Clinical trial NCT02310321
Conditions: Acute Myeloid Leukemia FLT3-mutated Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia Cytarabine Idarubicin ASP2215
Sponsor: Astellas Pharma Inc
Start date: 2015-02-26; Completion date: 2024-07-09
Enrollment: 97 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of phase 1 part in this study was to determine the maximum tolerated dose (MTD) and/or recommended expansion dose (RED) of ASP2215 concomitant with cytarabine/idarubicin as induction chemotherapy based on the status of the onset of dose-limiting toxicity (DLT) in newly diagnosed Acute Myeloid Leukemia (AML) subjects. Phase 1 part also evaluated safety and tolerability and characterized the pharmacokinetic (PK) parameters of ASP2215 concomitant with induction and consolidation chemotherapy as well as evaluated the PK parameters of cytarabine concomitant with ASP2215.

The purpose of phase 2 part was to evaluate efficacy of ASP2215 in combination with induction therapy. Phase 2 cohort also evaluated safety and characterized the PK parameters of ASP2215 in combination with induction and consolidation therapy followed by maintenance therapy in newly diagnosed FLT3-mutated AML subjects.

Detailed description:
This study was composed of Phase 1 part (the dose-evaluation part and the expansion part) and Phase 2 part.

In the dose-evaluation part of Phase 1 part, at least 3 subjects received ASP2215 at each dose (low, middle, and high) for determination of MTD and/or RED. Treatment of AML in Phase 1 part was composed of 3 periods of therapy: remission induction, consolidation, and maintenance. The decision of whether or not to proceed to the next dose was made based on the occurrence of DLT during Cycle 1 of the induction period.

In the expansion part of Phase 1 part, a maximum of 3 subjects received ASP2215 at RED that had been recommended in the dose-evaluation part and the safety was assessed based on the onset of DLTs during Cycle 1 of the induction and consolidation periods.

In Phase 2 part, Subjects received ASP2215 at the recommended dose established in Phase 1 part. The target population was limited to newly diagnosed FLT3-mutated AML.

Arms: arm 1: Induction period: Participants received 120 milligrams (mg) gilteritinib (3 tablets of 40 mg) orally, once daily from day 4 to 17 combined with chemotherapy (idarubicin: 12 mg per square meters per day \[mg/m\^2/day\] on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via intravenous (IV) infusion; in cycles (C) 1 and 2 (1 cycle= 42 days).

Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from day 1 to 14 combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days).

Duration of infusion was determined by site clinical practice and local package insert in both induction and consolidation periods..

Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or untill discontinuation criterion is met (1 cycle= 28 days). arm 2: Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days).

Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days).

Duration of infusion was determined based on site clinical practice and the local package insert in both induction and consolidation periods.

Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days). arm 3: Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 8 until blood recovery combined with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in C1 and 2. Each cycle was extended until blood recovery was observed.

Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 until blood recovery combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in C1 to 3. Each cycle was extended until blood recovery was observed.

Duration of infusion was based on site clinical practice and the local package insert in both induction and consolidation periods.

Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).
Interventions: intervention 1: Gilteritinib intervention 2: Idarubicin intervention 3: Cytarabine
Intervention descriptions: intervention 1: Once-daily oral administration on 14 consecutive days in every cycle in each period. intervention 2: Induction period: Once-daily intravenous injection of 12 mg/m\^2 idarubicin on 3 consecutive days. intervention 3: Induction period: Once-daily intravenous injection of 100 mg/m\^2 cytarabine on 7 consecutive days.

Consolidation period: Twice-daily intravenous injection of 1.5 g/m\^2 cytarabine on Days 1, 3, and 5.

Protocol documents:
Prot_000.pdf: 
Sponsor: API 
ISN/Protocol 2215-CL-0104 
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Astellas 
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A Phase 1/2 Study of ASP2215 in Combination with Induction 
and Consolidation Chemotherapy in Patients with Newly 
Diagnosed Acute Myeloid Leukemia  
 
ISN/Protocol 2215-CL-0104 
Version 8.0 
Incorporating Substantial Amendment 7 
29 Aug 2021 
 
 
Sponsor: 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku, 
Tokyo 103-8411, Japan 
 
 
 
 
 
 
 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research subject; and (4) where disclosure of such information is made to a member of the investigator’s team 
who agrees to hold this information in confidence.  
 


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Table of Contents 
SIGNATURES ································
································
·······························
 10 
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ································
·····  12 
1 
PROTOCOL SUMMARY ································
································
·······  13 
1.1 
Synopsis ································
································
························
 13 
1.2 
Study Schema ································
································
··················
 32 
1.3 
Schedules of Assessments ································
································
····  34 
2 
INTRODUCTION ································
································
·················
 43 
2.1 
Background ································
································
····················
 43 
2.1.1 
Nonclinical and Clinical Data ································
··························
 44 
2.1.1.1 
Nonclinical Pharmacology ································
························
 44 
2.1.1.2 
Safety Pharmacology and Toxicology ································
··········
 45 
2.1.1.3 
Non-Clinical Pharmacokinetics and Metabolism ······························
 46 
2.1.1.4 
Clinical Studies ································
································
····  47 
2.1.2 
Summary of Key Safety Information for Study Drug(s) ····························
 56 
2.2 
Study Rationale ································
································
················
 56 
2.3 
Risk Benefit Assessment ································
································
·····  57 
3 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ································
··············
 58 
4 
STUDY DESIGN AND DOSE RATIONALE ································
················
 60 
4.1 
Study Design ································
································
···················
 60 
4.1.1 
Administration Plan ································
································
·····  62 
4.1.2 
Definition of DLT ································
································
·······  64 
4.1.3 
Determination of Maximum Tolerated Dose and Recommended Expansion 
Dose ································
································
·······················
 65 
4.2 
Dose Rationale ································
································
················
 65 
4.3 
End of Study Definition ································
································
······  66 
5 
STUDY POPULATION ································
································
··········
 67 
5.1 
Inclusion Criteria ································
································
··············
 67 
5.2 
Exclusion Criteria ································
································
·············
 69 
5.3 
Restrictions during the Study ································
································
 72 
5.4 
Screen Failures ································
································
················
 73 
5.4.1 
Rescreening ································
································
··············
 73 


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5.5 
Pre-Registration, Registration and Registration Failures ································
· 73 
5.6 
Subject Replacement ································
································
··········
 74 
6 
STUDY DRUGS AND CONCOMITANT CHEMOTHERAPY ·························
 74 
6.1 
Study Drugs and Concomitant Chemotherapy ································
·············
 74 
6.1.1 
Dose/Dose Regimen and Administration Period ································
····  75 
6.2 
Preparation/Handling/Storage/Accountability ································
·············
 77 
6.2.1 
Packaging and Labeling ································
································
 77 
6.2.1.1 
ASP2215 ································
································
············
 77 
6.2.1.2 
Concomitant Chemotherapy (Idarubicin, Cytarabine) ························
 77 
6.2.2 
Handling, Storage and Accountability ································
················
 78 
6.3 
Randomization and Blinding ································
································
 78 
6.3.1 
Assignment and Allocation································
·····························
 79 
6.4 
Study Drug and Concomitant Chemotherapy Compliance ·······························
 79 
6.5 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ································
································
························
 79 
6.5.1 
Previous Medication (Drugs and Therapies) ································
·········  79 
6.5.2 
Concomitant Medication (Drugs and Therapies) ································
····  79 
6.6 
Dose Modification ································
································
············
 81 
6.7 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation ···········
 83 
7 
STUDY PROCEDURES AND ASSESSMENTS ································
············
 84 
7.1 
Efficacy Assessments ································
································
·········  84 
7.1.2 
Antitumor Response ································
································
····  84 
7.1.2.1 
Best Response ································
································
······  86 
7.1.3 
Survival Time, Duration and Other Efficacy Endpoints ····························
 86 
7.1.3.1 
Overall Survival ································
································
····  86 
7.1.3.2 
Event-free Survival ································
································
 87 
7.1.3.3 
Relapse-free Survival ································
·····························
 87 
7.1.3.4 
Transplantation Rate ································
······························
 87 
7.1.3.5 
Duration of Response ································
·····························
 87 
7.2 
Safety Assessments ································
································
···········
 87 
7.2.1 
Adverse Events ································
································
··········
 88 
7.2.2 
Laboratory Assessments ································
································
 88 
7.2.3 
Vital Signs ································
································
················
 88 
7.2.4 
Height and Weight ································
································
······  88 


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7.2.5 
Physical Examination ································
································
···  89 
7.2.6 
Electrocardiogram ································
································
·······  89 
7.2.7 
Chest X-ray or Computed Tomography Scan ································
········  90 
7.2.8 
Multigated Acquisition Scan or Echocardiogram ································
···  90 
7.2.9 
Pregnancy Tests ································
································
·········  90 
7.2.10 
DLT ································
································
·······················
 90 
7.3 
Adverse Events and Other Safety Aspects ································
·················
 90 
7.3.1 
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information ································
································
···············
 90 
7.3.2 
Adverse Event and Serious Adverse Event during HSCT ··························
 90 
7.3.3 
Method of Detecting Adverse Events and Serious Adverse Events ···············
 91 
7.3.4 
Follow-up of Adverse Events ································
··························
 91 
7.3.5 
Reporting of Serious Adverse Events ································
·················
 91 
7.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ································
··········
 92 
7.3.7 
Special Situations ································
································
········  92 
7.3.8 
Supply of New Information Affecting the Conduct of the Study ··················
 93 
7.3.9 
Urgent Safety Measures <For JP Region: Deviations from the Protocol 
and Other Actions Taken to Avoid Life-threatening Risks to Subjects> ·········  93 
7.3.10 
Reporting Urgent Safety Measures ································
····················
 94 
7.4 
Pharmacokinetics ································
································
··············
 95 
7.4.1 
Pharmacokinetic Assessment ································
··························
 95 
7.4.2 
Test Drug Concentration ································
·······························
 96 
7.4.2.1 
Measurement of Plasma ASP2215 Concentration ·····························
 96 
7.4.2.2 
Measurement of Plasma Cytarabine Concentration ···························
 97 
7.5 
Pharmacodynamics | Immunogenicity ································
······················
 98 
7.6 
Exploratory Biomarker(s) ································
································
····  98 
7.6.1 
FLT3 Mutation Assessment ································
····························
 98 
7.6.2 
Minimal Residual Disease (MRD) Assessment································
······  99 
7.6.3 
Other Biomarker Assessment ································
··························
 99 
7.6.4 
Sample for Banked Pharmacogenomic Sample Analysis ·························
 100 
7.7 
Total Amount of Blood and Bone Marrow Fluid ································
········  100 
8 
DISCONTINUATION ································
································
··········
 101 
8.1 
Discontinuation of Individual Subject(s) from Study Treatment ······················
 101 
8.2 
Discontinuation of Individual Subject(s) from Study ································
···  103 


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8.2.1 
Lost to Follow-up································
································
······  103 
8.3 
Discontinuation of the Study Site ································
·························
 103 
8.4 
Discontinuation of the Study································
·······························
 103 
9 
STATISTICAL METHODOLOGY ································
·························
 104 
9.1 
Sample Size ································
································
··················
 104 
9.1.1 
Target Sample Size ································
································
····  104 
9.1.2 
Justification of Sample Size ································
··························
 104 
9.2 
Analysis Sets ································
································
·················
 105 
9.2.1 
Full Analysis Set (FAS) ································
······························
 105 
9.2.2 
Safety Analysis Set (SAF) ································
····························
 105 
9.2.3 
Pharmacokinetic Analysis Set (PKAS) ································
·············
 105 
9.2.4 
Pharmacodynamic Analysis Set (PDAS) ································
···········
 106 
9.2.5 
Dose-Determining Analysis Set (DDAS)································
···········
 106 
9.2.6 
MRD Analysis Set (MAS) ································
···························
 106 
9.3 
Demographics and Baseline Characteristics ································
·············
 106 
9.3.1 
Demographics ································
································
··········
 106 
9.3.2 
Subject Disposition ································
································
····  107 
9.3.3 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ································
································
················
 107 
9.3.4 
Medical History ································
································
········  107 
9.3.5 
Study Drug Exposure ································
································
· 107 
9.4 
Analysis of Efficacy ································
································
········  107 
9.4.1 
Analysis of Primary Endpoint ································
·······················
 108 
9.4.1.1 
Primary Analysis ································
································
· 108 
9.4.1.2 
Subgroup Analysis ································
·······························
 108 
9.4.2 
Analysis of Secondary Endpoints ································
···················
 108 
9.4.3 
Analysis of Exploratory Endpoints ································
··················
 109 
9.5 
Analysis of Safety ································
································
···········
 109 
9.5.1 
Occurrence of DLTs ································
································
··  109 
9.5.2 
Adverse Events ································
································
········  110 
9.5.3 
Laboratory Assessments ································
······························
 110 
9.5.4 
Vital Signs ································
································
··············
 110 
9.5.5 
12-lead Electrocardiogram ································
···························
 110 
9.5.6 
Body Weight ································
································
···········
 110 
9.6 
Analysis of Pharmacokinetics ································
·····························
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9.6.1 
Estimation of Pharmacokinetic Parameters ································
········  110 
9.6.2 
Statistical Analysis of Pharmacokinetic Parameters ······························
 111 
9.7 
Analysis of Pharmacodynamics | Immunogenicity ································
······  111 
9.8 
Other Analyses ································
································
··············
 111 
9.8.1 
Analysis of Exploratory Biomarker(s) ································
··············
 111 
9.8.2 
Retrospective Pharmacogenomic Study ································
············
 111 
9.9 
Major Protocol Deviations ································
································
· 112 
9.10 
Interim Analysis (and Early Discontinuation of the Study) ····························
 112 
9.11 
Additional Conventions ································
································
····  112 
10 
OPERATIONAL CONSIDERATIONS ································
·····················
 112 
10.1 
Procedure for Clinical Study Quality Control ································
···········
 112 
10.1.1 
Data Collection ································
································
········  112 
10.1.2 
Specification of Source Documents ································
·················
 113 
10.2 
Demographics and Baseline Characteristics ································
·············
 114 
10.2.1 
Demographics ································
································
··········
 114 
10.2.2 
Medical History and Concurrent Diseases ································
·········  114 
10.2.3 
Diagnosis of the Target Disease, Severity and Duration of Disease ············
 115 
10.3 
Major Protocol Deviations ································
································
· 115 
10.4 
STUDY ORGANIZATION································
································
 116 
10.4.1 
Efficacy and Safety Evaluation Committee ································
········  116 
10.4.2 
Other Study Organization ································
····························
 116 
10.5 
Registration of Subjects ································
································
····  116 
11 
REFERENCES ································
································
··················
 117 
12 
APPENDICES ································
································
···················
 119 
12.1 
Ethical, Regulatory and Study Oversight Considerations ······························
 119 
12.1.1 
Ethical Conduct of the Study ································
·························
 119 
12.1.2 
Institutional Review Board/Independent Ethics Committee ·····················
 119 
12.1.3 
Protocol Amendment and/or Revision ································
··············
 119 
12.1.4 
Informed Consent of Subjects ································
·······················
 120 
12.1.4.1 
Subject Information and Consent ································
··············
 120 
12.1.4.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ···························
 121 
12.1.4.3 
Subject Information and Consent for Retrospective Pharmacogenomic 
Study ································
································
··············
 121 


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12.1.5 
Source Documents ································
································
····  122 
12.1.6 
Record Retention ································
································
······  122 
12.1.7 
Subject Confidentiality and Privacy ································
·················
 124 
12.1.8 
Arrangement for Use of Information and Publication of the Study ·············
 124 
12.1.9 
Insurance of Subjects and Others (UNIQUE to JP) ·······························
 125 
12.1.10 
Signatory Investigator for Clinical Study Report ································
··  125 
12.2 
Procedure for Study Quality Control ································
·····················
 125 
12.2.1 
Study Monitoring ································
································
······  125 
12.2.2 
Direct Access to Source Data/Documents ································
··········
 126 
12.2.3 
Data Management ································
································
·····  126 
12.3 
Contraception Requirements ································
·······························
 127 
12.4 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up and Reporting ································
································
············
 129 
12.4.1 
Definition of Adverse Events ································
························
 129 
12.4.1.1 
Abnormal Laboratory Findings ································
················
 129 
12.4.1.2 
Potential Cases of Drug-induced Liver Injury ································
 129 
12.4.2 
Definition of Serious Adverse Events································
···············
 129 
12.4.3 
Criteria for Causal Relationship to Study Drug ································
····  130 
12.4.4 
Criteria for Defining the Severity of an Adverse Event ··························
 132 
12.4.5 
Reporting Procedures for Serious Adverse Events ································
 132 
12.4.6 
Reporting Procedures for Special Situations ································
·······  134 
12.4.6.1 
Pregnancy ································
································
·········  134 
12.4.6.2 
Medication Error, Overdose and “Off-label Use” ···························
 135 
12.4.6.3 
Misuse/Abuse ································
································
····  135 
12.4.6.4 
Occupational Exposure ································
·························
 135 
12.4.6.5 
Suspected Drug-drug Interaction ································
··············
 136 
12.4.7 
Monitoring of Common Serious Adverse Events ································
· 136 
12.5 
Special terms ································
································
·················
 138 
12.6 
Liver Safety Monitoring and Assessment ································
················
 139 
12.7 
List of Excluded Concomitant Medications································
··············
 142 
12.8 
Laboratory Assessments ································
································
····  143 
12.9 
Acceptable Range of Schedule of Assessments ································
·········  146 
12.10 
Pharmacogenomic Analysis with Banked Sample (Optional) ·························
 158 
12.11 
Clinical Study Continuity ································
································
··  160 


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12.12 
List of Abbreviations and Definition of Key Study Terms ·····························
 167 
13 
ATTACHMENT 1 – SUBSTANTIAL AMENDMENT 7 ································
 172 
14 
SPONSOR SIGNATURE ································
································
······  216 
 
List of In-text Tables 
Table 1 
Phase 1 part Dose Evaluation flow chart ································
···················
 16 
Table 2 
Dose level of ASP2215 ································
································
·······  16 
Table 3 
Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 1) ········  25 
Table 4 
Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 2) ········  26 
Table 5 
Observed CR with Exact 90% CI (N=70 in Phase 2 part) ································
 30 
Table 6 
Schedule of Assessments [Phase 1 part] ································
····················
 34 
Table 7 
Schedule of Assessments [Phase 2 part] ································
····················
 38 
Table 8 
Study Objective(s) and Endpoint(s) ································
·························
 58 
Table 9 
Phase 1 Part Dose Evaluation Flow Chart ································
·················
 61 
Table 10 
Study Drugs and Concomitant Chemotherapy ································
·············
 74 
Table 11 
Dose level of ASP2215 ································
································
·······  75 
Table 12 
Evaluation Period for Previous Medications and eCRF Entry Items ···················
 79 
Table 13 
Evaluation Period for Concomitant Medications/Therapies and eCRF Entry 
Items ································
································
····························
 80 
Table 14 
Treatment Criteria in Event of a Study Drug-related Adverse Event ···················
 81 
Table 15 
Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 2) ········  82 
Table 16 
Evaluation time point for Plasma ASP2215 Concentration ······························
 95 
Table 17 
Evaluation time point for Plasma Cytarabine Concentration ····························
 95 
Table 18 
Approximate Amounts of Blood and Bone Marrow Fluid ·····························
 100 
Table 19 
Approximate Amounts of Blood and Bone Marrow Fluid ·····························
 101 
Table 20 
Observed CR with Exact 90% CI (N=70 in phase 2 part) ······························
 108 
Table 21 
Criteria for Determining Causal Relationship with the Study Drug ··················
 132 
Table 22 
Grading Scale Defining the Severity of an Adverse Event ·····························
 132 
Table 23 
ECOG Performance Status ································
································
· 138 
Table 24 
NYHA (New York Heart Association) Functional Classification ·····················
 138 
Table 25 
Definition of Liver Abnormalities ································
························
 139 
Table 26 
Laboratory Materials and Parameters (Phase 1) ································
·········  143 
Table 27 
Laboratory Materials and Parameters (Phase 2) ································
·········  145 
Table 28 
Acceptable Time Ranges for Laboratory Tests ································
··········
 147 
Table 29 
Acceptable Time Ranges for Vital Signs ································
·················
 148 
Table 30 
Acceptable Time Ranges for 12-lead ECG (Including assessment of QT 
interval) ································
································
·······················
 150 
Table 31 
Acceptable Time Ranges for ECOG Performance Status ······························
 152 
Table 32 
Acceptable Time Ranges for ECHO or MUGA ································
·········  153 
Table 33 
Acceptable Time Ranges for Chest X-Ray or Chest CT ·······························
 153 
Table 34 
Acceptable Time Ranges for Body Height/Weight ································
·····  153 


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Table 35 
Acceptable Time Ranges for Pregnancy Test ································
············
 154 
Table 36 
Acceptable Time Ranges for Bone Marrow Tests ································
······  155 
Table 37 
Acceptable Time Ranges for Blood Sampling for PK Analysis of ASP2215 and 
Cytarabine ································
································
····················
 156 
Table 38 
Acceptable Time Ranges for FLT3 Mutation Test (Sampling) ························
 157 
Table 39 
Alternative Schedule of Assessments in Response to a Crisis [Phase 2 part] ········  162 
Table 40 
List of Abbreviations ································
································
·······  167 
 
List of In-text Figures 
Figure 1 
Study Schema ································
································
··················
 32 
Figure 2 
Study Design ································
································
···················
 33 
 


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SIGNATURES 
1. AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR 
This study will be conducted in adherence to International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines and applicable laws and regulatory requirements, as well as this protocol. 
As the evidence of the agreement, the investigator (CHIKEN SEKININ ISHI) and 
responsible person of the sponsor (CHIKEN IRAI SEKININSHA) inscribe in the bipartite 
agreement by signature or “printed name and seal.” 
2. SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 14 
Sponsor’s Signatures]. 
 


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3. INVESTIGATOR’S SIGNATURE 
A Phase 1/2 Study of ASP2215 in Combination with Induction and Consolidation 
Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia 
ISN/Protocol 2215-CL-0104, Version 8.0 Incorporating Substantial Amendment 7 
29 Aug 2021 
I have read all pages of this 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 International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations. I will also 
ensure that (s) and other relevant members of my personnel 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: 
 
 
 
 
Date (DD Mmm YYYY) 
Printed Name: 
 
  
<Insert name and qualification of the investigator> 
Address: 
 
 
 
 
 
 
 
 
 
 
 


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CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL 
24-hour Contact for 
Serious Adverse Events 
 
See Section 12.4.5 
Please fax or email the serious adverse events 
(SAE)/special situations worksheet to: 
 
For investigational sites in Japan, 
Sponsor Contact: 
Astellas Pharma Inc., Development,  
Japan-Asia Clinical Development 1 
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan 
TEL: 03-3244-1097 
FAX: 03-3243-5737 
 
Contract Research Organizer (CRO) Contact: 
PPD-SNBL K.K., Global Clinical Development  
St Luke’s Tower 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo, 
Japan 
TEL: 03-6821-0932 
FAX:03-6740-7912 
 
For investigational sites in countries except for Japan, 
Astellas Pharma Inc. – Japan 
Pharmacovigilance 
Email: safety-jp@astellas.com 
Medical Monitor/Study 
Physician 
 
 
 
ASTELLAS PHARMA GLOBAL DEVELOPMENT 
1 Astellas Way, Northbrook, IL USA 60062 
 
 
Clinical Research Contact 
Pharmaceutical Product Development, LLC (PPD) 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Date and Version of Protocol Synopsis: 
29 Aug 2021, Version 8.0 
Sponsor: Astellas Pharma Inc. (API) 
Protocol Number: 2215-CL-0104 
Compound Name: ASP2215 
Phase of Development: Phase 1/2 
Title of Study:  
A Phase 1/2 Study of ASP2215 in Combination with Induction and Consolidation 
Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia 
Planned Study Period:  
From August 2014 to 4Q 2022 (including long-term follow-up period). 
Study Objective(s) and Endpoint(s):  
[Phase 1 part] 
Objective(s) 
Endpoint(s) 
Primary 
● 
Determine the maximum tolerated dose 
(MTD) and/or recommended expansion 
dose (RED) of ASP2215 concomitant 
with cytarabine/idarubicin as induction 
chemotherapy based on the status of the 
onset of dose-limiting toxicity (DLT) 
● 
MTD 
● 
RED  
● 
Occurrence of DLT 
● 
Evaluate the safety and tolerability of 
ASP2215 concomitant with 
cytarabine/idarubicin as induction 
chemotherapy and high-dose cytarabine 
as consolidation chemotherapy 
● 
Adverse events (AEs), safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
● 
Evaluate the safety and tolerability of 
ASP2215 in maintenance therapy after 
induction and consolidation therapy 
● 
AEs, safety laboratory tests, vital 
signs, and ECGs 
Secondary 
● 
Characterize the pharmacokinetic (PK) 
parameters of ASP2215 concomitant 
with induction and consolidation 
chemotherapy 
● 
PK parameters 
● 
Evaluate the PK parameters of 
cytarabine concomitant with ASP2215 
● 
PK parameters 
● 
Evaluate the pharmacodynamic (PD) 
parameters of ASP2215 
● 
PD parameters 
Table continued on next page 


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Objective(s) 
Endpoint(s) 
Exploratory 
● 
Evaluate the efficacy of ASP2215 
concomitant with induction and 
consolidation chemotherapy 
● 
CR (Complete Remission) 
● 
CRp (CR with incomplete platelet 
recovery) 
● 
CRi (CR with incomplete 
hematologic recovery) 
● 
PR (Partial Remission) 
● 
CRc (Composite CR): CR + CRp + 
CRi 
● 
Overall response rate: CRc + PR 
● 
Duration of response 
[Phase 2 part] 
Objective(s) 
Endpoint(s) 
Primary 
● 
Evaluate the efficacy of ASP2215 in 
combination with induction therapy in 
newly diagnosed FLT3-mutated acute 
myeloid leukemia (AML) subjects  
● 
Complete remission (CR) rate after 
induction therapy period for Phase 2 
part subjects 
Secondary 
● 
Characterize the pharmacokinetic (PK) 
parameters of ASP2215 concomitant 
with induction and consolidation 
chemotherapy 
● 
PK parameters 
● 
Evaluate the safety and efficacy of 
ASP2215 in combination with induction 
and consolidation therapy followed by 
maintenance therapy 
● 
Overall survival (OS) 
● 
Event free survival (EFS) 
● 
Relapse free survival (RFS) 
● 
CR rate after each treatment therapy 
● 
CR rate without minimal residual 
disease (MRD) after each treatment 
therapy 
● 
Complete remission with partial 
hematological recovery (CRh) rate 
after each treatment therapy 
● 
Composite complete remission 
(CRc) rate after each treatment 
therapy 
● 
CR/CRh rate after each treatment 
therapy 
Table continued on next page 


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Objective(s) 
Endpoint(s) 
● 
Evaluate the safety and efficacy of 
ASP2215 in combination with induction 
and consolidation therapy followed by 
maintenance therapy 
(continued) 
● 
Duration of CR, CRh, CR/CRh and 
CRc 
● 
Duration of response 
● 
Adverse events (AEs), safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
Exploratory 
● 
Evaluate the additional efficacy 
measures for ASP2215 in combination 
with induction and consolidation 
therapy followed by maintenance 
therapy 
● 
Transplantation rate 
● 
Cumulative incidence of relapse 
(CIR) after 1st CR (CR1) 
● 
Cumulative incidence of death (CID) 
after CR1 
● 
Time to hematopoietic recovery after 
each treatment cycle 
● 
MRD 
● 
MRD-negative CR rate after 
induction 
● 
Overall MRD-negative CR rate for 
any treatment period  
Planned Total Number of Study Sites and Location(s):  
Phase 1 part: Approximately 6 centers in Japan 
Phase 2 part: Approximately 50 centers in Asia Pacific 
Study Population:  
Phase 1 part: Newly diagnosed acute myeloid leukemia (AML) patients 
Phase 2 part: Newly diagnosed FLT3-mutated AML patients 
Number of Subjects to be Enrolled/Randomized:  
Phase 1 part: approximately 6 subjects 
● 
Dose-evaluation part: At least 3 subjects per cohort (which may be changed according 
to the status of the onset of DLT and the number of cohorts) 
● 
Expansion part: At least 3 subjects 
Phase 2 part: approximately 80 subjects 
Study Design Overview: 
This study is a Phase 1/2, open-label, single-arm study in patients with newly diagnosed 
AML. The Phase 1 part evaluates the dose of ASP2215 using the Bayesian-continual 
reassessment method (hereinafter, Bayesian-CRM) and the Phase 2 part evaluates the 
safety and the effect of ASP2215 in combination with induction and consolidation therapy 
followed by maintenance therapy in newly diagnosed FLT3-mutated AML patients. This 
study is composed of two Phase 1 parts and a Phase 2 part. The Phase 1 parts are 
composed of dose evaluation and expansion parts with the target population of patients 
 




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is defined as the highest dose of ASP2215 at which the posterior mean of the DLT 
incidence during Cycle 1 of induction therapy is estimated to be closest to 33%. 
[Phase 2 part] 
After achieving the objectives of the Phase 1 part, the Phase 2 part can be initiated. 
Subjects will receive ASP2215 at the recommended dose established in the Phase 1 part. 
The primary objective of the Phase 2 part is to evaluate the efficacy of ASP2215 in 
combination with induction therapy in newly diagnosed FLT3-mutated AML subjects. The 
target population will be limited to newly diagnosed FLT3-mutated AML. The primary 
analysis for the primary endpoint of the CR rate will be conducted when all registered 
subjects complete the induction therapy period.  
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, relapse and survival (cause and date of death). During 
the long-term follow-up period, the subject will be followed for 3 years after the last 
subject’s first treatment or completion of 30-day follow-up of the last subject, whichever is 
longer. 
Inclusion/Exclusion Criteria:  
[Phase 1 part] 
Inclusion Criteria: 
Subject is eligible for the study if all of the following apply at enrollment: 
1. Written informed consent has been obtained (However, if the subject is underage, 
consent must also be obtained from the subject’s legal guardian). 
2. Subject is ≥ 18 and < 70 years of age at the time of obtaining informed consent. 
3. Subject is defined as having previously untreated de novo AML according to the World 
Health Organization (WHO) criteria (2008) within 28 days prior to study enrollment. 
4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
of ≤ 2. 
5. Subject must meet all of the following criteria in the laboratory test at screening: 
● Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 
of ≤ 2.5 × institutional upper limit of normal (ULN) 
● Total serum bilirubin level of ≤ 1.5 × institutional ULN 
● Serum creatinine level of ≤ 1.5 × institutional ULN or an estimated glomerular 
filtration rate (eGFR) of > 50 mL/min† 
†Calculating formula: eGFR (mL/min/1.73 m2 = 194 × Cr−1.094 × Age−0.287 (× 0.739 
for female subjects) 
6. Subject is suitable for oral administration of ASP2215. 
7. Female subject falls under the following: 
Of non-childbearing potential: 
● Post-menopausal (defined as at least 1 year with no menses without a medical 
reason such as drug administration) at screening, or 
● Documented surgically sterile or status post-hysterectomy (at least 1 month prior to 
screening) 


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Of childbearing potential: 
● Agrees not to try to become pregnant during the study and for 60 days after the final 
study drug administration, 
● Has a negative result for the serum or urine pregnancy test at screening, and 
● If heterosexually active, agrees to consistently use two effective contraceptive 
methods (one of which must be the barrier method) per locally accepted standards 
starting at screening and throughout the study period and for 60 days after the final 
study drug administration. 
8. Female subject agrees not to breastfeed starting at screening and throughout the study 
period and for 60 days after the final study drug administration. 
9. Female subject agrees not to donate ova starting at screening and throughout the study 
period and for 60 days after the final study drug administration. 
10. Male subject and his female spouse/partner who is of childbearing potential agrees to 
use two effective contraceptive methods (one of which must be the barrier method) per 
locally accepted standards starting at screening and throughout the study period, and 
for 120 days after the final study drug administration. 
11. Male subject agrees not to donate sperm starting at screening and throughout the study 
period and for 120 days after the final study drug administration. 
12. Subject agrees not to participate in another interventional study while on study 
treatment. 
13. Subject can be admitted during the induction therapy period. 
Exclusion Criteria: 
Subject will be excluded from participation if any of the following apply at enrollment: 
1. Subject was diagnosed with acute promyelocytic leukemia (APL). 
2. Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic 
myelogenous leukemia in blast crisis). 
3. Subject has active malignant tumors other than AML or myelodysplastic syndrome 
(MDS). 
4. Subject has received prior AML treatment except for the following: 
● Urgent leukapheresis 
● Hydroxyurea administration for emergency treatment of hyperleukocytosis  
(≤ 7 days) 
● Administration of retinoic acid before the diagnosis to exclude APL (≤ 7 days) 
● Supportive care using growth factors or cytokines 
● Steroid administration to treat hypersensitivity or blood transfusion reactions 
5. Subject has clinically active central nervous system leukemia. 
6. Subject has disseminated intravascular coagulation (DIC). 
7. Subject has had major surgery within 28 days prior to the first study drug 
administration. 
8. Subject has had radiation therapy within 28 days prior to the first study drug 
administration. 


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9. Subject has congestive heart failure of New York Heart Association (NYHA) class 3 or 
4, or subject with a past history of congestive heart failure of NYHA class 3 or 4 and in 
whom echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed 
within 3 months prior to screening or at screening showed a left ventricular ejection 
fraction (LVEF) of < 45%. 
10. Subject has cardiac impairment or a clinically significant cardiac disease, including any 
one of the following: 
● Complete left bundle branch block 
● Obligate use of a cardiac pacemaker 
● Long QT syndrome 
● Prolongation of the mean QTc interval (> 450 ms) on electrocardiogram (ECG) at 
screening 
● Right bundle branch block + left anterior hemiblock (bifascicular block) 
● Angina pectoris within 3 months prior to study drug administration 
● Acute myocardial infarction within 3 months prior to study drug administration 
11. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 
12. Subject requires treatment with concomitant drugs that target serotonin 5HT1 or 5HT2B 
receptors or sigma nonspecific receptors, with the exception of drugs that are 
considered absolutely essential for treatment of the subject. 
13. Subject has an active uncontrollable infection. 
14. Subject is known to have human immunodeficiency virus (HIV) infection. 
15. Subject has active hepatitis B or C or other active hepatic disorders. 
16. Subject has any condition that, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
17. Subject has potassium and magnesium levels of below institutional lower limit of 
normal in the laboratory test at screening. 
18. 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). 
[Phase 2 part] 
Inclusion Criteria: 
Subject is eligible for participation in 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 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 form (ICF).  
3. Subject has a diagnosis of previously-untreated de novo AML according to World 
Health Organization (WHO) classification (2017) documented within 28 days prior to 
enrollment. 


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4. Subject is positive for FLT3-ITD and/or TKD mutation in bone marrow or whole blood 
as determined by the central lab. Registration by the local lab result is not acceptable. 
5. Subject has an ECOG performance status (PS) 0 or 1 (see Section 12.5). Subject who 
has an ECOG PS 2 is eligible only if investigators suspect that the primary disease 
related symptoms such as pneumonia and febrile neutropenia are the causes of PS 
score. 
6. Subject is suitable for oral administration of ASP2215. 
7. Female subject is not pregnant (see Section 12.3) and at least 1 of the following 
conditions apply: 
a. Not a woman of childbearing potential (WOCBP) (see Section 12.3) 
b. WOCBP who agrees to follow the contraceptive guidance (see Section 12.3) from 
the time of informed consent through at least 180 days after final study treatment 
administration. 
8. Female subject must agree not to breastfeed starting at screening and throughout the 
study period and for 60 days after the final study drug administration. 
9. Female subject must not donate ova starting at screening and throughout the study 
period and for 180 days after the final study drug administration. 
10. 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. 
11. Male subject must not donate sperm starting at screening and throughout the study 
period and for 120 days after the final study drug administration. 
12. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom 
for the duration of the pregnancy throughout the study period and for 120 days after the 
final study treatment administration. 
13. Subject agrees not to participate in another interventional study while on treatment. 
14. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
a. Serum creatinine ≤ 1.5  institutional upper limit of normal (ULN), or if serum 
creatinine outside normal range, then glomerular filtration rate (GFR) 
> 50 mL/min/1.73 m2 as calculated with the 4-parameter Modification of Diet in 
Renal Disease (MDRD) equation. 
b. Serum total bilirubin ≤ 2.5 mg/dL (43 µmol/L), except for subjects with Gilbert’s 
syndrome. 
c. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × 
ULN. If liver abnormality by the primary disease is suspected, subject may be pre-
registered to initiate the chemotherapy. Prior to registration, AST/ALT values must 
meet the criteria to continue the study. 
d. Serum magnesium ≥ institutional lower limit of normal (LLN). Subject may pre-
register without magnesium value, but subject must meet the criteria prior to the 
full registration on Day 8. 
e. Serum potassium ≥ institutional lower limit of normal (LLN).  
 


