baseline period and post-baseline period 
will be summarized in a two-by-two contingency table.  
Transfusion conversion rate and transfusion maintenance rate will be calculated based on the 
transfusion status. 95% confidence interval will be presented for both transfusion conversion 
and maintenance rates. 
LFS and duration of remission (including DCRc, DCR, and DR) will be analyzed for subjects 
who achieved remission using the stratified log-rank test with strata to control for response to 
first-line AML therapy and preselected salvage chemotherapy. The hazard ratio of the 
treatment effect along with 95% confidence interval will be calculated. The survival curve 
and the median will be estimated using the Kaplan-Meier method and will be reported along 
with the corresponding 95% confidence interval. 
CRc rate and transplantation rate will be analyzed in the same manner as CR rate using CMH 
test to control for response to first-line AML therapy and preselected salvage chemotherapy. 
The number and percentage of subject with CRc and transplantations will be summarized for 
each treatment group along with exact 95% confidence interval based on binomial 
distribution. The treatment difference along with 95% confidence interval will also be 
calculated. The CRc rate will be summarized by dose adjustment in ASP2215 Arm. 


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BFI global fatigue score will be summarized using mean, standard deviation, minimum, 
maximum and median by treatment group at each visit. Additionally, a within-subject change 
will be calculated as the post-baseline measurement minus the baseline measurement and 
summarized in the same way. Change from baseline BFI score will be analyzed using 
Analysis of Covariance (ANCOVA) including treatment as a fixed factor, baseline BFI score, 
response to first-line AML therapy and preselected salvage chemotherapy as covariates. 
7.4.4 
Analysis of Exploratory Endpoints 
Central FLT3 mutation status at screening, including subgroups of FLT3-ITD mutation and 
D835/I836 TKD mutations, will be summarized by the number and percentage of subjects in 
each category by treatment group. An exploratory analysis of FLT3 mutation type and 
selected clinical efficacy endpoints will be conducted (see Section 7.8).  
Additional biomarker exploratory analysis on AXL status, FLT3 related biomarkers and other 
genes mutations will be performed and the details will be included in a separate Biomarker 
Statistical Analysis Plan (Biomarker SAP). 
Incidence of resource utilization including hospitalization, blood transfusion, antibiotic 
intravenous infusions, medication for AEs and opioid medication during the entire study 
period will be summarized by treatment group. The difference between treatment groups will 
be tested using CMH test while controlling for response to first-line AML therapy and 
preselected salvage chemotherapy. Duration of hospital stays, medication for AEs and opioid 
medication will be summarized by treatment group using descriptive statistics (mean, 
standard deviation, minimum, maximum and median). The difference between treatment 
groups will be tested with ANOVA while controlling for response to first-line AML therapy 
and preselected salvage chemotherapy. 
FACIT-Dys-SF domain scores will be summarized by treatment group at each visit using 
descriptive statistics (mean, standard deviation, minimum, maximum and 
median).Additionally, a within-subject change will be calculated as the post-baseline score 
minus the baseline score and summarized in the same way. ANCOVA model will be used to 
analyze the change in the FACIT-Dys-SF domain scores from baseline to post-baseline visits 
including treatment as a fixed factor, baseline score, response to first-line AML therapy and 
preselected salvage chemotherapy as covariates. 
FACT-Leu global score and domain scores will be summarized by treatment group at each 
visit using descriptive statistics (mean, standard deviation, minimum, maximum and median). 
Additionally, a within-subject change will be calculated as the post-baseline score minus the 
baseline score and summarized in the same way. ANCOVA model will be used to evaluate 
change from baseline to post-baseline visits for the global and domain scores, of the FACT-
Leu including treatment as a fixed factor, baseline score, response to first-line AML therapy 
and preselected salvage chemotherapy as covariates. The same analytic approach will be used 
for the dizziness and mouth sore items. 
EQ-5D-5L VAS will be summarized by treatment group at each visit using descriptive 
statistics (mean, standard deviation, minimum, maximum and median). Additionally, a 


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within-subject change will be calculated as the post-baseline score minus the baseline score 
and summarized in the same way. ANCOVA model will be used to evaluate change from 
baseline to post-baseline visits for the EQ-5D-5L VAS including treatment as a fixed factor, 
baseline score, response to first-line AML therapy and preselected salvage chemotherapy as 
covariates. Shift table showing shift in each dimension score from baseline to each 
post-baseline visit will be provided for the 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression).  
Additional exploratory analysis of patient reported outcomes (BFI, FACIT-Dys, FACT-Leu, 
dizziness, mouth sore items) and heath outcome (EQ-5D-5L) will be performed and the 
details will be included in a separate Patient Reported Outcome Statistical Analysis Plan 
(PRO SAP).  
Additional exploratory analysis of resource utilization with regard to health economic model 
will be performed and the details will be included in a separate Health Economic Statistical 
Analysis Plan. 
7.4.5 
Analysis of Other Variables 
Best Response will be summarized by treatment group. The number and percentage of 
subjects in each category will be presented. The best response rate by prior FLT3 inhibitor 
use will also be summarized.  
At the first interim analysis, Time to first and best CR/CRh (TTCRCRh) will be summarized 
using descriptive statistics (mean, standard deviation, minimum, maximum and median) for 
subjects who achieved either CR or CRh in the same analysis set of CR/CRh rate.  
TTCRc, TTCR, TTR will be summarized by treatment group using descriptive statistics 
(mean, standard deviation, minimum, maximum and median) for subjects who achieved 
remission in the ITT. 
7.4.6 
Analysis of CR/CRh rate, Duration of CR/CRh and Time to first and best 
CR/CRh at Final Analysis 
The CR/CRh rate, Duration of CR/CRh and Time to first and best CR/CRh will be 
summarized descriptively on both arms at the final analysis. 
The CR/CRh rate will be evaluated in the same manner as CR rate using CMH test to control 
for response to first-line AML therapy and preselected salvage chemotherapy on ITT. The 
number and percentage of subjects with CR/CRh will be summarized for each treatment 
group along with exact 95% confidence interval based on binomial distribution. The 
treatment difference along with 95% confidence interval will be calculated. 
The sensitivity analysis for CR/CRh rate will be performed to assess the robustness of the 
CR/CRh rate as follows: 
● 
The same analysis as primary analysis but on FAS 
● 
The same analysis as primary analysis but on PPS 