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Exclusion Criteria: 
A subject will be excluded from participation in this clinical study if any of the following 
apply: 
1. Subject was diagnosed with acute promyelocytic leukemia (APL). 
2. Subject has known BCR-ABL-positive leukemia (chronic myelogenous leukemia in 
blast crisis). 
3. Subject has therapy-related AML. 
4. Subject has active malignant tumors other than AML. 
5. Subject has received previous therapy for AML, with the exception of the following: 
● 
Emergency leukapheresis, 
● 
Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 10 days, 
● 
Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days, 
● 
Growth factor or cytokine support, or 
● 
Steroids for the treatment of hypersensitivity or transfusion reactions. 
6. Subject has QTcF interval > 450 ms (average of triplicate determinations based on 
central reading). 
7. Subject with long QT syndrome. 
8. Subject has clinically active central nervous system leukemia. 
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 immediate life-threatening, severe complications of leukemia such as 
severe uncontrolled bleeding and/or severe disseminated intravascular coagulation. 
12. Subject is known to have human immunodeficiency virus infection. 
13. Subject has active hepatitis B or C. 
14. Subject has an uncontrolled infection. An infection controlled with an approved or 
closely monitored antibiotic/antiviral/antifungal treatment is allowed. 
15. Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
electrocardiographic evidence of acute ischemia, congestive heart failure New York 
Heart Association (NYHA) class 3 or 4 or subject with a past history of congestive 
heart failure of NYHA class 3 or 4 and in whom echocardiogram (ECHO) or Multiple 
Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at 
screening showed a left ventricular ejection fraction (LVEF) of < 45%. 
16. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 
17. Subject requires treatment with concomitant drugs that target serotonin 5HT2B 
receptors or sigma nonspecific receptors, with the exception of drugs that are 
considered absolutely essential for treatment of the subject. 
18. 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.  
19. Subject has prior malignancies, except resected basal cell carcinoma or treated cervical 
carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be 
allowed. Cancer treated with curative intent < 5 years previously will not be allowed.  
20. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 


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Study Drugs and Concomitant Chemotherapy:  
ASP2215, AS3329381/Cytarabine and idarubicin (if applicable) 
Name and Use:  
[Phase 1 part] 
ASP2215 
study drug 
Cytarabine 
concomitant chemotherapy 
Idarubicin 
concomitant chemotherapy 
[Phase 2 part] 
ASP2215 
study drug 
AS3329381/Cytarabine 
study drug and/or concomitant chemotherapy 
(based on the local regulation) 
Idarubicin 
concomitant chemotherapy 
 
Dose(s) and Mode(s) of Administration:  
[Phase 1 part] 
Induction therapy (per cycle) 
ASP2215 
The specified dose level (120 mg or 80 mg) QD from Day 4-17 
Idarubicin  
12 mg/m2/day by intravenous injection from Day 1 to 3 
Cytarabine 
100 mg/m2/day by intravenous injection from Day 1 to 7 
 
Consolidation therapy (per cycle) 
ASP2215 
The specified dose level (120 mg or 80 mg) QD from Day 1-14 
Cytarabine 
1.5 g/m2 twice a day by intravenous injection on Day 1, 3, 5 
 
Maintenance therapy (per cycle) 
ASP2215 
The specified dose level (120 mg or 80 mg) QD 
 
[Phase 2 part] 
Induction therapy (per cycle) 
ASP2215 
The specified dose level (120 mg) QD from Day 8-21 
Idarubicin  
12 mg/m2/day by intravenous injection from Day 1-3 
Cytarabine 
100 mg/m2/day by intravenous injection from Day 1-7 
 
Consolidation therapy (per cycle) 
ASP2215 
The specified dose level (120 mg) QD from Day 1-14 
Cytarabine 
1.5 g/m2 twice a day by intravenous injection on Day 1, 3, 5 
 
Maintenance therapy (per cycle) 
ASP2215 
The specified dose level (120 mg) QD 
 


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Study Treatment Period 
[Phase 1 part] 
Treatment of AML in this study is composed of 3 phases of therapy: induction therapy, 
consolidation therapy, and maintenance therapy. The decision of tolerability at ASP2215 
dose levels will be made based on the occurrence of DLT during Cycle 1 of the induction 
therapy period for the evaluation part. In the expansion part, at least 3 subjects will receive 
ASP2215 at RED that has been recommended in the dose evaluation part and the safety 
will be assessed based on the onset of DLTs during Cycle 1 of the induction and 
consolidation therapy period. RED will finally be assessed based on DLT in the dose-
evaluation part and that in the expansion part. 
Induction therapy period (42 days per cycle): 
During the induction therapy period, subjects will receive idarubicin (12 mg/m2/day by 
intravenous injection) on 3 consecutive days beginning from Day 1 and cytarabine 
(100 mg/m2/day by intravenous injection) on 7 consecutive days beginning from Day 1. 
Subjects will receive ASP2215 once daily on 14 consecutive days from Day 4 through Day 
17. Subjects will be hospitalized during the induction therapy period. Induction therapy 
may be conducted up to 2 cycles based on the response to the 1st cycle of therapy. 
Consolidation therapy period (28 days per cycle): 
Subjects who received 1 or 2 cycles of induction therapy and achieved CR, CRp, or CRi 
will receive consolidation therapy. Consolidation therapy will be started without delay 
when a subject has reached remission by induction therapy with blood count recovery. 
Consolidation therapy can be started during a cycle of the induction therapy period. A 
subject who cannot start consolidation therapy by Day 57 of the last cycle of induction 
therapy will be withdrawn from the study. During the consolidation therapy period, 
subjects will receive cytarabine (1.5 g/m2 by intravenous injection) twice daily at 12-hour 
intervals on Days 1, 3, and 5 of each cycle. Subjects will receive oral ASP2215 once daily 
on 14 consecutive days from Day 1 through Day 14. The subsequent cycle will be started 
after Day 22 of the previous cycle and recovery of the subject’s blood count. Consolidation 
therapy may be conducted up to 3 cycles. Withdrawal from the study will be considered for 
a subject who cannot enter the subsequent cycle of consolidation therapy or start 
maintenance therapy by Day 36 of each cycle. 
Maintenance therapy period (28 days per cycle): 
Subjects who completed at least 1 cycle of consolidation therapy will receive maintenance 
therapy. Maintenance therapy is 28 days per cycle and will be conducted up to 26 cycles 
with once-daily oral administration of ASP2215. 
Follow-up observation period: 
After treatment discontinuation, subjects will have a 28-day follow-up visit for safety. 


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[Phase 2 part] 
Induction therapy period: 
The same chemotherapy regimen is applied as the Phase 1 part. Subjects will receive 
ASP2215 once daily on 14 consecutive days from Day 8 through Day 21. Induction 
therapy may be conducted up to 2 cycles based on the response to the 1st cycle of therapy. 
Upon the investigator’s discretion, patients are allowed to proceed immediately to 
hematopoietic stem cell transplantation (HSCT) without receiving consolidation therapy. 
Postponing the initiation of consolidation therapy until blood recovery is preferred. The 
maximum number of days in 1 cycle for induction therapy period is not defined. 
Consolidation therapy period: 
The same chemotherapy regimen is applied as the Phase 1 part. Subjects will receive oral 
ASP2215 once daily on 14 consecutive days from Day 1 through Day 14. The maximum 
number of days in 1 cycle for the consolidation therapy period is not defined. Omission of 
consolidation therapy due to HCST is allowed. Consolidation therapy may be conducted 
up to 4 cycles.  
Maintenance therapy period (28 days per cycle): 
The same therapy is applied as the Phase 1 part. Maintenance therapy may be conducted up 
to 26 cycles. 
Resuming the study after HSCT: 
Subjects who have a donor identified and have achieved a response are allowed to undergo 
HSCT per each institution’s assessment and continue to receive the protocol specified 
maintenance therapy 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 HSCT 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 composite complete remission (CRc) 
For subjects resuming treatment, they will follow the procedures listed under initial or 
subsequent cycle day 1 of maintenance therapy in the Schedule of Assessments. Subjects 
who do not resume ASP2215 will be followed for the survival endpoints. 
Long-term follow-up period: 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, relapse and survival (cause and date of death). During 
the long-term follow-up period, the subject will be followed for 3 years after the last 
subject’s first treatment or completion of 30-day follow-up of the last subject, whichever is 
longer. 


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Dose Modifications:  
[Phase 1 part] 
ASP2215: 
Intra-subject dose escalation of ASP2215 is not permitted. If DLT occurs during the DLT 
assessment period, the study treatment will be discontinued without dose reduction. The 
investigator may interrupt the administration of ASP2215 when the safety of patient needs 
to be ensured. 
Interruption, discontinuation, or dose reduction of ASP2215 should be performed in 
accordance with the Table 3 if the study drug-related toxicities are observed in a subject in 
the maintenance period. Note that each dose reduction should be performed by 40 mg. 
After the initial dose reduction, additional dose reductions may be performed until the 
dosage reaches 40 mg. If no further dose reduction is possible, the study treatment will be 
discontinued. Dose re-escalation in subjects who had a dose reduction is not permitted. 
In addition, the investigator may interrupt or reduce the dose of ASP2215 when it is 
considered necessary to ensure the safety of the patients for reasons other than those 
presented in the table below. The investigator must promptly notify the sponsor of the 
interruption or dose reduction for reasons not specified in the table. 
Table 3 Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 1) 
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. 
Non-hematological events 
Grade 3 
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 
Treatment will be discontinued. 
QTcF > 500 ms 
If the mean triplicate QTcF is > 500 ms at any time point 
(according to values shown in an ECG chart or analyses in a central 
laboratory), the ECG will be repeated 3 times (within 2 hours if 
identified according to the ECG chart values or as soon as possible 
if identified from 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 the study drug may be 
interrupted temporarily based on ECG chart values, the central 
reading should be used for final treatment decisions. Cardiovascular 
medicine consult will be obtained as medically indicated. If QTcF 
resolves to ≤ 480 ms (Grade 1 or less severe) by central reading 
within 14 days, the subject may resume dosing from the reduced 
dose. 
Myelosuppression 
Grade 4 neutropenia and 
thrombocytopenia 
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. 
 
 


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Concomitant drugs (idarubicin and cytarabine): 
Intra-subject dose escalation of idarubicin or cytarabine is not permitted. 
Dose reduction of idarubicin and cytarabine will be conducted following the standard 
treatment method at each study site. If discontinuation, interruption, or dose reduction of 
idarubicin and/or cytarabine occurs during Cycle 1 of the induction period, the study 
sponsor will consider whether the subject is eligible for DLT assessment. 
[Phase 2 part] 
ASP2215: 
The starting dose of ASP2215 is 120 mg, the RED which was determined in the Phase 1 
part. Dose escalation of ASP2215 is not allowed and re-escalation after dose reduction is 
also not allowed in this study. 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 any time during the study drug treatment period based on the 
dose reduction guideline in Table 4 or any reason other than the ones listed on the table if 
the investigator deems it necessary to ensure subject safety. In the unusual circumstance 
that dosing is interrupted or reduced for reasons not specified in the tables, the investigator 
should promptly inform the Medical Monitor or his/her designee. Any subjects that have 
been off treatment for more than 14 days other than for HSCT or a study drug related AE, 
may only resume treatment after discussion with the Medical Monitor. However, if no 
further dose reduction is possible, the study treatment should be discontinued. 
Table 4 Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 2) 
ASP2215 Dosing Instructions 
Non-hematological Events 
Grade 3 toxicity at least 
possibly related to ASP2215 
Dosing will be interrupted for up to 14 days. 
If the adverse event 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. 
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 severe) by central reading within 14 
days, the subject may resume dosing at the reduced dose. 
Myelosuppression (Maintenance therapy only) 
Grade 4 neutropenia and 
thrombocytopenia 
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. 
ECG: electrocardiogram; QTcF: Fridericia-corrected QT interval 


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Concomitant drugs (idarubicin and cytarabine): 
Intra-subject dose escalation of idarubicin or cytarabine is not permitted. 
Dose reduction of idarubicin and cytarabine should not be performed. If discontinuation, 
interruption, or dose reduction of idarubicin and/or cytarabine occurs during Cycle 1 of the 
induction period, information should be reported to the sponsor. Based on the investigator 
decision, chemotherapy dosing of Induction Cycle 2 may be reduced after confirmation 
with the sponsor. 
Concomitant Treatment (Medication and Non-Medication Therapy) Restrictions or 
Requirements:  
● 
Any other treatments of AML (including but not limited to chemotherapy, 
radiotherapy, surgery, immunotherapy or cellular therapy) are prohibited during 
therapy with ASP2215 with the exception of hydroxyurea up to 6 g daily for up to 2 
weeks to keep the absolute blast count below 50 x 109/L, prophylactic intrathecal 
chemotherapy or cranial irradiation. 
● 
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 5HT2B receptor or sigma nonspecific receptor 
are to be avoided with ASP2215 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 ASP2215 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 closely monitored for AEs. 
● 
Precaution should be used in treatment of ASP2215 with concomitant drugs that are 
known to prolong QT or QTc intervals. 
● 
Intake of grapefruit juice should be avoided during the study to the greatest extent 
possible. 
For chemotherapy drugs, the instructions in the local package insert under “Special 
warnings and precautions for use” section should be followed. The treatment mentioned in 
the specified section should be avoided or used with caution and closely monitored during 
idarubicin and cytarabine administration. 
Duration of Treatment:  
[Phase 1 part] 
● 
Induction therapy period (maximum 2 cycles): Once-daily repeated oral administration 
from Day 4 through Day 17 of induction therapy in 42-day cycles. 
● 
Consolidation therapy period (maximum 3 cycles): Once-daily repeated oral 
administration from Day 1 through Day 14 of consolidation therapy in 28-day cycles. 
● 
Maintenance therapy period (maximum 26 cycles): Once-daily repeated oral 
administration in 28-day cycles until the end of Cycle 26, or a discontinuation 
criterion is met. 
 


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[Phase 2 part] 
● 
Induction therapy period (maximum 2 cycles): Once-daily repeated oral administration 
from Day 8 through Day 21 of induction therapy. 
● 
Consolidation therapy period (maximum 4 cycles): Once-daily repeated oral 
administration from Day 1 through Day 14 of consolidation therapy. 
● 
Maintenance therapy period (maximum 26 cycles): Once-daily repeated oral 
administration in 28-day cycles until the end of Cycle 26, or a discontinuation 
criterion is met. 
Treatment Discontinuation Criteria:  
[Phase 1 part] 
Subjects who meet any of the following criteria during the study will be withdrawn from 
study treatment. 
● 
Withdrawal of consent 
● 
Poor compliance (failure to make the scheduled visits and others) 
● 
A serious protocol deviation is found 
● 
Failure to achieve remission after 2 cycles of induction therapy 
● 
Relapse after remission 
● 
Occurrence of an unacceptable adverse event (AE) requiring discontinuation of 
treatment 
● 
The investigator determines that continuation of study treatment will be detrimental to 
the subject. 
● 
Subjects or their partners are found to be pregnant. 
[Phase 2 part] 
Discontinuation Criteria from Treatment for Individual Subjects who completed 
registration: 
● 
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 one 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 fails to achieve remission after 2 cycles of induction therapy. 
● 
Subject relapses following remission. 
● 
Subject develops an intolerable or unacceptable toxicity. 
● 
Subject receives any antileukemic therapy other than the assigned treatment with the 
exception of hydroxyurea up to 6 g daily for up to 2 weeks, prophylactic intrathecal 
chemotherapy cranial irradiation or HSCT. 
● 
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. 
● 
Female subject becomes pregnant. 
● 
Death. 
 


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Discontinuation Criteria from Post-Treatment Follow-up for Individual Subjects 
● 
Subject declines further study participation (i.e., withdrawal of consent). 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Death. 
[Only applies to Phase 2 part] 
The study meets the criteria to complete the long-term follow-up (i.e., During the long-
term follow-up period, the subject will be followed for 3 years after the last subject’s first 
treatment or completion of 30-day follow-up of the last subject, whichever is longer.) 
Statistical Methods: 
Sample Size Justification:  
[Phase 1 part] 
For dose evaluation part: To assess MTD and RED of ASP2215 as induction therapy 
concomitant with cytarabine/idarubicin in newly diagnosed AML subjects, 3 DLT 
evaluable subjects per dose level for 1 dose level were assumed.  
For dose expansion part: The sample size was set to 3 subjects to further assess the safety 
and efficacy of ASP2215 at the dose tested in the expansion part. 
[Phase 2 part] 
The sample size of Phase 2 part is approximately 80 subjects. An evaluable sample size of 
70 subjects in Phase 2 part provides more than 80% power to detect a 15% increase in CR 
rate from 55% (historical benchmark based on the RATIFY study, Stone et al, 2017.) to 
70% at one-sided significance level of 0.05. Assuming approximately 10% drop-out rate, a 
total of 80 subjects will be enrolled into Phase 2 part.  
Efficacy:  
[Phase 1 Part] 
CR rate, CRp rate, CRi rate, CRc (CR + CRp + CRi) rate, PR rate, overall response rate, 
duration of response will be summarized using summary statistics. 
[Phase 2 Part] 
Primary Efficacy Analysis: 
For the primary efficacy endpoint of CR rate after induction therapy period, the two-sided 
90% exact confidence interval (CI) by Clopper-Pearson method will be calculated for 70 
subjects who took at least one dose of ASP2215 and had at least one post-baseline bone 
marrow assessment. The lower limit of the CI will be used to compare with the benchmark 
of CR rate of 55%. Out of 70 evaluable subjects, at least 46 subjects who achieve CR after 
induction is necessary to exclude 55% based on the exact 90% CI of CR rate as 
summarized the Table 5 below.  


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Table 5 
Observed CR with Exact 90% CI (N=70 in Phase 2 part) 
Observed CR (n and %) 
Exact 90% CI 
56 (80.0%) 
(70.5%, 87.5%) 
49 (70.0%) 
(59.7%, 78.9%) 
48 (68.6%) 
(58.3%, 77.7%) 
47 (67.1%) 
(56.8%, 76.4%) 
46 (65.7%) 
(55.3%, 75.1%) 
45 (64.3%) 
(53.8%, 73.8%) 
 
Secondary Efficacy Analyses: 
The statistical analyses on secondary efficacy endpoints include the following descriptive 
analyses for ASP2215 in combination with induction and consolidation therapy followed 
by maintenance therapy: 
● 
Kaplan-Meier method for time-to-event endpoints including OS, EFS, RFS, duration 
of CR, CRh, CR/CRh, and CRc. 
● 
The two-sided 95% exact confidence interval of the binary endpoints including CR 
rate, CRh rate, CR/CRh rate, and CRc rate. 
Safety:  
[Phase 1 part] 
Posterior mean of DLT incidence will be estimated for each dosage. 
● 
All AEs and AEs for which a causal relationship with the study drug and with the 
remission induction or consolidation therapy including the study drug cannot be ruled 
out will be summarized by frequency, by System Organ Class (SOC), and by Preferred 
Term (PT). 
● 
Summary statistics will be calculated or a summary of frequency will be produced for 
the following parameters depending on the nature of the data. 
● 
Laboratory parameters 
● 
Vital signs 
● 
Body weight 
● 
12-lead ECG (including QT assessment) 
[Phase 2 part] 
● 
All AEs and AEs for which a causal relationship with the study drug and with the 
remission induction or consolidation therapy including the study drug cannot be ruled 
out will be summarized by frequency, by System Organ Class (SOC), and by Preferred 
Term (PT). 
● 
Summary statistics will be calculated or a summary of frequency will be produced for 
the following parameters depending on the nature of the data. 
● 
Laboratory parameters 
● 
Vital signs 
● 
Body weight 
● 
12-lead ECG (including QT assessment) 
 


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Pharmacokinetics:  
[Phase 1 part] 
Using the plasma ASP2215 and cytarabine concentration measurements, pharmacokinetic 
parameters and summary statistics will be calculated.  
[Phase 2 part] 
Using the plasma ASP2215 concentration measurements, pharmacokinetic parameters and 
summary statistics will be calculated. 
Pharmacodynamics | Immunogenicity:  
[Phase 1 part] 
Percent inhibition of phosphorylation of FLT3 and AXL as compared to those at baseline 
sampling will be summarized by cohort. 
[Phase 2 part] 
Not applicable 
Interim Analyses:  
[Phase 1 part] 
Not applicable 
[Phase 2 part] 
Not applicable 
 
 


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1.2 
Study Schema 
Figure 1 
Study Schema 
[Phase 1 part: Dose-evaluation] 
CONSENT 
Screening 
 
 
 
DLT observation  
(to the end of Cycle 1) 
Consent for study 
continuation 
Consolidation perioda 
(Cycles 1–3: 28 days/cycle) 
Maintenance period 
(Cycles 1–26: 28 days/cycle) 
 
After 
discontinuation 
Follow-up 
observation  
Induction period 
(Cycles 1 and 2: 42 days/cycle) 
Day −7~ Day 
−1b 
Idarubicin: 12 mg/m2/day (Day 1–Day 3) 
Cytarabine: 100 mg/m2/day (Day 1–Day 7) 
ASP2215: Once daily (Day 4–Day 17) 
Cytarabine: 1.5 g/m2, twice daily 
(Days 1, 3, and 5) 
ASP2215: Once daily (Day 1–
Day 14) 
ASP2215: Once daily (Day 1–
Day 28) 
Until Cycle 26 or a 
discontinuation criterion is met. 
28 days after the last 
administration of 
ASP2215 
[Phase 1 part: Expansion part] 
CONSENT 
Screening 
 
 
 
DLT observation  
(to the end of Cycle 1 of consolidation therapy period) 
Maintenance period 
(Cycles 1–26: 28 days/cycle) 
 
After 
discontinuation 
Follow-up 
observation  
Induction period 
(Cycles 1 and 2: 42 days/cycle) 
Consent for study 
continuation 
Consolidation period* 
(Cycles 1–3: 28 days/cycle) 
Day −7 ~ 
Day −1b 
Idarubicin: 12 mg/m2/day (Day 1–Day 3) 
Cytarabine: 100 mg/m2/day (Day 1–Day 7) 
ASP2215: Once daily (Day 4–Day 17) 
Cytarabine: 1.5 g/m2, twice daily 
(Days 1, 3, and 5) 
ASP2215: Once daily (Day 1–
Day 14) 
ASP2215: Once daily (Day 1–
Day 28) 
Until Cycle 26 or a 
discontinuation criterion is met. 
28 days after the last 
administration of 
ASP2215 
 
 
 
                                                 
a Cycle 1 will be started without delay when a subject has reached remission with blood count recovery (within 57 days from the start of the last cycle of induction chemotherapy). 
Subsequent cycles will be started after the completion of the assessment scheduled on Day 28 of the previous cycle, which is to be performed after Day 22 of the previous cycle, 
following recovery of the subject’s blood count. 
b Treatment on Day 1 may be started on the day informed consent is obtained when the investigator or subinvestigator judges that immediate treatment is required due to rapid 
proliferative disease progression. In this case, among the test items specified in both screening and Day 1 of Cycle 1, tests to determine body height, body weight, vital signs, and 
ECOG-PS and laboratory tests are not required to be performed twice. 




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1.3 
Schedules of Assessments 
Table 6 
Schedule of Assessments [Phase 1 part] 
Assessments (Induction therapy) 
Screening 
(Day −7–Day −1) i 
Day 1 i 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 11 Day 15 Day 17 Day 28 
Day 
42 
Visit window 
- 
0 
0 
0 
0 
0 
0 
0 
0 
0 
±1 
−1 
±7 
+14 
Signed ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/concurrent disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
Height and weight j 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X  
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X  
ECOG PS 
X  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Prior and concomitant medications 
X k 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBP l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or chest CT m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG n 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
Table continued on next page 
                                                 
i Cycle 1 Day 1 may be started on the day informed consent is obtained when the investigator or subinvestigator judges that immediate treatment is required due to rapid proliferative 
disease progression. In this case, among the test items specified in both screening and Cycle 1 Day 1 twice, tests to determine body height, body weight, vital signs, and ECOG-PS and 
laboratory tests are not required to be performed twice. 
j Height will be measured only at screening. Body surface area will be calculated when body weight is measured. 
k Includes medications taken within 28 days prior to Day 1 of remission induction. 
l WOCBP must undergo a serum or urine pregnancy test. 
m Not necessary to perform if chest X-ray or chest CTs were performed within 7 days prior to enrollment even before obtaining consent. Chest X-ray or chest CTs will be performed 
when they are determined to be clinically necessary. 
n QT interval measurements will be performed at the central ECG laboratory on Day 1 (at pre-dose of idarubicin and cytarabine), Day 4 (at pre-dose and 4 hours post-dose), Day 11 (at 
pre-dose), Day 17 (at pre-dose and 4 hours post-dose), and Day 28. The 12-lead ECGs for QT interval measurement will be recorded in triplicate (3 separate ECGs with approximately 
2-minute intervals) and transmitted electronically for central reading. When the timing for PK blood sampling and ECG is close, ECG will be performed prior to PK blood sampling. 


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Assessments (Induction therapy) 
Screening 
(Day −7–Day −1) i 
Day 1 i 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 11 Day 15 Day 17 Day 28 
Day 
42 
Laboratory tests (hematology, biochemistry, thyroid 
function test, coagulation test and urinalysis) o 
X 
X 
 
 
X 
 
 
 
X  
 
X 
 
X 
X 
ECHO or MUGA p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling for FLT3 mutation test (bone marrow or 
whole blood) q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow test 
X r 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK plasma sampling s, t 
 
X 
 
X 
X 
X 
 
 
X  
X 
 
X 
X 
 
Sampling for PGx banking u, t 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Idarubicin dosing 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Cytarabine dosing 
 
X 
X 
X  
X 
X  
X  
X 
 
 
 
 
 
 
ASP2215 dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
o To be performed at pre-dose of idarubicin and cytarabine during Cycle 1. 
p To be performed on patients with a history of congestive heart failure of NYHA class 3 or 4 (however, not necessary to be repeated at screening if ECHO or MUGA performed 
within 3 months prior to enrollment showed LVEF of ≥ 45%). 
q The bone marrow sample will be collected at screening for the FLT3 mutation test. If bone marrow samples cannot be obtained, whole blood samples will be collected at screening. 
r Not necessary to perform if the bone marrow test was performed within 28 days prior to enrollment even before obtaining consent. 
s Plasma PK samples for ASP2215 will be collected on Day 4 at pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose (on Day 5 at pre-dose), and on Days 8, 11, and 17 at pre-dose, and on 
Day 28. Plasma PK samples for cytarabine will be collected on Days 1 and 3 at pre-dose of idarubicin and cytarabine and on Day 8 at pre-dose. 
t These samples will be collected only during Cycle 1. 
u Buccal swab and blood will be collected from subjects who have consented to sampling for future PGx study. 


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Consolidation therapy 
Assessments 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 8 
Day 14 
Day 15 
Day 28 
Visit window 
0 
0 
0 
0 
0 
0 
0 
0 
−1 
±7 
Signed ICF 
X v 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
X 
X 
Weight 
X  
 
 
 
 
 
 
 
 
 
Vital signs 
X  
 
 
 
 
 
X 
 
X 
X 
ECOG PS 
X  
 
 
 
 
 
X 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG w 
X 
X 
 
 
 
 
 
 
X 
 
Laboratory tests (hematology, biochemistry, thyroid 
function test, coagulation test) 
X 
 
 
X 
 
 
X  
 
X 
X 
Sampling for FLT3 mutation test (bone marrow or whole 
blood) x 
X 
 
 
 
 
 
 
 
 
 
Bone marrow test 
X y 
 
 
 
 
 
 
 
 
 
AE assessment 
 
 
 
 
 
 
 
 
 
 
PK plasma sampling z 
X 
X 
 
 
 
X 
 
 
X 
 
Cytarabine dosing  
X 
 
X 
 
X 
 
 
 
 
 
ASP2215 dosing 
 
 
 
 
 
 
 
 
 
 
 
                                                 
v Obtain written informed consent for continuous participation in the study before starting ASP2215 dosing for consolidation chemotherapy. 
w QT interval measurements will be performed at the central ECG laboratory on Day 1 at pre-dose and 4 hours post-dose, Day 2 at pre-dose, and Day 15 (at pre-dose if performed on 
Day 14 within the allowed visit window [−1] for Day 15). The 12-lead ECGs for QT interval measurement will be recorded in triplicate (3 separate ECGs with approximately 2-minute 
intervals) and transmitted electronically for central reading. When the timing for PK blood sampling and ECG is close, ECG will be performed prior to PK blood sampling. 
x The bone marrow sample will be collected on Day 1 for the FLT3 mutation test. If bone marrow samples cannot be obtained, whole blood samples will be collected on Day 1. 
y The bone marrow test will be performed only for starting Cycle 1 of consolidation chemotherapy within 7 days prior to chemotherapy start. It is not necessary to repeat the test if the 
bone marrow test was performed during the induction therapy period within this period. 
z Plasma sampling for PK will be performed only during Cycle 1. Plasma PK samples for ASP2215 will be collected on Day 1 at pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose 
(before dosing on Day 2), on Day 6 at pre-dose, and on Day 15 (at pre-dose if performed on Day 14 within the allowed visit window [−1] for Day 15). Plasma PK samples for 
cytarabine will be collected on Day 2 and Day 6 at pre-dose. 


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Maintenance therapy and End of Treatment 
Assessments 
Cycle 1 
Cycle ≥ 2 
At discontinuation or the end of Cycle 26 
Follow-up observation aa 
Day 1 
Day 15 
Day 1 
Day of judgment of discontinuation or Day 28 of 
Cycle 26 
Last day of dosing 
+28 days 
Allowed visit window 
0 
±3 
±3 
Day of judgment of discontinuation or Day 28 of 
Cycle 26 +7 
±7 
Physical examination 
X 
X 
X 
X 
X 
Weight 
X  
 
 
X bb 
 
Vital signs 
X  
 
X 
X bb 
 
ECOG PS 
X  
 
 
X bb 
 
Concomitant medications 
 
 
 
 
 
Pregnancy test for WOCBP 
X 
 
 
X bb 
 
12-lead ECG 
 
 
 
X bb 
 
Laboratory tests (hematology, biochemistry, thyroid function test, 
coagulation test and urinalysis) 
X 
 
X 
X bb 
 
Sampling for FLT3 mutation test (bone marrow or whole blood) cc 
X 
 
 
 
 
Bone marrow test dd 
X 
 
 
X bb 
 
AE assessment 
 
 
 
 
 
PK plasma sampling 
 
 
 
X ee 
 
ASP2215 dosing 
 
 
 
 
 
 
 
 
                                                 
aa Follow up observation will be skipped if it is difficult to be conducted due to initiation of a successive treatment after discontinuation or for another reason. 
bb Not necessary to repeat these tests if they were performed at a scheduled visit after the last dosing of ASP2215. 
cc The bone marrow sample will be collected on Day 1 for the FLT3 mutation test. If bone marrow samples cannot be obtained, whole blood samples will be collected on Day 1. 
dd The bone marrow test will be performed within 7 days prior to the start of maintenance therapy. It will be also performed whenever it was determined to be clinically necessary 
during the period of ASP2215 dosing. 
ee PK blood sampling for ASP2215 is strongly recommended even in the case of discontinuation. 


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Table 7 
Schedule of Assessments [Phase 2 part] 
Induction therapy 
Assessments 
Screening ff 
D1 ff 
D2-3 
D4-7 
D8 
D9-14 
D15 
D16-20 
D21 
D28 
D42 h 
D56 gg 
Visit window 
Within 7 days 
0 
0 
0 
0 
0 
+/- 2 
0 
+/- 2 
+7 
+7 
+7 
Signed ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and Disease History 
MUGA or ECHO hh 
Pregnancy Test for WOCBP ii 
Chest X-ray (or CT of Chest) jj 
Idarubicin Administration 
 
X 
X 
 
 
 
 
 
 
 
 
 
Cytarabine Administration 
 
X 
X 
X 
 
 
 
 
 
 
 
 
ASP2215 Administration 
 
 
 
 
X 
X 
X 
X 
X kk 
 
 
 
Registration to the study ll 
X 
 
 
 
X 
 
 
 
 
 
 
 
Physical Examination  
X mm 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X mm 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Height, Weight and BSA nn 
X mm 
X 
 
 
X 
 
 
 
 
 
 
 
ECOG Performance 
X mm 
X 
 
 
X 
 
 
 
 
 
 
 
Prior and Concomitant Medications 
X oo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Table continued on next page 
                                                 
ff Consent, Screening, and Cycle 1 Day 1 may be performed on the same day if investigator(s) judges it is necessary due to rapid disease progression and subject meets all 
inclusion/exclusion criteria except for Inclusion criteria (IC) #4, #14-c, and #14-d for pre-registration. Cycle 1 Day 1 must be initiated within 7 days of consent. 
gg The end of induction therapy period is not defined. Peripheral blood sample at blood recovery should be submitted to a central lab. If full blood recovery has been observed, 
scheduled visit for Day 56 may be omitted as long as samples after blood recovery has been submitted to central labs. 
hh ECHO or MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4. ECHO or MUGA performed prior to consent and 
within 3 months prior to screening may be used. 
ii WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study treatment. 
jj Chest X-ray/CT of Chest performed prior to consent and within 1 week prior to Screening may be used. 
kk Administration of ASP2215 should not be more than 14 days even if the scheduled visit has been shifted within the visit window. 
ll Pre-registration is required before the initiation of induction therapy (Day 1). Registration is required before initiation of ASP2215 treatment. For registration failure subjects, no 
follow up visits should be conducted. 
mm If the Screening visit and Day 1 are performed on the same day, only Day 1 data is mandatory.  
nn Height is only required at Screening. BSA will be calculated when the body weight is measured. 
oo Includes medications taken within 28 days prior to Day 1. 


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Assessments 
Screening ff 
D1 ff 
D2-3 
D4-7 
D8 
D9-14 
D15 
D16-20 
D21 
D28 
D42 h 
D56 gg 
Bone Marrow Aspiration/Biopsy pp, qq 
X rr 
 
 
 
 
 
 
 
 
X ss 
Response Assessment (including extramedullary 
leukemia) 
FLT3 Mutation Status (bone marrow aspirate or 
whole blood) qq 
X tt 
 
 
 
 
 
 
 
 
 
 
 
PGx uu 
 
 
 
 
X 
 
 
 
 
 
 
 
12-lead ECG vv 
X mm 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Clinical Laboratory Tests (chemistry, hematology, 
thyroid function, coagulation, urinalysis) ww 
X mm, rr, xx 
X 
 
 
X yy 
 
X 
 
X 
X 
X 
X 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK ASP2215 zz 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
                                                 
pp On days when a bone marrow is performed including unscheduled visits, hematology will also be sent to a central lab.  
qq Remaining bone marrow aspirate will be used for MRD analysis in applicable countries. 
rr At screening, 2 bone marrow aspirate samples are required: one will be sent to Invivoscribe (central FLT3 mutation testing laboratory) and the other to Hematogenix (central disease assessment 
laboratory). A bone marrow aspirate is preferred for FLT3 assessment. However, if a bone marrow aspirate sample is unavailable at screening, a whole blood sample can be sent to Invivoscribe for FLT3 
testing, provided there are measureable leukemic cells present and the bone marrow biopsy from initial diagnosis and a whole blood sample should be sent to Hematogenix for disease assessment. Aspirate 
from initial diagnosis can be sent to Invivoscribe if it was collected in sodium heparin, stored at 2-8°C and can be sent within 5 days of collection and testing can occur within 7 days of sample collection. 
Aspirate from initial diagnosis can be sent to Hematogenix if it was collected in EDTA or sodium heparin tube and can be shipped out on the same day of collection or within 1 day of collection. The most 
recent local bone marrow data before or after informed consent will be collected in eCRF if the central assessment result could not be obtained. 
ss Bone marrow assessment will be performed any time after Day 28 for response assessment per institutional guidelines.  
tt FLT3 mutation status will be assessed from bone marrow sample taken at the Screening Visit or at the visit prior to consent. If bone marrow sample is unavailable, the whole blood sample taken at the 
Screening Visit will be used. Cycle 1 only. 
uu Buccal swab and/or peripheral blood on screening for optional pharmacogenetic study. Sample collection may be performed any time between registration and ASP2215 administration on Day 8. 
vv ECG assessment will be evaluated at day 1 (pre-dose), day 8 (pre-dose and 4-hour post-dose [+/- 30 minutes]), day 15 (pre-dose), day 21 (pre-dose) and on day 28. The 12-lead ECGs will be recorded in 
triplicate (3 separate ECGs 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 
all treatment decisions, however in case of emergency, local ECG or central ECG paper printout results can be considered. Central ECG data should be submitted if urgent treatment decision was made 
based on the local ECG result. 
ww All lab tests should be obtained pre-dose unless noted otherwise. Thyroid function test is only performed at Screening. 
xx Eligibility criteria laboratory tests can be confirmed by the local lab. The values used for eligibility evaluation should be entered in eCRF and the central sample at the same timing of local lab tests 
should be submitted. Lab values prior to informed consent may be collected in the eCRF in case the local bone marrow assessment result before informed consent was collected. 
yy Liver function values should be reconfirmed before registration if abnormality due to the primary disease was observed at pre-registration. Local lab assessment is allowed, but samples should be 
submitted to central lab. 
zz PK samples for ASP2215 will be collected pre-dose on Day 15, and on Day 21. Pre-dose samples should be collected within 1 hour before ASP2215 administration. If Day 21 scheduled visit is 
performed within the visit window, PK sampling on Day 19 or 20 is preferred. Cycle 1 only. 


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Consolidation therapy 
Assessments 
D1 D2 D3 D4 D5 D6-D7 D8 D9-D14 D15 D21 aaa 
Visit window 
0 
0 
0 
0 
0 
0 
0 
0 
+/- 2 
+7 
Cytarabine Administration 
X 
 
X 
 
X 
 
 
 
 
 
ASP2215 Administration 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examination  
X 
 
 
 
 
 
X 
 
X 
X 
Vital Signs 
X 
 
 
 
 
 
X 
 
X 
X 
Weight and BSA 
X 
 
 
 
 
 
 
 
 
 
ECOG Performance 
X 
 
 
 
 
 
X 
 
 
 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Response Assessment (including 
extramedullary leukemia)  
Xbbb 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration/Biopsy pp, qq 
12-lead ECG ccc 
X 
 
 
 
 
 
X 
 
X 
 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation, thyroid function, 
urinalysis) ddd 
X 
 
 
 
 
 
X 
 
X 
X eee 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK ASP2215 fff 
 
 
 
 
 
 
X 
 
X 
 
 
 
                                                 
aaa Initiation of the next cycle may be postponed until blood recovery is observed.  
bbb May be done within 7 days prior to initiation of consolidation. First consolidation cycle only.  
ccc ECG assessment will be evaluated at day 1 at pre-dose and 4-hour post-dose (+/- 30 minutes), day 8, and day 
15. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs at least 5 minutes apart per time point) 
and transmitted electronically for central reading. 
ddd All lab tests should be obtained pre-dose unless noted otherwise. Thyroid function test is only performed at 
Cycle 1 Day 1. 
eee Peripheral blood sample should be sent to central lab when blood count recovery is observed any time after 
Day 21. 
fff PK samples for ASP2215 will be collected at pre-dose on Cycle 1 Day 8 and anytime on Day 15. 


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Maintenance therapy 
Assessments 
Cycle 1 
Day 1 
Cycle 1 
Day 15 
Cycle 2 
Day 1 
Cycle 2 
Day 15 
Cycle X 
Day 1 ggg 
Visit window 
 
+/- 2 
+/- 7 
+/- 2 
+/- 7 
ASP2215 Administration hhh 
X 
X 
X 
X 
X 
Physical Examination  
X 
 
 
 
 
Vital Signs and Weight 
ECOG Performance 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
Response Assessment (including 
extramedullary leukemia) 
 
X iii 
X jjj 
Bone Marrow Aspiration/Biopsy pp, qq 
Pregnancy Test for WOCBP 
X 
 
 
 
X 
Clinical Laboratory Tests (chemistry, 
hematology, coagulation, thyroid function, 
urinalysis) kkk 
X  
 
X 
 
X 
AE/SAE Assessment 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
X 
 
X 
 
 
 
                                                 
ggg One Scheduled visit for maintenance therapy is required every 3 cycle. 
hhh ASP2215 should be administered in the clinic on scheduled visit days after laboratory assessment. All other 
days, ASP2215 will be taken at home. ASP2215 is administered daily. 
iii May be done within 7 days prior to initiation of maintenance therapy. 
jjj Frequency should be determined by clinical practice at each site. 
kkk All lab assessments should be obtained pre-dose unless noted otherwise. Thyroid function test is only 
performed at Cycle 1 Day 1. 


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End of Treatment 
Assessments 
Pre-HSCT Visit  
EOT Visit lll 
30-Day 
Follow-up 
mmm 
Long-term 
Follow-up nnn 
Visit window 
 
+ 7 days 
+/- 7 days 
Physical Examination 
X ooo 
X  
 
Vital Signs 
X ooo 
 
 
ECOG Performance 
X ooo 
 
 
Concomitant Medications 
X ppp 
X ppp 
 
12-lead ECG 
X 
 
 
Clinical Laboratory Tests (chemistry, 
hematology, thyroid function, urinalysis) 
X ooo 
 
X qqq 
Response Assessment (including 
extramedullary leukemia) 
X rrr 
 
X sss 
Bone Marrow Aspiration/Biopsy pp, qq 
AE/SAE Assessment 
X ttt 
X 
X uuu 
Survival and Subsequent Antileukemic 
Treatments and Their Outcomes 
 
X 
X vvv 
EOT: End of Treatment, HSCT: Hematopoietic Stem Cell Transplant  
                                                 
lll In addition to the subjects who discontinued the study, subjects who complete the maintenance therapy will 
also perform the End of Treatment (EOT) visit. 
mmm On-site visit is preferred for safety assessment, however, a phone call follow-up is acceptable. 
nnn During the long-term follow-up period, the subject will be followed for 3 years after the last subject’s first 
treatment or completion of 30-day follow-up of the last subject, whichever is longer. The first follow-up will be 
performed 3 months after the 30-day follow-up visit. On site visit assessment will be performed at the timing of 
relapse. 
ooo Does not need to be repeated if data are obtained at a regularly scheduled visit within 3 days of the 
scheduled Visit. 
ppp All concomitant treatments administered from Induction Cycle 1 Day 1 to the EOT visit must be recorded. 
Concomitant medications used for reported AE/SAE should be collected during the AE reporting period 
(Section 7.3.1 and 7.3.2). Concomitant medications during the long-term follow-up do not need to be collected 
even if they are used for reported AEs. 
qqq Only peripheral blood samples for hematology should be collected and submitted to central laboratory at the 
timing of relapse. 
rrr Does not need to be repeated if collected at a regularly scheduled visit within 7 days of the Pre-HSCT visit or 
End of Treatment visit. If bone marrow aspirate is unobtainable (e.g., dry tap), the whole blood sample will be 
used. 
sss Bone marrow sample (aspiration or biopsy) should be collected and submitted to central laboratory at the 
timing of relapse. 
ttt ASP2215 related SAE should always be reported regardless of the time of the HSCT during the study 
participation. 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 will resume upon the resumption 
of ASP2215 treatment until 30-day follow-up visit. 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 ASP2215, whichever comes first. However, the following AE/SAEs will continue to be collected 
until 30 days after the last dose of ASP2215, regardless of the time of the HSCT conditioning regimen, the 
HSCT, and the resumption of ASP2215 treatment: 
• 
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 
Above AE/SAEs will be collected throughout the HSCT period for the subjects who plan to resume ASP2215. 


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2 
INTRODUCTION 
2.1 
Background 
Globally, 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]. In Japan, it was estimated that 5600 patients were diagnosed with AML in 2017 
[Kantar Health, 2017]. It is estimated that 21450 people will be diagnosed with AML, and 
10920 will die from the disease in 2019 in the US [American Cancer Society, 2019]. 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. 
In Japan, the standard method of induction chemotherapy for previously untreated adult 
patients with AML is a combination of cytarabine and anthracycline (idarubicin or 
daunorubicin) [Miyawaki S, et al., 2009]. Although approximately 80% of patients achieve 
CR with this therapy, nearly 70% of them experience relapse, and only about 30% maintains 
remission and survive for the long-term. Furthermore, roughly 15% of patients have AML 
that is resistant to the initial induction chemotherapy. Consequently, the current treatment for 
newly diagnosed AML is not yet satisfactory, and it is very important to develop new drugs 
to improve the prognosis of AML patients. 
FLT3 is a member of the class III receptor tyrosine kinase 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 over-
expressed in the majority of AML cases. In addition, FLT3 constantly activated with ITD 
mutation at the juxtamembrane domain or tyrosine kinase domain (TKD) mutations at around 
D835 in the activation loop are present in 28% to 34% or 11% to 14% of AML cases, 
respectively [Schlenk & Dohner, 2009]. These mutations which constantly activate FLT3 are 
oncogenic and show transforming activity in cells [Yamamoto et al., 2001]. Furthermore, 
patients with activated FLT3 show poor prognosis, with a higher relapse rate, more rapid 
relapse, and reduced disease-free survival and overall survival [Gale et al., 2008; Moreno et 
al., 2003; Patel et al., 2012; Yanada, Matsuo, Suzuki, Kiyoi, & Naoe, 2005]. 
AXL is a receptor tyrosine kinase. It has been suggested that AXL is overexpressed in AML 
patients who are FLT3-ITD mutation-positive and the activation of AXL is involved in the 
activation of FLT3 [Park et al., 2013]. Expression of AXL was also observed in FLT3 
mutation-negative AML cells, and inhibition of AXL resulted in cell growth suppression 
[Ben-Batalla et al., 2013]. Moreover, it was reported that a high expression of AXL 
contributed to chemotherapy resistance of AML [Hong et al., 2008]. Mutation of the c-CBL, 
                                                 
uuu Only SAE data that is related to ASP2215 will be collected. 
vvv Telephone contact every 3 months until completion of the study. 


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E3 ubiquitin protein ligase has been noted in some AML cases, and it has been suggested that 
c-CBL is involved in the activation of FLT3 by suppressing the degradation of FLT3 [Sanada 
et al., 2009]. 
Gilteritinib hemifumarate, also referred to as ASP2215 and gilteritinib, is a new chemical 
entity discovered by Astellas Pharma Inc. in collaboration with Kotobuki Pharmaceutical 
Co., Ltd. It is a third-generation oral FLT3 inhibitor under development for the treatment of 
AML. ASP2215 also has inhibitory activities for AXL, leukocyte receptor tyrosine kinase 
(LTK) 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. 
Based on the result of a phase 3 study which showed superior efficacy over salvage 
chemotherapy, XOSPATA (ASP2215) tablets have been approved by Food and Drug 
Administration (FDA) and Ministry of Health, Labor, and Welfare (MHLW) for the 
treatment of patients who have relapsed or refractory AML with an FLT3 mutation. 
2.1.1 
Nonclinical and Clinical Data 
2.1.1.1 Nonclinical Pharmacology 
ASP2215 inhibited the activity of FLT3, NPM1-ALK, LTK, ALK, and AXL at 1 and 
5 nmol/L and of TRKA, ROS, RET, and MER at 5 nmol/L by over 50%. ASP2215 inhibited 
FLT3, EML4-ALK, and KIT with half maximal inhibitory concentration (IC50) values of 
0.291, 1.2, and 229 nmol/L, respectively. 
The affinity of ASP2215 to 46 receptors, 5 ion channels, 3 transporters, and the inhibitory 
effect of ASP2215 on 3 enzyme reactions were evaluated. ASP2215 inhibited radioligand 
binding to adenosine A1 receptor (rat), serotonin 5HT1 receptor (non-selective, rat), serotonin 
5HT2B receptor (human), and sigma nonspecific receptor (non-selective, guinea pig) with 
IC50 values of 4.57, 4.90, 0.190, and 0.615 µmol/L, respectively. Examination of the activity 
of ASP2215 on human 5HT2B receptor function in a cell function assay revealed the 
inhibitory effect of ASP2215, with an IC50 value of 5.82 µmol/L; however, it showed no 
agonistic activity against the receptor to 10 µmol/L.  
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, which endogenously express FLT3-ITD mutation, 
with an IC50 value of 0.92 nmol/L. 
The activity of ASP2215 against MV4-11 cells was further examined in an in vitro study. 
ASP2215 suppressed FLT3 phosphorylation in the cells; treatment at 0, 0.1, 1, and 10 nmol/L 
resulted in phosphorylation of 100%, 86%, 19%, and 7%, respectively. In addition, ASP2215 
suppressed phosphorylation of the signal transducer and activator of transcription 5 (STAT5), 
AKT, and extracellular signal-regulated kinase in the cells. Furthermore, treatment with 


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ASP2215 at 3 or 10 nmol/L considerably increased the population of the cells in the G1 
phase, suggesting that ASP2215 arrests the cell growth cycle of the cells. In addition, 
treatment with ASP2215 at 10 or 30 nmol/L considerably increased the annexin V-positive 
population in the cells, thereby suggesting that ASP2215 induces the apoptosis of the cells. 
The antitumor effect of ASP2215 was examined in mice to which MV4-11 tumor was 
transplanted. Once-daily oral administration of ASP2215 induced growth inhibition of 
MV4-11 tumors and tumor regression. In particular, its administration at 6 or 10 mg/kg/day 
induced complete tumor regression for 4 and 6 out of 6 mice, respectively. In this case, the 
body weight of the mice treated with ASP2215 was not affected at any tested dose. A single 
oral dose of ASP2215 at 1, 3, 6, and 10 mg/kg administered to mice xenografted with 
MV4-11 cells inhibited the phosphorylation of FLT3 and STAT5 in MV4-11 tumors. In a 
combined administration study in mice xenografted with MV4-11 cells, when ASP2215 
alone (3 mg/kg/day, oral administration), or 2 drugs of cytarabine (50 mg/kg/day, 
intraperitoneal administration) and idarubicin (0.5 mg/kg/day, intravenous administration) 
were administered to mice xenografted with MV4-11 cells, no individual with tumor 
regression was found, whereas the combination of 3 drugs induced complete tumor 
regression in 6 of 8 mice [Ueno Y, 2014].  
These results indicate that ASP2215 should exhibit antitumor response in patients with AML 
with FLT3-ITD mutation or FLT3 mutation at D835. ASP2215 in combination with 
cytarabine and daunorubicin or in combination with cytarabine and idarubicin showed 
superior antitumor efficacy in mice xenografted with MV4-11 cells compared to ASP2215 
alone or to either chemotherapy combinations without ASP2215. 
2.1.1.2 Safety Pharmacology and Toxicology 
Major findings in the safety pharmacology studies were vomiting, positive fecal occult blood 
and increased/decreased blood Ca2+ in dogs, and decreased urination and defecation in rats. 
In the oral 13-week repeated dose toxicity study in rats, and the 4- and 13-week repeated dose 
toxicity studies in dogs, mortality occurred at 20, 10 and 5 mg/kg per day, respectively. With 
respect to other major target organ toxicities, effects on the urinary bladder, epithelial tissue, 
gastrointestinal tract, lymphohematopoietic system, eye, liver, kidney and/or lung were 
observed in rats and dogs at 2.5 mg/kg per day or more. All major findings were reversible 
and monitorable. 
Gilteritinib has a potential to induce genotoxicity in vivo. 
Gilteritinib showed suppressed fetal growth, embryo-fetal deaths and teratogenicity in the 
embryo-fetal development studies in rats. 
Gilteritinib showed no potential to induce phototoxicity to cultured mammalian cells. 
In juvenile rats (dosing from postnatal day [PND] 4 to 42), no mortality was noted at 5 mg/kg 
per day, but 1 animal was moribund sacrificed at 2.5 mg/kg per day. The cause of 
moribundity was considered to be deteriorated general conditions due to the unexpectedly 
high exposure. In the preliminary non-Good Laboratory Practice (GLP) dose range finding 


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study (dosing from PND 4 to 21), gastrointestinal bleeding detected as abnormal stool color 
(dark red) was noted at 10 mg/kg per day and higher. Gastrointestinal tract was suggested to 
be a target organ of toxicity at doses of 10 mg/kg per day or higher in juvenile rats, as well as 
in adult rats in the 13-week dose study (2215-TX-0002). The minimum lethal dose level of 
2.5 mg/kg per day in juvenile rats was lower than that in adult rats in the 13-week dose study 
(20 mg/kg per day). 
2.1.1.3 Non-Clinical Pharmacokinetics and Metabolism 
After a single intravenous administration, terminal t1/2 values for ASP2215 were 6.93 hours 
in rats and 25.4 hours in dogs. After a single oral administration, Cmax and AUCinf increased 
more-than-dose-proportionally from 1 to 10 mg/kg in rats, and slightly more-than-dose-
proportionally from 0.3 to 3 mg/kg in dogs. The absolute oral bioavailability was 26.8% at 
1 mg/kg in rats and 88.2% at 0.3 mg/kg in dogs. 
[14C]ASP2215-derived radioactivity in nonpigmented rats was most distributed to the liver 
and was detectable at 72-hour post-dose in many tissues. The concentration of 
[14C]ASP2215-derived radioactivity administered to pigmented rats fell below the limit of 
detection by 4-week post-dose in many tissues. However, the elimination of radioactivity 
from the ciliary body and retina and choroid were notably slow, and Ct/Cmax ratios at 17-
week post-dose were 32.7% and 42.8%, respectively. The plasma protein binding ratios of 
ASP2215 in mice, rats, rabbits, dogs, and monkeys ranged between approximately 75% and 
90%, and ranged from 90.2% to 90.5% in humans. The major binding protein in human 
plasma was human serum albumin (HSA). Except one minor metabolite in human 
hepatocytes, 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 CYP3A4. 
ASP2215 has a potential to induce CYP enzyme activities (CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 and CYP3A4/5) and mRNA 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. After oral administration of [14C]ASP2215 at 1 mg/kg to 
albino rats, the urinary and fecal excretion of radioactivity within 168-hour post-dose was 
1.4% and 89.9% of the dose, respectively. The urinary and biliary excretion of radioactivity 
within 48-hour post-dose was 8.6% and 29.3% of the dose, suggesting that oral absorption 
was at least 37.9%. A part of biliary excretion is assumed to undergo enterohepatic 
circulation. 
In Caco-2 cells, the permeability of ASP2215 was between that of known low and high 
permeability markers. ASP2215 is a substrate for P-glycoprotein (P-gp), but not for BCRP, 
organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or organic cation 


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transporter (OCT) 1. ASP2215 demonstrated a potential to inhibit BCRP and multidrug and 
toxin extrusion (MATE)1 at clinically relevant concentrations of ASP2215. However, 
preliminary results from the drug-drug interaction assessment of co-administration of 
ASP2215 and cephalexin, a MATE1 substrate, in patients with relapsed or refractory AML 
(Study 2215-CL-0101) indicate lack of a clinically-significant interaction between ASP2215 
and MATE1 substrates (see Section 1.2.4.1). Based on EMA Guideline on the Investigation 
of Drug Interaction (Jun 2012), ASP2215 may also inhibit liver transporters OCT1 and 
OATP1B1 at clinically relevant drug exposures.  
2.1.1.4 Clinical Studies 
2.1.1.4.1 
Clinical Pharmacokinetics and Pharmacodynamics 
The pharmacokinetic parameters of unchanged drug after single and multiple doses of 
ASP2215 to AML patients were investigated in the dose escalation cohort of Study 2215-CL-
0101. Assessment of 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 from the samples collected pre-dose and 
post-dose 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 cytochrome P450(CYP)3A4 inhibitors and strong 
CYP3A4 inducers on ASP2215 exposure was assessed in patients with relapsed or refractory 
AML (Study 2215-CL-0101) and healthy subjects (Study 2215-CL-0108). In relapsed or 
refractory patients with AML, there was a less than 2-fold increase in ASP2215 exposure 
when ASP2215 was co-administered with moderate or strong CYP3A4 inhibitors. In healthy 
subjects, ASP2215 exposure increased approximately 2-fold when ASP2215 was co-
administered with itraconazole, a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor. 
Co-administration 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 patients with 
relapsed or refractory AML (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 
co-administration of MATE1 substrates and ASP2215 is not expected to result in a 
clinically-relevant drug-drug interaction. 
Primary 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, 2215-CL-0102 and 2215-CL-0301 study. This assessment included 3344 
observations from 487 patients. A concentration-related increase in ΔQTcF was observed; 
however, the mean ΔQTcF at the mean steady-state Cmax at 120 mg was predicted to be less 


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than 10 msec and the upper one-sided 95% confidence interval was predicted to be less than 
10 msec and not considered as clinically significant. In addition, less than 5% of 
relapse/refractory subjects had a maximum post baseline QTcF interval > 500 msec and 
approximately 7% of subjects had a > 60 msec change in their maximum QTc relative to 
baseline. Although these data indicate that clinically relevant QTc prolongation is not 
anticipated, the sponsor has implemented additional eligibility criteria for enrollment in 
ASP2215 clinical trials (exclusion of subjects with QTcF > 450 msec, long QT syndrome, 
hypokalemia or hypomagnesemia) and electrocardiogram (ECG) assessments at multiple 
time points. Astellas will continue to monitor for arrhythmias and clinically significant QT 
prolongation during the conduct of ASP2215 clinical trials. 
An exposure-related increase was observed between ASP2215 plasma concentration and 
creatine phosphokinase (CK) change from baseline (ΔCK) in patients with 
relapsed/refractory AML based on pharmacokinetic/pharmacodynamic modeling that 
included 3361 time-matched data points (n = 497 patients). In addition, the incidence of 
higher Common Terminology Criteria for Adverse Events (CTCAE) grades related to 
elevated CK appears to have increased with an increasing ASP2215 dose. However, almost 
all of the observed elevations in CK laboratory values were Grade 1 and Grade 2, and the 
incidence of Grade ≥ 3 related adverse events reported in the study population was low. The 
preferred term of blood creatine phosphokinase increased has been identified as an expected 
adverse drug reaction (ADR) of ASP2215. 
There was a trend toward an increasing incidence of AEs and shifts in laboratory values 
related to hepatotoxicity with increasing ASP2215 doses as well. Similar to ΔCK, an 
exposure-related increase was observed between ASP2215 plasma concentration and AST 
change from baseline (ΔAST) based on pharmacokinetic/pharmacodynamic modeling that 
included 1517 time-matched data points (n = 243) with low incidence of Grade ≥ 3 related 
adverse events observed (6.0%). The preferred terms of alanine aminotransferase increased 
and aspartate aminotransferase increased have been identified as expected ADRs. 
2.1.1.4.2 
Clinical Studies 
Clinical studies of ASP2215 are conducted as a monotherapy in relapsed or treatment-
refractory patients with AML as a phase 1/2 clinical study in the US (Protocol No.: 2215-CL-
0101) and a phase 1 clinical study in Japan (Protocol No.: 2215-CL-0102), and currently 
ongoing in relapsed or treatment-refractory FLT3 mutation-positive patients with AML as a 
phase 3 global study (Protocol No.: 2215-CL-0301) as a validation upon determining the 
recommended dose in the subsequent phase as 120 mg.  
In addition, a phase 1 study in the US (Protocol No.: 2215-CL-0103) in newly diagnosed 
AML patients is currently ongoing as a combination study with the initial dose of 40 mg. 


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[Phase 1/2 monotherapy study in the US: 2215-CL-0101] 
In 2215-CL-0101, the safety of ASP2215, including ≥ Grade 2 AEs and DLTs, was evaluated 
at each dose level, and the recommended dose for the next phase in the study was determined 
to be 120 mg. 
2215-CL-0101 consists of dose-escalation and expansion parts. The dose levels examined in 
each part are as follows: 
● 
Dose-escalation part (20, 40, 80, 120, 200, 300, and 450 mg) 
● 
Expansion part (20, 40, 80, 120, 200, and 300 mg) 
As of the data cutoff date of 07 Mar 2018, a total of 265 patients were enrolled in Study 
2215-CL-0101 and 252 received at least 1 dose of ASP2215. 
A total of 189 (75.0%) of patients 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 patients) included diarrhea (17.1%); fatigue (14.7%), AST increased (13.5%); 
ALT increased (11.5%); blood creatine phosphokinase increased (9.9%); anemia (9.1%); 
constipation and edema peripheral (8.7% each); nausea and platelet count decreased (8.3% 
each); dysgeusia (7.5%); dizziness (7.1%); thrombocytopenia and vomiting (6.7% each); 
ECG QT prolonged (6.3%); neutrophil count decreased, transaminases increased and 
decreased appetite (5.6% each); and neutropenia (5.2%). 
The majority of patients (229 [90.9%]) experienced at least 1 grade 3 or higher TEAE. 
Common grade 3 or higher TEAEs (occurring in at least 5% of patients) included febrile 
neutropenia (39.7%); anemia (25.4%); AML disease progression (19.0%); platelet count 
decreased and sepsis (15.1% each); thrombocytopenia (13.1%); pneumonia (14.3%); 
neutrophil count decreased (8.7%); neutropenia (8.3%); hypoxia (7.5%); hypotension, 
bacteremia and hypophosphatemia (7.1% each); AST increased (6.7%); fatigue, white blood 
cell count decreased, hypocalcemia, dyspnea and, respiratory failure (6.0% each); ALT 
increased (5.6%); and leukocytosis, diarrhea, pyrexia and syncope (5.2% each). Overall, 
53 (21.0%) patients experienced a TEAE of maximum grade 3, 71 (28.2%) experienced a 
TEAE of maximum grade 4 and 105 (41.7%) patients experienced a TEAE of maximum 
grade 5. The incidence of grade 3 or higher TEAEs in the 20 mg, 40 mg, 80 mg, 120 mg, 
200 mg, 300 mg and 450 mg dose groups was 70.6%, 93.8%, 91.7%, 87.0%, 98.1%, 80.0% 
and 100%, respectively. 
Overall, 105 (41.7%) patients experienced TEAEs with an outcome of death, 6 of which 
occurred more than 28 days after the last dose of ASP2215. The incidence of deaths in the 
20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups was 29.4%, 37.5%, 
45.8%, 34.8%, 48.5%, 40.0% and 33.3%, respectively. The majority of the deaths were 
attributed to disease progression. Six of the deaths were possibly attributed to ASP2215 
administration (1 case each of hemorrhage intracranial, pulmonary embolism, hemoptysis, 
septic shock, neutropenia and ventricular fibrillation) and 1 death was probably attributed to 
ASP2215 administration (respiratory failure).  


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The majority of patients (210 [83.3%]) experienced a serious TEAE. The incidence of serious 
TEAEs in the 20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups was 
58.8%, 87.5%, 87.5%, 76.8%, 91.3%, 80.0% and 66.7%, respectively. The most frequent 
serious TEAEs (occurring in at least 10% of patients overall) were febrile neutropenia 
(31.7%); AML disease progression (19.0%); sepsis (15.5%), pneumonia (13.1%) and acute 
kidney injury (10.7%). 
Overall, 76 (30.2%) patients experienced a serious TEAE that was considered related to the 
study drug by the investigator. The incidence of drug-related serious TEAEs in the 20 mg, 
40 mg, 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups was 11.8%, 6.3%, 41.7%, 
29.0%, 35.9%, 20.0% and 66.7%, respectively. Drug-related serious TEAEs that occurred in 
2 or more patients included febrile neutropenia, blood creatine phosphokinase increased and 
acute kidney injury (2.0% each); AST increased; diarrhea, and pyrexia (1.6% each); 
gastrointestinal hemorrhage, blood bilirubin increased and hypotension (1.2% each); and 
neutropenia, myocarditis, supraventricular tachycardia, lower gastrointestinal hemorrhage, 
nausea, small intestinal obstruction, vomiting, mucosal inflammation, streptococcal 
bacteremia, ALT increased, liver function test increased, transaminases increased, muscular 
weakness, posterior reversible encephalopathy syndrome (PRES) and hypoxia (0.8% each).  
As of 07 Mar 2018, 31 (14.0%) patients experienced DLTs; most (29/31) patients were in the 
dose expansion cohort. The following DLTs were experienced in each of the dose groups 
(number of patients with DLTs in dose group): 
● 
20 mg dose group (1 patient): grade 5 hemorrhage intracranial.  
● 
40 mg dose group (1 patient): grade 3 toxic shock syndrome.  
● 
80 mg dose group (2 patients): grade 3 conjunctival edema and grade 5 septic shock.  
● 
120 mg dose group (7 patients): grade 3 events of hypoxia, pleural effusion, 
hematochezia, lower gastrointestinal hemorrhage, hyperbilirubinemia, blood lactate 
dehydrogenase increased and liver function test increased; grade 4 renal tubular necrosis; 
and grade 5 ventricular fibrillation.  
● 
200 mg dose group (15 patients): grade 2 events of dysgeusia, nausea, fatigue and 
decreased appetite; grade 3 events of transaminases increased, abdominal pain, 
hematochezia, intestinal perforation, ALT increased, blood creatine phosphokinase 
increased, ECG QT prolonged, acute promyelocytic leukemia differentiation syndrome, 
gamma-glutamyl transferase increased, hypotension, dizziness, myalgia, and acidosis 
and pelvic pain; grade 4 events of hypoxia and PRES. The grade 3 events of 
transaminases increased and hypotension and grade 4 events of hypoxia were 
experienced by 2 patients each. All other events occurred in 1 patient each. 
● 
300 mg dose group (3 patients): grade 3 events of disseminated intravascular coagulation 
(DIC), gastrointestinal hemorrhage, hypertension, AST increased and rhabdomyolysis; 
grade 4 blood creatine phosphokinase increased; and grade 5 pulmonary embolism.  
● 
450 mg dose group (2 patients): grade 3 events of diarrhea and AST increased.  
The maximum tolerated dose (MTD) in Study 2215-CL-0101 is considered to be 300 mg. 


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Results from Study 2215-CL-0101 indicate that of the 252 patients who received at least 
1 dose of ASP2215, the majority of composite complete remission (CRc) and partial 
remission (PR) events were observed in FLT3 mutation-positive AML patients in dose 
groups of 80 mg and greater. The derived response rate (CRc + PR) at the end of treatment in 
the 191 FLT3 mutation-positive patients was 48.7% overall and 66.7%, 53.6%, 48.3%, 
60.0% and 50.0% in the 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups, 
respectively. The median duration of response in FLT3 mutation positive patients in ≥ 80 mg 
dose levels was 147.0 days (95% CI: 97.0, 307.0). In FLT3 mutation positive patients with a 
response of complete remission (CR)/ complete remission with partial hematological 
recovery (CRh), the median duration of response was 383.0 days (95% CI: 136.0, NE). The 
median overall survival (OS) from Kaplan-Meier estimates in FLT3 mutation positive 
patients in ≥ 80 mg dose levels were 218.0 days, with survival probabilities of 56.2% at 
26 weeks and 24.9% at 1 year. 
[Phase 1 monotherapy study in JP: 2215-CL-0102] 
Twenty-seven Japanese patients with AML were enrolled in Study 2215-CL-0102. Of these, 
24 received the study drug and 3 discontinued before the start of study drug. 
Overall, all patients receiving the study drug experienced at least 1 AE and 91.7% (22/24) of 
patients experienced a drug-related AE. Common AEs, occurring in ≥ 20% of all patients, 
were hepatic function abnormal and blood creatine phosphokinase increased (37.5%, 9/24), 
blood lactate dehydrogenase increased (33.3%, 8/24), diarrhea and pyrexia (29.2%, 7/24) and 
febrile neutropenia, stomatitis, renal impairment and hypertension (20.8%, 5/24). Of these 
common AEs, hepatic function abnormal, blood creatine phosphokinase increased and 
diarrhea appeared to have increased incidence with increasing doses. Blood creatine 
phosphokinase and diarrhea have been identified as expected adverse reactions for ASP2215. 
Overall, AEs with maximum National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) grade 3 or higher were reported in 66.7% (16/24) of all 
patients, including 100% (1/1) of patient in 20 mg dose group, 50.0% (2/4) of patients in the 
40 mg, 80 mg and 120 mg dose groups, 77.8% (7/9) of patients in the 200 mg dose group and 
100% (2/2) of patients in the 300 mg dose group.  
The NCI-CTCAE grade 3 or higher AEs reported in ≥ 10% of all patients were platelet count 
decreased (16.7%, 4/24) and disseminated intravascular coagulation, febrile neutropenia, 
pneumonia and blood creatine phosphokinase increased (12.5%, 3/24). In the 200 mg dose 
group, the most common (occurring in 2 or more patients) AEs of NCI-CTCAE grade 3 or 
higher were platelet count decreased (33.3%, 3/9) and blood creatine phosphokinase 
increased (22.2%, 2/9). 
The majority of the common AEs, including hepatic function abnormal, blood creatine 
phosphokinase increased and diarrhea, were considered by the investigator to be related to 
study drug. Drug-related AEs were reported in 91.7% (22/24) of all patients, including 75.0% 
(3/4) of patients in the 40 mg and 80 mg dose groups and 100.0% of patients in all of the 
remaining dose groups (n = 1 to 9). The most common SOC that included drug-related AEs 


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was Investigations (50.0%, 12/24), followed by Gastrointestinal Disorders (37.5%, 9/24) and 
Hepatobiliary Disorders (33.3%, 8/24).  
One patient in the 80 mg dose group died due to an SAE (subdural hematoma possibly 
related to study drug). Seven patients (29.2%) experienced a serious TEAE, including 25.0% 
(1/4) of patients in the 40 mg and 80 mg dose groups, and 55.6% (5/9) of patients in the 
200 mg dose group. No SAE was reported in the 20 mg, 120 mg or 300 mg dose groups. The 
only SAE reported in ≥ 2 patients was subdural hematoma (8.3%, 2/24).  
Within the 24 DLT-evaluable patients, 3 patients experienced a DLT during cycle 0 and cycle 
1, specifically 1 patient (25.0%) in the 120 mg dose group and 2 patients (100%) in the 
300 mg dose group. All 3 patients had a dose interruption due to DLT. 
After ASP2215 treatment at doses ranging from 20 mg to 300 mg per day, a CRc rate of 
36.8% and a response rate of 47.4% was attained. Patients in the 200 mg dose group had the 
highest CRc and response rate, of 57.1% (for both measures) at end of treatment. At end of 
treatment, 3 of the FLT3 mutation-positive patients achieved CRc (60.0%) and the response 
rate in this group was 80.0%. Across all dose groups, the median duration of CRc was 
86.5 days and the median duration of remission was 113.5 days. 
[Phase 1 combination study in the US: 2215-CL-0103] 
In Study 2215-CL-0103, 5 patients were enrolled before the change of dosing schedule of the 
study drug. One patient was found to have decrease ejection fraction (Grade 3), which was 
transient. The other patient was found to have low ANC and platelets by Day 42. Both of the 
events are considered as DLTs. The dosing schedule of the study drug had been as follows: In 
the induction phase, idarubicin (12 mg/m2/day, intravenous administration) is administered 
for 3 days from Day 1, cytarabine (100 mg/m2/day, intravenous administration) is 
administered for 7 days from Day 1, and ASP2215 is administered once daily for 28 days 
from Day 1 repeatedly until proceeding to the subsequent treatment cycle; in the 
consolidation phase, cytarabine (1.5 g/m2, intravenous administration) is administered twice 
daily on Days 1, 3, and 5 in each cycle and ASP2215 is administered once daily for 28 days 
from Day 1 repeatedly; and in the maintenance phase, ASP2215 is orally administered once 
daily for 28 days from Day 1 repeatedly. However, based on the abovementioned facts, this 
schedule was changed as follows: In the induction phase, idarubicin (12 mg/m2/day, 
intravenous administration) is administered for 3 days from Day 1, cytarabine (100 
mg/m2/day, intravenous administration) is administered for 7 days from Day 1, and ASP2215 
is administered for 14 days from Day 4, when idarubicin administration has ended, to Day 
17, which should be completed after the end of idarubicin administration and 25 days prior to 
the start of consolidation therapy; in the consolidation phase, cytarabine (1.5 g/m2, 
intravenous administration) is administered twice daily on Days 1, 3, and 5 in each cycle and 
ASP2215 administration is limited to 14 days from Day 1 to Day 14; and in the maintenance 
period, ASP2215 is orally administered once daily for 28 days from Day 1 repeatedly.  
As of the data cutoff date of 23 Oct 2017, 98.0% (48/49) of patients reported at least 1 TEAE. 
The most frequently reported TEAEs occurring in ≥ 20% of patients in the gilteritinib total 


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group included febrile neutropenia (65.3% [32/49]); diarrhea (63.3% [31/49]); nausea (42.9% 
[21/49]); edema peripheral (36.7% [18/49]); pyrexia (34.7% [17/49]) constipation; stomatitis 
(30.6% [15/49]); abdominal pain, ALT increased, fatigue and vomiting (26.5% [13/49]); AST 
increased, blood ALP increased and headache (24.5% [12/49]); drug eruption (22.4% 
[11/49]); and blood creatine increased, dizziness, hypertension, hypokalaemia, mucosal 
inflammation and thrombocytopenia (20.4% [10/49]). 
Overall, 91.8% (45/49) of patients reported at least 1 drug-related TEAE. The most 
frequently reported drug-related TEAEs occurring in ≥ 10% of patients in the gilteritinib total 
group included diarrhea (44.9% [22/49]), febrile neutropenia and nausea (36.7% [18/49], 
each), ALT increased (22.4% [11/49]) and AST increased (20.4% [10/49]). 
As of the data cutoff date of 23 Oct 2017, no TEAEs leading to death were reported. 
Overall, 42.9% (21/49) of patients reported at least 1 drug-related serious TEAE. The most 
frequently reported drug-related serious TEAE was febrile neutropenia (16.3% [8/49]); the 
other drug-related serious TEAEs were reported in ≤ 2 patients in the gilteritinib total group. 
As of the data cutoff date of 23 Oct 2017, 16.3% (8/49) of patients experienced a DLT during 
the induction period. Ejection fraction decreased and small intestinal obstruction were 
experienced by 4.1% (2/49) of patients, each; all other DLTs during the induction period 
were experienced by 2.0% (1/49) of patients each. 
DLTs were experienced by more patients in the gilteritinib 120 mg group (16.7% [6/36]) 
compared with the gilteritinib 40 mg group (22.2% [2/9]); 1 patient experienced neutropenia 
and thrombocytopenia and 1 patient experienced ejection fraction decreased; no patients in 
the gilteritinib 80 mg group experienced a DLT during the induction period. 
During the consolidation period, 7.7% (1/13) of patients in the gilteritinib 120 mg group 
experienced a DLT of febrile neutropenia; no patients in the gilteritinib 40 mg or the 
gilteritinib 80 mg group experienced a DLT. 
As of the data cutoff date of 23 Oct 2017, there were 22 evaluable patients with a positive 
FLT3 mutation status in Study 2215-CL-0103. By end of treatment, 19/22 patients had a best 
overall response of CR (82.6%; 95% CI: 61.2, 95.0). The CRc rate was 91.3% (95% CI: 72.0, 
98.9). 
[Phase 1 part of combination study in JP: 2215-CL-0104] 
Similar to the 2215-CL-0103 study, the dosing schedule of the study drug was also changed 
in this study. Although one patient was enrolled in the ASP2215 40 mg group prior to the 
change of the dosing schedule of the study drug and has received the study drug, no serious 
TEAE or DLT, which was considered to be related to the study drug by the investigator, was 
found. 
A total of 13 patients were enrolled after the change of the dosing schedule of the study drug. 
As of Mar 4, 2019, among the 13 patients who received at least one dose of ASP2215, 
13 patients (100.0%) had at least one drug-related TEAE. Drug-related TEAEs that were 