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● 
The same analysis as primary analysis but only including ITT subjects who took at 
least one dose of study drug 
● 
The same analysis as primary analysis but only including ITT subjects who had at 
least one post baseline bone marrow assessment 
● 
Apply the same analysis method used for primary analysis to evaluate CR/CRh rate 
prior to HSCT (as defined in Section 6.1.2) 
● 
The same analysis as primary analysis for CR/CRh rate will be performed by dose 
adjustment in ASP2215 arm. 
 
Duration of CR/CRh (DCRCRh) and Time to first and best CR/CRh (TTCRCRh) will be 
summarized in the same manner as Duration of CR (as specified in Section 7.4.3.2) and Time 
to CR (as specified in Section 7.4.5), respectively, for subjects who achieved either CR or 
CRh on ITT. Median follow-up of DCRCRh estimated from reverse Kaplan-Meier curve will 
be provided. 
As a sensitivity analysis, Duration of CR/CRh will also be analyzed with deaths without 
report of relapse considered as events (as defined in Section 6.1.3.2). In addition, Duration of 
CR/CRh will also be analyzed by subjects with or without transplantation during the study 
period.  
7.5 
Analysis of Safety 
All analysis of safety will be presented by treatment group for SAF, unless specified 
otherwise.  
7.5.1 
Adverse Events 
All adverse event (AE) recorded on treatment including within 30 days from the last study 
treatment will be summarized.  
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on review of the Sponsor’s list of Always Serious terms if any upgrade was done. 
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
SOC and PT. AEs will be graded using National Cancer Institute’s Common Terminology 
Criteria for AEs (NCI-CTCAE).  
An overview table to report the number and percentage of subjects and an overview table to 
report number of events and events adjusted by patient year from drug exposure will include 
the following details:  
● 
TEAEs, 
● 
Drug-related TEAEs, 
● 
Serious TEAEs,  
● 
Drug-related serious TEAEs, 
● 
TEAEs leading to death 
● 
Drug-related TEAEs leading to death 
● 
TEAEs leading to withdrawal of treatment, 


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● 
Drug-related TEAEs leading to withdrawal of treatment,  
● 
Grade 3 or higher TEAEs,  
● 
Drug-related Grade 3 or higher TEAEs,  
● 
Any death  
The number and percentage of subjects with TEAEs and the number of events and events 
adjusted by patient year from drug exposure, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for: 
● 
TEAEs 
● 
Drug-related TEAEs,  
● 
Serious TEAEs,  
● 
Drug-related serious TEAEs,  
● 
TEAEs leading to death 
● 
Drug-related TEAEs leading to death 
● 
TEAEs leading to withdrawal of treatment,  
● 
Drug-related TEAEs leading to withdrawal of treatment,  
● 
Grade 3 or higher TEAEs,  
● 
Drug-related Grade 3 or higher TEAEs 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will also 
be summarized for each treatment group for the following: 
● 
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5% in any 
treatment group,  
The number and percentage of subjects with TEAEs, as classified by PT only, will also be 
summarized for each treatment group for the following: 
● 
TEAEs 
● 
Drug-related TEAEs,  
The number and percentage of subjects with TEAE of special safety interest (AESI), as 
classified by AESI category and PT will be summarized for each treatment group for the 
following: 
● 
TEAEs with special safety interest, 
● 
Grade 3 or higher TEAEs with special safety interest,  
● 
Drug-related Grade 3 or higher TEAEs with special safety interest 
AE summary tables will include subject counts as opposed to AE counts. If a subject 
experiences more than one episode of a particular AE, that subject will be counted only once 
for that event. If a subject has more than one AE that code to the same preferred term, the 
subject will be counted only once for that preferred term. Similarly, if a subject has more than 
one AE within a body system, the subject will be counted only once in that body system.   
All AEs, deaths, SAEs and withdrawals due to adverse events will be displayed in listings.  


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7.5.2 
Clinical Laboratory Evaluation 
The baseline visit is the last measurement taken prior to initial study drug administration.   
Quantitative clinical laboratory variables, i.e., hematology and biochemistry based on central 
assessment will be summarized using mean, standard deviation, minimum, maximum and 
median for each treatment group at each visit. Additionally, a within-subject change will be 
calculated as the post-baseline measurement minus the baseline measurement and 
summarized in the same way. Each laboratory result will be classified as low (L), normal (N), 
or high (H) at each visit according to the laboratory supplied reference ranges.  
The number and percentage of subjects below and above reference range will be summarized 
for each treatment group at each visit. 
Laboratory results will also be graded using NCI-CTCAE, where possible. Parameters that 
have criteria available for both low and high values, i.e., hypo- and hyper-, will be 
summarized for both criteria. The same subject can be counted for both values if the subject 
has different laboratory values meeting each criterion. The number and percentage of 
subjects with grade 3 or 4 laboratory test result will be summarized by treatment group and 
laboratory parameter (the name of the adverse event associated with the abnormal laboratory 
test result will be presented).  
Laboratory results based on local assessment and bone marrow results will be listed only.  
7.5.2.1 Liver Enzymes and Total Bilirubin  
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the 
investigational period will be used.  