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found in at least 3 patients were as follows: anemia (61.5%), febrile neutropenia (61.5%), 
alopecia, diarrhea, platelet count decreased, white blood cell count decreased (38.5% each), 
neutropenia, neutrophil count decreased, pneumonia (30.8% each), electrocardiogram QT 
prolonged, leukopenia, and thrombocytopenia (23.1% each). 
At least one serious TEAE was found in 3 patients (23.1%). Serious TEAEs that were found 
were hepatic function abnormal (7.7%) and liver function test abnormal (15.4%). 
At least one more than Grade 3 TEAE was found in 11 patients (84.6%). More than Grade 3 
TEAEs that were found in 2 or more patients were as follows: anemia (53.8%), febrile 
neutropenia (76.9%), leukopenia (30.8%), neutropenia (46.2%), thrombocytopenia (30.8%), 
diarrhea (23.1%), device related infection (15.4%), liver function test abnormal (23.1%), 
neutrophil count decreased (15.4%), platelet count decreased (38.5%), white blood cell count 
decreased (38.5%), decreased appetite (15.4%). At least one more than Grade 3 TEAE that 
was considered related to the study drug by the investigator was found in 8 patients (61.5%). 
More than Grade 3 TEAEs that were considered related to the study drug by the investigator 
were found in 2 or more patients were as follows: anemia (38.5%), febrile neutropenia 
(46.2%), leukopenia (23.1%), neutropenia (30.8%), thrombocytopenia (23.1%), diarrhea 
(23.1%), platelet count decreased (15.4%), white blood cell count decreased (15.4%).  
One patient was found DLT (Grade3 Diarrhea). No TEAE resulting in death was found. 
7 patients completed DLT evaluation period, so 7 patients are evaluable for efficacy 
assessment. Based on the efficacy at the end of the induction phase, 7 patients (100.0%) 
achieved CRc overall, 4 patients (57.1%) achieved CR, 2 patients (28.6%) achieved CR with 
incomplete hematologic recovery (CRi) and 1 patient (14.3%) achieved CR with incomplete 
platelet recovery (CRp). No patients achieved PR. 
[Phase 3 monotherapy study in the US: 2215-CL-0301] 
Study 2215-CL-0301 is a phase 3, open-label, multicenter, randomized study of ASP2215 
versus salvage chemotherapy in patients with relapsed or refractory AML with FLT3 
mutation. As of the data cutoff date of 04 Jan 2018, 219 patients had received at least 1 dose 
of ASP2215 120 mg in Study 2215 CL 0301. The majority of patients (63.9% [140/219]) had 
ended treatment. The most common reasons for end of treatment (occurring in ≥ 10% of 
discontinued patients) were progressive disease (37.1% [52/219]), death (20.0% [28/219]), 
disease relapse (11.4% [16/219]) and AEs (10.7% [15/219]). 
As of the data cutoff date of 04 Jan 2018, 219 patients have received at least 1 dose of 
ASP2215 120 mg. A total of 213 (97.3%) patients experienced at least 1 TEAE and 173 
(79.0%) patients experienced at least 1 drug related TEAE. Common TEAEs, occurring in 
≥ 10% of all patients, were febrile neutropenia (45.7%), anemia (41.6%), pyrexia (35.2%), 
ALT increased (34.7%), AST increased (33.3%), diarrhea (30.6%), constipation (30.1%), 
nausea (28.3%), fatigue (26.0%), cough (25.6%), hypokalemia (25.6%), headache (22.4%), 
platelet count decreased (21.9%), dyspnea (21.5%), edema peripheral (21.5%), 
thrombocytopenia (21.5%), blood ALP increased (19.6%), vomiting (19.2%), hypotension 


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(17.8%), neutrophil count decreased (16.9%), dizziness (16.9%), hypocalcemia (16.4%), 
insomnia (15.5%), decreased appetite (15.1%), epistaxis (15.1%), abdominal pain (14.6%), 
pneumonia (14.6%), hypophosphatemia (14.2%), stomatitis (14.2%), hypomagnesemia 
(13.7%), hyperglycemia (13.2%), myalgia (13.2%), white blood cell count decreased 
(12.8%), pain in extremity (12.8%), AML disease progression (12.3%), asthenia (11.9%), 
hyponatremia (11.9%), hypoalbuminemia (11.9%), rash (11.9%), blood creatinine increased 
(11.4%), blood creatine phosphokinase increased (11.4%), neutropenia (10.5%), back pain 
(10.5%), arthralgia (10.0%) and pruritus (10.0%). Diarrhea, blood creatine phosphokinase 
increased, ALT increased and AST increased and edema peripheral and myalgia have been 
identified as expected adverse reactions for ASP2215. 
Common drug-related TEAEs, occurring in ≥ 10% of all patients, were ALT increased 
(24.7%), AST increased (24.2%), anemia (18.3%), febrile neutropenia (15.1%), 
thrombocytopenia (13.2%), platelet count decreased (12.8%), nausea (11.9%), blood ALP 
increased (11.0%), neutrophil count decreased (11.0%), white blood cell count decreased 
(11.0%), diarrhea (10.5%) and fatigue (10.0%). 
The NCI-CTCAE grade 3 or higher TEAEs reported in ≥ 10% of patients were febrile 
neutropenia (45.7%), anemia (34.2%), platelet count decreased (20.5%), thrombocytopenia 
(18.7%), neutrophil count decreased (16.9%), AST increased (13.2%), AML disease 
progression (12.3%), white blood cell count decreased (12.3%), ALT increased (11.4%), 
hypokalemia (11.4%) and neutropenia (10.5%). 
As of the data cutoff date of 04 Jan 2018, 25.6% (56/219) of patients experienced TEAEs 
leading to death. AML disease progression was the most common TEAE leading to death 
(9.1% [20/219]), followed by septic shock (2.7% [6/219]), cardiac arrest (1.8% [4/219]) and 
pneumonia (1.4% [3/219]); all other TEAEs leading to death were reported in < 1% of 
patients. TEAEs leading to death were considered drug-related for 4.1% (9/219) of patients. 
The majority of patients (76.7% [168/219]) experienced at least 1 serious TEAE. The most 
frequently reported serious TEAEs, occurring in ≥ 10% of all patients, were febrile 
neutropenia (29.2% [64/219]) and AML disease progression and pyrexia (12.3% [27/219], 
each). Drug-related serious TEAEs were experienced by 35.2% (77/219) of patients. The 
most frequently reported drug-related serious TEAEs were febrile neutropenia (7.8% 
[17/219]), ALT and AST increased (3.7% [8/219], each) and pneumonia (3.2% [7/219]). 
In the final analysis for this study, the co-primary study objective of OS was achieved (HR: 
0.637; 95% CI: 0.490, 0.830; 1-sided P-value: 0.0004); the median OS was 9.3 months in the 
ASP2215 arm versus 5.6 months in the salvage chemotherapy arm. The survival probability 
was higher in the ASP2215 arm compared with the salvage chemotherapy arm at 6 months 
and 12 months. When censoring patients at the time of HSCT, OS was also significantly 
longer in the ASP2215 arm compared with the salvage chemotherapy arm (median OS: 8.3 
months versus 5.3 months) (HR: 0.575; 95% CI: 0.434, 0.762; 1-sided P-value: < 0.0001). 
The key secondary study objective of EFS was not achieved, but showed a favorable trend in 
the ASP2215 arm (HR: 0.793; 95% CI: 0.577, 1.089; 1-sided P-value: 0.0415). The median 


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EFS duration was 2.8 months in the ASP2215 arm versus 0.7 months in the salvage 
chemotherapy arm. Another key secondary study objective was to determine the overall 
efficacy in CR rate of ASP2215 compared to salvage chemotherapy. The treatment difference 
of CR rate between the ASP2215 and the salvage chemotherapy arms was 10.6% (95% CI: 
2.8, 18.4; 1-sided nominal P-value: 0.0053). 
2.1.2 
Summary of Key Safety Information for Study Drug(s)  
Overall, ASP2215 has a nonclinical safety pharmacology and toxicology profile that is 
acceptable for the treatment of patients with relapsed or refractory FLT3 mutation positive 
AML at the proposed therapeutic dose. The integrated relapsed and refractory (R/R) AML 
safety population consisted of FLT3 mutation positive and negative patients from phase 1/2 
studies 2215-CL-0101 and 2215-CL-0102 and the phase 3 study 2215-CL-0301. 
The safety profile of ASP2215 was similar for the integrated ASP2215 120 mg group in both 
the R/R AML safety population and the subset of the integrated R/R AML safety population 
that was positive for FLT3 mutation. Based on an assessment of TEAE by subpopulations of 
demographic variables, no specific safety precautions are warranted by sex, age, or other 
demographic factors. The tolerability profile of ASP2215 in these ongoing studies appears to 
be similar to the integrated R/R AML safety population. Important identified risks associated 
with ASP2215 treatment, based on the clinical data, include PRES and QT prolongation. 
Pancreatitis is an important potential risk associated with treatment with ASP2215. 
The safety evaluation of ASP2215 is based on 319 patients (including 246 patients in the 
ADMIRAL trial) with relapsed or refractory AML who received at least one dose of 120 mg 
ASP2215 daily. At the time of final analysis cutoff, the median duration of exposure to 
ASP2215 was 111 days (range 4 to 1320 days).  
The most common adverse reactions (≥10%) were alanine aminotransferase (ALT) increased, 
aspartate aminotransferase (AST) increased, diarrhea, fatigue, nausea, constipation, cough, 
peripheral edema, dyspnea, blood alkaline phosphatase increased, dizziness, hypotension, 
pain in extremity, asthenia, blood creatine phosphokinase increased, arthralgia and myalgia. 
The most frequent serious adverse reactions (≥2%) reported in patients were ALT increased, 
diarrhea, AST increased, hypotension and dyspnea.  
For the most updated information, see the latest “ASP2215 Investigator’s Brochure.” 
2.2 
Study Rationale 
Mutations in FLT3 (either ITD or TKD) are observed in approximately 30% of patients with 
newly diagnosed AML. FLT3 mutations have oncogenic potential and most patients carrying 
these mutations in their leukemic cells have a particular dismal prognosis. Treatment results 
of patients with FLT3-mutated AML are still unsatisfactory with the majority of patients 
succumbing from their disease. Treatment using compounds that specifically target mutant 
cells may be beneficial in improving outcome of patients with these subtypes of AML. 
ASP2215 is a third-generation oral FLT3 inhibitor that has been approved by FDA and 
MHLW for the treatment of patients who have relapsed or refractory AML with an FLT3 


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mutation. In 2215-CL-0301 study, ASP2215 demonstrated prolonged OS, supported by 
improved CR rate with durable responses, and improved transfusion dependencies in patients 
with FLT3-mutated R/R AML, as compared to salvage chemotherapy. Non-clinical data 
suggest that addition of ASP2215 to the intensive chemotherapy induced superior antitumor 
efficacy compared to standard chemotherapy alone. 
Despite advances in AML therapy, the majority of patients die of their disease. The first 
hurdle to achieve on the road to potential curative therapy in AML is achievement of 
remission with induction therapy. Pharmacologic targeting of FLT3 (both ITD and TKD) 
represents an important potential approach for improving these outcomes. While midostaurin, 
which is a small molecule that inhibits multiple receptor tyrosine kinases including FLT3, 
demonstrated an improvement in CR and in survival in FLT3-mutated AML patients in 
RATIFY trial [Stone et al., 2017], ASP2215, as a more selective/potent FLT3 inhibitor, may 
induce higher CR rate and Minimal Residual Disease (MRD) negative CRs and decreased 
risk of relapse after CR for FLT3-mutated AML. Together, the data provide a strong rationale 
to evaluate whether addition of ASP2215 to standard chemotherapy improves clinical benefit 
in newly diagnosed FLT3-mutated AML patients, comparing with historical benchmark of 
standard chemotherapy. 
2.3 
Risk Benefit Assessment 
The potential undesirable effects of ASP2215 in humans based on toxicities observed in the 
nonclinical studies and in the recent clinical study in patients with AML are summarized in 
previous sections. As with any investigational agent, subjects may experience side effects 
that are more severe than those observed in the nonclinical and clinical studies or may 
experience side effects not observed in nonclinical and clinical studies. Findings of potential 
concern for clinical trials with ASP2215 include effects on the gastrointestinal tract, immune 
system, hematopoietic system, eye, liver and kidney. ASP2215 has the potential to induce 
genotoxicity in vivo. In the embryo-fetal development toxicity study in rats, ASP2215 
showed teratogenic effects and embryo-fetal lethal effects.  
In vitro, ASP2215 inhibited the cell growth of Ba/F3 cells expressing FLT3-ITD, FLT3-
D835Y, and FLT3-ITD-D835Y. In addition, ASP2215 induced complete regression of 
tumors in the xenograft tumor bearing model mice transplanted with a human AML cell line 
expressing FLT3-ITD. Furthermore, ASP2215 has shown anti-leukemic activity in an 
ongoing trial in FLT3 mutation-positive patients with AML. 
When a combination of ASP2215 (at a low dose), cytarabine, and idarubicin was tested in 
mice xenografted with MV4-11 cells, tumor regression was not induced in groups receiving 
ASP2215 alone or dual drug administration of cytarabine/idarubicin, whereas complete tumor 
regression was induced in the group receiving triple drug administration. 
These nonclinical study results suggest that ASP2215 will show antitumor responses in AML 
patients, and concomitant administration of ASP2215 with cytarabine and idarubicin will 
enhance the antitumor effect of these chemotherapy drugs. 


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Tolerability and efficacy of ASP2215 has been shown in the previous monotherapy studies 
conducted. Currently available therapy for FLT3-mutated R/R AML consists of intensive 
salvage chemotherapy, which is generally associated with severe AEs and poor survival 
outcomes. Additionally, a large number of these patients are over the age of 60 with multiple 
comorbidities and are therefore not eligible for intensive chemotherapy. In 2215-CL-0301 
Study, ASP2215 demonstrated prolonged OS, supported by improved CR/CRh rate with 
durable responses, and improved transfusion dependencies in patients with FLT3-mutated 
R/R AML, as compared to salvage chemotherapy. 2215-CL-0101 study provides further 
evidence, which includes prolonged survival and deep molecular responses in this patient 
population [Levis et al., 2018]. ASP2215 was well tolerated, associated risks are manageable, 
and only a small fraction of patients discontinued treatment due to ADRs. Although the 
safety profile of ASP2215 concomitant with cytarabine and idarubicin has not yet been fully 
investigated, the safety information obtained from the 2215-CL-0103 study shows good 
tolerability in the dosage up to 120 mg. Therefore, the benefits of ASP2215 treatment 
outweigh the risks in patients with FLT3 mutation positive newly diagnosed AML. 
3 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
Table 8 
Study Objective(s) and Endpoint(s) 
[Phase 1 part] 
Objective(s) 
Endpoint(s) 
Primary 
● 
Determine the maximum tolerated dose 
(MTD) and/or recommended expansion dose 
(RED) of ASP2215 concomitant with 
cytarabine/idarubicin as induction 
chemotherapy based on the status of the 
onset of dose-limiting toxicity (DLT) 
● 
MTD 
● 
RED  
● 
Occurrence of DLT 
● 
Evaluate the safety and tolerability of 
ASP2215 concomitant with 
cytarabine/idarubicin as induction 
chemotherapy and high-dose cytarabine as 
consolidation chemotherapy 
● 
Adverse events (AEs), safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
● 
Evaluate the safety and tolerability of 
ASP2215 in maintenance therapy after 
induction and consolidation therapy 
● 
AEs, safety laboratory tests, vital 
signs, and ECGs 
Secondary 
● 
Characterize the pharmacokinetic (PK) 
parameters of ASP2215 concomitant with 
induction and consolidation chemotherapy 
● 
PK parameters 
● 
Evaluate the PK parameters of cytarabine 
concomitant with ASP2215 
● 
PK parameters 
Table continued on next page 


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Objective(s) 
Endpoint(s) 
Exploratory 
● 
Evaluate the pharmacodynamic (PD) 
parameters of ASP2215 
● 
PD parameters 
● 
Evaluate the efficacy of ASP2215 
concomitant with induction and 
consolidation chemotherapy 
● 
CR (Complete Remission) 
● 
CRp (CR with incomplete platelet 
recovery) 
● 
CRi (CR with incomplete 
hematologic recovery) 
● 
PR (Partial Remission) 
● 
CRc (Composite CR): CR + CRp 
+ CRi 
● 
Overall response rate: CRc + PR 
● 
Duration of response 
 
[Phase 2 part] 
Objective(s) 
Endpoint(s) 
Primary 
● 
Evaluate the efficacy of ASP2215 in 
combination with induction therapy in 
newly diagnosed FLT3-mutated acute 
myeloid leukemia (AML) subjects  
● 
Complete remission (CR) rate after 
induction therapy period for Phase 2 
part subjects 
Secondary 
● 
Characterize the pharmacokinetic (PK) 
parameters of ASP2215 concomitant with 
induction and consolidation 
chemotherapy 
● 
PK parameters 
● 
Evaluate the safety and efficacy of 
ASP2215 in combination with induction 
and consolidation therapy followed by 
maintenance therapy 
● 
Overall survival (OS) 
● 
Event free survival (EFS) 
● 
Relapse free survival (RFS) 
● 
CR rate after each treatment therapy 
● 
CR rate without minimal residual 
disease (MRD) after each treatment 
therapy 
● 
Complete remission with partial 
hematological recovery (CRh) rate 
after each treatment therapy 
Table continued on next page 


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Objective(s) 
Endpoint(s) 
● 
Evaluate the safety and efficacy of 
ASP2215 in combination with induction 
and consolidation therapy followed by 
maintenance therapy 
(continued) 
● 
Composite complete remission (CRc) 
rate after each treatment therapy  
● 
CR/CRh rate after each treatment 
therapy  
● 
Duration of CR, CR/CRh, CRh, and 
CRc 
● 
Duration of response 
● 
Adverse events (AEs), safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
Exploratory 
● 
Evaluate the additional efficacy measures 
for ASP2215 in combination with 
induction and consolidation therapy 
followed by maintenance therapy 
● 
Transplantation rate 
● 
Cumulative incidence of relapse 
(CIR) after 1st CR (CR1) 
● 
Cumulative incidence of death (CID) 
after CR1 
● 
Time to hematopoietic recovery after 
each treatment cycle 
● 
MRD 
● 
MRD-negative CR rate after 
induction 
● 
Overall MRD-negative CR rate for 
any treatment period  
4 
STUDY DESIGN AND DOSE RATIONALE 
4.1 
Study Design 
This study is a Phase 1/2, open-label, single-arm study in patients with newly diagnosed 
AML. The phase 1 part evaluates the dose of ASP2215 using the Bayesian-continual 
reassessment method (hereinafter, Bayesian-CRM) and the Phase 2 part evaluates the safety 
and the effect of ASP2215 in combination with induction and consolidation therapy followed 
by maintenance therapy in newly diagnosed FLT3-mutated AML patients. This study is 
composed of two Phase 1 parts, which are the dose-evaluation part and the expansion part, 
and the Phase 2 part; the target population for each part is newly diagnosed AML patients 
and newly diagnosed AML patients with FLT3 mutation, respectively. Phase 1 part will be 
conducted in Japan and Phase 2 part will be conducted in Asia Pacific countries. 
[Phase 1 part (dose-evaluation part and dose expansion part)] 
The dose evaluation part and the expansion part are considered as the Phase 1 part. The 
primary objective of the Phase 1 part is to determine the MTD and/or recommended 




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primary endpoint of the CR rate will be conducted when all registered subjects complete the 
induction therapy period.  
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, relapse and survival (cause and date of death). During the 
long-term follow-up period, the subject will be followed for 3 years after the last subject’s 
first treatment or completion of 30-day follow-up of the last subject, whichever is longer. 
4.1.1 
Administration Plan 
[Phase 1 part] 
In the Phase 1 part of this study, the next dose level to which subjects are enrolled is 
determined sequentially using Bayesian-CRM (O'Quigley, Pepe, & Fisher, 1990). The 
starting dose level of ASP2215 in this study will be 120 mg per day, and the study should 
examine dose levels as the safety is assessed. To assess the safety of the dose levels 
determined to be administered, 3 subjects, in principle, will be enrolled to receive each dose 
level, which will be considered as 1 cohort. The procedure for determining the dose levels for 
subject enrollment is as follows. The details of the procedure will be specified separately. 
1. The sponsor will obtain the safety information for Cycle 1 from 3 subjects, in principle, 
in the same cohort. 
2. The sponsor, the medical expert, and the investigator (or the when assigned by the 
investigator) will review the safety information submitted by the study site and confirm 
whether or not the reported DLT events meet the definition in Section 4.1.2. 
3. At the end of the Cycle 1 assessment for the given cohort, the sponsor will use all of the 
DLT data obtained to date from the study, and using Bayesian-CRM, calculate the 
posterior mean of the DLT incidence for each dose level. Then, the sponsor will propose 
the next recommended dose level for subject enrollment. 
4. If there is safety information from Cycle 1 and from prior cohorts, if any, the sponsor, 
the medical expert and the investigator (or the when assigned by the investigator) will 
comprehensively assess the safety information from Cycles subsequent to 1, and by 
referring to the recommended dose indicated by Bayesian-CRM, discuss the next dose 
level for subject enrollment (dose escalation by 1 level, continue with the same dose 
level without escalation, dose reduction or, if necessary, addition of an intermediate 
dosage) or the end of enrollment. Based on the outcome of the discussion, the sponsor 
will make the final decision on the next dose level. 
5. When the next dose level is finalized, in principle, 3 subjects will be enrolled to receive 
that dosage, and the same assessment procedure will be repeated. 
Subject enrollment and DLT assessment will be continued until the criterion for ending 
enrollment shown in the Table 9 for Bayesian-CRM is met. 




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Establishment of the Statistical Model 
The dose-response relationship against DLT occurrence assumes a power model (O'Quigley 
& Shen, 1996), as shown below. 
The occurrence of DLTs for each patient should follow the Bernoulli distribution. 
Power model: 
Pr(𝑌𝑖= 1|𝑑𝑜𝑠𝑒= 𝑑𝑖) = 𝜋(𝑥𝑖, 𝛼) = 𝑥𝑖
exp(𝛼), 
where α is the parameters, xk is the skeleton of DLT incidence probability in the dose for 
number k used in the statistical model, Yj is the presence/absence of DLT in subject j (1 is 
present), dj is the administered dose of subject j, and π(•) is the probability of DLT 
occurrence under given conditions. 
Prior distribution of parameters assumed a normal distribution with the mean as 0 and 
variance as 1.26. Using the Effective Sample Size (ESS) (Morita, Thall, & Muller, 2008), the 
variance of the prior distribution of a parameter α was set so that the information content of 
prior distribution in the power model is approximately 1 subject (Takeda & Morita, 2015).  
The skeletons to be used in the statistical model are x1 = 0.08 and x2 = 0.17. 
[Phase 2 part] 
Not applicable 
4.1.2 
Definition of DLT 
[Phase 1 part] 
A DLT is defined as any of the following events that occurs during the DLT assessment 
period, and that is considered to be possibly, probably, or definitely related to induction or 
consolidation therapies including the study drugs. The DLT assessment period for making a 
decision of whether or not to proceed to the next dose is defined as the shorter of the 
following 2 periods: 39 days from the start of the treatment with ASP2215 in the induction 
period or days between the start of induction therapy and the start of the first consolidation 
therapy. For safety assessment during the expansion part, the DLT assessment period 
includes Cycle 1 of consolidation therapy in addition to the period defined above. 
Any Grade ≥ 3 non-hematologic or extramedullary toxicity or any events that require dose 
reduction of ASP2215. However, the following exceptions are noted: 
● 
Anorexia, or fatigue 
● 
Grade 3 nausea and/or vomiting that do not require tube feeding or total parenteral 
nutrition (TPN), and Grade 3 diarrhea that does not require prolonged hospitalization. 
However, they are limited to the ones that can be managed to Grade ≤ 2 with standard 
antiemetic or antidiarrheal medications used at the prescribed dose within 7 days of onset 
● 
Grade 3 mucositis that resolves to Grade ≤ 2 within 7 days of onset 


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● 
Grade 3 pyrexia with neutropenia, with or without infection 
● 
Grade 3 infection 
The following hematologic toxicities that occur after the first dose of ASP2215 that does not 
resolve by Day 42 of the last induction therapy cycle or before the start of the first 
consolidation cycle, whichever is sooner, will be considered a DLT. However, hematologic 
toxicity in subjects who did not achieve remission is not included in assessment. 
● 
Peripheral neutrophil count < 500/mm3 (Grade 4) 
● 
Platelet count < 20,000/mm3 due to bone marrow hypoplasia (except for cases caused by 
leukemic infiltration or other causes). Bone marrow hypoplasia is defined as bone 
marrow cellularity less than 20%. 
● 
Platelet count < 50,000/mm3 accompanying bleeding (≥ Grade 3) 
● 
Platelet count < 25,000/mm3 requiring platelet transfusion (Grade 4) 
[Phase 2 part] 
Not applicable 
4.1.3 
Determination of Maximum Tolerated Dose and Recommended Expansion 
Dose 
[Phase 1 part] 
Determination of MTD: 
The dose at which the posterior mean of DLT incidence is estimated to be closest to 33% 
when calculated using Bayesian-CRM from the status of DLT occurrence accumulated from 
this study during Cycle 1 of the induction period will be the candidate MTD. Through 
discussion with the medical expert, investigator, and advisor of medical statistics, the sponsor 
will comprehensively review the data obtained from Cycle 1, and decide the final MTD. The 
detailed procedure will be specified separately. 
Determination of RED: 
The sponsor will decide the RED considering the MTD, safety, pharmacokinetic, and 
efficacy of ASP2215. The final RED will be decided by the sponsor’s responsible person by 
comprehensively assessing the data obtained from the study, and taking into account the 
discussion held between the sponsor, the medical expert, the investigator, and the advisor of 
medical statistics. The detailed procedure will be specified separately. 
[Phase 2 part] 
Not applicable 
4.2 
Dose Rationale 
The starting dose of ASP2215 of 120 mg in this clinical study was established because good 
tolerability had been found in the phase 1 combination study in the US (Protocol No.: 2215-


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CL-0103) in the newly diagnosed patients with AML and the dose had been set as a 
recommended dose. 
Good tolerability was also found at a dose of 120 mg in dose-escalation clinical studies of 
ASP2215 monotherapy, which are currently ongoing in patients with relapsed or treatment-
refractory AML in the US as Phase 1/2 study (Protocol No.: 2215-CL-0101) and domestic 
Phase 1 study (Protocol No.: 2215-CL-0102), and a phase 3 global study in relapsed or 
treatment-refractory FLT3 mutation-positive patients with AML (Protocol No.: 2215-CL-
0301) is currently ongoing as a validation study upon determining the recommended dose in 
the subsequent phase as 120 mg. 
As a result of comparison and evaluation of the safety, efficacy, and pharmacokinetics of 
ASP2215 in the 2215-CL-0101 and 2215-CL-0102 study, no substantial ethnical difference 
was considered between Westerners and Japanese. In addition, there was no substantial racial 
difference in pharmacokinetics of cytarabine, the dosing period of which overlaps that of 
ASP2215, in the induction and consolidation phases. Furthermore, because the metabolic and 
elimination pathways are different between ASP2215 and cytarabine, it is estimated to be less 
likely to have pharmacokinetic interactions. Because the dosing period of idarubicin does not 
overlap, the effect on the pharmacokinetics is considered to be small. Based on these 
discussions in the monotherapy, no substantial ethnical difference is assumed in the 
pharmacokinetics at the combined administration; therefore, it is appropriate to set the 
120 mg, in which tolerability was found in the 2215-CL-0103 study, as the starting dose of 
the 2215-CL-0104 study. 
The ASP2215 dosage in the expansion part will be RED that has been recommended based 
on the results of the dose-evaluation part. 
Chemotherapy regimen dose will not be changed to ensure that each subject is able to receive 
the minimum standard therapy for Phase 1 part (For Phase 2 part, based on the investigator 
decision, chemotherapy dosing of Induction Cycle 2 may be reduced after confirmation with 
the sponsor). The ASP2215 dosing schedule was changed in order to avoid concomitant 
administration with idarubicin, an anthracycline agent that should be carefully administered. 
4.3 
End of Study Definition  
Study completion is defined as the conclusion of data collection for the defined study 
endpoints. The study may be closed within a participating country per local regulations once 
the study has been completed and if all subjects enrolled in the country are no longer 
receiving study drug. Study will continue until all long-term follow-ups are completed. 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
terminated for any reason. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject’s involvement in the study at any time if the 
subject’s clinical condition warrants it. 


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5 
STUDY POPULATION 
All screening assessments must be completed and reviewed to confirm the potential subject 
meets all eligibility criteria. Prospective approval of protocol deviations to eligibility criteria 
(also known as protocol waivers or exemptions) is not permitted. 
[Phase 1 part] 
Newly diagnosed AML patients 
[Phase 2 part] 
Newly diagnosed FLT3-mutated AML patients 
5.1 
Inclusion Criteria 
[Phase 1 part] 
Subject is eligible for participation in the study if all of the following apply: 
1. Written informed consent has been obtained (However, if the subject is underage, 
consent must also be obtained from the subject’s legal guardian). 
2. Subject is ≥ 18 and < 70 years of age at the time of obtaining informed consent. 
3. Subject is defined as having previously untreated de novo AML according to the World 
Health Organization (WHO) criteria (2008) within 28 days prior to study enrollment. 
4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
(refer to Section 12.5). 
5. Subject must meet all of the following criteria in the laboratory test at screening: 
● 
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
levels of ≤ 2.5 × institutional upper limit of normal (ULN) 
● 
Total serum bilirubin level of ≤ 1.5 × institutional ULN 
● 
Serum creatinine level of ≤ 1.5 × institutional ULN or an estimated glomerular 
filtration rate (eGFR) of > 50 mL/min† 
†Calculating formula: eGFR (mL/min/1.73 m2 = 194 × Cr-1.094 × Age-0.287 (× 0.739 for female 
subjects) 
6. Subject is suitable for oral administration of ASP2215. 
7. Female subject falls under the following: 
Of non-child bearing potential: 
● 
Post-menopausal (defined as at least 1 year with no menses without a medical 
reason such as drug administration) at screening, or 
● 
Documented surgically sterile or status post-hysterectomy (at least 1 month 
prior to screening) 


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Of childbearing potential: 
● 
Agrees not to try to become pregnant during the study and for 60 days after the 
final study drug administration,  
● 
Has a negative result for the serum or urine pregnancy test at screening, and 
● 
If heterosexually active, agrees to consistently use two effective contraceptive 
methods (one of which must be the barrier method) per locally accepted 
standards starting at screening and throughout the study period and for 60 days 
after the final study drug administration. 
8. Female subject agrees not to breastfeed starting at screening and throughout the study 
period and for 60 days after the final study drug administration. 
9. Female subject agrees not to donate ova starting at screening and throughout the study 
period and for 60 days after the final study drug administration. 
10. Male subject and his female spouse/partner who is of childbearing potential agrees to use 
two effective contraceptive methods (one of which must be the barrier method) per 
locally accepted standards starting at screening and throughout the study period, and for 
120 days after the final study drug administration. 
11. Male subject agrees not to donate sperm starting at screening and throughout the study 
period and for 120 days after the final study drug administration. 
12. Subject agrees not to participate in another interventional study while on study treatment. 
13. Subject can be admitted during the induction period. 
[Phase 2 part] 
Subject is eligible for the clinical 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 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 form (ICF).  
3. Subject has a diagnosis of previously-untreated de novo AML according to World Health 
Organization (WHO) classification (2017) documented within 28 days prior to 
enrollment. 
4. Subject is positive for FLT3-ITD and/or TKD mutation in bone marrow or whole blood 
as determined by the central lab. Registration by the local lab result is not acceptable. 
5. Subject has an ECOG performance status (PS) 0 to 1 (see Section 12.5). Subject who has 
an ECOG PS 2 is eligible only if investigators suspect that the primary disease related 
symptoms such as pneumonia and febrile neutropenia are the causes of PS score. 
6. Subject is suitable for oral administration of ASP2215. 


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7. Female subject is not pregnant (see Section 12.3) and at least 1 of the following 
conditions apply: 
a. Not a woman of childbearing potential (WOCBP) (see Section 12.3) 
b. WOCBP who agrees to follow the contraceptive guidance (see Section 12.3) from the 
time of informed consent through at least 180 days after final study treatment 
administration. 
8. Female subject must agree not to breastfeed starting at screening and throughout the 
study period and for 60 days after the final study drug administration. 
9. Female subject must not donate ova starting at screening and throughout the study period 
and for 180 days after the final study drug administration. 
10. 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. 
11. Male subject must not donate sperm starting at screening and throughout the study period 
and for 120 days after the final study drug administration. 
12. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for 
the duration of the pregnancy throughout the study period and for 120 days after the final 
study treatment administration. 
13. Subject agrees not to participate in another interventional study while on treatment. 
14. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
a. Serum creatinine ≤ 1.5  institutional upper limit of normal (ULN), or if serum 
creatinine outside normal range, then glomerular filtration rate (GFR) > 50 
mL/min/1.73 m2 as calculated with the 4-parameter Modification of Diet in Renal 
Disease (MDRD) equation. 
b. Serum total bilirubin ≤ 2.5 mg/dL (43 µmol/L), except for subjects with Gilbert’s 
syndrome. 
c. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x 
ULN. If liver abnormality by the primary disease is suspected, subject may be pre-
registered to initiate the chemotherapy. Prior to registration, AST/ALT values must 
meet the criteria to continue the study. 
d. Serum magnesium ≥ institutional lower limit of normal (LLN). Subject may pre-
register without magnesium value, but subject must meet the criteria prior to the full 
registration on Day 8. 
e. Serum potassium ≥ institutional lower limit of normal (LLN).  
5.2 
Exclusion Criteria 
[Phase 1 part] 
Subject will be excluded from participation if any of the following apply at enrollment: 
1. Subject was diagnosed with acute promyelocytic leukemia (APL). 
2. Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic 
myelogenous leukemia in blast crisis). 


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3. Subject has active malignant tumors other than AML or myelodysplastic syndrome 
(MDS).  
4. Subject has received prior AML treatment except for the following: 
● Urgent leukapheresis 
● Hydroxyurea administration for emergency treatment of hyperleukocytosis  
(≤ 7 days) 
● Administration of retinoic acid before the diagnosis to exclude APL (≤ 7 days) 
● Supportive care using growth factors or cytokines 
● Steroid administration to treat hypersensitivity or blood transfusion reactions 
5. Subject has clinically active central nervous system leukemia. 
6. Subject has disseminated intravascular coagulation (DIC). 
7. Subject has had major surgery within 28 days prior to the first study drug administration. 
8. Subject has had radiation therapy within 28 days prior to the first study drug 
administration. 
9. Subject has congestive heart failure of NYHA class 3 or 4 (see Section 12.5), or subject 
with a past history of congestive heart failure of NYHA class 3 or 4 and in whom 
echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 
3 months prior to screening or at screening showed a left ventricular ejection fraction 
(LVEF) of < 45%. 
10. Subject has cardiac impairment or a clinically significant cardiac disease, including any 
one of the following: 
● 
Complete left bundle branch block 
● 
Obligate use of cardiac pacemaker 
● 
Long QT syndrome 
● 
Prolongation of the mean QTc interval (> 450 ms) on electrocardiogram (ECG) 
at screening 
● 
Right bundle branch block + left anterior hemiblock (bifascicular block) 
● 
Angina pectoris within 3 months prior to study drug administration 
● 
Acute myocardial infarction within 3 months prior to study drug administration 
11. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 
12. Subject requires treatment with concomitant drugs that target serotonin 5HT1 or 5HT2B 
receptors or sigma nonspecific receptors, with the exception of drugs that are considered 
absolutely essential for treatment of the subject. 
13. Subject has an active uncontrolled infection. 
14. Subject is known to have human immunodeficiency virus (HIV) infection. 
15. Subject has active hepatitis B or C or other active hepatic disorders. 
16. Subject has any condition that, in the investigator’s opinion, makes the subject unsuitable 
for study participation. 
17. Subject has potassium and magnesium levels of below institutional lower limit of normal 
in the laboratory test at screening. 


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18. 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). 
[Phase 2 part] 
A subject will be excluded from participation in this clinical study if any of the following 
apply: 
1. Subject was diagnosed with acute promyelocytic leukemia (APL). 
2. Subject has known BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast 
crisis). 
3. Subject has therapy-related AML. 
4. Subject has active malignant tumors other than AML. 
5. Subject has received previous therapy for AML, with the exception of the following: 
● Emergency leukapheresis, 
● Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 10 days, 
● Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days, 
● Growth factor or cytokine support, or 
● Steroids for the treatment of hypersensitivity or transfusion reactions. 
6. Subject has QTcF interval > 450 ms (average of triplicate determinations based on 
central reading). 
7. Subject with long QT syndrome. 
8. Subject has clinically active central nervous system leukemia. 
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 immediate life-threatening, severe complications of leukemia such as severe 
uncontrolled bleeding and/or severe disseminated intravascular coagulation 
12. Subject is known to have human immunodeficiency virus infection. 
13. Subject has active hepatitis B or C. 
14. Subject has an uncontrolled infection. An infection controlled with an approved or 
closely monitored antibiotic/antiviral/antifungal treatment is allowed. 
15. Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
electrocardiographic evidence of acute ischemia, congestive heart failure New York 
Heart Association (NYHA) class 3 or 4 or subject with a past history of congestive heart 
failure of NYHA class 3 or 4 and in whom echocardiogram (ECHO) or Multiple Gate 
Acquisition (MUGA) scan performed within 3 months prior to screening or at screening 
showed a left ventricular ejection fraction (LVEF) of < 45%. 
16. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP) 3A. 
17. Subject requires treatment with concomitant drugs that target serotonin 5HT2B receptors 
or sigma nonspecific receptors, with the exception of drugs that are considered 
absolutely essential for treatment of the subject. 


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18. 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. 
19. Subject has prior malignancies, except resected basal cell carcinoma or treated cervical 
carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be 
allowed. Cancer treated with curative intent < 5 years previously will not be allowed.  
20. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
5.3 
Restrictions during the Study 
The investigator and study coordinators will instruct the subjects on the following during the 
study: 
1. General precautions 
Subjects must visit the study site on the scheduled examination dates. If a subject cannot visit 
the study site for any reason, they must immediately contact the investigator, or study 
coordinator and ask for their instruction. 
2. Behavior 
If any symptom has occurred, the subject should contact the investigator or study coordinator 
as soon as possible. 
3. Treatment compliance 
Subjects must follow the instructions of the investigator or study coordinator and comply 
with the study treatment. 
The study drug must not be chewed or dissolved in the mouth before swallowing. 
If a subject vomits after taking the study drug, no more drugs should be taken to replace it. 
During the outpatient period, the subject must comply with the above, as well as the 
following: 
● 
Any remaining study drugs that the subject has forgotten to take should be 
brought in at the next visit, and after confirmation by the investigator or study 
coordinator, the status of treatment compliance should be reported. Any study 
drugs that the subject is not scheduled to take must be returned and should never 
be disposed of by the subjects themselves. 
● 
If the study treatment is discontinued at the subject’s discretion, the subject must 
visit the study site as soon as possible and undergo examination by the 
investigator. 


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4. Communications about concomitant drugs and therapies 
Subjects must not take any prescription drugs or OTC drugs at their own discretion without 
talking first with the investigator or study coordinator. Subjects must consult the investigator 
or study coordinator in advance if they wish to take such medication. 
If a subject is consulting or planning to consult another department of the study site or a 
different hospital, they should contact the investigator or study coordinator beforehand 
whenever possible. If the subject cannot contact the investigator or study coordinator 
beforehand, they should do so afterward as soon as possible. 
5. Other 
Subjects must use contraception throughout the study period, and male subjects for 120 days 
and female subjects for 180 days following the final study drug administration. 
Subjects must not donate blood during the study period (See Section 12.3). 
5.4 
Screen Failures 
A screen failure is defined as a potential subject who signed the ICF but did not meet 1 or 
more criteria required for participation in the study and was not pre-registered. 
For screen failures, the minimum data (the demographic data, date of signing the ICF, 
inclusion and exclusion criteria, AEs up to the time of screen failure and reason for screen 
failure) will be collected in the screening failure log (SFL). This information can be entered 
into the study database. 
5.4.1 
Rescreening 
[Phase 1 part] 
Not applicable 
[Phase 2 part] 
Results of screening assessments that do not meet the parameters required by eligibility 
criteria (e.g., clinical laboratory tests, ECG, etc.) may be repeated within the 7-day screening 
period without the need to register the subject as a screen failure. The registration criteria 
described in Section 5.5 should be met before Day 8 and assessments may be repeated. If 
more than 7 days elapse from the date of signing the ICF or did not meet all registration 
criteria by Day 8, the subject must be documented as a screen failure. In order to re-screen, a 
new ICF must be signed and the subject entered into screening with a new subject 
identification number. Rescreening is only allowed once for an individual subject. 
5.5 
Pre-Registration, Registration and Registration Failures 
[Phase 1 part] 
Not applicable 


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[Phase 2 part] 
Pre-registration occurs when a subject meets all eligibility criteria except for Inclusion 
criteria #4, #14-c, and #14-d and is prepared for Day 1. Subjects must meet all criteria by the 
planned administration of ASP2215 on Day 8 in order to be registered and to continue the 
study. Confirmation of criteria and the process of registration by Day 8 by investigator 
should be documented. If the subject did not meet all criteria by planned administration of 
ASP2215 on Day 8, the subject should be considered as registration failure. For Inclusion 
criteria #14-c, and #14-d, the most recent value prior to registration should meet the criterion. 
5.6 
Subject Replacement 
[Phase 1 part] 
If a subject is found to meet any of the following criteria, the subject will be considered 
unevaluable for DLT, and a new subject will be added to this cohort. 
● 
The subject has received less than 80% of the intended dose of ASP2215 during DLT 
assessment period specified in each part (e.g., subject in the dose-evaluation part who 
misses ≥ 3 daily doses during DLT assessment period and interrupts the study treatment 
for reasons other than a DLT). 
● 
The safety of the subject cannot be assessed adequately during DLT assessment period 
specified in each part such as due to the lack of required safety assessment(s). 
[Phase 2 part] 
Not applicable 
6 
STUDY DRUGS AND CONCOMITANT CHEMOTHERAPY 
6.1 
Study Drugs and Concomitant Chemotherapy  
Table 10 
Study Drugs and Concomitant Chemotherapy 
Name 
ASP2215 
(gilteritinib fumarate) 
Cytarabine 
Idarubicin 
Code name 
ASP2215 
AS3329381 (unique to JP 
region) 
Not applicable 
Use 
Study drug 
Study drug/Concomitant 
chemotherapy 
(based on the local 
regulation) 
Concomitant 
chemotherapy 
Dosage 
Formulation 
Tablet 
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Table continued on next page 


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Name 
ASP2215 
(gilteritinib fumarate) 
Cytarabine 
Idarubicin 
Physical 
Description 
Round light yellow film-
coated tablet 
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor.  
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Unit Dose 
Strength 
40 mg tablet 
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Packaging and 
Labeling 
HDPE bottle containing 30 
tablets  
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Refer to the country 
Package Insert or 
equivalent information 
provided by the 
manufacturer or the 
Sponsor. 
Route of 
Administration 
Oral  
IV infusion 
IV infusion 
Administration 
Instruction 
Once daily with water  
Administered 
intravenously and duration 
of infusion can be 
determined based on site 
clinical practice and the 
local package insert 
Administered 
intravenously and duration 
of infusion can be 
determined based on site 
clinical practice and the 
local package insert 
Sourcing 
Provided centrally by 
Sponsor 
Provided centrally by 
Sponsor or supplied 
locally by investigational 
site 
Provided centrally by 
Sponsor or supplied 
locally by investigational 
site 
IV: intravenous 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding preparation, handling and storage of the study drug and concomitant chemotherapy. 
6.1.1 
Dose/Dose Regimen and Administration Period 
Dose/Dose Regimen: 
[Phase 1 part] 
Subjects will receive the specified dose of ASP2215 shown in Table 11 once a day orally 
with water. The study drug should be taken as close as possible to the same time each day. 
The daily dose in the dose expansion part will be RED recommended in the dose-evaluation 
part. 
Table 11 
Dose level of ASP2215 
Dose level 
ASP2215 dose (mg/day) 
−1  
80 
1 
120 
 


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[Phase 2 part] 
The daily dose in the Phase 2 part will be the RED determined in the Phase 1 part. 
Administration Period: 
ASP2215 
[Phase 1 part] 
● 
Induction period (maximum of 2 cycles): Once-daily repeated oral administration on 14 
consecutive days from Day 4 through Day 17. One cycle lasts for 42 days or from the 
start of induction chemotherapy to the start of the subsequent chemotherapy regimen. 
● 
Consolidation period (maximum of 3 cycles): Once-daily repeated oral administration on 
14 consecutive days from Day 1 through Day 14. One cycle lasts for 28 days or until the 
start of the subsequent consolidation or maintenance therapy. 
● 
Maintenance period (maximum of 26 cycles): Once-daily repeated oral administration in 
28-day cycles until the end of Cycle 26 or a discontinuation criterion is met. 
[Phase 2 part] 
● 
Induction period (maximum of 2 cycles): Once-daily repeated oral administration on 
14 consecutive days from Day 8 through Day 21. One cycle lasts until investigator 
judges to proceed to next cycle or consolidation therapy. Postponing the initiation of 
consolidation therapy until blood recovery is preferred. 
● 
Consolidation period (maximum of 4 cycles): Once-daily repeated oral administration on 
14 consecutive days from Day 1 through Day 14. One cycle lasts until investigator 
judges to proceed to next cycle or maintenance therapy.  
● 
Maintenance period (maximum of 26 cycles): Once-daily repeated oral administration in 
28-day cycles until the end of Cycle 26 or a discontinuation criterion is met. 
Concomitant Chemotherapy 
Idarubicin and cytarabine will be intravenously administered using the dosage and regimen 
below. Ideal body weight with correction may be used for chemotherapy calculation per 
Institutional standard of care. 
Induction period: 
● 
Once-daily intravenous injection of 12 mg/m2 idarubicin on 3 consecutive days 
beginning from Day 1. 
● 
Once-daily intravenous injection of 100 mg/m2 cytarabine on 7 consecutive days 
beginning from Day 1. 
Consolidation period: 
● 
Twice-daily intravenous injection of 1.5 g/m2 cytarabine at 12-hour intervals on Day 1, 
3, and 5. 


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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and Labeling 
All study drugs supplied by the sponsor in this study will be prepared, packaged and labeled 
under the responsibility of qualified personnel at API or sponsor’s designee in accordance 
with API or sponsor’s designee standard operating procedures (SOPs), Good Manufacturing 
Practice (GMP) guidelines, International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines and applicable local laws/regulations. 
Each study drug will bear a label conforming to regulatory guidelines, GMP and local laws 
and regulations that identifies the contents as investigational drug. 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding packaging and labeling of the study drug and concomitant chemotherapy. 
6.2.1.1 ASP2215 
All medications used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person at API in accordance with API Standard Operation 
Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, 
and applicable local laws/regulations. 
Packaging form: 
Thirty ASP2215 Tablets 40 mg are packaged in a HDPE bottle with a deoxidizing agent. 
Labeling: 
The following items should be stated on the package of the study drugs: 
● 
That the drugs are intended “for investigational use” 
● 
Study number 
● 
Name of the study drug 
● 
Lot number, package unit, storage method, and other precautions 
● 
Name and address of the sponsor 
6.2.1.2 Concomitant Chemotherapy (Idarubicin, Cytarabine) 
[Phase 1 part] 
Commercially available idarubicin hydrochloride for injection (brand name: Idamycin for 
Intravenous Use) and cytarabine for injection (brand names: Cylocide Injection/Cylocide N 
Injection/Cytarabine Intravenous Infusion) will be used at each study site. 
[Phase 2 part] 
All chemotherapy drugs provided by the Sponsor will be packaged and labeled under the 
responsibility of API in accordance with API’s designee SOP, GMP guidelines, ICH GCP 
guidelines. 


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6.2.2 
Handling, Storage and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported 
and resolved before use of the study drug. 
2. Only subjects enrolled in the study may receive study drug and only authorized study site 
personnel may supply or administer study drug. Only study drug with appropriate 
expiry/retest dating may be dispensed. 
3. All study drug must be stored in a secure, environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions and access 
must be limited to the investigator and authorized study site personnel. 
4. The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).  
5. Further guidance and instruction on final disposition of used and unused study drug is 
provided in the pharmacy manual. 
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the study drug and concomitant chemotherapy. 
[UNIQUE to JP REGION] 
The head of the study site or the study drug storage manager will take responsibility for the 
following tasks related to the study drugs. 
● 
The study drug storage manager will store and manage the study drugs in accordance 
with the procedures for handling the study drugs written by the sponsor. 
● 
The study drug storage manager will prepare and retain records of the receipt of study 
drugs, the inventory at the study site, use by each subject, and return of unused study 
drugs to the sponsor or alternative disposal of unused study drugs. These records should 
include dates, quantities, batch/serial numbers or codes, expiration dates (if applicable), 
and the subject identification codes. 
● 
The study drug storage manager will prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol, and that 
the number and quantity of all the study drugs supplied from the sponsor were properly 
managed. 
6.3 
Randomization and Blinding 
This is an open-label study. For Phase 2 part, subject enrollment and dispensation of study 
drug and concomitant chemotherapy will be performed via the interactive response 
technology (IRT) system. Specific IRT procedures will be described in the respective study 
manual. 


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6.3.1 
Assignment and Allocation 
Since this is an open-label, uncontrolled study, allocation of the study drugs will not be 
performed. 
6.4 
Study Drug and Concomitant Chemotherapy Compliance 
During hospitalization, the treatment compliance of subjects will be confirmed by the 
investigator and the study drug storage manager. For outpatients, the treatment compliance 
will be confirmed from the information provided by subjects at each visit or the amount of 
returned study drugs. If there are any unreturnable study drugs, the reason should be 
confirmed and entered into the study drug storage management table. Even if a subject is 
failing to visit and it becomes difficult to ask about the status of treatment compliance, the 
subject should be contacted by phone or letter and every effort should be made to confirm 
their treatment compliance and collect the unused study drugs. Treatment compliance should 
be monitored closely and deviation in compliance should be reported to the sponsor. 
If the study treatment has been interrupted, the duration and reason for the interruption, 
deviations from the prescribed dose regimen will be recorded in the electronic case report 
form (eCRF). 
6.5 
Previous and Concomitant Treatment (Medication and Non-
Medication Therapy) 
6.5.1 
Previous Medication (Drugs and Therapies) 
All previous Medication (except for the medications for the purpose other than treatment 
such as contrast agent, laboratory examination, etc.) administered from 28 days prior to 
Induction Cycle 1 Day 1 must be recorded in the eCRF. The period of evaluation for previous 
medications and the items to be entered into the eCRF are as follows. 
Table 12 
Evaluation Period for Previous Medications and eCRF Entry Items 
Previous medication 
Evaluation period 
eCRF entry item 
All drugs 
28 days before Day 1 of induction 
therapy period – before Day 1 of 
induction therapy period  
Drug name, route of administration, 
treatment duration, reason(s) for treatment 
All therapies 
Therapy name, treatment duration, 
reason(s) for treatment 
 
6.5.2 
Concomitant Medication (Drugs and Therapies) 
All concomitant treatments (except for the medications for the purpose other than treatment 
such as contrast agent, laboratory examination, etc.) administered from Induction Cycle 1 
Day 1 to the EOT visit must be recorded in the Case Report Form (CRF) for registered 
subjects. Concomitant medications used for reported AE/SAE should be collected during the 
AE reporting period (Section 7.3.1 and 7.3.2). Concomitant medications during the long-term 
follow-up do not need to be collected even if they are used for reported AEs. For 
screen/registration failure subjects, collection should can be terminated when failure from the 
study is confirmed.  


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The period of evaluation for concomitant medications and the items to be entered into the 
eCRF are as follows.  
Table 13 
Evaluation Period for Concomitant Medications/Therapies and eCRF 
Entry Items 
Concomitant medication 
Evaluation period 
eCRF entry items 
All drugs 
Day 1 of induction therapy period – 
EOT 
From EOT to 30-day follow-up, 
only medications/therapies for 
reported AE/SAE will be collected. 
Drug name, route of 
administration, treatment duration, 
reason(s) for treatment 
All therapies 
Therapy name, treatment duration, 
reason(s) for treatment 
 
Prohibited concomitant medications: 
● 
Any treatments of AML except for the ones specified in this study (including but not 
limited to chemotherapy, radiotherapy, surgery, immunotherapy, or cellular therapy) are 
prohibited during treatment with ASP2215, except for hydroxyurea (6 g/day, up to 
14 days) to keep the absolute blast count below 50 x 109/L, intrathecal chemotherapy, 
and cranial irradiation used as prophylaxis. 
● 
Drugs that are strong inducers of CYP3A. 
● 
Drugs that are strong inhibitors or inducers of P-gp, those that target serotonin 5HT2B 
receptors or sigma nonspecific receptors (except drugs that are considered absolutely 
essential for treatment of the subject). 
Concomitant medications requiring caution: 
● 
Treatment with concomitant drugs that are strong inhibitors of CYP3A should be 
avoided with the exception of antibiotics, antifungals, and antivirals, which are used as 
the standard of care to prevent or treat infections. If strong CYP3A inhibitors are used 
concomitantly, subjects should be closely monitored for AEs. 
● 
Precaution should be taken in the use of ASP2215 with concomitant drugs that are 
known to prolong QT intervals or QTc. 
● 
Intake of grapefruit juice should be avoided during the study to the greatest extent 
possible. 
For chemotherapy drugs, the instructions in the local package insert under “Special warnings 
and precautions for use” section should be followed. The treatment mentioned in the 
specified section should be avoided or used with caution and closely monitored during 
idarubicin and cytarabine administration. 


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6.6 
Dose Modification 
[Phase 1 part] 
ASP2215 
Intra-subject dose escalation of ASP2215 is not permitted. If DLT occurs during the DLT 
assessment period, the study treatment will be discontinued without dose reduction. The 
investigator may interrupt the administration of ASP2215 when the safety of patient needs to 
be ensured. 
If a study drug-related AE occurs in the maintenance period, interruption, discontinuation, or 
dose reduction of ASP2215 should be performed in accordance with Table 14. Each dose 
reduction should be performed by 40 mg. Additional dose reductions are permitted until the 
dosage reaches 40 mg. However, if no further dose reduction is possible, the study treatment 
should be discontinued. Dose re-escalation in subjects who had a dose reduction is not 
permitted. 
In addition, the investigator may interrupt or reduce the dose of ASP2215 when it is 
considered necessary to ensure the safety of the patients for reasons other than those 
presented in Table 14. The investigator must promptly notify the sponsor of the interruption 
or dose reduction for reasons not specified in the table. 
Table 14 
Treatment Criteria in Event of a Study Drug-related Adverse Event 
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 
a reduced dose. 
Grade 3/4  
Treatment will be discontinued. 
Non-hematological Events 
Grade 3 
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 
a reduced dose. 
Grade 4 
Treatment will be discontinued. 
QTcF > 500 ms 
If the mean triplicate QTcF is > 500 ms at any time point (according to values 
shown in an ECG chart or analyses in a central laboratory), the ECG will be 
repeated 3 times (within 2 hours if identified according to the ECG chart values 
or as soon as possible if identified from 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 the study drug may be interrupted 
temporarily based on ECG chart values, central reading should be used for final 
treatment decisions. Cardiovascular medicine consult will be obtained as 
medically indicated. If QTcF resolves to ≤ 480 ms (Grade 1 or less severe) by 
central reading within 14 days, the subject may resume dosing from the reduced 
dose. 
Myelosuppression 
Grade 4 neutropenia and 
thrombocytopenia  
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. 
 


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Concomitant drugs (idarubicin and cytarabine): 
Intra-subject dose escalation of idarubicin or cytarabine is not permitted. 
Dose reduction of idarubicin and cytarabine will be conducted following the standard 
treatment method at each study site. If discontinuation, interruption, or dose reduction of 
idarubicin and/or cytarabine occurs during Cycle 1 of the induction period, the study sponsor 
will consider whether the subject is eligible for DLT assessment. 
[Phase 2 part] 
ASP2215 
Dose escalation of ASP2215 is not allowed and re-escalation after dose reduction is also not 
allowed in this study.  
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 any time 
during the study drug treatment period based on the dose reduction guideline in Table 15 or 
any reason other than the ones listed on the table if the investigator deems it necessary to 
ensure subject safety. 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 or a study drug related AE, may only resume treatment after discussion 
with the Medical Monitor. However, if no further dose reduction is possible, the study 
treatment should be discontinued. 
Table 15 should be followed if the specified events occurred during the ASP2215 dosing 
period. If the events occurred outside the ASP2215 dosing period, reduction of ASP2215 
dosing may be determined upon the investigator’s discretion. 
Table 15 
Guidelines for ASP2215 Dose Interruption or Reduction Event (for 
Phase 2) 
ASP2215 Dosing Instructions 
Non-hematological Events 
Grade 3 toxicity at least possibly related to 
ASP2215 
Dosing will be interrupted for up to 14 days. 
If the adverse event 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. 
Table continued on next page 


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ASP2215 Dosing Instructions 
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 severe) by central reading 
within 14 days, the subject may resume dosing at the 
reduced dose. 
Myelosuppression (Maintenance therapy only) 
Grade 4 neutropenia and/or 
thrombocytopenia 
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. 
ECG: electrocardiogram; QTcF: Fridericia-corrected QT interval 
Concomitant drugs (idarubicin and cytarabine): 
Intra-subject dose escalation of idarubicin or cytarabine is not permitted. 
Dose reduction of idarubicin and cytarabine should not be performed. If discontinuation, 
interruption, or dose reduction of idarubicin and/or cytarabine occurs during Cycle 1 of the 
induction period, information should be reported to the sponsor. Based on the investigator 
decision, chemotherapy dosing from Cycle 2 of the induction period may be reduced after 
confirmation with the sponsor. 
6.7 
Resumption of Treatment After Hematopoietic Stem Cell 
Transplantation 
Subjects who have a donor identified and achieve a response allowing them to undergo 
HSCT per each institution’s assessment can undergo HSCT without leaving the study. 
However, ASP2215 should be stopped and a pre-HSCT visit should be performed prior to 
starting the conditioning regimen for HSCT. ASP2215 can be resumed after stem cell 
transplantation if the following conditions are met: 
● Subject is between 30 - 90 days post HSCT 
● Subject has had successful engraftment as demonstrated by 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, they will follow the procedures listed under initial or 
subsequent cycle day 1 of maintenance therapy in the Schedules of Assessments. Subjects who 
do not resume ASP2215 will be followed for the survival endpoints. 


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7 
STUDY PROCEDURES AND ASSESSMENTS 
7.1 
Efficacy Assessments 
7.1.1 
Bone Marrow Aspirate and Biopsy 
[Phase 1 part] 
Bone marrow samples will be analyzed locally according to Table 6. Bone marrow aspirate is 
required and bone marrow biopsy in addition is preferred. In case of inadequate aspirate, bone 
marrow biopsy is required.  
[Phase 2 part] 
Bone marrow samples will be analyzed centrally and/or locally according to Table 7. Bone 
marrow aspirate is required and bone marrow biopsy in addition is preferred. In case of 
inadequate aspirate, bone marrow biopsy is required. If bone marrow aspirate is unavailable, 
then collection tube of whole blood along with bone marrow core biopsy (block or slides) 
should be collected instead and sent to the central lab. Additional sampling may be needed for 
assessment at the local laboratory for diagnosis and disease assessment. All local bone marrow 
assessment along with local hematology results will also be collected on the eCRF. 
7.1.1.1 Minimal Residual Disease (MRD) 
[Phase 1 part] 
Left-over samples (bone marrow aspirate) sent for central laboratory may be used for 
assessment of MRD. 
[Phase 2 part] 
MRD will be analyzed by a central laboratory according to Table 7. Bone marrow aspirate will 
be collected and sent by overnight courier to the central laboratory for assessment of MRD. A 
peripheral blood sample is not acceptable for MRD assessment. 
7.1.2 
Antitumor Response 
Antitumor response will be assessed on the days of bone marrow sampling based on the bone 
marrow findings, and peripheral blast count, neutrophil count, and platelet count. Preferably, 
samples from both bone marrow aspiration and biopsy should be obtained, but if the bone 
marrow aspiration was determined to be sufficient, biopsy may be omitted. The bone marrow 
samples will be collected on the dates shown in Table 6 and Table 7. 
Antitumor response is defined per modified Cheson criteria (2003) or modified European 
LeukemiaNet (ELN) recommendations (2017) as outlined below and samples are evaluated at 
central laboratories [Döhner et al, 2017; Cheson et al, 2003].  
[Phase 1 part] 
The assessment will be performed by the investigator. The results of bone marrow findings 
and peripheral blast count will be entered into the eCRF.  


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[Phase 2 part] 
Bone marrow aspiration and/or biopsy samples and hematology samples are evaluated 
centrally. If bone marrow samples were obtained for unscheduled visits, those samples along 
with hematology samples should be submitted for central assessment. All local bone marrow 
assessments along with local hematology results should be collected in the eCRF. 
Definitions 
Complete Remission (CR): 
CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a 
neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow blasts 
< 5%. There must be no evidence of Auer rods and no evidence of extramedullary leukemia. 
The blast counts in peripheral blood must be ≤ 2%. 
Complete Remission with Partial Hematologic Recovery (CRh): 
CRh is defined as a condition at the post baseline visit, having bone marrow blasts < 5%, 
partial hematologic recovery neutrophil count≥ 500/mm3 and platelet count ≥ 50,000/mm3, 
no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in 
peripheral blood must be ≤ 2%. 
Complete Remission with Incomplete Platelet Recovery (CRp): 
CRp is defined as a condition that meets all of the CR criteria at the post-baseline visit, 
except for the unrecovered platelet count (< 100,000/mm3). 
Complete Remission with Incomplete Hematological Recovery (CRi): 
CRi is defined as a condition that meets all of the CR criteria at the post-baseline visit, except 
for the unrecovered neutrophil count (< 1,000/mm3; whether or not having unrecovered 
platelet counts). 
Composite Complete Remission (CRc): 
To be classified as being in CRc at a post-baseline visit, a subject must either achieve CR, 
CRp or CRi at the visit. 
Partial Remission (PR): 
At a post-baseline visit, PR is defined as a condition with regeneration of normal 
hematopoietic cells in the bone marrow, no detectable (or trace of residual) blasts, ≥ 50% 
decrease of blasts in the bone-marrow aspirate and total bone marrow blasts of 5–25%. 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 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. 


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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. 
7.1.2.1 Best Response 
Best response is defined as the best assessment (CR, CRp, CRi, or PR) obtained at each 
efficacy assessment time point after the start of treatment. 
7.1.3 
Survival Time, Duration and Other Efficacy Endpoints 
Information on survival status, remission and relapse status, subsequent anti-leukemic 
treatments and outcomes will be collected for all subjects during long-term follow-up. 
The first survival status will occur at the 30-day follow-up. 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. Data may be supplemented by site records when available at the time of 
the contact (e.g., treatment records, outcomes).  
For the Phase 1 part, follow-up will continue until when the last subject enrolled reaches the 
28-day follow-up visit. For the Phase 2 part, follow-up will continue until 3 years after the 
last subject’s first treatment or completion of 30-day follow-up of the last subject, whichever 
is longer. 
Reasonable effort should be made to contact any subjects lost to follow-up during the course 
of the study in order to complete study-related assessments and retrieve any outstanding data 
and study drug. Following unsuccessful telephone contact, an effort to contact the subject by 
mail using a method that provides proof of receipt should be attempted. Contact via an 
alternate, preapproved contact is permissible if the subject is not reachable. Such efforts 
should be documented in the source documents. 
If a subject death occurs during the serious adverse event (SAE) reporting period or if the 
death occurs after the SAE reporting period but is determined by the investigator to be related 
to study drug, then the associated AE with outcome of death will also be reported on the 
eCRF and SAE Worksheet. If a subject death does not meet the criteria of an SAE, then death 
and anti-leukemic treatment and outcome up through the date of death should be collected 
and entered in the eCRF. 
7.1.3.1 Overall Survival 
[Phase 1 part] 
Not applicable. 


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[Phase 2 part] 
Overall survival (OS) is defined as the time from the date of first dose of day 1 to the date of 
death due to any cause. Patients still alive or lost to follow up will be censored at the time 
they were last known to be alive. 
7.1.3.2 Event-free Survival 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Event-free survival (EFS) is defined as the time from the date of first dose of study regimen 
(day 1) until the date of documented relapse, treatment failure or death from any cause, 
whichever occurs first. For a subject with none of these events, EFS is censored at the date of 
last disease assessment. 
7.1.3.3 Relapse-free Survival 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Relapse-free survival (RFS) is defined as time from the date of achievement of first CRc until 
relapse or death from any cause, whichever comes first. For a subject who is not known to 
have relapsed or died, RFS is censored on the date of last relapse-free disease assessment 
date. 
7.1.3.4 Transplantation Rate 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Transplantation rate is defined as the percentage of subjects undergoing HSCT during the 
study period. 
7.1.3.5 Duration of Response 
Duration of response is defined as the period from the first day of achieving CR, CRp, CRi, 
or PR to the first day of confirmed relapse. 
7.2 
Safety Assessments 
Study procedures and their timing is summarized in the schedule of assessments. Protocol 
waivers or exemptions are not allowed unless mentioned in the protocol. 


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Procedures conducted as part of a subject’s routine clinical management (i.e., standard of 
care) obtained before signing the ICF may be utilized for screening or baseline purposes, 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame, as defined in the schedule of assessments. 
7.2.1 
Adverse Events 
See Section 12.4 for information regarding AE collection and data handling. 
7.2.2 
Laboratory Assessments 
A list of laboratory test items is shown in Section 12.8. Samples (blood and urine) will be 
collected at the times shown in Table 6 and Table 7. The date of sampling and the test results 
will be entered into the eCRF. The investigator will compare the test results with the baseline 
values and if any clinically significant abnormalities are found, will enter them into the eCRF 
as AEs. Baseline laboratory values are defined as the laboratory values obtained on Induction 
Day 1. 
[Phase 1 part] 
Measurements will be performed locally at each study site. No central laboratory assessment 
is performed. 
[Phase 2 part] 
Measurements will be performed centrally for both scheduled and unscheduled visits. Local 
lab assessments can be performed. The local hematology assessment will be recorded in the 
eCRF if the central assessment was not evaluable. 
7.2.3 
Vital Signs 
Systolic blood pressure, diastolic blood pressure, pulse rate, body temperature, and arterial 
oxygen saturation will be measured after rest at the times shown in Table 6 and Table 7. Each 
of the measurements will be recorded and entered into the eCRF. The investigator will 
compare the measurements with the baseline values, and if any clinically significant 
abnormalities are found, will enter them into the eCRF as AEs. Baseline vital signs are 
defined as the vital signs measured on Day 1. 
7.2.4 
Height and Weight 
The weight of the subjects will be measured at the times shown in Table 6 and Table 7. Each 
of the measurements will be recorded and entered into the eCRF. Body surface area will be 
calculated when the body weight is measured. The investigator will compare the 
measurements with the baseline values, and if any clinically significant abnormalities are 
found, will enter them into the eCRF as AEs. Baseline body weight is defined as the body 
weight measured on Induction Day 1. 
The height of the subjects will be measured at screening, and the measurements will be 
entered into the eCRF as subject demographics. 


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7.2.5 
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 
examinations are to be performed only if clinically indicated. Physical examinations will be 
conducted at the visits outlined in Table 6 and Table 7. If clinically significant worsening of 
findings from pre-dose (Cycle 1 Day 1) is noted at any study visit, the changes will be 
documented as AEs on the AE page of the eCRF. 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. 
The investigator will assess the subject’s ECOG Performance Status from among the 5 stages 
(see Section 12.5) at the times shown in Table 6 and Table 7, and enter the results into the 
eCRF. 
7.2.6 
Electrocardiogram  
The 12-lead ECG will be measured at the times shown in Table 6 and Table 7. 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.  
Assessments scheduled at the same times as the pharmacokinetic plasma sampling should be 
performed before the sampling. 
QT interval and other interval measurements: 
The ECG chart measured at the times shown in Table 6 and Table 7 will be sent to the central 
ECG laboratory for measuring the QT interval and other intervals. The sent ECG charts will 
be analyzed at the central ECG laboratory to measure the QT, PR, RR, and QRS intervals.  
[Phase 1 part] 
The investigator will confirm the ECG chart, and enter the result of the assessment as either 
“normal,” “abnormal (not clinically significant),” or “abnormal (clinically significant)” into 
the eCRF. If the ECG chart was assessed as “abnormal (clinically insignificant abnormality)” 
or “abnormal (clinically significant abnormality),” the abnormal finding will be entered into 
the eCRF. 
[Phase 2 part] 
The investigator will confirm the central ECG chart and assess whether any AEs should be 
reported. Confirmation by an investigator should be documented. 


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7.2.7 
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 1 week prior to 
consent. 
7.2.8 
Multigated Acquisition Scan or Echocardiogram 
A MUGA or ECHO is to be performed at screening for subjects with a history of NYHA 
Class 3 or 4 congestive heart failure (unless MUGA or ECHO performed within 3 months 
prior to screening revealed left ventricular ejection fraction ≥ 45%). 
7.2.9 
Pregnancy Tests  
If the subject is a woman of childbearing potential, a pregnancy test will be performed locally 
on serum or urine samples, and the results will be entered into the eCRF. 
7.2.10 DLT 
See Section 4.1.2. 
7.3 
Adverse Events and Other Safety Aspects 
The definitions of an AE or SAE can be found in Section 12.4.  
The investigator and medically qualified designee(s) are responsible for detecting, 
documenting and recording events that met the definition of an AE or SAE.  
7.3.1 
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information 
[Phase 1 part] 
AE monitoring will begin from the start of induction therapy through to the end of the 
follow-up observation. 
[Phase 2 part] 
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug. AE collection begins after the signing of the ICF and will be collected 
until 30-day follow-up visit or when the subject is determined to be a screen/registration 
failure. In case the chemotherapy is provided from the sponsor, AE collection will continue 
until the drug administration is completed. During the long-term follow-up period, only SAE 
data that the investigator assesses as possibly or probably related to study drug will be 
collected. 
7.3.2 
Adverse Event and Serious Adverse Event during HSCT 
ASP2215 related SAE should always be reported regardless of the time of the HSCT during 
the study participation. 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 


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regimen and will resume upon the resumption of ASP2215 treatment until 30-day follow-up 
visit. 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 ASP2215, whichever comes first. However, the following AE/SAEs will continue to be 
collected until 30 days after the last dose of ASP2215, regardless of the time of the HSCT 
conditioning regimen, the HSCT, and the resumption of ASP2215: 
● 
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 
Above AE/SAEs will be collected throughout the HSCT period for the subjects who plan to 
resume ASP2215. 
7.3.3 
Method of Detecting Adverse Events and Serious Adverse Events 
The methods of recording, evaluating and assessing seriousness, causality and severity of 
AEs and SAEs are described in Section 12.4. Care will be taken not to introduce bias when 
detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is 
the preferred method to inquire about AE occurrences. 
If the severity/ National Cancer Institute-Common Terminology Criteria for Adverse Event 
(NCI-CTCAE) grade of an AE changes, the event should be relisted on eCRF with the new 
severity/NCI-CTCAE grade and new onset date. 
If the severity/NCI-CTCAE grade decreases, the AE should be relisted on eCRF with the new 
severity/NCI-CTCAE grade and new onset date. The exception is ongoing pre-dose events 
that continue post-dose and improve post-dose. Such events should not be re-listed. 
If the severity of an SAE reduces, then also provide the details of the AE on the SAE 
worksheet for the medical assessor to be able to assess the course of the event. 
7.3.4 
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 by the investigator.  
If after the protocol-defined AE collection period, an AE progresses to an SAE, or the 
investigator learns of any (S)AE including death, where he/she considers there is reasonable 
possibility it is related to the study drug or study participation, the investigator must promptly 
notify the sponsor. 
7.3.5 
Reporting of Serious Adverse Events 
Prompt notification by the investigator to the sponsor of an SAE is essential, so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
intervention under clinical investigation are met. 


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Procedures for reporting SAEs to the sponsor are described in Section 12.4.5. 
7.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Under this protocol, the following event(s) will not be considered as an(S)AE: 
● 
Disease progression: events including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs. These data will be captured as efficacy assessment data. If there is any 
uncertainty as to whether an event is due to anticipated disease progression and/or if 
there is evidence suggesting a causal relationship between the study drug and the event, 
it should be reported as an (S)AE. All deaths up to 30 days after the final administration 
of study drug must be reported as an SAE, even if attributed to disease progression.  
● 
Pre-planned and elective hospital/clinical procedures/interventions or procedures for 
diagnostic, therapeutic, or surgical procedures for a pre-existing condition that did not 
worsen during the course of the study. These procedures are collected per the eCRF’s 
completion guidelines. 
7.3.7 
Special Situations  
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Certain special situations observed in association with the study drug, such as incorrect 
administration (e.g., wrong dose of study drug or background therapy) are collected in the 
eCRF, as protocol deviation or may require special reporting, as described below. These 
special situations are not considered AEs, but do require to be communicated to Astellas as 
per the timelines defined below. 
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the electronic data source. If 
the AE meets the definition of an SAE, the SAE is to be reported as described in 
Section 12.4.5 and the details of the associated special situation are to be included in the 
clinical description on the SAE worksheet. Cases of pregnancy is reported to the sponsor (the 
reporting procedure is the same as SAE reporting) using the Pregnancy Form provided by the 
sponsor. 


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The special situations are: 
● 
Pregnancy  
● 
Medication error, overdose and “Off-label Use” (i.e., use outside of what is stated in the 
protocol) 
● 
Misuse/abuse 
● 
Occupational exposure 
● 
Suspected drug-drug interaction 
Instructions and procedures for reporting special situations are provided in Section 12.4.6.  
7.3.8 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for conducting the study properly, 
the sponsor will inform all investigators involved in the study as well as the appropriate 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the study. 
[UNIQUE to JP REGION] 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 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 Pharmaceutical Affairs Law, the sponsor should inform all 
investigators involved in the study, head of the study site and appropriate regulatory 
authorities of such information. The head of the study site who receives such information 
will decide whether the 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 12.1.4.2. 
2. In addition, when the head of the study site receives the revisions of the investigator’s 
brochure, protocol, written information, information on the matters covering the quality 
of the test product, efficacy and safety, information necessary for conducting the study 
properly or documents to be examined by the IRB, these documents should be sent to the 
IRB. 
7.3.9 
Urgent Safety Measures <For JP Region: Deviations from the Protocol and 
Other Actions Taken to Avoid Life-threatening Risks to Subjects>  
[Phase 1 part] 
[UNIQUE to JP REGION] 
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.  


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1. 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. 
2. 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. 
[Phase 2 part] 
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities (CA), IRB/IEC, where applicable, in order to protect 
subjects from any immediate hazard to their health and/or safety. Either the investigator or 
the sponsor can initiate a USM. The cause of a USM can be safety-, product- or procedure-
related. 
[UNIQUE to JP REGION] 
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.  
1. 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. 
2. 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. 
7.3.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the study physician and 
Astellas team member within 24 hours of awareness. Full details of the potential USM are to 
be recorded in the subject’s medical records. The sponsor may request additional information 
related to the event to support their evaluation.  
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the subjects. These actions may include but are not limited to a change 
in study procedures or study treatment, halting further enrollment in the study, or stopping 
the study in its entirety. The sponsor or sponsor's designee will notify the relevant competent 
authorities and concerned ethics committee within the timelines required per current local 
regulations, and will inform the investigators, as required. When required, investigators must 
notify their IRB/IEC within timelines set by regional regulations. 