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Parameter 
Criteria 
ALT 
> 3xULN 
 
> 5xULN 
> 10xULN 
> 20xULN 
 
AST 
> 3xULN 
 
> 5xULN 
> 10xULN 
> 20xULN 
 
ALT or AST 
> 3xULN 
 
Total Bilirubin  
> 2xULN 
 
ALP 
> 1.5xULN 
 
ALT and/or AST AND Total Bilirubin(*) 
(ALT and/or AST > 3xULN) and  
total bilirubin > 2xULN 
(*) Combination of values measured within same sample 
The number and percentage of subjects with potentially clinically significant values in liver 
enzymes and total bilirubin during the investigational period will be presented by treatment 
group. 
7.5.3 
Vital Signs 
The baseline visit is the last measurement taken prior to initial study drug administration.   
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, and body 
temperature) will be summarized using mean, standard deviation, minimum, maximum and 
median by treatment group and visit. Additionally, a within-subject change will be calculated 
per visit as the post-baseline measurement minus the baseline measurement and summarized 
by treatment group and visit.   
Tables for potentially clinically significant vital signs will be generated using baseline value 
and highest value obtained during treatment for each subject for each treatment group. 
The following potentially clinically significant criteria are defined for each parameter: 
Vital Sign Variable 
Criteria 
SBP 
≥180 mmHg AND ≥20 mmHg change from baseline 
DBP 
≥105 mmHg AND ≥15 mmHg change from baseline 
Pulse Rate 
≥120 bpm AND ≥15 bpm change from baseline 
 


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7.5.4 
Electrocardiograms (ECGs) 
12-lead ECGs will be recorded in triplicate at the scheduled time points. Each ECG tracing 
will be taken 5 minutes apart. ECGs will be read at the site for clinical decision making and 
transmitted to a central reviewer. Data from the central reviewer will be used in summary 
presentations. The three values of each ECG parameter within a time point from the central 
reviewer will be averaged to determine time-specific parameter for a subject, and used in 
summaries. 
The QT interval corrected for heart rate by Fridericia’s formula, QTcF, is defined as: 
QTc (F) = QT/(RR)0.33, where RR interval is inversely proportional to heart rate 
(approximately RR = 60/heart rate). 
The QTcF interval will be summarized using frequency tables for each treatment group at 
each treatment visit and time point for values of clinical importance using the range criteria 
below. 
 
QTc Interval Criteria Value (msec) 
 
Interval Category 
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450 to  ≤ 480 
> 480 to ≤ 500 
> 500 
 
Number and percent of subjects with maximum postbaseline QTcF > 480 msec and the time 
to maximum post baseline QTcF value > 480 msec will be summarized by treatment group. 
7.5.5 
Pregnancies 
A detailed listing of all pregnancies will be provided. 
7.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores 
Number of percent of subjects for each category of the ECOG performance status at each 
assessment time will be provided by treatment group. Negative change scores indicate an 
improvement and positive scores indicate a decline in performance. 
7.5.7 
Ophthalmologic Assessment  
Quantitative ophthalmologic variable (logmar score for visual acuity) will be summarized 
using mean, standard deviation, minimum, maximum and median by treatment group at each 
visit for each eye. 
7.6 
Analysis of PK 
PK analysis will be conducted on the PKAS.  
Plasma concentrations of ASP2215 will be summarized by treatment group and where 
appropriate by nominal time points using descriptive statistics, including number of subjects, 


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mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of 
variation (CV).  
Population pharmacokinetic analysis will be performed. Data from this study may be pooled 
with other studies for analysis. Details of this analysis will be specified in a separate 
population pharmacokinetic analysis plan.  
7.7 
Analysis of PD 
Not applicable. 
7.8 
Subgroups of Interest  
There will be no efficacy analysis and subgroup analysis performed for the end of study 
report. 
Co-primary efficacy endpoints (OS and CR/CRh rate) and key secondary endpoints (EFS and 
CR rate) will be summarized by treatment groups at the appropriate interim/final analysis 
timing for the subgroups defined on the basis of the categorized variables listed below: 


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Grouping variable 
Subgroups 
Age group  
< 65 years 
>=65 years 
 
Sex 
Female 
Male 
 
Race 
White 
 
Black or African American 
 
Asian 
 
Other  
 
Baseline ECOG  
0-1 
>=2 
 
Region 
North America 
 
Europe (including Turkey and Israel) 
 
Asia 
 
 
Central FLT3 Mutation Type 
FLT3-ITD alone 
 
FLT3-TKD alone 
                                                            FLT3-ITD & TKD 
                                                            Others (Unknown/Missing/Negative) 
 
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 
 
Salvage Chemotherapy 
High intensity chemotherapy (FLAG-IDA, MEC) 
Low intensity chemotherapy (LoDAC or azacitidine) 
 
Prior Use of FLT3 inhibitor 
Yes 
 
No 
 
Cytogenetic Risk Status 
Favorable 
 
Intermediate 
 
Unfavorable 
 
Other 
Pooled stratification factors, if used for stratified analysis, will also be included in subgroup 
analysis.  