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7.4 
Pharmacokinetics 
7.4.1 
Pharmacokinetic Assessment 
Samples will be collected to measure plasma ASP2215 and cytarabine concentrations at the 
times shown in Table 6 and Table 7. The dates and times of sampling will be recorded in the 
eCRF.  
[Phase 1 part]  
Table 16 
Evaluation time point for Plasma ASP2215 Concentration 
Induction period 
Cycle 1 Day 4 
Pre-dose 
1, 2, 4, 6, and 10 hours post-dose 
Cycle 1 Day 5 
Pre-dose (24 hours post-dose of Day 4 administration) 
Cycle 1 Day 8 
Pre-dose 
Cycle 1 Day 11 
Pre-dose 
Cycle 1 Day 17 
Pre-dose 
Cycle 1 Day 28 
 
Consolidation period 
Cycle 1 Day 1 
Pre-dose 
1, 2, 4, 6, and 10 hours post-dose 
Cycle 1 Day 2 
Pre-dose (24 hours post-dose of Day 1 administration) 
Cycle 1 Day 6 
Pre-dose 
Cycle 1 Day 15 
Pre-dose 
 
[Phase 2 part] 
Induction period 
Cycle 1 Day 15  
Pre-dose  
Cycle 1 Day 21 
Pre-dose 
Consolidation period 
Cycle 1 Day 8 
Pre-dose  
Cycle 1 Day 15 
Pre-dose 
 
[Phase 1 part] 
Table 17 
Evaluation time point for Plasma Cytarabine Concentration 
Induction period 
Cycle 1 Day 1 
Pre-dose 
Cycle 1 Day 3 
Pre-dose 
Cycle 1 Day 8 
Pre-dose 
Consolidation period 
Cycle 1 Day 2 
Pre-dose 
Cycle 1 Day 6 
Pre-dose 
 
[Phase 2 part] 
Not applicable. 


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7.4.2 
Test Drug Concentration 
7.4.2.1 Measurement of Plasma ASP2215 Concentration 
Sample collection will be performed as follows. The plasma ASP2215 concentration will be 
measured for all samples collected, even for discontinuations. The drug concentration 
laboratory will perform the measurements in accordance with the separately prepared 
measurement plan. 
1. Plasma sample processing 
To obtain 0.5 mL of plasma, 1 mL of blood will be collected from the cutaneous vein of 
the forearm or the cubital fossa using a sampling tube containing EDTA-2K as an 
anticoagulant. The blood samples will be stored at room temperature until centrifugation. 
The blood samples will be centrifuged (at room temperature for 10 minutes at 
approximately 1700 g) within 2 hours of sampling. The plasma obtained will be divided 
into 2 polypropylene tubes (0.25 mL into the primary, and the rest into the back-up), then 
immediately freeze stored (at ≤ −20°C) to be used as samples for measuring test drug 
concentration. The sampling date and time will be recorded for each subject into the 
medical record or other source document, and entered into the eCRF. 
2. Sample shipment 
Samples for measuring test drug concentration will be shipped to the drug concentration 
laboratory by a sample collection/transport organization in a frozen state cooled by dry 
ice. 
3. Concentration measurement 
Measurement of plasma test drug concentrations will be performed at the drug 
concentration laboratory by an LC-MS/MS method established through a validation test 
(ISN No.: 2215-ME-0015 and 2215-ME-0033). When 0.05 mL of plasma is used, the 
lower limit of quantification of the test drug concentration is 0.5 and 10 ng/mL 
respectively (ISN No.: 2215-ME-0015 and 2215-ME-0033). 
4. Precision control of measured data 
The person responsible at the drug concentration laboratory will confirm that there are no 
quality problems. If a quality problem is detected, the necessity of re-measuring or 
improving measurement methods should be discussed. 
5. Obtaining the measurement results 
The sponsor will obtain the measurement report and the electronic files of the 
concentration measurements from the drug concentration laboratory, and a record of the 
receipt will be prepared. 
6. Handling of remaining plasma 
Plasma samples for concentration measurement will be stored frozen (at ≤ −20°C or 
lower) at the drug concentration laboratory until the measurement report is finalized. 
Thereafter, the samples will be discarded after contacting the sponsor. 


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7.4.2.2 Measurement of Plasma Cytarabine Concentration 
[Phase 1 part] 
Sample collection for measurement of the plasma cytarabine concentration will be performed 
at the times shown in Table 6 and Table 7. A blood sample of 2 mL will be collected at each 
time point. The plasma cytarabine concentration will be measured for all samples collected, 
even for discontinuations. The drug concentration laboratory will perform the measurements 
in accordance with the separately prepared measurement plan. 
1. Plasma sample processing 
Blood of 2 mL will be collected from the cutaneous vein of the forearm or the cubital 
fossa using a syringe without any additive such as anticoagulant. The collected blood 
will be promptly transferred to a blood collection tube containing EDTA-2K as 
anticoagulant and tetrahydrouridine as stabilizer, gently mixed and stored at room 
temperature. The blood samples will be centrifuged (at room temperature for 10 minutes 
at 1500 to 2000 g) within 30 minutes of sampling. The plasma obtained will be divided 
into 2 polypropylene tubes (0.75 mL into the primary, and the rest into the back-up), then 
freeze stored (at ≤ −20°C) as promptly as possible to be used as samples for measuring 
concentration. The sampling date and time will be recorded for each subject into the 
medical record or other source document, and entered into the eCRF. 
2. Sample shipment 
Samples for measuring concentration will be shipped to the drug concentration 
laboratory by a sample collection/transport organization in a frozen state cooled by dry 
ice. 
3. Concentration measurement 
Measurement of plasma cytarabine concentrations will be performed at the drug 
concentration laboratory by an LC-MS/MS method established through a validation test. 
When 0.050 mL of plasma is used, the lower limit of quantification of cytarabine 
concentration is 0.5 ng/mL. 
4. Precision control of measured data 
The person responsible at the drug concentration laboratory will confirm that there are no 
quality problems. If a quality problem is detected, the necessity of remeasuring or 
improving measurement methods should be discussed. 
5. Obtaining the measurement results 
The sponsor will obtain the measurement report and the electronic files of the 
concentration measurements from the drug concentration laboratory, and a record of the 
receipt will be prepared. 
6. Handling of remaining plasma 
Plasma samples for concentration measurement will be stored frozen (at ≤ −20°C) at the 
drug concentration laboratory until the measurement report is finalized. Thereafter, the 
samples will be discarded after contacting the sponsor. 


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[Phase 2 part] 
Not applicable. 
7.5 
Pharmacodynamics | Immunogenicity 
[Phase 1 part] 
The inhibitory effect of ASP2215 on blood FLT3 and AXL phosphorylation will be 
investigated to assess the pharmacodynamics of a single or repeated oral administration of 
ASP2215. This investigation will be terminated after assessment in some subjects in this 
study, taking into account that qualitative pharmacodynamic assessment has been completed 
in the domestic phase I study (Protocol No.: 2215-CL-0102). 
The pharmacodynamic measurement organization will perform the measurements in 
accordance with a separately prepared measurement procedure by the organization. The 
sponsor will obtain the measurement results and records whose quality has been assured from 
the pharmacodynamic measurement organization. 
Samples will be collected and processed using the following procedures. The exact sampling 
time for each subject will be recorded. 
2 mL of blood will be sampled from the vein using a blood collection tube containing sodium 
heparin as an anti-coagulant. The sample obtained will be immediately frozen for storage 
(approximately –70°C or lower) to be used as a sample for pharmacodynamic measurement. 
The samples will be sent to the pharmacodynamic measurement organization by a sample 
collection/transport organization in a frozen state cooled by dry ice. After the 
pharmacodynamic measurement organization performs the pharmacodynamic assessments, 
the remaining blood samples will be stored frozen (approximately –70°C or lower) until the 
measurement records are finalized. Thereafter, the samples will be discarded after contacting 
the sponsor. 
[Phase 2 part] 
Not applicable. 
7.6 
Exploratory Biomarker(s) 
7.6.1 
FLT3 Mutation Assessment 
In order to investigate the presence/absence of the ITD mutation of FLT3 and point mutation 
at D835/I836 residues, samples will be collected on the dates shown in Schedule of 
Assessment. 
[Phase 1 part] 
Subjects’ consent for sample collection for the FLT3 mutation test will be obtained at the 
same time as informed consent for this study. 1 mL of bone marrow aspirate will be collected 
before the start of Cycle 1 of the induction period (at screening) and on Day 1 of Cycle 1 of 
the consolidation and maintenance periods, from each subject who provided consent. If 


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collection of bone marrow aspirate is difficult, blood may be collected instead (4 mL in the 
case of blood). The bone marrow aspirate or peripheral blood collected will be stored 
refrigerated at the study site until sample collection. The samples will be collected by the 
sample collection/transport organization, and analyzed for the presence or absence of the 
following FLT3 mutations at the FLT3 mutation testing laboratory. Details will be specified 
in a separate procedure. 
● 
FLT3-ITD mutation 
● 
FLT3 point mutation (D835, I836) 
The sponsor will obtain the test results from the FLT3 mutation testing laboratory as a 
separate report. This test is an exploratory analysis to investigate the relationship between the 
efficacy of the study drug and the FLT3 gene. Therefore, the results of the genetic analysis 
will not be disclosed. (Analysis results of the FLT3-mutation test obtained for the screening 
test will be disclosed to the study sites.) 
[Phase 2 part] 
FLT3 mutation status will be assessed from bone marrow samples taken at the screening visit 
and may be assessed from bone marrow or blood samples at other time points during the 
study.  
The FLT3 companion diagnostic being used to determine a subject’s FLT3 mutation status is 
approved by the PMDA and FDA. 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 Laboratory Manual. Samples will be shipped to and analyzed by a Sponsor designated 
analytical laboratory. All biomarker samples collected will be stored for a period up to 
15 years following study database hard lock. Please refer to the Laboratory Manual for more 
detailed information on this topic. 
7.6.2 
Minimal Residual Disease (MRD) Assessment 
FLT3 MRD may be measured from bone marrow samples taken at the screening visit, end of 
treatment/disease progression and from bone marrow samples taken at other time points 
during the study. FLT3 mutation will be measured in relation to total FLT3. Changes in 
FLT3 mutation to total FLT3 will be compared with baseline/screening samples. 
7.6.3 
Other Biomarker Assessment 
If leftover bone marrow samples are available, FLT3 sequencing analysis can be performed 
at the screening visit, and end of treatment/disease progression. Samples at other time points 
and/or peripheral blood samples can also be provided for FLT3 sequencing analysis. In 
addition, samples may be analyzed for mutations in AML related genes (e.g., IDH1, NPH1) 
and changes in proteins in relation to treatment effects at the screening visit, and end of 


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treatment/disease progression with using appropriate method (e.g. Archer VariantPlex Core 
Myeloid Kit etc.). 
7.6.4 
Sample for Banked Pharmacogenomic Sample Analysis 
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety issues. After registration, buccal swab 
and blood will be collected from subjects who have consented to sampling for future PGx 
study. Samples will be shipped to a Sponsor designated banking CRO. 
Labels should uniquely identify each sample and contain at least: 
● 
Protocol number (2215-CL-0104) 
● 
Subject number and 
● 
Purpose and biological matrix (i.e., “biobanking,” “buccal sample”) 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate Laboratory Manual. 
7.7 
Total Amount of Blood and Bone Marrow Fluid 
[Phase 1 part] 
The test parameters, the number of samplings, and the approximate sampling amounts for 
blood and bone marrow fluid in this study are as follows. If a follow-up of a laboratory test 
becomes necessary, blood sampling will be performed whenever necessary. 
Table 18 
Approximate Amounts of Blood and Bone Marrow Fluid 
 
Screening 
Induction 
period 
(1 cycle) 
Consolidation 
period 
(1 cycle) 
Maintenance period 
End of 
treatment 
Cycle 1 
Cycle 2 and beyond 
Blood 
13.5 mL 
or 
17.5 mL* 
100 mL 
78.5 mL 
or  
82.5 mL* 
13.5 mL 
or 
17.5 mL* 
13.0 mL 
14.5 mL 
Bone 
marrow 
fluid 
3 mL 
or 
4 mL* 
3 mL 
3 mL 
or 
4 mL* 
3 mL 
or 
4 mL* 
- 
3 mL 
 
* If blood or bone marrow fluid was collected for FLT3 mutation test 
The approximate amounts of blood and bone marrow fluid to be sampled for each purpose 
are as follows: 
● 
Hematology: 2 mL/test 
● 
Biochemistry: 7 mL/test 
● 
Thyroid function test: 2 mL/test 
● 
Coagulation test: 2 mL/test 
● 
Pregnancy test: 0.5 mL/test (blood) 
● 
Plasma drug concentrations: 1 mL/test (ASP2215), 2 mL/test (cytarabine) 


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● 
Bone marrow test: 3 mL/test (bone marrow fluid) 
● 
Blood sample for biobanking: 5 mL 
● 
FLT3 mutation test: 4 mL (blood), 1 mL (bone marrow fluid) 
[Phase 2 part] 
The test parameters, the number of samplings, and the approximate sampling amounts for 
blood and bone marrow fluid in this study are as follows. If a follow-up of a laboratory test 
becomes necessary, blood sampling will be performed whenever necessary. 
Table 19 
Approximate Amounts of Blood and Bone Marrow Fluid 
 
Screening 
Induction 
period 
(1 cycle) 
Consolidation 
period 
(1 cycle) 
Maintenance period 
End of 
treatment 
At relapse 
(during the 
long term 
follow up) 
Cycle 1 
Cycle 2 
and 
beyond 
Blood 
13 - 19.5 
mL* 
81-86 mL 
50-52 mL 
13 - 15.5 
mL** 
13 - 17 
mL 
13 – 17 
mL* 
13 mL 
Bone 
marrow 
fluid 
3 - 4 mL* 
3 mL 
3 mL 
3 mL 
0 - 3 mL 
3 - 4 mL* 
3 mL 
*  If blood or bone marrow fluid was collected for FLT3 mutation test. 
** If blood sample was used for pregnancy test. 
The approximate amounts of blood and bone marrow fluid to be sampled for each purpose 
are as follows: 
● 
Hematology: 2 mL/test 
● 
Biochemistry: 7 mL/test 
● 
Thyroid function test: 2 mL/test 
● 
Coagulation test: 2 mL/test 
● 
Pregnancy test: 0.5 mL/test (blood) 
● 
Plasma drug concentrations: 1 mL/test (ASP2215) 
● 
Bone marrow test: 3 mL/test (bone marrow fluid) 
● 
Blood sample for biobanking: 3 mL 
● 
FLT3 mutation test: 4 mL (blood), 1 mL (bone marrow fluid) 
8 
DISCONTINUATION 
8.1 
Discontinuation of Individual Subject(s) from Study Treatment  
A discontinuation from treatment is defined as 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 discontinue the subject from study treatment or to terminate a 
subject’s involvement in the study at any time if the subject’s clinical condition warrants it. 


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The reason for discontinuation from study treatment must be documented in the subject’s 
medical records. 
For withdrawn cases, the date of the final study drug administration, date of the end of 
treatment (discontinuation; date the investigator decided the discontinuation), and the reason 
for the discontinuation will be entered into the eCRF. 
When discontinuing the treatment, the investigator will take appropriate measures/treatment 
as required, and perform the tests/assessments scheduled at the end of treatment 
(discontinuation). At 30 days after the final study drug administration, tests and assessments 
scheduled as follow-up observation will be performed. However, if the setting up of follow-
up observation is difficult, such as when another treatment must be started after study 
discontinuation, the follow-up observation may be omitted or shortened.  
A subject must discontinue study treatment for any of the following reasons: 
[Phase 1 part] 
● 
Withdrawal of consent 
● 
Poor compliance (failure to make the scheduled visits and others) 
● 
A serious protocol deviation is found 
● 
Failure to achieve remission after 2 cycles of induction therapy 
● 
Relapse after remission 
● 
Occurrence of unacceptable AE requiring discontinuation of treatment 
● 
The investigator determines that continuation of the study treatment will be detrimental 
to the subject 
● 
Subjects or their partners are found to be pregnant 
[Phase 2 part] 
● 
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 one 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 fails to achieve remission after 2 cycles of induction therapy. 
● 
Subject relapses following remission. 
● 
Subject develops an intolerable or unacceptable toxicity. 
● 
Subject receives any antileukemic therapy other than the assigned treatment, with the 
exception of hydroxyurea up to 6 g daily for up to 2 weeks, HSCT, prophylactic 
intrathecal chemotherapy or cranial irradiation. 
● 
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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● 
Female subject becomes pregnant. 
● 
Death. 
8.2 
Discontinuation of Individual Subject(s) from Study 
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in Schedules of 
Assessments. The only exception to this is when the subject specifically withdraws consent 
for any further contact with him/her or persons previously authorized by the subject to 
provide this information. 
For the Phase 2 part, all subjects who discontinue study treatment are to be followed for 
survival status until completion of the study. 
Discontinuation Criteria from Post-Treatment Follow-up for Individual Subjects: 
● 
Subject declines further study participation (i.e., withdrawal of consent). 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Death. 
[Only applies to Phase 2 part] 
● 
The study meets the criteria to complete the long-term follow-up (i.e., During the 
long-term follow-up period, the subject will be followed for 3 years after the last 
subject’s first treatment or completion of 30-day follow-up of the last subject, whichever 
is longer.). 
8.2.1 
Lost to Follow-up 
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data and 
retrieve study drug.  
8.3 
Discontinuation of the Study Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor (UNIQUE to JP Region: and the head of the study site.) 
8.4 
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.  


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9 
STATISTICAL METHODOLOGY 
[Phase 1 part] 
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. Statistical analysis will 
be performed based on the following principles. In principle, the analysis will be separately 
performed for the dose-evaluation and expansion parts. In addition, when necessary, the 
analysis of RED will be performed for the dose-evaluation and expansion parts as a whole. 
[Phase 2 part] 
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 lock at the latest. Changes from the planned analyses in the final 
SAP that impact the statistical analyses will be justified in the clinical study report (CSR). 
In general, continuous data will be summarized with descriptive statistics, frequency and 
percentage for categorical data. 
9.1 
Sample Size 
9.1.1 
Target Sample Size 
[Phase 1 part] 
6 subjects 
Dose-evaluation part: At least 3 subjects per cohort (which may be changed according to the 
status of the onset of DLT and the number of cohorts) 
Expansion part: At least 3 subjects 
[Phase 2 part] 
Approximately 80 subjects 
9.1.2 
Justification of Sample Size 
[Phase 1 part] 
Dose-evaluation part: 
To assess MTD and RED of ASP2215 as induction therapy concomitant with 
cytarabine/idarubicin in newly diagnosed AML subjects, 3 DLT evaluable subjects per dose 
level for 1 dose level were assumed. The sample size may increase depending on the 
occurrence of toxicities. 
Expansion part: 
The sample size was set to 3 subjects to further assess the safety and efficacy of ASP2215 at 
the dose tested in the expansion part. 


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[Phase 2 part] 
The sample size of Phase 2 part is approximately 80 subjects. An evaluable sample size of 
70 subjects in phase 2 part provides more than 80% power to detect a 15% increase in CR 
rate from 55% (historical benchmark based on the RATIFY study, Stone et al, 2017.) to 70% 
at one-sided significance level of 0.05. Assuming approximately 10% drop-out rate, a total of 
80 subjects will be enrolled into Phase 2 part. 
9.2 
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 lock. 
In principle, the analysis sets will be selected as in from Section 9.2.1 to 9.2.6. However, 
when necessary, the analysis sets will be determined considering the cases by referring to the 
opinions and advice from medical experts and statistical advisors. 
9.2.1 
Full Analysis Set (FAS) 
[Phase 1 part] 
Subjects who meet all of the following criteria will be included: 
● 
Received at least 1 dose of the study drug 
● 
Assessed for at least 1 efficacy variable after study drug administration 
[Phase 2 part] 
Subjects who meet all of the following criteria will be included: 
● 
Received at least 1 dose of ASP2215 
● 
Had at least one post-baseline bone marrow assessment 
9.2.2 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the Safety Analysis Set (SAF) will be used. 
[Phase 1 part] 
All subjects who received at least 1 dose of ASP2215 will be included. 
[Phase 2 part] 
The SAF will be defined as the same as phase 1 part. 
9.2.3 
Pharmacokinetic Analysis Set (PKAS) 
Subjects who received the study drug, from whom samples for drug concentration 
measurement have been collected for at least 1-time point after the study drug administration, 
and from whom drug concentration measurement has been obtained will be included. 


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9.2.4 
Pharmacodynamic Analysis Set (PDAS) 
[Phase 1 part] 
Subjects who received the study drug, from whom samples for pharmacodynamic assessment 
have been collected for at least 1-time point after the study drug administration, and from 
whom pharmacodynamic measurement has been obtained will be included. 
[Phase 2 part] 
Not applicable. 
9.2.5 
Dose-Determining Analysis Set (DDAS) 
[Phase 1 part] 
Subjects who do not fall under any of the following criteria will be included: 
● 
Received less than 80% of the intended dose of ASP2215 during DLT assessment period 
specified in each part (e.g., subject in dose evaluation part who misses ≥ 3 daily doses 
during DLT assessment period and interrupts the study for a reason other than a DLT) 
● 
Unable to assess safety adequately during DLT assessment period specified in each part 
such as due to the lack of required safety assessment(s). 
[Phase 2 part] 
Not applicable. 
9.2.6 
MRD Analysis Set (MAS) 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
The MRD Analysis Set (MAS) consists of all subjects who were enrolled and received at 
least 1 dose of study drug, were centrally confirmed as FLT3-ITD positive and had a baseline 
and at least post-baseline sample with MRD data. 
9.3 
Demographics and Baseline Characteristics  
9.3.1 
Demographics 
[Phase 1 part] 
The following analyses will be performed in the FAS, SAF, DDAS, PKAS, and PDAS. 
Analyses will be performed by dosage for the dose-evaluation part. 
● 
The discrete variables will be summarized by frequency. 
● 
Summary statistics will be calculated for the continuous variables. 


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[Phase 2 part] 
Descriptive statistics will include number of subjects, mean, standard deviation, minimum, 
Q1, median, Q3 and maximum for continuous endpoints and frequency and percentage for 
categorical endpoints. The analyses will be performed in the FAS, SAF, PKAS, and MAS. 
9.3.2 
Subject Disposition  
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented. Similar tables for screening 
disposition, investigational period disposition and follow-up disposition will also be 
presented. All disposition details and dates of first and last evaluations for each subject will 
be listed. 
9.3.3 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy)  
All previous and concomitant treatment will be listed. 
9.3.4 
Medical History  
Medical history for each subject will be listed. 
9.3.5 
Study Drug Exposure 
The number and percentage of subjects exposed to study drug will be summarized. 
All study drug exposure data will be listed. 
9.4 
Analysis of Efficacy  
[Phase 1 part] 
The following analyses will be performed in the FAS. Analyses will be performed by dosage 
for the dose-evaluation part. 
The following endpoints will be summarized by the Bruce D. Cheson standard (2003) or 
modified ELN recommendations (2017). 
● 
CR (Complete Remission) rate 
● 
CRp (CR with incomplete platelet recovery) rate 
● 
CRi (CR with incomplete hematologic recovery) rate 
● 
PR (Partial Remission) rate 
● 
CRc (Composite CR) rate: CR + CRp + CRi 
● 
Overall response rate: CRc + PR 
Summary statistics will be calculated for the duration of response. 
[Phase 2 part] 
Efficacy analysis will be conducted on the FAS. The interpretation of statistical results will 
be based on the FAS.  


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9.4.1 
Analysis of Primary Endpoint  
9.4.1.1 Primary Analysis 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
For the primary efficacy endpoint of CR rate after induction therapy period, the two-sided 
90% exact confidence interval (CI) by Clopper-Pearson method will be calculated for 
70 subjects who took at least one dose of ASP2215 and had at least one post-baseline bone 
marrow assessment. The lower limit of the CI will be used to compare with the benchmark of 
CR rate of 55%. Out of 70 evaluable subjects, at least 46 subjects who achieve CR after 
induction is necessary to exclude 55% based on the exact 90% CI of CR rate as summarized 
in Table 20.  
Table 20 
Observed CR with Exact 90% CI (N=70 in phase 2 part) 
Observed CR (n and %) 
Exact 90% CI 
56 (80.0%) 
(70.5%, 87.5%) 
49 (70.0%) 
(59.7%, 78.9%) 
48 (68.6%) 
(58.3%, 77.7%) 
47 (67.1%) 
(56.8%, 76.4%) 
46 (65.7%) 
(55.3%, 75.1%) 
45 (64.3%) 
(53.8%, 73.8%) 
 
9.4.1.2 Subgroup Analysis 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Subgroup analysis will be conducted using the FAS. Subgroups are defined on the basis of 
the categorized variables such as sex, age group, country and FLT3 mutation status. 
9.4.2 
Analysis of Secondary Endpoints  
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
The statistical analyses on secondary efficacy endpoints include the following descriptive 
analyses for ASP2215 in combination with induction and consolidation therapy followed by 
maintenance therapy: 


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● 
Kaplan-Meier method for time-to-event endpoints including OS, EFS, RFS, duration of 
CR, CRh, CR/CRh, CRc and response. 
● 
The two-sided 95% exact confidence interval of the binary endpoints including CR rate, 
CRh rate, CR/CRh rate, and CRc rate. 
For each of the secondary responder endpoints, analyses are conducted after each treatment 
therapy. 
9.4.3 
Analysis of Exploratory Endpoints  
[Phase 1 part] 
The statistical analyses on exploratory endpoints include the following descriptive analyses 
for ASP2215 in combination with induction and consolidation therapy followed by 
maintenance therapy: 
● 
Kaplan-Meier method for time-to-event endpoints duration of response, CR and CRc. 
● 
The 2-sided 95% exact confidence interval of the binary endpoints CR rate, CRp rate, 
CRi rate, PR rate, CRc rate and response rate. 
[Phase 2 part] 
The statistical analyses on exploratory endpoints include the following descriptive analyses 
for ASP2215 in combination with induction and consolidation therapy followed by 
maintenance therapy: 
● 
Kaplan-Meier method for time-to-event endpoints including Cumulative incidence of 
relapse (CIR) after CR1, Cumulative incidence of death (CID) after CR1, and time to 
hematopoietic recovery after each treatment cycle. 
● 
The two-sided 95% exact confidence interval of the binary endpoints including 
transplantation rate, MRD, MRD-negative CR rate and overall MRD-negative CR rate. 
Transplantation rate and MRD is analyzed after each treatment therapy. MRD-negative 
CR rate is analyzed after induction therapy period. Overall MRD-negative CR rate is 
analyzed at any treatment period. 
Exploratory biomarker analysis of MRD will be performed using MAS. 
9.5 
Analysis of Safety 
The analyses in Section 9.5.1 will be performed in the DDAS, and the analyses in 
Sections 9.5.2 to 9.5.6 will be performed in the SAF. Analyses will be basically performed 
for Phase 1 part and Phase 2 part. Some analyses that do not depend on the measurement time 
point such as the summary of adverse events will be performed for Phase 1/Phase 2 part 
totally. 
9.5.1 
Occurrence of DLTs 
● 
The posterior mean of DLT incidence will be estimated using Bayesian-CRM. 
● 
The occurrence of DLTs will be summarized by frequency. 


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9.5.2 
Adverse Events  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
graded using NCI-CTCAE. A treatment-emergent adverse event (TEAE) is defined as an AE 
observed after starting administration of the study drug and within 30 days (for phase 1 part, 
28 days) after the last administration of study drug. A drug-related TEAE is defined as any 
TEAE with a causal relationship assessed as YES by the investigator. 
The number and percentage of subjects with TEAEs, drug-related TEAEs, serious TEAEs, 
drug-related serious TEAEs, TEAEs leading to withdrawal of treatment and drug-related 
TEAEs leading to withdrawal of treatment will be summarized by System Organ Class 
(SOC), Preferred Term (PT). The number and percentage of TEAEs by severity will also be 
summarized.  
9.5.3 
Laboratory Assessments  
● 
For continuous variables, summary statistics will be calculated using measured values by 
measurement time point. 
● 
For continuous variables, a case plot of measured values will be prepared. 
● 
The discrete variables will be summarized by frequency by measurement time point. 
9.5.4 
Vital Signs  
● 
For each parameter, summary statistics of the measured values will be calculated by 
measurement time point. 
● 
For each parameter, a case plot of measured values will be prepared. 
9.5.5 
12-lead Electrocardiogram 
The result of assessment will be summarized by frequency for each measurement time point. 
9.5.6 
Body Weight 
Summary statistics of measured values will be calculated for each measurement time point. 
9.6 
Analysis of Pharmacokinetics 
In the PKAS, pharmacokinetic parameters and summary statistics will be calculated using the 
plasma drug concentration measurements. If any measured values are BQL, their drug 
concentration will be handled as 0 (zero). Details of the analytical method including the 
figures and tables to be prepared in the pharmacokinetic analysis will be described in the 
pharmacokinetic analysis plan. 
9.6.1 
Estimation of Pharmacokinetic Parameters  
The following pharmacokinetic parameters will be calculated using the plasma drug 
concentrations: 
[Phase 1 part] 
● 
ASP2215: Cmax, tmax, AUC24, CL/F, AUClast, t1/2, Vz/F, and Ctrough 
● 
Cytarabine: Ctrough 


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[Phase 2 part] 
Not applicable. 
9.6.2 
Statistical Analysis of Pharmacokinetic Parameters  
Calculation of Summary Statistics: 
The number of subjects (N), arithmetic mean (Mean), standard deviation (SD), coefficient of 
variation (CV), minimum (Min), median (Median), maximum (Max), and geometric mean 
(GM) will be calculated for the plasma drug concentrations and the pharmacokinetic 
parameters calculated in Section 7.4 by dosage and assessment time point. 
9.7 
Analysis of Pharmacodynamics | Immunogenicity 
[Phase 1 part] 
The calculated amount of phosphorylated protein relative to total protein for each sampling 
time point for FLT3 and AXL will be obtained, and the rate of variability from the pre-dose 
value on Day 1 during the induction period will be calculated. Whenever possible, the 
relationship between the rate of variability and the pharmacokinetic parameters should be 
investigated. 
[Phase 2 part] 
Not applicable. 
9.8 
Other Analyses 
9.8.1 
Analysis of Exploratory Biomarker(s) 
The presence/absence of the following FLT3 mutations will be summarized by frequency. 
● 
FLT3-ITD mutation 
● 
FLT3 point mutation (D835, I836) 
9.8.2 
Retrospective Pharmacogenomic Study 
The content of analysis for the retrospective pharmacogenomic investigation has not been 
determined at this point. An exploratory investigation to determine whether there is a 
relationship between the results of genetic analysis and the results of this trial (clinical 
information; for example, drug reaction, toxicity, survival rate, pharmacokinetics, etc.) may 
be conducted in the future. The sponsor will begin the study once the specific content of the 
investigation has been determined, at which point the sponsor will prepare the study plan, the 
appropriateness of conducting the study will be assessed from ethical and scientific 
viewpoints by the sponsor’s IEC, and approval will be obtained prior to the study. The results 
of this study will not be included in the clinical study report; a separate report will be 
prepared instead. 


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9.9 
Major Protocol Deviations 
Major protocol deviations as defined in Section 10.3 will be summarized for all subjects who 
received study drug by study site. 
Major protocol deviation data will be listed by study site and subject. 
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. 
9.10 
Interim Analysis (and Early Discontinuation of the Study) 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Not applicable. 
9.11 
Additional Conventions 
The handling of missing data, outliers, and visit windows in the final analysis will be decided 
before the data hard lock, as necessary, by referring to the opinions and advice from medical 
experts and statistical advisors. For standards for handling the visit windows, refer to the 
acceptable time ranges described in Section 12.9. If any subjects or data are excluded from 
analysis, they should be included in lists but excluded from summaries such as summary 
statistics.  
If the start and stop dates of AEs and concomitant medications are incomplete, imputed dates 
will be used to determine whether an AE is/is not treatment emergent or to allocate a 
concomitant medication to the study period it was taken. 
See the SAP for details of the definition for analysis windows to be used for analyses by visit. 
Study sites that do not enroll at least 1 subject will be pooled for analyses by study site. The 
pooling decisions will be made and documented prior to study hard lock. 
10 
OPERATIONAL CONSIDERATIONS 
10.1 
Procedure for Clinical Study Quality Control 
10.1.1 Data Collection 
The investigator or site designee will enter data using an Electronic Data Capture (EDC) 
system. The investigator is responsible for ensuring that all data in the eCRFs and queries are 
accurate and complete. The source documents should be appropriately maintained by the site. 
For screening failures, the minimum data (the demographic data, date of signing the ICF, 
inclusion and exclusion criteria, AEs up to the time of screen failure and reason for screen 
failure) will be collected in the SFL. This information can be entered into the study database. 


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The Data Science department of API will obtain the test results from the following 
organizations in the form of an electronic file. 
[Phase 1 part] 
● 
Assessments of QT interval and other intervals: Central ECG laboratory 
● 
Pharmacodynamic assessments: Pharmacodynamics laboratory 
● 
FLT3 mutation test: FLT3 mutation testing laboratory 
● 
Plasma drug concentration assessments: Drug concentration laboratory 
[Phase 2 part] 
● 
Assessments of QT interval and other intervals: Central ECG laboratory 
● 
FLT3 mutation test: FLT3 mutation testing laboratory 
● 
Plasma drug concentration assessments: Drug concentration laboratory 
● 
Assessment of peripheral blood, urine, bone marrow aspirate/biopsy: Central laboratories 
● 
Registration information: Interactive Response Technology (IRT) 
10.1.2 Specification of Source Documents 
Source documents must be available at the site to document the existence of study subjects 
and substantiate the integrity of study data collected. Source documents must include the 
original documents relating to the study, as well as the medical treatment and medical history 
of each subject. 
In this study, the following study-related records will be used as source documents, and these 
records will contain the source information (source data) entered into the eCRFs. 
● 
Medical record 
● 
Records attached to the medical record 
● 
Subject registration record 
● 
Participation in study and signed and dated informed consent forms 
● 
Demographic data (birth date, sex, race, height, etc.) 
● 
Results of relevant examinations (ECG chart, X-ray films, and photographs) 
● 
Laboratory test slip  
● 
Detailed records of dispensing and return of study drug such as a study drug storage 
management table, and dispensing of concomitant medications 
For the following data, the data entered into the eCRF will be considered the source 
document. However, if they are described in the medical record or records that are attached 
or stored together, or can be determined from the source document, data described in the 
source document will be used as source data. 
● 
Time of vital signs measurements 
● 
Blood sampling time, performing blood sampling 
● 
Route of administration of prior and concomitant medications, administration periods 
● 
Treatment duration of prior and concomitant medications 
● 
Date, reason, and details of discontinuation 


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● 
Severity and seriousness, assessment of causal relationship with the study drug and with 
the induction or consolidation therapy including the study drug, reason for assessment, 
measures taken, and the outcome of AEs 
● 
Time, measured value, and contents of the diagnosis and assessment of ECG 
measurement 
● 
Comments in the eCRF 
10.2 
Demographics and Baseline Characteristics 
10.2.1 Demographics 
The following demographics will be confirmed at screening and entered into the eCRF. 
● 
Date of informed consent 
● 
Date of birth 
● 
Sex 
● 
Race 
● 
Height 
● 
Target disease information  
● 
Medical history  
● 
ECOG Performance Status  
● 
Chest X-ray or chest CT (if performed) 
● 
ECHO or MUGA (if performed) 
● 
Pregnancy test (for WOCBP) 
10.2.2 Medical History and Concurrent Diseases 
Medical history is any disease from which the subject has recovered before the start of study 
drug administration. 
The diagnosis and the duration of circulatory disease, hematologic disease, and malignant 
tumors (excluding AML, which is the target disease of this study) will be investigated and 
entered into the eCRF. 
Any medical conditions from which the subject has not recovered before the start of study 
drug administration should also be collected as concurrent diseases in the eCRF. 
The following disease related events if present at baseline (ongoing at the time of Informed 
Consent) should be reported on the Medical History eCRF as ongoing and with the highest 
grade: 
- 
Leukocytosis / Elevated white blood cells (WBC) 
- 
Leucopenia / Decreased WBC 
- 
Neutropenia / Decreased ANC 
- 
Anemia / Low RBC / Low hemoglobin 
- 
Thrombocytopenia / Decreased platelets 


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10.2.3 Diagnosis of the Target Disease, Severity and Duration of Disease  
The diagnosis and findings of AML, which is the target disease of this study, will be 
confirmed at screening, and the following items will be entered into the eCRF. 
● 
Date of diagnosis 
● 
Bone marrow findings (FAB classification, WHO classification, classification of 
prognosis) 
● 
FLT3 mutation 
10.3 
Major Protocol Deviations 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. All deviations from the protocol are to be 
recorded. A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol. Protocol waivers are strictly prohibited. 
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 
well-being 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 subjects.  
A major protocol deviation is 1 that may potentially impact the completeness, accuracy or 
reliability of data contributing to the primary endpoint or affect the rights, safety or well-
being of a subject. Major protocol deviations will have additional reporting requirements. 
When a major 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.  
The major protocol deviation criteria that will be summarized at the end of the study are as 
follows: 
● 
PD1 - Entered into the study even though the subject 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 investigator will also assure that deviations meeting IRB/IEC and appropriate regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and appropriate regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File. 


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10.4 
STUDY ORGANIZATION 
10.4.1 Efficacy and Safety Evaluation Committee 
[Phase 1 part] 
The Efficacy and Safety Evaluation Committee will be comprised of members of a third 
party who are not directly involved in the clinical study. The committee will be responsible 
for evaluating safety issues submitted by the sponsor in accordance with the SOP primarily 
from the viewpoint of the subjects. In the case of an event that poses a safety issue, the 
committee will discuss and recommend to the sponsor whether to continue, modify, or stop 
the trial. 
[Phase 2 part] 
Not applicable. 
10.4.2 Other Study Organization 
Please refer to the Attachment. 
10.5 
Registration of Subjects  
[Phase 1 part] 
The investigator will confirm each subject’s eligibility to participate in this study at 
screening. Once the subject’s eligibility is confirmed, the investigator will enter the necessary 
information into the subject registration form and inform the sponsor. Administration of the 
study drug will start within 7 days of registration. 
Similarly, the investigator will enter the necessary information into the subject registration 
form for screen failures and inform the sponsor. 
The registration procedure will be specified separately. 
[Phase 2 part] 
The investigator will confirm each subject’s eligibility to participate in this study at 
screening. Pre-registration occurs when a subject meets all eligibility criteria except for 
Inclusion criteria #4, #14-c, and #14-d and is prepared for Day 1. Subjects must meet all 
criteria by the planned administration of ASP2215 on Day 8 in order to be registered and to 
continue the study. Confirmation of criteria and the process of registration by Day 8 by 
investigator should be documented. If the subject did not meet all criteria by planned 
administration of ASP2215 on Day 8, the subject should be considered as registration failure. 
For Inclusion criteria #14-c, and #14-d, the most recent value prior to registration should 
meet the criterion. 