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7.9 
Other Analyses 
7.9.1 
PK-PD Analysis 
There will be no exploratory PKPD analysis performed for the end of study report. 
Exploratory PKPD analysis will be performed on safety and efficacy variables.  Graphical 
approaches will be performed on selected variables.  Modeling (including mixed effect 
modeling) may be performed if warranted. 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
To evaluate whether ASP2215 is particularly beneficial or harmful compared to the 
benchmark data or the salvage chemotherapy group while the study is ongoing, two interim 
analyses are planned. At the interim analyses, production of tables and listings will be 
performed by an independent data analysis center (IDAC). The interim analysis outputs will 
be reviewed by IDMC. No member of the clinical study team will have access to the tables 
and listings created for the IDMC. For more details consult the IDMC Charter. 
First Interim Analysis 
The first interim analysis is planned when approximately 141 subjects are randomized into 
ASP2215 arm and at least 112 days (4 treatment cycles) post first dose or randomization (for 
subjects who received no study drug. At the first interim analysis, only the co-primary 
endpoint of CR/CRh rate will be evaluated for subjects in ASP2215 arm. The two-sided 95% 
exact confidence interval of CR/CRh rate will be calculated for approximately 141 subjects 
who are randomized into ASP2215 arm and at least 112 days (4 treatment cycles) post first 
dose or randomization (for subjects who received no study drug), i.e., ASP2215 group in 
RAS. The IDMC will inform Sponsor the outcome on CR/CRh endpoint as favorable or 
unfavorable at the first interim analysis, using the decision rules specified in table below: 
Decision Rules based on lower limit of two-sided 95% exact confidence interval of CR/CRh 
rate in ASP2215 arm at First Interim Analysis 
CR/CRh Rate with two-sided 95% exact confidence interval 
Lower limit <=12% 
Lower limit > 12% 
Unfavorable 
Favorable 
The Sponsor may prepare a regulatory submission for conditional approval using the first 
interim analysis data. However, the study conduct will not be impacted by the first interim 
analysis result.  
A nominal 1-sided p-value 0.0005 (i.e., 2-sided p-value 0.001) which is arbitrarily selected, 
will be spent to acknowledge the single-arm CR/CRh rate evaluation at the first interim 
analysis and will not be recycled in the second interim analysis and final analysis. No formal 
hypothesis testing will be conducted for CR/CRh rate for the study, only the descriptive 
statistics including two-sided 95% exact CI of CR/CRh rate will be provided to IDMC at the 
first interim. The hypothesis testing for the primary and secondary endpoints of OS, EFS and 
CR rate at the secondary interim analysis and final analysis are well controlled at an overall 
1-sided type I error rate 0.0245 based on a sequential testing procedure. 


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Second Interim Analysis 
The second interim analysis will be performed when approximately 50% of the total planned 
death events (death event = 129) have occurred for the study. OS will be tested at 1-sided 
0.00147/0.38674 significant level for efficacy/futility according to the O’Brien-Fleming type 
alpha/beta spending function. The IDMC may recommend terminating the trial for favorable 
or unfavorable results at the second interim analysis based on OS endpoint, using the 
decision rules specified in table below: 
Decision Rules based on 1-sided P-Value obtained at Second Interim Analysis 
Overall Survival 
P-value ≥ 0.38674 
0.38674>P-value ≥ 0.00147 
P-value < 0.00147 
Unfavorable: Trial may be 
stopped for Futility 
Trial continues 
Favorable: Trial may be stopped 
for Efficacy 
 
The futility bound of this study is non-binding and is considered guidance rather than strict 
bound. Depending on the recommendations of the IDMC, the Sponsor may prepare a 
regulatory submission, if the outcome on OS at the second interim analysis is favorable. 
If the study is not stopped after the second interim analysis, a final analysis based on OS will 
occur after 100% of the total planned death events (death events = 258) have been observed. 
The 1-sided significance level for the final analysis is 0.02402 for OS.  
According to the sequential testing procedure on controlling overall type I error rate for 
multiple endpoints, EFS will be tested when the null hypothesis of OS is rejected at the 
second interim or at the final analyses. CR rate will be tested when the null hypotheses of 
both OS and EFS are rejected hierarchically at the second interim or at the final analyses. 
Their significance levels at the second interim and final analyses will be based on Pocock/ 
O’Brien-Fleming alpha/beta spending function. The details about the significance levels at 
each interim and final analyses for each co-primary and secondary endpoints are specified in 
Section 7.4 Table 4.  
Details for the two formal interim analyses and the IDMC safety review procedures will be 
included in either Interim Analysis Plan (IAP) or IDMC Charter. The statistical analysis plan 
for the interim analyses will be described in interim analysis plan (IAP).  Safety data 
including AE, lab, vital signs and ECG will be reviewed by IDMC on a periodic basis. The 
procedures for IDMC safety review will be described in the IDMC charter. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.11.1 Missing Data  
Every effort will be made to resolve incomplete dates for death and disease relapse. If a 
partial date cannot be resolved, the most conservative imputation methods will be used to 
complete the missing information.  


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For primary endpoint OS, missing or incomplete death date will be imputed as the earliest 
feasible date on or after the date of last contact as the examples shown in the table below. 
The date of last contact will be obtained as described in Section 6.1.1. 
Incomplete Date of Death 
(YYYY MMM  DD) 
Date of Last Contact 
(YYYY MMM  DD) 
Imputed Date of Death 
(YYYY MMM  DD) 
2005 APR ?? 
2005 MAR 31 
2005 APR 01 
2005 ??? 13 
2005 MAR 31 
2005 APR 13 
2005 ??? ?? 
2005 MAR 31 
2005 MAR 31 
???? APR ?? 
2005 MAR 31 
2005 APR 01 
???? APR 13 
2005 MAR 31 
2005 APR 13 
???? ??? ?? 
2005 MAR 31 
2005 MAR 31 
 
Partial relapse dates will be imputed to the first day of the month of the missing parameter 
but not earlier than the last disease assessment date. A month and year must be present or the 
date will remain missing. 
Missing centrally evaluated bone marrow assessment will be imputed with local bone 
marrow assessment as described in Section 6.1.3.3. Non-responder imputation will be used 
for binary response variables.  
Missing or partial start and stop dates of adverse events and concomitant medication will be 
imputed using the following algorithm: 
● Imputation rules for partial or missing stop dates: 
o If the month and year are present, then impute as the last day of that month.  
o If only the year is present, impute as December 31 of that year. 
o If the stop date is entirely missing, assume the event or medication is ongoing. 
● Imputation rules for partial or missing start dates: 
Start Date 
Stop Date 
Complete: yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
missing 
< 1st dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
 
 
      3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute as the date of first dose; 2 = Impute as the first of the month; 3 = Impute as January 1 of the year; 4 = 
Impute as January 1 of the stop year 


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The imputed dates will be used to determine whether an AE is/is not treatment emergent. 
Listings of AEs and concomitant medications will present the actual partial dates; imputed 
dates will not be shown. 
In the case of partial date of initial diagnosis of AML, the date will be imputed to the first day 
of the month. A month and year must be present or the date will remain missing. 
In the case of partial starting date of subsequent AML therapy, the date will be imputed to the 
first day of the month but not earlier than the last dosing date of the study drug. A month and 
year must be present or the date will remain missing. 
Concentrations below the lower limit of quantification (BQL) in PK should be treated as 
missing when the terminal elimination rate constant is evaluated. Otherwise BQL should be 
treated as zero in the estimation of individual pharmacokinetic parameters.  
7.11.2 Outliers 
All values will be included in the analyses. 
7.11.3 Visit Windows 
Visit windows are allowed for certain visits per the schedule of assessments. Subject data 
will not be excluded from analyses due to the subject’s failure to comply with the visit 
schedule. CRF visit will be used for analysis. In the case of multiple observations at a 
specific visit, the observation which is closest to the target date will be used. If the 
observations have the same distance to the target visit, the latest one will be used. If more 
than one observation is made on the same day, an average value if continuous or the worst 
value if categorical will be included in the analysis.  
7.11.4 Pooling Strata 
For OS and EFS analyses, if all events are from one treatment group in at least one stratum 
combination, or the Cox proportional hazard model does not converge due to small event size 
in some stratum combinations, the stratum combinations will be pooled per following steps 
until the issue is resolved or the normal (un-stratified) Cox proportional hazard model is 
applied. 
Step1: Pooling within preselected chemotherapies 
Within each preselected chemotherapy (high intensity or low intensity), if the criterions 
described above don’t meet, pool the 5 levels of response to first-line therapy into 3 levels: 
● 
Relapse after allogeneic HSCT 
● 
Primary refractory without HSCT 
● 
Relapse after CRc and no HSCT 
After the above pooling, if the criterions still don’t meet, pool the 3 levels into 2 levels: 
● 
Relapse after allogeneic HSCT or after CRc without HSCT 
● 
Primary refractory without HSCT 
After the above pooling, if the criterions still don’t meet, pool the 2 levels into 1 level: 


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● 
Relapse after allogeneic HSCT or after CRc without HSCT or Primary refractory without 
HSCT 
Step2: Pooling across preselected chemotherapies 
If after Step1 pooling, the criterions still don’t meet, pool the preselected high and low dose 
chemotherapies into one level: 
● 
High intensity chemotherapy (FLAG-IDA, MEC) or Low intensity chemotherapy 
(LoDAC or azacitidine) 
After the above pooling, re-evaluate the pooling of response to first-line therapy after 
merging the subjects from both preselected high and low intensity chemo groups, i.e., start 
the pooling from the 5 levels and follow the similar order described in Step1 until the 
criterions meet. 
For CR rate analysis using CMH test, similar pooling strategy will be applied when all the 
CR subjects are from one treatment group appears in at least one stratum combination. For 
CR/CRh rate analysis using CMH test, if all the CR/CRh subjects are from one treatment 
group in at least one stratum combination, the same pooled strata used for CR will be applied.  
All sensitivity analyses for the above primary and key secondary endpoints will apply the 
same pooled strata used for the primary analysis. In the case that the criterions don’t meet, 
the un-stratified analysis will be used. For other secondary efficacy endpoints, if stratified 
analysis cannot be conducted based on original stratification factors, un-stratified analysis 
will be used.   
7.11.5 Blinding 
Although the study is an open label study, to maintain trial integrity and increase the 
credibility of study results, the sponsor statisticians’ access to the randomized treatment 
assignment information will be limited.  This will reduce potential bias due to the sponsor 
knowing the treatment effect due to unintentional efficacy and safety summary by treatment. 
On the other hand, the clinical data should be used appropriately for clinical operation, data 
cleaning and generating statistical programs. Thus, we will follow the procedures specified 
below (more details can be found in Section 10.2):  
● The study statistician, supporting statisticians and statistical programmers will have 
no access to the randomized treatment information before the database lock. The 
randomized treatment code will not be transferred to study statistical programmers, 
study statistician and supporting statisticians before the database lock. Instead, 
datasets with scrambled treatment code will be used to prepare analysis programs. 
● Study manager and other study team members may have the access to the treatment 
information at the individual subject level. 
● No by treatment summary and treatment difference will be generated during the 
study, except planned interim analysis conducted by IDAC, or early submission 
package preparation conducted by an external independent data analysis team. 


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8 
DOCUMENT REVISION HISTORY  
Version 
Date 
Changes 
Comment/rationale for 
change 
1.0 
24-Aug-2015 
NA 
Document finalized 
2.0 
(Amendment 
1) 
23-Sep-2017 
Updated Schedule of Assessment 
and footnote 
Updated due to the 
following protocol 
amendments: 
Protocol amendment 4 
dated 9-Dec-2015; 
Protocol amendment 7 
dated 8-Aug-2016 
 
 
 
Updated Section 3 Study objectives 
and design: 
• 
Added another primary 
objective to evaluate 
CR/CRh rate; 
• 
Added secondary objective 
to evaluate CRh rate; 
• 
Added secondary objective 
to evaluate transfusion 
conversion and maintenance 
rates 
• 
Added another interim 
analysis for IDMC to 
evaluate the CR/CRh rate 
Updated due to Protocol 
amendment 8 dated 20-
Sep-2017 
 