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11 
REFERENCES 
American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 
2014. 
American Cancer Society. Key statistics for acute myeloid leukemia (AML). Revised 08 Jan 
2019. Available from:https://www.cancer.org/cancer/acute-myeloid-
leukemia/about/keystatistics.html. Accessed 14 Feb 2019. 
Ben-Batalla, I., Schultze, A., Wroblewski, M., Erdmann, R., Heuser, M., Waizenegger, J. S., 
Loges, S., et al. (2013). Axl, a prognostic and therapeutic target in acute myeloid 
leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. 
Blood, 122(14), 2443-2452. doi: 10.1182/blood-2013-03-491431 
Cheson, B. D., Bennett, J. M., Kopecky, K. J., Buchner, T., Willman, C. L., Estey, E. H., et 
al. Reporting Standards for Therapeutic Trials in Acute Myeloid, L. (2003). 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, 21(24), 4642-4649. doi: 
10.1200/JCO.2003.04.036 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an 
international expert panel. Blood. 2017;129:424-47. 
Foundation for Promotion of Cancer Research. Cancer Statistics in Japan:2013. 
Gale, R. E., Green, C., Allen, C., Mead, A. J., Burnett, A. K., Hills, R. K., et al. Medical 
Research Council Adult Leukaemia Working, P. (2008). 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, 111(5), 
2776-2784. doi: 10.1182/blood-2007-08-109090 
Hong, C. C., Lay, J. D., Huang, J. S., Cheng, A. L., Tang, J. L., Lin, M. T., et al. Chuang, S. 
E. (2008). Receptor tyrosine kinase AXL is induced by chemotherapy drugs and 
overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer 
Lett, 268(2), 314-324. doi: 10.1016/j.canlet.2008.04.017 
Kantar Health. Treatment architecture: Japan acute myeloid leukemia. CancerMPact® Japan. 
2017. 
Levis, M. J., Perl, A. E., Altman, J. K., Gocke, C. D., Bahceci, E., Hill, J., et al. (2018). A 
next-generation sequencing-based assay for minimal residual disease assessment in 
AML patients with FLT3-ITD mutations. Blood Adv, 2(8), 825-831. doi: 
10.1182/bloodadvances.2018015925 
Moreno, I., Martin, G., Bolufer, P., Barragan, E., Rueda, E., Roman, J., et al. (2003). 
Incidence and prognostic value of FLT3 internal tandem duplication and D835 
mutations in acute myeloid leukemia. Haematologica, 88(1), 19-24.  
Morita, S., Thall, P. F., & Muller, P. (2008). Determining the effective sample size of a 
parametric prior. Biometrics, 64(2), 595-602. doi: 10.1111/j.1541-0420.2007.00888.x 
Miyawaki S, et al. (Eds.). Therapeutic manual of leukemia (3rd ed.) (Japanese). Nankodo, 
Japan 2009; 27-41 
O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Arber, D. A., Attar, E., et al. 
(2012). NCCN Clinical Practice Guidelines Acute myeloid leukemia. J Natl Compr 
Canc Netw, 10(8), 984-1021.  


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Version 8.0 Incorporating Substantial Amendment 7 
O'Quigley, J., Pepe, M., & Fisher, L. (1990). Continual reassessment method: a practical 
design for phase 1 clinical trials in cancer. Biometrics, 46(1), 33-48.  
O'Quigley, J., & Shen, L. Z. (1996). Continual reassessment method: a likelihood approach. 
Biometrics, 52(2), 673-684.  
Park, I. K., Mishra, A., Chandler, J., Whitman, S. P., Marcucci, G., & Caligiuri, M. A. 
(2013). 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, 121(11), 2064-2073. doi: 10.1182/blood-2012-
07-444018 
Patel, J. P., Gonen, M., Figueroa, M. E., Fernandez, H., Sun, Z., Racevskis, J., et al. (2012). 
Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N 
Engl J Med, 366(12), 1079-1089. doi: 10.1056/NEJMoa1112304 
Sanada, M., Suzuki, T., Shih, L. Y., Otsu, M., Kato, M., Yamazaki, S., et al. (2009). Gain-of-
function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature, 
460(7257), 904-908. doi: 10.1038/nature08240 
Schlenk, R. F., & Döhner, K. (2009). Impact of new prognostic markers in treatment 
decisions in acute myeloid leukemia. Curr Opin Hematol, 16(2), 98-104. doi: 
10.1097/MOH.0b013e3283257adb 
Society, A. C. (2014). Cancer facts & figures 2014.: Atlanta. 
Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., et 
al. (2017). Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 
Mutation. N Engl J Med, 377(5), 454-464. doi: 10.1056/NEJMoa1614359 
Takeda, K., & Morita, S. (2015). Incorporating Historical Data in Bayesian Phase I Trial 
Design: The Caucasian-to-Asian Toxicity Tolerability Problem. Ther Innov Regul Sci, 
49(1), 93-99. doi: 10.1177/2168479014546333 
Tallman, M. S. (2005). New strategies for the treatment of acute myeloid leukemia including 
antibodies and other novel agents. Hematology Am Soc Hematol Educ Program, 143-
150. doi: 10.1182/asheducation-2005.1.143 
Temple, R. (2006). Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug 
Saf, 15(4), 241-243. doi: 10.1002/pds.1211 
Ueno Y, Kaneko N, Saito R, Kondoh Y, Shimada I, Mori M, et al. ASP2215, a novel 
FLT3/AXL inhibitor: Preclinical evaluation in combination with cytarabine and 
anthracycline in acute myeloid leukemia (AML). ASCO2014 #356 
Yamamoto, Y., Kiyoi, H., Nakano, Y., Suzuki, R., Kodera, Y., Miyawaki, S., et al. (2001). 
Activating mutation of D835 within the activation loop of FLT3 in human 
hematologic malignancies. Blood, 97(8), 2434-2439.  
Yanada, M., Matsuo, K., Suzuki, T., Kiyoi, H., & Naoe, T. (2005). Prognostic significance of 
FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute 
myeloid leukemia: a meta-analysis. Leukemia, 19(8), 1345-1349. doi: 
10.1038/sj.leu.2403838 


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12 
APPENDICES 
12.1 
Ethical, Regulatory and Study Oversight Considerations 
12.1.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
laws, regulations and guidelines governing study conduct and the ethical principles that have 
their origin in the Declaration of Helsinki.  
The pharmacogenomic study will be conducted in accordance with the “Ethical Guidelines 
for Human Genome and Genetic Analysis Research” (MECSST/MHLW/METI Notification 
No. 1 of 2004) and “Use of Pharmacogenomics in Clinical Trials of Medicinal Products” 
(PFSB Notification dated September 30, 2008) in addition to the above. 
12.1.2 Institutional Review Board/Independent Ethics Committee 
GCP requires that the protocol, any protocol amendments, investigator’s brochure, ICF 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 IRB/IEC. The IRB/IEC will 
review the ethical, scientific and medical appropriateness of the study before it is conducted. 
IRB/IEC approval of the protocol, ICF and subject information and/or advertising, as 
relevant, will be obtained prior to initiation of any study-specific procedures. 
Any substantial amendments to the protocol will require competent authority and IRB/IEC 
approval before implementation, except for changes necessary to eliminate an immediate 
hazard to subjects. 
The investigator will be responsible for the following: 
● 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies and procedures established by 
the IRB/IEC.  
● 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.  
● 
Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Regulation No. 536/2014 for 
studies (if applicable), and all other applicable local regulations. 
12.1.3 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 or competent authority approval 
or notification may be required. The changes will become effective only after the approval of 
the sponsor, investigator, IRB/IEC and appropriate regulatory authorities (if applicable).  
Amendments to this protocol must be signed by the sponsor and investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 


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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 ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor. An approved copy of the new ICF must also be forwarded to the sponsor. 
12.1.4 Informed Consent of Subjects 
12.1.4.1 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 (if applicable) and answer all questions regarding this 
study. Prior to any study-related screening procedures being performed on the subject, the 
ICF will be reviewed, signed (UNIQUE to JP Region: place a personal seal) and dated by 
the subject or his/her guardian or legal representative (if applicable), the person who 
administered the ICF and any other signatories according to local requirements. A copy of the 
signed (UNIQUE to JP Region: or sealed) 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 the ICF was signed prior to any study-related 
procedures and that the subject received a signed copy of the ICF. 
The signed ICFs will be retained by the investigator and made available (for review only) to 
the study monitor, auditor and appropriate regulatory authorities and other applicable 
individuals upon request. 
Prior to execution of the clinical study, the investigator should prepare the written informed 
consent form and other written information in collaboration with the sponsor and revise the 
information whenever necessary. The written informed consent form and any other written 
information should be submitted to the sponsor and be subject to prior approval by the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC).  
The investigator is responsible for explaining the nature and purpose of the study as well as 
other study-related matters to subjects, using the written information, and for obtaining their 
full understanding and written consent to participate in the study of their own free will. 
However, if the subject is underage, informed consent must also be obtained from the 
subject’s legal guardian besides the subject. 
The investigator or other responsible personnel should note the following when obtaining 
consent from subjects: 
● 
No subject may be subjected to undue influence, such as compulsory enrollment in a 
study. 
● 
The language and expression used in the written information should be as plain and 
understandable as possible. Subjects should be given the opportunity to ask questions 
and receive satisfactory answers to the inquiry, and should have adequate time to decide 
whether or not to participate in the study. Written information should not contain any 
language or contents that causes the subject to waive or appears to waive any legal 


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rights, or that releases/mitigates or appears to release/mitigate the study site, the 
investigator, study coordinators, or the sponsor from liability for negligence. 
[Phase 1 part] 
Informed consent for continuing ASP2215 treatment must be obtained before the start of 
study drug administration in the consolidation period. 
[Phase 2 part] 
No consent is required to at the beginning of consolidation therapy. 
12.1.4.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue participating in the study 
(e.g., report of serious adverse drug reaction). The communication must be documented 
in the subject’s medical records and whether the subject is willing to remain in the study 
or not must be confirmed and documented.  
2. The investigator must update the subject’s 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 re-consent subjects with the updated ICF even if 
relevant information was provided verbally. The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the ICF 
(UNIQUE to JP Region: place a personal seal). A copy of the signed (UNIQUE to JP 
Region: or sealed) 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 re-consent process. 
12.1.4.3 Subject Information and Consent for Retrospective Pharmacogenomic Study 
In addition to the informed consent for participation in the study, a written informed consent 
form must be obtained from subjects who also consent to the collection and storage of 
samples for retrospective pharmacogenomic study. The process of subject information and 
consent for the retrospective pharmacogenomic study should also follow Section 12.1.4.1. 
The informed consent for retrospective pharmacogenomic study can be obtained only from 
subjects who have consented to participate in this study. Subjects who have consented to the 
retrospective pharmacogenomic study may withdraw only their consent to the retrospective 
pharmacogenomic study without withdrawing their consent to participate in this study. The 
pharmacogenomic samples of subjects who withdraw their consent to retrospective 
pharmacogenomic study will be destroyed except in the case where the samples have already 
been irreversibly anonymized. 


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The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor upon request. 
12.1.5 Source Documents 
Source data must be available at the study site to document the existence of the 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 investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
archived, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electronic devices) as part of regulated study activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health 
records, protocol-related assessments, AE tracking, and/or drug accountability.  
Paper records from electronic systems used in place of electronic format must be certified 
copies. A certified copy must be an exact copy and must have all the same attributes and 
information as the original. Certified copies must include signature and date of the individual 
completing the certification. Certified copies must be a complete and chronological set of 
study records (including notes, attachments, and audit trail information, if applicable). All 
printed records must be kept in the subject file and be available for archiving.  
12.1.6 Record Retention 
The investigator will archive all study data (e.g., subject identification code list, source data 
CRFs and investigator's file) and relevant correspondence. These documents are to be kept on 
file for the appropriate term determined by local regulation. The sponsor will notify the study 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/investigational 
medicinal product dossier (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 subject’s 
medical records and/or study progress notes. 
[UNIQUE to JP Region] 
The records to be retained at the study sites are those 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 appropriate regulatory authorities. 


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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 (1) or (2) below, whichever comes later. 
1. 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). 
2. Until 3 years after discontinuation or termination of the study. 
The following are the major documents to be retained at the study site. 
1. Source documents (clinical data, documents and records for preparing the eCRF) 
hospital records, medical records, test records, memoranda, administration records, data 
recorded by automatic measuring instruments, reproductions or transcripts verified as 
precise copies, 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 study selected from those 
verified in other departments or hospitals.  
2. Study contracts, written ICFs, written information and other documents or their copies 
prepared by the study personnel. A letter of request for study (including a request for 
continuation/amendment), letter of request for review, notice of study contract, 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), curriculum vitae of investigators, list of 
signatures and print of seals (copy) and eCRF (copy), etc.  
3. The protocol, documents obtained from the IRB related to the adequacy of conducting 
the study by the head of the study sites (Article 32-1, MHW Ordinance No. 28), 
documents obtained from the IRB related to the adequacy of conducting a study whose 
period exceeds 1 year or the adequacy of continuously conducting the study from which 
information on adverse drug reactions is obtained, and other documents obtained. A 
finalized protocol (including revisions), finalized 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.), operational procedures for the IRB, the list of names of 
the IRB members, materials for IRB review (including continuous deliberation), IRB 
review records (including continuous deliberation) and the review result report of the 
IRB (including continuous deliberation), etc.  
4. Records of control for study drug and other duties related to the study. Procedure for 
controlling the study drug, drug inventory and accountability record, vouchers for the 
receipt and return of the study drug, and the prescriptions for concomitant medications 


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[Phase 1 part] 
(If applicable) The documents of the efficacy and safety evaluation committee (minutes and 
SOPs and others) and the judgment committee outside the study sites (minutes and SOPs and 
others) shall be retained by the sponsor. 
[Phase 2 part] 
Not applicable. 
12.1.7 Subject Confidentiality and Privacy 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the subject provides written 
consent or approval. Additional medical information may be given only after approval of the 
subject to the investigator 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 study without justifiable reasons. 
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to a subject’s privacy due to direct access to source 
documents, or from other sources, they may not disclose the content to third parties.  
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number 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 agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and privacy laws in the US. If the services will involve the collection 
or processing of personal data (as defined by applicable data protection legislation) within the 
European Economic Area (EEA), then the sponsor shall serve as the controller of such data, 
as defined by the EU Data Protection Directive (DPD), and investigator and/or third party 
shall act only under the instructions of the sponsor in regard to personal data. If the sponsor is 
not based in the EEA, the sponsor must appoint a third party to act as its local data protection 
representative or arrange for a co-controller established in the EU for data protection 
purposes in order to comply with the DPD. 
12.1.8 Arrangement for Use of Information and Publication of the Study 
Information concerning the test product, 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 


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information obtained during the 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 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 may be discussed in the study agreement. 
12.1.9 Insurance of Subjects and Others (UNIQUE to JP) 
If a subject suffers any study-related injury, the sponsor will compensate the subject 
appropriately according to the severity and duration of the damage. However, if the injury 
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: 
1. If a subject incurs an injury as a result of participation in the study, the study site should 
provide medical treatment and other necessary measures. The sponsor should be notified 
of the injury.  
2. 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 a 
compensation settlement. 
3. The sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the study contract. 
4. The sponsor shall make an arrangement for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above.  
12.1.10 Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final CSR that 
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 the coordinating 
investigator(s) or the principal investigator(s) will be selected from the participating 
investigators by the sponsor prior to database hard-lock. 
12.2 
Procedure for Study Quality Control 
12.2.1 Study Monitoring 
The sponsor or delegated CRO is responsible for monitoring the study to ensure that the 
rights, safety and well-being of subjects are protected, the study is properly conducted in 
adherence to the current protocol and GCP. The sponsor is responsible for assigning the 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  


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12.2.2 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 appropriate regulatory 
authorities. In these instances, they must provide all study-related records including source 
documents when they are requested by the sponsor monitors and auditors, the CRO, the 
IRB/IEC or appropriate regulatory authorities. The confidentiality of the subject’s identity 
shall be well protected consistent with local and national regulations when the source 
documents are subject to direct access. 
12.2.3 Data Management 
Data management will be coordinated by the Data Science department of the sponsor in 
accordance with the SOPs for data management. All study-specific processes and definitions 
will be documented by the data management team. eCRF completion will be described in the 
eCRF instructions. Coding of medical terms and medications will be performed using 
MedDRA and the WHO Drug Dictionary, respectively.  


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12.3 
Contraception Requirements 
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the schedule of assessments. Pregnancy 
test results must confirm that the subject is not pregnant. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS 
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile.  
Females in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal with 1 of the following (i.e., permanently sterile): 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
● 
Postmenopausal 
A postmenopausal state is defined as at least 12 months after last menstrual bleeding without 
an alternative medical cause.  
In case the last menstrual bleeding cannot be clearly determined, confirmation with more 
than 1 follicle-stimulating hormone (FSH) measurement of at least > 40 IU/L (or higher per 
local institutional guidelines) is required.  
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use 1 of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status by repeated FSH 
measurements before study enrollment. 
Documentation of any of these categories can come from the study site personnel’s review of 
the female subject’s medical records, medical examination or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time of 
signing the ICF and until the end of relevant systemic exposure, defined as 180 days after the 
final study drug administration.a 
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b: 
● 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 


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o Oral 
o Intravaginal 
o Transdermal 
● 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral 
o Injectable 
o Implantable 
● 
Other combined (estrogen- and progesterone-containing) methods 
o Vaginal ring 
o Injectable 
o Implantable 
o Intrauterine hormone-releasing system or intrauterine device 
o Bilateral tubal occlusion 
● 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
● 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subject. It is not 
necessary to use any other method of contraception when complete abstinence is elected. 
a Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
b Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL. 
Male subjects with female partners of childbearing potential are eligible for participation in 
the study if they agree to the following during treatment and until the end of relevant 
systemic exposure defined as 120 days after final drug administration.a 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator 
● 
Use a condom 
● 
Female partners of male subjects who have not undergone a vasectomy with the absence 
of sperm confirmed or a bilateral orchiectomy should consider use of effective methods 
of contraception 
a Local laws and regulations may require use of alternative and/or additional contraception 
methods. 


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12.4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
12.4.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject administered a study drug, and which 
does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of study drug 
whether or not considered related to the study drug. 
12.4.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g. hematology, biochemistry or urinalysis) or other 
safety assessment (e.g., vital signs, physical examination, ECGs or radiographic scans), 
including those that worsen from baseline, that is considered to be clinically significant in the 
medical and scientific judgment of the investigator and not related to underlying disease, is to 
be reported as an (S)AE. 
Any clinically significant abnormal laboratory finding or other abnormal safety assessment, 
which is associated with the underlying disease, does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE. 
12.4.1.2 Potential Cases of Drug-induced Liver Injury 
Refer to Section 12.6 for detailed instructions on drug induced liver injury. Abnormal values 
in AST and/or ALT concurrent or with abnormal elevations in TBL that meet the criteria 
outlined in Section 12.6, in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and are always to be 
considered important medical events and reported per Section 12.4.5. 
12.4.2 Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or sponsor, the event:  
● 
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 


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● 
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE)  
● 
Other medically important events (defined in paragraph below) 
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 one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
usually are 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.  
12.4.3 Criteria for Causal Relationship to Study Drug 
A medically qualified investigator is obligated to assess the relationship between study 
drug/concomitant chemotherapy and each occurrence of each (S)AE. This investigator will 
use medical judgment as well as the reference safety information to determine the 
relationship. The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
The investigator is requested to provide an explanation for the causality assessment for each 
(S)AE and must document in the medical notes that he/she has reviewed the (S)AE and has 
provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the study 
drug/concomitant chemotherapy and each (S)AE will be assessed by answering “yes” or “no” 
to the question “Do you consider that there is a reasonable possibility that the event may have 
been caused by the study drug/concomitant chemotherapy?” For this study, causality of with 
each study drug/concomitant chemotherapy (ASP2215, cytarabine, and idarubicin) should be 
determined and reported by investigator. 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the study drug/concomitant chemotherapy (rather 
than a relationship cannot be ruled out) or if there is evidence to reasonably deny a causal 
relationship: 
● 
Has the subject been administered study drug/concomitant chemotherapy?  
● 
Plausibility (i.e., could the event have been caused by the suspect drug? Consider 
biologic and/or pharmacologic mechanism, half-life, literature evidence, drug class, 
preclinical and study data, etc.) 
● 
Dechallenge/dose reduction/rechallenge:  
o Dechallenge: Did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment? 


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o Dose reduction: Did the (S)AE resolve or improve after reducing the dose of the 
suspect drug? 
o Rechallenge: Did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped?  
● 
Laboratory or other test results: a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the IP (e.g., based on values pre-, during and 
post-treatment) 
● 
Available alternative explanations independent of IP exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc., and strength of the 
alternative explanation  
● 
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible 
temporal relationship between exposure to the IP and (S)AE onset and/or resolution will 
be provided. Did the (S)AE occur in a reasonable temporal relationship to the 
administration of the IP? 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor contact personnel (Section 12.4.5). 
However, it is very important that the investigator always assesses causality for every event 
before the initial transmission of the SAE data to the Sponsor contact personnel 
(Section 12.4.5). With limited or insufficient information about the event to make an 
informed medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered. In such instance, the 
investigator is expected to obtain additional information regarding the event as soon as 
possible and to re-evaluate the causality upon receipt of additional information. The 
medically qualified investigator may revise his/her assessment of causality in light of new 
information regarding the SAE and shall send an SAE follow-up report and update the eCRF 
with the new information and updated causality assessment.  
AEs that fall under either “Possible” or “Probable” should be defined as “AEs whose 
relationship with the study drugs could not be ruled out.”  


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Table 21 
Criteria for Determining Causal Relationship with the Study Drug 
Causal relationship with IP 
Criteria for causal relationship 
Not related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship with 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 re-administration (rechallenge) or 
withdrawal (dechallenge). 
 
12.4.4 Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute-common terminology criteria for adverse event (NCI-CTCAE) guidelines 
version 4.0. The items that are not stipulated in the NCI-CTCAE version 4.0 will be assessed 
according to the criteria below and entered into the eCRF: 
Table 22 
Grading Scale Defining the Severity of an Adverse Event 
Grade 
Assessment Standard 
1 - Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
2 - Moderate 
Minimal local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL† 
3 - Severe 
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization indicated; disabling; limiting self-care ADL‡ 
4 - Life-threatening 
Life threatening consequences, urgent intervention indicated 
5 - Death 
Death related to AE 
ADL: activities of daily living; AE: adverse event 
†Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
‡Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications and 
not bedridden. 
12.4.5 Reporting Procedures for Serious Adverse Events 
[Non-Japanese clinical sites] 
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the Sponsor contact personnel by fax or 
email immediately (within 24 hours of awareness).  
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log). Signature confirms accuracy and completeness of the SAE data 


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as well as the investigator causality assessment including the explanation for the causality 
assessment. 
For contact details, see [Contact Details of Sponsor's Key Personnel]. Email the SAE/special 
situations worksheet to:  
Astellas Pharma Inc. – Japan 
Pharmacovigilance 
Email: safety-jp@astellas.com  
[UNIQUE to JP Region] 
In the case of a SAE, the investigator must report to the head of the study site and must 
contact the sponsor via the delegated CRO by fax or email immediately (within 24 hours of 
awareness).  
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the appropriate regulatory 
authorities to the sponsor via the delegated CRO by fax or email immediately (within 
24 hours of awareness) and to the head of the hospital.  
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE/special situations worksheet to: 
Sponsor Contact: 
Astellas Pharma Inc., Development, Japan-Asia Clinical Development 1 
Location: 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan 
TEL: 03- 3244-1097 
Sponsor Contact [Contract Research Organizer (CRO) Contact]: 
PPD-SNBL K.K., Global Clinical Development 
St Luke’s Tower 12F, 8-1 Akashi-cho, Chuo-ku, Tokyo, Japan 
TEL: 03-6821-0932 
FAX:03-6740-7912 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or their designee [Contact Details of Sponsor’s 
Key Personnel].  
Follow-up information for the event should be sent promptly (as soon as available, but no 
longer than within 7 days of the initial notification [UNIQUE to JP Region: within 2 days 
for the initial notification]). 
Full details of the SAE should be recorded on the medical records, SAE/special situation 
worksheet and on the eCRF. 
The following minimum information is required: 
● 
International study number/study number  
● 
Subject number, sex and age 


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● 
Date of report 
● 
Description of the SAE (event and seriousness criteria)  
● 
Causal relationship to the IP (including reason) 
● 
Drug provided (if any) 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 
regulatory requirements. The sponsor or sponsor's designee will submit expedited safety 
reports to competent authorities and concerned ethics committee 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/IEC within timelines set by regional 
regulations (e.g., EMA, FDA) where required. Documentation of the submission to and 
receipt by the IRB/ IEC of expedited safety reports should be retained by the study site. In the 
US, FDA expedited IND reporting guidelines will be followed. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the test 
product of all SUSARs, which require submission per local requirements. 
The investigators (UNIQUE to JP REGION: the heads of the study sites) should provide 
written documentation of IRB/IEC notification for each report to the sponsor. 
The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the subject. 
12.4.6 Reporting Procedures for Special Situations 
12.4.6.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 120 days from 
the discontinuation of dosing, the investigator is to report the information to the Sponsor 
contact personnel according to the timelines in Section 12.4.5 using the SAE worksheet as a 
special situation and in the eCRF.  
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period and report the 
information to the Sponsor contact personnel according to the timelines in Section 12.4.5 
using the Pregnancy form provided by the sponsor as a special situation.  
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. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
subject as an AE in the eCRF or SAE per Section 12.4.5. For (S)AEs experienced by a 
female partner of a male subject, (S)AEs are to be reported via the SAE worksheet.  


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Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below: 
● 
"Spontaneous abortion" includes miscarriage, abortion and missed abortion. 
● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the IP. 
● 
If an infant dies more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator. 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination or other 
means as appropriate. (S)AEs experienced by the newborn/infant should be reported via the 
pregnancy reporting form. Generally, follow up will be no longer than 6 to 8 weeks following 
the estimated delivery date. 
12.4.6.2 Medication Error, Overdose and “Off-label Use” 
If a medication error (defined as an unintended failure in the treatment process that leads to, 
or has the potential to lead to, harm to the subject), overdose or “off-label use” (i.e., use 
outside of what is stated in the protocol) is suspected, refer to Section 10.3. Any associated 
(S)AEs are to be reported in the eCRF. If the AE meets the definition of an SAE, the SAE is 
also to be reported as described in Section 12.4.5 together with the details of the medication 
error, overdose and/or “off-label use.” 
In the event of suspected ASP2215 overdose, the subject should receive supportive care and 
monitoring. The medical monitor/expert should be contacted as applicable. 
12.4.6.3 Misuse/Abuse 
Definition of misuse: Situations where the IP is/are intentionally and inappropriately used not 
in accordance with the intended use as defined in the protocol. 
Definition of abuse: Persistent or sporadic, intentional excessive use of medicinal products 
which is accompanied by harmful physical or psychological effects. 
If misuse or abuse of the IP is suspected, the investigator must forward the special situation 
worksheet to the Sponsor contact personnel (Section 12.4.5) by fax or email immediately 
(within 24 hours of awareness). Any associated (S)AEs are to be reported in the eCRF. If the 
AE meets the definition of an SAE, the SAE is also to be reported as described in 
Section 12.4.5 together with details of the misuse or abuse of the IP. 
12.4.6.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the subject) to the IP occurs, the investigator must forward 
the special situation worksheet to the Sponsor contact personnel (Section 12.4.5) by fax or 
email immediately (within 24 hours of awareness). Any associated (S)AEs occurring to the 


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individual associated with or resulting from the special situation are to be reported on the 
special situations worksheet. 
12.4.6.5 Suspected Drug-drug Interaction 
If a drug-drug interaction associated with the IP is suspected, the investigator must forward 
the special situation worksheet to the Sponsor contact personnel (Section 12.4.5) by fax or 
email immediately (within 24 hours of awareness). Any associated (S)AEs are to be reported 
in the eCRF. If the AE meets the definition of an SAE, the SAE is also to be reported as 
described in Section 12.4.5 together with details of the suspected drug-drug interaction. 
12.4.7 Monitoring of Common Serious Adverse Events 
The following is a list of SAEs commonly anticipated to occur in the study population 
independent of drug exposure that will be monitored by the Sponsor 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 (Section 12.4.5).  
SAEs associated with the primary disease (AML) 
Grade commonly 
seen in AML 
Hematologic AEs 
 
Anemia 
0–4 
Hypocellular marrow 
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 
Leukopenia 
0–4 
Infection AEs 
 
Bacterial infection (regardless of the organ or cause by specific bacteria) 
0–3 
Chills 
0–3 
Cough 
0–3 
Febrile neutropenia (without infection) 
0–4 
Pyrexia 
0–5 
Flu–like symptoms 
0–3 
Fungal infection (regardless of the organ or cause) 
0–3 
Mucositis 
0–4 
Periodontal disease 
0–3 
Pneumonia 
0–5 
Sepsis/bacteraemia (any cause) 
0–5 
Sinusitis 
0–4 
Pharyngeal pain 
0–3 
Table continued on next page 


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SAEs associated with the primary disease (AML) 
Grade commonly 
seen in AML 
Psychiatric and neurological AEs 
 
Anxiety 
0–2 
Cognitive disorder 
0–3 
Confusion 
0–5 
Depressed level of consciousness 
0–5 
Depression 
0–3 
Libido decreased 
0–2 
Meningism 
0–5 
Seizure 
0–5 
Somnolence 
0–5 
Syncope 
3 
Other AEs 
 
Activated partial thromboplastin time prolonged 
0–2 
Alanine aminotransferase increased 
0–2 
Alkaline phosphatase increased 
0–2 
Inappetence 
0–2 
Aspartate aminotransferase increased 
0–2 
Blood bilirubin increased 
0–2 
Bone and joint pain 
0–2 
Contusion 
0–2 
Hemorrhage 
0–5 
Diarrhea 
0–2 
Dyspnea 
0–5 
Fatigue 
0–3 
Flushing 
0–2 
Gamma–glutamyltransferase increased 
0–1 
Graft versus host disease (GVHD) acute and chronic 
0–2 
Gingiva hypertrophia 
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 attack 
0–2 
Tumor lysis syndrome 
3–5 
Vasculitis 
0–5 
Vomiting 
0–2 
Weight decreased 
0–2 
 


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12.5 
Special terms 
Table 23 
ECOG Performance Status 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
Common Toxicity Criteria, Version 2.0 Publication Date April 30, 1999 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf 
http://www.jcog.jp/doctor/tool/C_150_0050.pdf  
Table 24 
NYHA (New York Heart Association) Functional Classification 
Class I 
No limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
Class II 
Slight limitation of physical activity. Patient is asymptomatic at rest. 
Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Marked limitation of physical activity. Patient is asymptomatic at rest. 
Less than ordinary activity will lead to fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Inability to carry out any physical activity without discomfort. 
Symptoms of heart failure and anginal pain are present at rest. Any physical activity will 
aggravate these symptoms. 
 


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12.6 
Liver Safety Monitoring and Assessment 
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury during the course of the study. It should be noted that this section does not specify the 
End of Study analyses of liver enzymes. The end of study liver enzymes analyses will be 
described in the SAP. Any subject enrolled in a study with active drug therapy and reveals an 
increase of serum aminotransferases (AT) to > 3 × ULN or bilirubin > 2 × ULN should 
undergo detailed testing for liver enzymes (including at least ALP, ALT, AST and TBL). 
Testing should be repeated within 72 hours of notification of the test results. For studies for 
which a central laboratory is used, alerts will be generated by the central laboratory regarding 
moderate and severe liver abnormality to inform the investigator 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 is as 
shown below. 
Table 25 
Definition of Liver Abnormalities 
 
ALT or AST 
 
TBL 
Moderate 
> 3 × ULN 
or 
> 2 × ULN 
Severe 
> 3 × ULN 
and† 
> 2 × ULN 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal 
†Samples taken simultaneously or within maximum 24 hours. 
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. 
● 
ALT or AST > 3 × ULN and† and* TBL > 2 × ULN or international normalized 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%)  
† Samples taken simultaneously or within a maximum of 24 hours. 
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 clinical laboratory tests. The study site personnel are to complete 
the liver abnormality case report form (LA-CRF). Subjects with confirmed abnormal liver 
function testing should be followed as described below. 


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Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
subject is asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to IP 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 are to be recorded as “AEs” within the 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 AT 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 are to be entered in 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:  
○ 
Acute viral hepatitis (A, B, C, D, E or other infectious agents) 
○ 
Ultrasound or other imaging to assess biliary tract disease 
○ 
Other clinical laboratory tests, including INR and 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 Treatment Discontinuation 
In the absence of an explanation for increased liver function tests, such as viral hepatitis, 
preexisting or acute liver disease, or exposure to other agents associated with liver injury, the 
subject may be discontinued from study treatment. The investigator may determine that it is 
not in the subject’s best interest to continue study treatment. Discontinuation of study 
treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and† TBL > 2 × ULN or 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%)  
† Samples taken simultaneously or within a maximum of 24 hours. 


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In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
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% to 50% 
mortality (or transplant).  
The two “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in AT elevations > 3 × ULN (“2 × ULN elevations are too common in treated and 
untreated subjects to be discriminating”).  
2. Cases of increased total bilirubin (at least 2 × ULN) with concurrent AT elevations at 
least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
ALP) or Gilbert’s syndrome (Temple, 2006). 
FDA Guidance for Industry titled, “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo. 
2. Among subjects showing such AT elevations, often with ATs much greater than 3 × 
ULN, 1 or more also show elevation of serum TBL to > 2 × ULN, without initial findings 
of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 


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12.7 
List of Excluded Concomitant Medications 
For strong CYP3A inhibitors and strong CYP3A inducers, refer to the below link for details. 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 


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12.8 
Laboratory Assessments 
Table 26 
Laboratory Materials and Parameters (Phase 1) 
 
Collecting tube 
Parameters to be analyzed 
Hematology 
Blood: 
EDTA tube 
Erythrocytes (RBC) 
Reticulocytes 
Hemoglobin 
Hematocrit 
Leukocytes (WBC) 
Differential WBC (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Platelets 
MCV 
MCH 
MCHC 
Blast count 
Biochemistry 
Blood: 
Serum tube 
CK 
Triglyceride 
Total cholesterol 
Albumin 
A/G ratio 
ALP 
ALT 
AST 
BUN 
Serum creatinine 
Na 
Ca 
Cl 
Glucose 
LDH 
Mg 
P 
K 
Total bilirubin 
Total protein 
Thyroid function test 
Blood: 
Serum tube 
TSH 
FT4 
Coagulation test 
Blood: 
Na Citrate tube 
PT 
PT/INR 
APTT 
Fibrinogen (only at screening) 
D-Dimer (only at screening) 
Urinalysis 
Urine test strips 
Gravity 
pH 
Bilirubin 
Occult blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Protein 
Urobilinogen 
Table continued on next page 


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Collecting tube 
Parameters to be analyzed 
Pregnancy test 
Serum or urine sample: 
Serum tube or urine test strips 
hCG 
Bone marrow test 
Bone marrow fluid: 
Na heparin tube 
or tissue biopsy 
Blast count and cell count 
FLT3 mutation 
Bone marrow fluid: 
Tube containing heparin 
sodium, or 
Blood: 
Tube containing heparin sodium 
FLT3 mutation 
 
 
 


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[Phase 2 part] 
Laboratory tests will be performed according to the schedule of assessments and sent to a 
central laboratory for analysis. 
Table 27 
Laboratory Materials and Parameters (Phase 2) 
 
Collecting tube 
Parameters to be analyzed 
Hematology 
EDTA tube 
White Blood Cell Count 
White Blood Cell Differential 
Red Blood Cell Count 
Hemoglobin 
Hematocrit 
Mean Corpuscular Volume 
Platelet Count 
Mean Corpuscular Hemoglobin Concentration 
Mean Corpuscular Hemoglobin 
Blast count 
Biochemistry 
Serum tube 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Uric Acid 
Glucose 
Calcium 
Phosphate 
Magnesium 
Albumin 
Total Protein 
Alkaline Phosphatase 
Lactate Dehydrogenase 
Creatine Kinase 
Aldolase 
Triglycerides 
Total Cholesterol 
Phospholipid 
Globulin 
Liver Function Tests including: 
Total Bilirubin 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Thyroid function test 
Serum tube 
Thyroid Function Tests including TSH and Free T4 
Coagulation test 
Na Citrate tube 
INR (with PT if reported) 
aPTT 
Fibrinogen (only at screening) 
D-Dimer (only at screening) 
Table continued on next page 


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Collecting tube 
Parameters to be analyzed 
Urinalysis 
Urine test strips 
Color 
Appearance 
Specific Gravity 
pH 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
Protein 
Urobilinogen 
Pregnancy test 
Serum or urine sample: 
Serum tube or urine test 
strips 
hCG 
Bone marrow test 
Aspirate 3-mL EDTA 
(disease 
assessment/MRD) and a 
3-mL Heparin (FLT3 
status), 2 to 3 bedside 
smear slides and/or 
biopsy (or whole blood) 
Blast Count and Cell Counts 
Flow Cytometry for Blasts 
FLT3 Mutation Status 
Minimal Residual Disease (FLT3 allelic frequency) 
Future biomarkers (protein or genetic) related to 
ASP2215 and/or AML 
FLT3 mutation 
Bone marrow fluid: 
Tube containing heparin 
sodium, or 
Blood: 
Tube containing heparin 
sodium 
FLT3 mutation 
Pharmacokinetic 
2 mL blood into 
dipotassium EDTA 
tube, processed to 1 mL 
plasma in transfer tube 
Plasma ASP2215 concentration 
Pharmacogenomics 
(For subjects who 
provide separate 
PGx consent) 
3 mL into EDTA tube 
Buccal swab 
PGx Analyses to be determined. 
aPTT: activated partial thromboplastin time; FLT3: FMS-like tyrosine kinase; INR: international normalized 
ratio; PGx: pharmacogenomics; PT: prothrombin time; T4: thyroxine; THU: tetrahydrouridine; TSH: thyroid 
stimulating hormone. 
 