 
Updated Section 3 Study design: 
Modified description on high dose 
chemo therapy 
Updated due to Protocol 
amendment 7 dated 8-
Aug-2016 
 
 
Updated Section 4 Sample size to 
add the sample size justification to 
evaluate CR/CRh at the first interim 
analysis 
Updated due to protocol 
amendment 8 dated 20-
Sep-2017 
 
 
Updated Section 5 Analysis Sets: 
• 
Added RAS and mRAS for 
the purpose of evaluate 
CR/CRh at first interim 
analysis; 
• 
Changed the primary 
efficacy analysis set from 
FAS to ITT 
Updated due to protocol 
amendment 8 dated 20-
Sep-2017 
 
 
Updated Section 6 Analysis 
variables: 
• 
Added co-primary endpoint 
of CR/CRh rate; 
• 
Added the definition of 
transfusion conversion and 
maintenance rates; 
Updated due to protocol 
amendment 8 dated 20-
Sep-2017 


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Version 
Date 
Changes 
Comment/rationale for 
change 
• 
Modified response definition 
per protocol change; 
• 
Added duration of CR/CRh; 
• 
Added time to CR/CRh; 
• 
Modified the treatment 
failure event time to be 
randomization time for EFS 
endpoint; 
• 
Deleted the adverse event 
during HSCT period; 
 
 
Updated Section 6 Analysis 
variables: 
Clarified the definition of last 
contact day for OS endpoint; 
Previous definition of last 
contact day didn’t cover 
all possible dates to 
support subject alive status 
 
 
Updated Section 6 Analysis 
variables: 
Clarified the derivation of exposure 
related variables including duration 
of exposure, cumulative dose, dose 
intensity and relative dose intensity 
Previous definition may 
not be appropriate for 
chemotherapy 
 
 
Updated Section 6 Analysis 
variables: 
Clarified the exclusion of HSCT 
period when defining the 
concomitant medication and 
transfusion 
Previous definitions were 
not clear 
 
 
Updated Section 7 Statistical 
Methodology: 
Added analysis method for 
clinical/Diagnostic procedure and 
subsequent AML therapy 
Due to new CRF pages 
added 
 
 
Updated Section 7 Statistical 
Methodology: 
Removed treatment compliance 
analysis due to unreliable drug 
accountability data 
Updated due to Protocol 
amendment 7 dated 8-
Aug-2016 
 
 
Updated Section 7 Statistical 
Methodology: 
• 
Added a table to summarize 
the timing, sample size and 
decision guidance for all 
planned analyses; 
• 
Changed the primary 
analysis method from Cox 
proportional hazard model to 
stratified log-rank test; 
Updated due to protocol 
amendment 8 dated 20-
Sep-2017 


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Version 
Date 
Changes 
Comment/rationale for 
change 
• 
Added several new 
sensitivity analyses for OS, 
EFS and CR rate; 
• 
Changed the hypothesis from 
2-sided to 1-sided for OS, 
EFS and CR rate 
• 
Added the entire section to 
describe the CR/CRh rate 
analysis method; 
• 
Added the analysis for 
duration of CR/CRh and 
time to CR/CRh; 
• 
Removed the analysis of AE, 
SAE during the on-study 
HSCT period; 
• 
Added the grade 3 and 4 
summary for selected lab test 
parameters; 
• 
Added the CR/CRh endpoint 
for subgroup analysis; 
• 
Modified the category for 
central FLT3 mutation type 
and region for subgroup 
variables; 
• 
Modifed the interim analysis 
section; 
• 
Modified the blinding 
section 
 
 
Updated Section 7 Statistical 
Methodology: 
Added how to handle partial date in 
subsequent AML therapy; 
Modified the pooling strata section 
For clarification purpose 
 
 
Updated Section 7 Statistical 
Methodology: 
Removed the visit window table 
It is redundant 
3.0 
(Amendment 
2) 
27-SEP-2018 
Updated Section 5.4.1 Reasons for 
Exclusion From PPS to add two 
criteria: 
- Neither central FLT3 mutation nor 
local FLT3 mutation with rapidly 
progressing disease at baseline 
-No active relapse at baseline 
To clarify the detailed 
Reasons for Exclusion 
From PPS criteria. 
 
 
Updated Section 5.7 
Pharmacokinetics Analysis Set 
(PKAS) to clarify that the PKAS is 
for ASP2215 patients only and both 
To clarify the detailed 
PKAS criteria. 


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Version 
Date 
Changes 
Comment/rationale for 
change 
dosing date/time and sampling 
date/time must be available. 
 
 
Updated Section 6.1.3.1 and 7.4.3.1 
to clarify the definition of EFS and 
add additional sensitivity analysis: 
-Clarify that only death from any 
cause within 30 days after the last 
dose of study drug will be considered 
as EFS event. 
-Clarify that only subject that 
discontinued the treatment and has 
achieved best response of PR or NR 
will be considered as treatment 
failure in primary EFS analysis. 
-Added the new sensitivity analysis 
to define only subject that 
discontinued the treatment and has 
achieved only best response of NR as 
treatment failure 
-Added the new sensitivity analysis 
to define only subject that 
discontinued the treatment and has 
achieved best response of PR or NR 
or NE as treatment failure 
Clarify the EFS definitions 
regarding to handling of 
deaths (for EFS event of 
death) and PR (for EFS 
event of treatment failure). 
 
 
Updated Section 6.1.3.1 and 7.4.3.1 
to add sensitivity of CR rate prior to 
HSCT. 
Add the sensitivity 
analysis to keep consistent 
with analysis on CR/CRh 
rate. 
 
 
Updated Section 6.1.3.2 to add the 
alternate definition of Duration of 
CR/CRh to consider deaths without 
report of relapse as events for 
sensitivity analysis. 
Add the sensitivity 
analysis per regulatory 
review comments. 
 
 
Updated Section 6.1.3.2: 
-To add sensitivity of Transfusion 
conversion rate and transfusion 
maintenance rate to include 
transfusion status of not-evaluable 
post-baseline as transfusion 
dependent 
-To clarify transfusion conversion 
rate and transfusion maintenance rate 
will only be defined for subjects in 
ASP2215 arm 
Add the sensitivity 
analysis per regulatory 
review comments. 
 
 
Updated Section 6.2 and added 
Section 10.3 to clarify Adverse 
events of special safety interest 
(AESI) searching strategy 
Include AESI for more 
comprehensive analysis on 
AEs. 


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Version 
Date 
Changes 
Comment/rationale for 
change 
 
 
Updated Section 6.4: 
-To clarify the post-baseline BSA 
per cycle will be used to calculate 
planned dose intensity 
-To correct typos in dose unit 
-To add the definition of Prior Use of 
FLT3 inhibitor 
-To clarify end date for concomitant 
medications and concomitant 
transfusions 
Clarify the details in 
variables defined in this 
section. 
 
 
Updated Section 7.2.3 and 7.8 to add 
two subgroups prior use of FLT3 
inhibitor and cytogenetic risk status 
for demographics and subgroup 
analysis. 
Add two new subgroups 
per knowledge learned in 
IA1. 
 
 
Updated Section 7.4.4 to clarify: 
-The additional biomarker 
exploratory analysis will be covered 
by a separate Biomarker SAP. 
-The exploratory analysis of resource 
utilization, patient reported outcomes 
(BFI, FACIT-Dys, FACT-Leu, 
dizziness, mouth sore items) and 
heath outcome (EQ-5D-5L) will be 
conducted in the separate Patient 
Reported Outcome Statistical 
Analysis Plan (PRO SAP) and 
Health Economic Statistical Analysis 
Plan. 
Adjust the contents 
covered by main SAP and 
other supplemental 
analysis plan. 
 
 
Added a new Section 7.4.6 to clearly 
describe CR/CRh related summaries 
at final analysis. 
Clarify how CR/CRh rate 
will be summarized at 
primary hardlock. 
 
 
Updated Section 7.5.1 to include 
additional summaries of AEs and AE 
summaries by patient-year. 
Update to keep consistent 
with ISS. 
 
 
Updated 7.11.1 to include the 
imputation rule of partial date of 
initial diagnosis of AML 
Clarify the missing date 
handling. 
 
 
Updated 7.11.4 to clarify that strata 
pooling will only be performed for 
OS, EFS, CR rate (and CR/CRh rate) 
as appropriate. 
Clarify details in strata 
pooling. 
 
 
Added Section 10.4 to cover Region 
Specific Analyses of Japan 
Add this section to fulfill 
PMDA request. 
4.0 
(Amendment 
3) 
27-MAY-
2022 
Specified that there will be no 
efficacy analysis performed for the 
end-of-study report. 
 
Summaries of the primary, 
secondary, and exploratory 
efficacy endpoints results 
were already produced and 


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Version 
Date 
Changes 
Comment/rationale for 
change 
available in the primary 
CSR dated 24 JAN 2019. 
 


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9 
REFERENCES 
Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality 
of life in leukemia: the Functional Assessment of Cancer Therapy--Leukemia (FACT-Leu) 
questionnaire. Value Health. 2012;15:1051-8. 
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(24):4642-4649. 
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. 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 
Karnofsky DA, Burchenal JH. “The Clinical Evaluation of Chemotherapeutic Agents in Cancer." In: 
MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. 1949;196. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659-63. 
Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 
1999;85:1186-96. 
Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of Gemtuzumab Ozogamicin in 
Patients with CD33-Positive Acute Myeloid Leukemia in First Relapse. J Clin Oncol. 
2001;19:3244-3254.  
Hajime Uno, Lu Tian, Brian Claggettc and L. J.Wei  A versatile test for equality of two survival 
functions based on weighted differences of Kaplan–Meier curves. Statistics in Medicine 2015 
Hajime Uno, Janet Wittes, Haoda Fu, Scott D. Solomon, Brian Claggett, Lu Tian, Tianxi Cai, Marc 
A. Pfeffer, Scott R. Evans and Lee-Jen Wei. Alternatives to Hazard Ratios for Comparing the 
Efficacy or Safety of Therapies in Noninferiority Studies. Annals of Internal Medicine 
2015. 163(2), 127–12. 
 
 


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10 
APPENDICES 
10.1 
Appendix 1: Approvers 
 
Author and Approver Signatories 
(E-signatures are attached at end of document)  
Global Data 
Science was the study statistician for this study and the primary author of this Statistical 
Analysis Plan 
 
 
 
Global Data Science was the GSTATL 
for this study and biostatistics peer reviewer of this Statistical Analysis Plan 
 
 
 
This Statistical Analysis Plan was approved by: 
 
 Global Medical Science 
 
 
PPD
PPD
PPD


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10.2 
Appendix 2: Blinding Process 
As specified in SAP Section 7.11.5, although the study is an open label study, to increase the 
credibility of study results, the sponsor statistician’s access to the randomized treatment 
assignment information in study database will be limited.  This will reduce potential bias due 
to the sponsor knowing the treatment effect due to unintentional efficacy and safety summary 
by treatment.   
For the purpose of controlling unintentional assessment of efficacy and safety summary by 
treatment, the study statisticians and programmers will have no access to treatment codes 
until the time of final database lock (DBL). For this study, treatment codes can be obtained 
from two sources: IRT vendor and EDC system. The following procedures should be applied 
when handling data extraction, data transferring and TLFs preparation to maintain the 
blinding during the entire study conducting period before the final DBL. 
● The treatment codes collected in EDC system will not be extracted until the final 
DBL. The treatment variable will be blocked during any data extraction before the 
final DBL. The option for blocking treatment variable will be set up before the first 
data extraction. 
● Dummy treatment codes will be created by study programmers for preparing the 
SDTM, ADaM and TLFs for interim analysis validation and final data analysis. 
● Raw data (SDTM/ADAM if needed) without treatment codes (or with dummy codes) 
will be provided by the study team to IDAC to conduct interim analysis or other 
IDMC requested analysis, and may be provided to an external independent data 
analysis team to conduct analysis for submission based on first interim analysis data 
before final DBL. 
● Separate IRT transfer requests will be sent directly by Independent Contact 
Statistician to IRT vendor for transferring treatment codes. The Independent Contact 
statistician will transfer the treatment codes to IDAC during the formal interim 
analysis or other IDMC requested analysis, and may transfer the treatment codes to an 
external independent data analysis team to prepare the early submission package 
before final DBL.     
● Dosing or other data (including PK data) which may reveal treatment assignment will 
be extracted/transferred to an unblinding folder which is only accessible to the 
unblinding programmers. 
Study manager and other study team members may have the access to the treatment 
assignment information at the individual subject level. Efficacy and safety information will 
not be summarized by treatment during the study, except at the planned interim analysis or 
other IDMC requested analysis conducted by IDAC, or early submission package preparation 
conducted by an external independent data analysis team.  
 
 


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10.3 
Appendix 3: Search Strategy for Adverse Events of Interest 
Risk 
Search Strategy: MedDRA Version 23.0 
Anaphylactic reaction 
Anaphylactic reaction (SMQ Broad) 
Cardiac failure 
Cardiac failure (SMQ Narrow) 
Creatine phosphokinase 
increased 
Rhabdomyolysis/ myopathy (SMQ Narrow) 
Blood creatine phosphokinase abnormal (PT=10005468 and 
Grade >=3) 
Blood creatine phosphokinase increased (PT=10005470 and 
Grade>=3) 
Blood creatine phosphokinase MM increased 
(PT=10005477 and Grade>=3) 
PT: Myalgia 
PT: Myositis 
PT: Muscular weakness 
Diarrhea 
Noninfectious diarrhoea (SMQ Broad) 
Differentiation Syndrome* 
PT: Acute interstitial pneumonitis, Acute kidney injury, 
Acute lung injury, Acute pulmonary oedema, Acute 
respiratory distress syndrome, Acute respiratory failure, 
Anuria, Atypical pneumonia, Blood creatinine increased, 
Blood pressure systolic decreased, Body temperature 
increased, Capillary leak syndrome, Cardiopulmonary 
failure, Cardiorenal syndrome, Cardiorespiratory distress, 
Cough, Differentiation syndrome, Dyspnoea, Febrile 
neutropenia, Fluid overload, Fluid retention, Generalised 
oedema, Hepatorenal failure, Hydraemia, Hypervolaemia, 
Hypotension, Lower respiratory tract infection, Lower 
respiratory tract inflammation, Lung infection, Lung 
infiltration, Multiple organ dysfunction syndrome, 
Noncardiogenic pulmonary oedema, Oedema, Oedema 
peripheral, Pericardial effusion, Pleural effusion, 
Pneumonia, Pneumonitis, Prerenal failure, Pulmonary 
congestion, Pulmonary oedema, Pulmonary toxicity, 
Pyrexia, Renal failure, Renal impairment, Renal injury, 
Respiratory arrest, Respiratory distress, Respiratory failure, 
Weight increased PTs 
Gastrointestinal obstruction 
Gastrointestinal obstruction (SMQ Narrow) 
Gastrointestinal perforation 
Gastrointestinal perforation (SMQ Narrow) 
Liver transaminase 
increased 
Liver related investigations, signs, and symptoms (SMQ 
Narrow) 


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Pancreatitis 
Acute pancreatitis (SMQ Broad) 
Pericarditis/Pericardial 
effusion 
HLT Noninfectious pericarditis  
PT Pericardial effusion 
PRES 
Noninfectious encephalopathy/delirium (SMQ Narrow) 
QT Prolongation 
Torsade de pointes/QT prolongation (SMQ Narrow) 
Teratogenicity and Embryo- 
Fetal Deaths 
SMQ Broad-All Pregnancy 
*Only AEs occur within the first 90 days 
 
 
 


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10.4 
Appendix 4: Japan Specific Analysis 
10.4.1 Introduction  
This appendix describes the planned regional specific analyses in addition to the analyses 
defined by the main body of this SAP. The regional analyses specified in this appendix are 
for the PMDA submission only. 
10.4.2 Region Specific Analyses of Japan  
The following regional specific analyses of Japan will be performed as appropriate: 
● 
All analyses as described in the main body of this SAP will be repeated for the 
subgroups of Japan vs Non-Japan 
● 
All listings will be presented by sites ordered as Japan followed by Non-Japan sites 
Below shows a couple of examples where the regional specific analyses of Japan will be 
handled differently from what are described in the main body of this SAP. The exceptions 
will be reflected in the corresponding TLF specifications, where the detailed Specifications 
for table, figure, and data listing formats can be found.  
Example(s) of Region Specific Analyses of Japan with Difference 
Section(s) 
Change(s) 
Comment/rationale for change 
7.2.3 
Geographical Region will not be included 
in the summary of demographic and other 
baseline characteristics 
The summary of demographic and other 
baseline characteristics will be repeated for 
the subgroups of Japan vs Non-Japan  
7.4 
The endpoints of OS, EFS, CR rate and 
CR/CRh rate will be evaluated using un-
stratified analysis only. 
Due to the small number of Japan patients, all 
these efficacy analysis will be performed 
using un-stratified analysis instead of 
stratified analysis.  
7.8 
Subgroup analyses won’t be performed for 
Geographical Region 
The subgroup analyses will be repeated for the 
subgroups of Japan vs Non-Japan