12.9 
Acceptable Range of Schedule of Assessments  
[Phase 1 part] 
The acceptable time ranges of the examinations, observations, etc., specified in the schedule 
are as follows. 
[Acceptable Time Ranges of Safety and Efficacy Tests] 
Laboratory Tests (Hematology, Biochemistry, Coagulation Test, Thyroid Function Test, 
Urinalysis): 


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Table 28 
Acceptable Time Ranges for Laboratory Tests 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 
1 day before dosing* 
* Before dosing if the 
screening and Day 1 
of Cycle 1 overlap. 
Treatment on Day 1 may 
be started on the day 
informed consent is 
obtained when the 
investigator or 
subinvestigator judges 
that immediate treatment 
is required due to rapid 
proliferative disease 
progression. In this case, 
among the test items 
specified in both 
screening and Day 1 of 
Cycle 1 are not required 
to be performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
Day 4 
Day 4 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
± 1 day  
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
Day 42 
Day 42 
Scheduled date 
+ 14 days 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
Day 4 
Day 4 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
– 1 day 
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
Table continued on next page 


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Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time 
range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
Cycle X Day 1 
Day 28 (X − 1) + 1 
Scheduled date 
± 3 days 
X = Cycle 2 and 
subsequent cycles 
End of treatment (for 
any period) or at the 
end of Cycle 26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date 
+ 7 days 
If the scheduled tests at 
discontinuation have 
been performed after the 
final study drug 
administration, the tests 
do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 
Table 29 
Acceptable Time Ranges for Vital Signs 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing –
1 day before dosing* 
* Before dosing if the 
screening and Day 1 
of Cycle 1 overlap. 
Treatment on Day 1 may 
be started on the day 
informed consent is 
obtained when the 
investigator or 
subinvestigator judges 
that immediate treatment 
is required due to rapid 
proliferative disease 
progression. In this case, 
among the test items 
specified in both 
screening and Day 1 of 
Cycle 1 are not required 
to be performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
± 1 day  
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
Day 42 
Day 42 
Scheduled date 
+ 14 days 
 
Table continued on next page 


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Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
− 1 day 
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time 
range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
Cycle X Day 1 
Day 28 (X − 1) + 1 
Scheduled date 
± 3 days 
X = Cycle 2 and 
subsequent cycles 
End of treatment (for 
any period) or at the 
end of Cycle 26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date 
+ 7 days 
If the scheduled tests at 
discontinuation have 
been performed after the 
final study drug 
administration, the tests 
do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 


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Table 30 
Acceptable Time Ranges for 12-lead ECG (Including assessment of QT 
interval) 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the 
screening and Day 1 of Cycle 
1 overlap. 
QT interval 
assessments will not 
be performed at the 
central ECG 
laboratory 
Day 1  
pre-dose 
Day 1 
Scheduled date, within 30 
minutes before dosing 
Performed prior to PK 
blood sampling 
Day 4  
pre-dose 
Day 4 
Scheduled date, within 
30 minutes before dosing 
Day 4  
4 hours post-dose 
Day 4 
Scheduled date, within 
± 30 minutes of the scheduled 
time 
Day 11  
pre-dose 
Day 11 
Scheduled date, within 30 
minutes before dosing 
Day 17  
pre-dose 
Day 17 
Scheduled date – 1 day, within 
30 minutes before dosing 
Day 17  
4 hours post-dose 
Day 17 
Scheduled date – 1 day, within 
± 30 minutes of the scheduled 
time 
Day 28  
Day 28 
Scheduled date ± 7 days 
Table continued on next page 


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Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle 
Start of treatment) 
Acceptable time range 
Remarks 
Day 1  
pre-dose 
Day 1 
Scheduled date, within 30 
minutes before dosing 
Performed prior to PK 
blood sampling 
Day 1  
4 hours post-dose 
Day 1 
Scheduled date, within 
± 30 minutes of the scheduled 
time 
Day 2  
pre-dose 
Day 2 
Scheduled date, within 30 
minutes before dosing 
Day 15  
 
Day 15 
 
Scheduled date − 1 day 
 
Performed prior to PK 
blood sampling. If 
performed on Day 14 
within the allowed 
visit window [−1] for 
Day 15, 12-lead ECG 
will be performed at 
pre-dose. 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
QT interval 
assessments will not 
be performed at the 
central ECG 
laboratory. If the 
scheduled tests at 
discontinuation have 
been performed after 
the final study drug 
administration, the 
tests do not have to be 
repeated even if they 
were performed before 
the date of judgment 
of discontinuation. 
 


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Table 31 
Acceptable Time Ranges for ECOG Performance Status 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the 
screening and Day 1 of Cycle 
1 overlap. 
Treatment on Day 1 
may be started on the 
day informed consent 
is obtained when the 
investigator or 
subinvestigator judges 
that immediate 
treatment is required 
due to rapid 
proliferative disease 
progression. In this 
case, among the test 
items specified in both 
screening and Day 1 of 
Cycle 1 are not 
required to be 
performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
Day 8 
Day 8 
Scheduled date  
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date  
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
If the scheduled tests at 
discontinuation have 
been performed after 
the final study drug 
administration, the 
tests do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 


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Table 32 
Acceptable Time Ranges for ECHO or MUGA 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the screening 
and Day 1 of Cycle 1 overlap. 
To be performed on 
patients with a history of 
congestive heart failure of 
NYHA class 3 or 4 
(however, not necessary to 
be repeated at screening if 
ECHO or MUGA 
performed within 3 months 
prior to enrollment showed 
LVEF of ≥ 45%). 
 
Table 33 
Acceptable Time Ranges for Chest X-Ray or Chest CT 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the screening 
and Day 1 of Cycle 1 overlap. 
 
 
Table 34 
Acceptable Time Ranges for Body Height/Weight 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of 
each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the screening 
and Day 1 of Cycle 1 overlap. 
Height is measured only at 
screening. 
 
Treatment on Day 1 may 
be started on the day 
informed consent is 
obtained when the 
investigator or 
subinvestigator judges that 
immediate treatment is 
required due to rapid 
proliferative disease 
progression. In this case, 
among the test items 
specified in both screening 
and Day 1 of Cycle 1 are 
not required to be 
performed twice. 
Day 1 
Day 1 
Before dosing on the scheduled 
date 
Same as above 
Table continued on next page 


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Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of 
each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 
Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of 
the maintenance 
period 
Scheduled date + 7 days 
If the scheduled tests 
at discontinuation 
have been performed 
after the final study 
drug administration, 
the tests do not have to 
be repeated even if 
they were performed 
before the date of 
judgment of 
discontinuation. 
 
Table 35 
Acceptable Time Ranges for Pregnancy Test 
Induction period 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day before 
dosing* 
* Before dosing if the screening and 
Day 1 of Cycle 1 overlap. 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of 
each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
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Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 
Day 1 
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of 
the maintenance 
period 
Scheduled date + 7 days 
If the scheduled tests at 
discontinuation have 
been performed after 
the final study drug 
administration, the 
tests do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 
Table 36 
Acceptable Time Ranges for Bone Marrow Tests 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the 
screening and Day 1 of Cycle 
1 overlap. 
Not necessary to repeat 
if the test was 
performed within 
28 days prior to study 
enrollment even before 
obtaining consent.  
Day 28 
Day 28 
Scheduled date ± 7 days 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date – 7 days 
Performed only at the 
start of Cycle 1 of 
consolidation period 
Table continued on next page 


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Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date – 7 days 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
If the scheduled tests at 
discontinuation have 
been performed after 
the final study drug 
administration, the 
tests do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 
Table 37 
Acceptable Time Ranges for Blood Sampling for PK Analysis of ASP2215 
and Cytarabine 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1 
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
pre-dose 
Day 1 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
cytarabine 
Cycle 1 Day 3 
pre-dose 
Day 3 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
cytarabine 
Cycle 1 Day 4 
pre-dose 
Day 4 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215 
Cycle 1 Day 4 
1 hour post-dose 
Day 4 
Scheduled date, scheduled 
time ± 10 minutes 
Cycle 1 Day 4 
2 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 10 minutes 
Cycle 1 Day 4 
4 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 4 
6 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 4 
10 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 4 
24 hours post-dose 
Day 5 
Scheduled date, scheduled 
time ± 60 minutes and prior to 
Day 5 dosing 
Cycle 1 Day 8 
pre-dose 
Day 8 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215 and 
cytarabine 
Cycle 1 Day 11 
pre-dose 
Day 11 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215 
Cycle 1 Day 17 
pre-dose 
Day 17 
Scheduled date − 1 day, within 
30 minutes before dosing 
Cycle 1 Day 28 
Day 28 
Scheduled date ± 7 days 
 


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Table 38 
Acceptable Time Ranges for FLT3 Mutation Test (Sampling) 
Induction period 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing* 
* Before dosing if the 
screening and Day 1 of Cycle 
1 overlap. 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date + 7 days 
Performed only for 
Cycle 1 of 
consolidation period 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
 
[Phase 2 part] 
The definitions for windows to be used by visit will be outlined in Table 7 (Schedule of 
Assessments [Phase 2 Part]). 


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12.10 Pharmacogenomic Analysis with Banked Sample (Optional)  
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring differences in a 
subject’s gene and/or expression of genes 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 clinical response, pharmacokinetics and/or toxicity/safety. 
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 the PGx sub-study. Subjects must provide 
written consent prior to providing any blood samples that may be used at a later time for PGx 
analysis. 
SAMPLE COLLECTION AND STORAGE 
Subjects who consent to participate in this sub-study will provide 4 to 6 mL sample of whole 
blood/buccal swab per Astellas’ instructions. Each sample will be identified by the unique 
subject number. Samples will be shipped to a designated banking CRO as directed by 
Astellas. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis if evidence suggests that genetic variants may be influencing the drug’s 
pharmacokinetics, efficacy and/or safety.  
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hard-lock. 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 unless otherwise specified by local regulation. 


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INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the study, if 
applicable. The results of the PGx 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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12.11 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 subject level during any crisis (e.g., natural disaster, pandemic).  
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study subjects 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 schedules of assessments [Table 6 and Table 7] unless the site 
principal investigator discusses the need with the Astellas medical monitor to implement the 
alternate measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the subject, 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 as described in [Section 7 Study 
Procedures and Assessments] due to a crisis. 
INFORMED CONSENT 
Subjects 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 subject to provide written consent 
prior to implementation, the principal investigator or designee will obtain oral agreement 
from the subject followed by written documentation as soon as feasible. A separate 
addendum to the study informed consent will be provided to document the subject’s consent 
of the changes. 
SUBJECT PROCEDURES ASSESSMENT 
Sites with subjects 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 subject 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 subject with respect to time and travel. 
● 
Subject(s) have temporarily relocated from the current study site to an alternate study site 
to avoid placing a burden on the subject with respect to travel. 


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● 
Subject(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. 
● 
Subject has risk factors for which traveling to the site poses an additional risk to the 
subject’s health and safety. 
Adherence to the original protocol as reflected in the schedules of assessments [Table 6 and 
Table 7] is expected, where plausible, in the case of a crisis. The alternate measures as noted 
in [Table 39] 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 study drug and maintaining critical safety and efficacy assessments 
for subjects in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a subject, the site 
should document in the subject’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). 
 


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Table 39 
Alternative Schedule of Assessments in Response to a Crisis [Phase 2 part] 
Assessments 
Alternate Approach(es) 
Treatment phase 
EOT/Pre-HSCT 
Follow-up 
(30-day and 
Long-term) 
Screening/Induction 
Consolidation 
Maintenance 
Informed consent 
Not applicable 
X 
 
 
 
 
Eligibility criteria 
Not applicable 
X 
 
 
 
 
Medical and disease 
history 
Not applicable 
X 
 
 
 
 
Vital Signs 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within the induction treatment 
period and consolidation treatment period. 
• For the remaining visits including maintenance 
phase, this exam can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
 
Height and Weight 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within the induction treatment 
period and consolidation treatment period. 
• For the remaining visits including maintenance 
phase, this exam can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
 
 
ECOG Performance 
Status 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within the induction treatment 
period and consolidation treatment period. 
• For the remaining visits including maintenance 
phase, this exam can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
 
Table continued on next page 


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Assessments 
Alternate Approach(es) 
Treatment phase 
EOT/Pre-HSCT 
Follow-up 
(30-day and 
Long-term) 
Screening/Induction 
Consolidation 
Maintenance 
Physical 
examination 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within the induction treatment 
period and consolidation treatment period. 
• For the remaining visits including maintenance 
phase, this exam can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
X 
Pregnancy test for 
WOCBP (serum) 
• No alternative approach during screening period 
and both cytarabine and idarubicin/HIDAC 
treatment period within consolidation treatment 
period. 
• For the maintenance phase, these exams can be 
performed at a local clinic per SOC and results 
can be submitted to PI for evaluation. 
X 
 
X 
 
 
Pregnancy test for 
WOCBP (urine) 
• No alternative approach during screening period 
and both cytarabine and idarubicin/HIDAC 
treatment period within consolidation treatment 
period. 
• For the maintenance phase, these exams can be 
performed at a local clinic per SOC and results 
can be submitted to PI for evaluation. 
X 
 
X 
 
 
Chest x-ray (or chest 
CT) 
No alternative approach 
X 
 
 
 
 
12-lead ECG 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within the induction treatment 
period and consolidation treatment period. 
• For the remaining visits including maintenance 
phase, this exam can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
 
Table continued on next page 


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Assessments 
Alternate Approach(es) 
Treatment phase 
EOT/Pre-HSCT 
Follow-up 
(30-day and 
Long-term) 
Screening/Induction 
Consolidation 
Maintenance 
Clinical laboratory 
tests (chemistry, 
hematology, 
coagulation, 
urinalysis) 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within induction treatment 
period and consolidation treatment period. 
• For the remaining visits including maintenance 
phase, these exams can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
X 
Thyroid function 
tests 
• No alternative approach during the screening 
period and both cytarabine and idarubicin/HIDAC 
treatment period within the consolidation 
treatment period. 
• For the maintenance phase, these exams can be 
performed at a local clinic per SOC and results 
can be submitted to PI for evaluation. 
X 
X 
X 
X 
 
MUGA or ECHO 
No alternative approach 
X 
 
 
 
 
PK Sample 
Collection 
No alternative approach 
X 
X 
 
 
 
PGx 
No alternative approach 
X 
 
 
 
 
FLT3 mutational 
status 
No alternative approach 
X 
 
 
 
 
Bone marrow 
aspirate/biopsy and 
MRD analysis 
• No alternative approach during the screening 
period and HIDAC treatment period within the 
consolidation treatment period. 
• For the remaining visits including maintenance 
phase, these exams can be performed at a local 
clinic per SOC and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
X 
AE/SAE assessment 
Remote/Virtual/Telemedicine Visits allowed for 
non-dosing visits. Please refer to protocol schedule 
of assessments. 
X 
X 
X 
X 
X 
Table continued on next page 


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Assessments 
Alternate Approach(es) 
Treatment phase 
EOT/Pre-HSCT 
Follow-up 
(30-day and 
Long-term) 
Screening/Induction 
Consolidation 
Maintenance 
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 
Subsequent anti-
leukemic 
treatments/outcomes 
Remote/Virtual/Telemedicine Visits allowed 
 
 
 
 
X 
Survival  
Remote/Virtual/Telemedicine Visits allowed 
 
 
 
 
X 
Cytarabine 
administration 
No alternative approach  
X 
X 
 
 
 
Idarubicin 
administration 
No alternative approach  
X 
 
 
 
 
ASP2215 
administration 
If necessary, ASP2215 could be delivered from the 
hospital to the patient 
X 
X 
X 
 
 
AE: adverse event; CT: computed tomography; ECG: electrocardiogram; ECHO: echocardiogram; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; HIDAC: high-dose 
cytarabine; HSCT: hematopoietic stem cell transplant; PGx: pharmacogenomic; MRD: minimal residual disease; MUGA: multigated acquisition; PI: principal investigator; 
PK: pharmacokinetic; SAE: serious adverse event; SOC: standard of care; WOCBP: woman of childbearing potential. 
 


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STUDY DRUG SUPPLY 
If any of the conditions outlined above in the Subjects Procedures Assessment are met, one or 
all of the following mitigating strategies will be employed, as needed, to ensure continuity of 
study drug supply to the subjects: 
● 
Increase stock of study drug on site to reduce number of shipments required, if site space 
will allow. 
● 
Direct-to-Subject shipments of study drug from the site to the subject’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 subject 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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12.12 List of Abbreviations and Definition of Key Study Terms 
Table 40 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AML 
Acute Myeloid Leukemia 
ALK 
Anaplastic lymphoma receptor tyrosine kinase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase (GPT) 
ANCOVA 
Analysis of Covariance 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase (GOT) 
AUC 
Area under the plasma concentration-time curve 
AUC24 
Area under plasma concentration-time curve from time 0 to 24 
AXL 
AXL receptor tyrosine kinase 
BCR-ABL 
Breakpoint cluster region-Abelson 
BCRP 
Breast cancer resistant protein 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
c-CBL 
Cbl proto-oncogene, E3 ubiquitin protein ligase 
CCSI 
Company Core Safety Information 
CI 
Confidence interval 
Cmax 
Maximum concentration 
Cl 
Chloride 
CL/F 
Oral clearance 
CR 
Complete remission 
CRc 
Composite complete remission (antitumor response criterion) 
CRi 
CR with incomplete hematologic recovery 
CRp 
CR with incomplete platelet recovery 
CRF 
Case Report Form 
CRM 
Continual Reassessment Method 
CRO 
Contract Research Organizer 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Plasma trough concentration 
CYP 
Cytochrome P450 
CV 
Coefficient of Variation 
DDAS 
Dose-Determining Analysis Set 
DIC 
Disseminated Intravascular Coagulation 
DILI 
Drug-induced Liver Injury 
DLT 
Dose-Limiting Toxicity 


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Abbreviations 
Description of abbreviations 
DPD 
Data Protection Directive 
ECG 
Electrocardiogram 
eCOA 
electronic Clinical Outcome Assessment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
ECHO 
Echocardiogram 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
eGFR 
estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
FLT3 
FMS-like tyrosine kinase-3, fms-related tyrosine kinase 3 
FLT3-ITD 
FLT3- Internal Tandem Duplication 
FT4 
Free T4 
GCP 
Good Clinical Practice 
GM 
Geometric mean 
GMP 
Good Manufacturing Practice 
GMR 
Geometric mean ratio 
GGT 
Gamma-Glutamyltransferase  
GVHD 
Graft versus host disease 
hERG 
Human ether-à-go-go related gene 
HDPE 
High density polyethylene 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-severely Toxic Dose 
HSA 
Human serum albumin 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IC50 
Half Maximal (50%) Inhibitory Concentration 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVR 
Interventional Radiology 
ISN 
International Study Number 
K 
Potassium 
LA-CRF 
Liver Abnormality Case Report Form 
LDH 
Lactate Dehydrogenase 
LTK 
Leukocyte receptor tyrosine kinase 
LVEF 
Left Ventricular Ejection Fraction 
MAS 
MRD Analysis Set 


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Abbreviations 
Description of abbreviations 
MATE 
Multidrug and toxin extrusion protein 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDS 
Myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MER 
c-mer proto-oncogene tyrosine kinase 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple Gate Acquisition Scan 
NASH 
Nonalcoholic Steatohepatitis 
NOAEL 
No Observed Adverse Effect Level 
NYHA 
New York Heart Association 
OATP 
Organic anion transporting polypeptide 
OCT 
Organic cation transporter 
PD 
Pharmacodynamic 
PDAS 
Pharmacodynamic Analysis Set 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic Analysis Set 
PPS 
Per Protocol Set 
PR 
Partial Remission 
PS 
Performance Status 
PT 
Preferred term 
PT 
Prothrombin time 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell 
RED 
Recommended Expansion Dose 
RET 
ret proto-oncogene tyrosine kinase 
ROS 
c-ros oncogene 1, receptor tyrosine kinase 
RSI 
Reference Safety Information 
(S)AE 
Serious Adverse Event or Adverse Event 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SDV 
Source Data Verification 
SFL 
Screening Failure Log 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 


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Abbreviations 
Description of abbreviations 
STD10 
Severely Toxic Dose in 10% of the Animals 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t½ 
terminal elimination half-life 
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent adverse event 
tmax 
time of maximum concentration  
TPN 
Total Parenteral Nutrition 
TRKA 
Neurotrophic tyrosine kinase, receptor, type 1 
TSH 
Thyroid Stimulating Hormone 
QT 
QT interval 
QTc 
QT interval corrected 
t1/2 
Apparent terminal elimination half-life 
tmax 
Time to attain Cmax 
ULN 
Upper Limit of Normal 
Vz/F 
Apparent Volume of Distribution During the Terminal Elimination Phase 
after Oral Dosing 
WBC 
White Blood Cell 
WOCBP 
Woman of childbearing potential 


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Definition of Key Study Terms 
Terms 
Definition of Terms 
Baseline 
Assessments of subjects as they enter a study before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
Note: Not all endpoints are themselves assessments since certain endpoints 
might apply to populations or emerge from analysis of results. That is, 
endpoints might be facts about assessments (e.g., prolongation of survival). 
Enroll 
To register or enter a subject into a study. Note: Once a subject has received 
the IP or placebo, the protocol applies to the subject.  
Intervention 
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study (e.g., health-
related quality of life, efficacy, safety and pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test product or comparative drug (sometimes without 
randomization) is given to a subject, and continues until the last assessment 
after completing administration of the test product 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 
A process of active consideration of potential subjects for enrollment in a 
study. 
Screen failure 
Potential subject who signed the ICF, but did not meet 1 or more criteria 
required for participation in the study and was not enrolled. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent form until just before the test product 
or comparative drug (sometimes without randomization) is given to a 
subject.  
Study period 
Period of time from the first study site initiation date to the last study 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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13 
ATTACHMENT 1 – SUBSTANTIAL AMENDMENT 7 
I.  The purpose of this amendment is: 
Substantial Changes 
1. Remove Interim Analysis 
DESCRIPTION OF CHANGE:  
The Phase 2 part interim analysis is removed from the protocol. 
 
RATIONALE: 
This revision is made to ensure consistency in the assessment of efficacy endpoints (e.g., 
response definitions) between ASP2215 studies in de novo acute myeloid leukemia (AML) 
patients who are eligible for intensive chemotherapy. Given the timing of the interim 
analysis and enrollment status, the sponsor decided to remove the planned interim analysis 
and perform the primary analysis with the revised response definitions based on the 
targeted enrollment of approximately 80 subjects in the Phase 2 part. There are no potential 
new safety signals or lack of efficacy for subjects who are in the ASP2215 studies; 
therefore, the removal of the interim analysis does not affect the safety of subjects. 
 
2. Update Definition of Complete Response (CR) 
DESCRIPTION OF CHANGE: 
The definition of CR is updated and ‘transfusion dependency’ is removed. Antitumor 
response is defined per modified Cheson criteria or modified European LeukemiaNet 
recommendations. 
 
RATIONALE: 
The Response definition for de novo AML population was aligned at the program level to 
avoid the differences between studies potentially leading to inconclusive interpretation. 
 
Nonsubstantial Changes 
1. Update Key Study Personnel 
DESCRIPTION OF CHANGE:  
Contact details for medical monitor/study physician and clinical research contact are 
updated. 
 
RATIONALE: 
Contact details of medical monitor/study physician and clinical research contact are 
updated based on changes to study personnel. 
 


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2. Update Study Period 
DESCRIPTION OF CHANGE: 
The planned study period is updated from 1Q 2022 to 4Q 2022. 
 
RATIONALE: 
This revision is made due to an extension of the study duration. 
 
3. Add Extramedullary Leukemia to Response Assessment 
DESCRIPTION OF CHANGE: 
In the Schedules of Assessments, extramedullary leukemia is added as part of the response 
assessment. 
 
RATIONALE: 
This revision is made for clarification 
 
4. Update Nonclinical Pharmacology and Toxicology 
DESCRIPTION OF CHANGE: 
Section 2.1.1.2, Safety Pharmacology and Toxicology section is updated. 
 
RATIONALE: 
This update is made based on the latest information made to the Investigator’s Brochure, 
Version 8.0. 
 
5. Provide Timing of Primary Analysis for Primary Endpoint 
DESCRIPTION OF CHANGE: 
Text is added to clarify when the primary analysis for the primary endpoint will be 
conducted. 
 
RATIONALE: 
This revision is made for clarification. 
 
6. Remove the Per Protocol Set (PPS) and Add MRD Analysis Set (MAS) 
DESCRIPTION OF CHANGE: 
PPS is removed and a MAS is added for analysis of the Phase 2 Part. 
 
RATIONALE: 
This revision is made for consistency with other 2215 studies. 
 


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7. Update Reporting Information for Serious Adverse Events (SAEs) 
DESCRIPTION OF CHANGE: 
The reporting information for SAEs is updated to clarify that SAEs must be reported to the 
sponsor via the delegated contract research organization. 
 
RATIONALE: 
This revision is made for clarification of the SAE reporting information. 
 
8. Add Appendix for Clinical Study Continuity 
DESCRIPTION OF CHANGE: 
A Clinical Study Continuity appendix is added to the protocol. This appendix contains 
procedures for continuity of care during a crisis. An alternative schedule of assessments is 
provided. 
 
RATIONALE: 
This appendix is added 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 
subject level during any crisis (e.g., natural disaster or pandemic). 
 
9. Update Study Monitoring 
DESCRIPTION OF CHANGE: 
The term ‘verifiable’ and related language is removed from the protocol. 
 
RATIONALE: 
Monitoring strategy is updated due to COVID-19 and the sponsor’s policy. 
 
10. Minor Administrative-type Changes 
DESCRIPTION OF CHANGE:  
Include minor administrative-type changes (e.g., typos, format, numbering AND 
consistency throughout the protocol). The term ‘investigational product’ is replaced with 
‘study drug’ and ‘concomitant chemotherapy.’ The word ‘drug’ is removed from 
‘concomitant chemotherapy drugs.’ The link to the FDA’s Drug Development and Drug 
Interactions | Table of Substrates, Inhibitors and Inducers is updated. Correct symbol errors 
in Table 7. A reference for Döhner et al, 2017 is added to the reference list. Duration of 
response is added to study objective sections. Definition of ‘Duration of Response’ is 
corrected (Section 7.1.3.5) and missing information for ‘Analysis of Exploratory 
Endpoints’ is added (Section 9.4.3). 
 
RATIONALE: 
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures. 


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II.  Amendment Summary of Changes: 
IIA. Substantial Changes 
1 Protocol Summary 
1.1 Synopsis, Interim Analysis 
WAS: 
[Phase 2 part] 
At the timing when 35 subjects (50%) in Phase 2 part are evaluable for the primary 
endpoint of CR rate after induction therapy period, the interim analysis for futility stopping 
of Phase 2 part will be conducted. Predictive probability that 46 or more subjects will 
achieve CR at the final analysis of 70 evaluable subjects will be calculated as futility 
criteria. When the predictive probability is less than 10%, further enrollment into Phase 2 
part may be stopped, taking into account other efficacy and safety results. 
 
IS AMENDED TO: 
[Phase 2 part] 
Not applicable At the timing when 35 subjects (50%) in Phase 2 part are evaluable for the 
primary endpoint of CR rate after induction therapy period, the interim analysis for futility 
stopping of Phase 2 part will be conducted. Predictive probability that 46 or more subjects 
will achieve CR at the final analysis of 70 evaluable subjects will be calculated as futility 
criteria. When the predictive probability is less than 10%, further enrollment into Phase 2 
part may be stopped, taking into account other efficacy and safety results. 
 
7 Study Procedures and Assessments 
7.1.2 Antitumor Response 
WAS: 
Antitumor response is defined by the following revised standard by Bruce D. Cheson 
(2003) and samples are evaluated at central laboratories [Cheson et al., 2003]. 
[Phase 2 part] 
Bone marrow aspiration and/or biopsy samples and hematology samples are evaluated 
centrally. If bone marrow samples were obtained for unscheduled visits, those samples 
along with hematology samples should be submitted for central assessment.  
Definitions 
Complete Remission (CR):  
CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a 
neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow 
blasts < 5%, not being dependent on red blood cell (RBC) and platelet transfusion. There 
must be no presence of Auer rods and moreover being free of extramedullary leukemia. 
The blast counts in peripheral blood must be ≤ 2%. 
Complete Remission with Incomplete Hematological Recovery (CRi): 


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CRi is defined as a condition that meets all of the CR criteria at the post-baseline visit, 
except for the unrecovered neutrophil count (< 1,000/mm3; whether or not having 
unrecovered platelet counts, or receiving RBC and platelet transfusion ). 
 
IS AMENDED TO: 
Antitumor response is defined per modified Cheson criteria by the following revised 
standard by Bruce D. Cheson (2003) or modified European LeukemiaNet (ELN) 
recommendations (2017) as outlined below and samples are evaluated at central 
laboratories [Döhner et al, 2017; Cheson et al., 2003]. 
[Phase 2 part] 
Bone marrow aspiration and/or biopsy samples and hematology samples are evaluated 
centrally. If bone marrow samples were obtained for unscheduled visits, those samples 
along with hematology samples should be submitted for central assessment. All local bone 
marrow assessments along with local hematology results should be collected in the 
eCRF. 
Definitions 
Complete Remission (CR):  
CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a 
neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow 
blasts < 5%, not being dependent on red blood cell (RBC) and platelet transfusion. There 
must be no evidence of Auer rods and no evidence of extramedullary leukemia 
presence of Auer rods and moreover being free of extramedullary leukemia. The blast 
counts in peripheral blood must be ≤ 2%. 
Complete Remission with Incomplete Hematological Recovery (CRi): 
CRi is defined as a condition that meets all of the CR criteria at the post-baseline visit, 
except for the unrecovered neutrophil count (< 1,000/mm3; whether or not having 
unrecovered platelet counts, or receiving RBC and platelet transfusion). 
Composite Complete Remission (CRc): 
To be classified as being in CRc at a post-baseline visit, a subject must either achieve 
CR, CRp or CRi at the visit. 
 
7 Study Procedures and Assessments 
7.1.2.1 Best Response 
WAS: 
Best response is defined as the best assessment (CR, CRh, CRp, CRi, or PR) obtained at 
each efficacy assessment time point after the start of treatment. 
 
IS AMENDED TO: 
Best response is defined as the best assessment (CR, CRh, CRp, CRi, or PR) obtained at 
each efficacy assessment time point after the start of treatment. 
 


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9 Statistical Methodology 
9.4 Analysis of Efficacy 
WAS: 
[Phase 1 part] 
The following classifications according to the Bruce D. Cheson standard (2003) will be 
summarized by frequency after each treatment period. 
[Phase 2 part] 
Efficacy analysis will be conducted on the FAS and PPS. The interpretation of statistical 
results will be based on the FAS. The PPS will be used to assess the robustness of 
statistical results based on the FAS. 
 
IS AMENDED TO: 
[Phase 1 part] 
The following endpoints will be summarized by classifications according to the Bruce D. 
Cheson standard (2003) or modified ELN recommendations (2017)will be summarized 
by frequency after each treatment period. 
[Phase 2 part] 
Efficacy analysis will be conducted on the FAS and PPS. The interpretation of statistical 
results will be based on the FAS. The PPS will be used to assess the robustness of 
statistical results based on the FAS. 
 
9 Statistical Methodology 
9.10 Interim Analysis (and Early Discontinuation of the Study) 
WAS: 
[Phase 2 part] 
At the timing when 35 subjects (50%) in Phase 2 part are evaluable for the primary 
endpoint of CR rate after induction therapy period, the interim analysis for futility stopping 
of Phase 2 part will be conducted. The interim analysis is based on Bayesian predictive 
probability approach. Binomial distribution is assumed to the number of responders among 
35 subjects at the interim analysis and Jeffreys prior is assigned to the prior distribution as 
follows: 
Y ∼Bin(35, p), 0 ≤𝑝≤1, 
p ∼Beta(0.5,0.5) 
Where Y is the number of responders at the interim analysis and p is the CR rate. 
Consequently, the posterior distribution of the CR rate follows a beta distribution 
p|y ∼Beta(0.5 + y, 0.5 + 35 −y). 
Thus, let X denote the number of responders after the interim analysis, the posterior 
predictive distribution of X given Y=y is a beta-binomial distribution as follows:  
Pr(x|y) = (35
𝑥) Beta (0.5 + y + x, 0.5 + 70 −y −x)
Beta (0.5 + y, 0.5 + 35 −y)
 


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The predictive probability is defined as the probability that 46 or more subjects will 
achieve CR at the final analysis of 70 evaluable subjects. Thus the predictive probability 
can be expressed as Pr(x + y ≥46|y). 
This will be calculated as futility criteria at the interim analysis. When the predictive 
probability is less than 10%, further enrollment into phase 2 part may be stopped, taking 
into account other efficacy and safety results. 
For the interim analysis, an Independent Data Monitoring Committee (IDMC) will not be 
organized. 
 
IS AMENDED TO: 
[Phase 2 part] 
Not applicable.At the timing when 35 subjects (50%) in Phase 2 part are evaluable for the 
primary endpoint of CR rate after induction therapy period, the interim analysis for futility 
stopping of Phase 2 part will be conducted. The interim analysis is based on Bayesian 
predictive probability approach. Binomial distribution is assumed to the number of 
responders among 35 subjects at the interim analysis and Jeffreys prior is assigned to the 
prior distribution as follows: 
Y ∼Bin(35, p), 0 ≤𝑝≤1, 
p ∼Beta(0.5,0.5) 
Where Y is the number of responders at the interim analysis and p is the CR rate. 
Consequently, the posterior distribution of the CR rate follows a beta distribution 
p|y ∼Beta(0.5 + y, 0.5 + 35 −y). 
Thus, let X denote the number of responders after the interim analysis, the posterior 
predictive distribution of X given Y=y is a beta binomial distribution as follows:  
Pr(x|y) = (35
𝑥) Beta (0.5 + y + x, 0.5 + 70 −y −x)
Beta (0.5 + y, 0.5 + 35 −y)
 
The predictive probability is defined as the probability that 46 or more subjects will 
achieve CR at the final analysis of 70 evaluable subjects. Thus the predictive probability 
can be expressed as Pr(x + y ≥46|y). 
This will be calculated as futility criteria at the interim analysis. When the predictive 
probability is less than 10%, further enrollment into phase 2 part may be stopped, taking 
into account other efficacy and safety results. 
For the interim analysis, an Independent Data Monitoring Committee (IDMC) will not be 
organized. 
 


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IIB. Nonsubstantial Changes 
Contact Details of Sponsor’s Key Personnel 
 
WAS: 
Medical Monitor/Study 
Physician 
 
 
 
ASTELLAS PHARMA GLOBAL DEVELOPMENT 
1 Astellas Way, N6-163, Northbrook, IL USA 60062 
 
 
 
Clinical Research Contact 
Pharmaceutical Product Development, LLC (PPD) 
 
 
 
 
 
 
 
IS AMENDED TO: 
Medical Monitor/Study 
Physician 
 
 
 
ASTELLAS PHARMA GLOBAL DEVELOPMENT 
1 Astellas Way, N6 163, Northbrook, IL USA 60062 
 
 
 
Clinical Research Contact 
Pharmaceutical Product Development, LLC (PPD) 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


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1 Protocol Summary 
1.1 Synopsis, Planned Study Period 
WAS: 
From August 2014 to 1Q 2022 (including long-term follow-up period). 
 
IS AMENDED TO: 
From August 2014 to 4Q1Q 2022 (including long-term follow-up period). 
 
1 Protocol Summary 
1.1 Synopsis, Study treatment period 
WAS: 
[Phase 1 part] 
[Phase 2 part] 
Consolidation therapy period: 
The same chemotherapy regimen is applied as the Phase 1 part. Omission of consolidation 
therapy due to HCST is allowed. Consolidation therapy may be conducted up to 4 cycles.  
 
Maintenance therapy period: 
The same therapy is applied as the Phase 1 part. Maintenance therapy may be conducted up 
to 26 cycles. 
 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, relapse and survival (cause and date of death). Duration 
of long-term follow-up is until 3 years after the last subject’s first treatment or completion 
of 30-day follow-up of the last subject, whichever is longer. 
 
IS AMENDED TO: 
[Phase 1 part] 
Follow-up observation period: 
After treatment discontinuation, subjects will have a 28-day follow-up visit for safety. 
 
[Phase 2 part] 
Consolidation therapy period: 
The same chemotherapy regimen is applied as the Phase 1 part. Subjects will receive oral 
ASP2215 once daily on 14 consecutive days from Day 1 through Day 14. The 
maximum number of days in 1 cycle for the consolidation therapy period is not 
defined. Omission of consolidation therapy due to HCST is allowed. Consolidation 
therapy may be conducted up to 4 cycles.  
 
Maintenance therapy period (28 days per cycle): 


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The same therapy is applied as the Phase 1 part. Maintenance therapy may be conducted up 
to 26 cycles. 
 
Long-term follow-up period: 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, relapse and survival (cause and date of death). During 
the long-term follow-up period, the subject will be followed for Duration of long term 
follow up is until 3 years after the last subject’s first treatment or completion of 30-day 
follow-up of the last subject, whichever is longer. 
 
1 Protocol Summary 
1.1 Synopsis, Investigational Products (Study drugs and concomitant drugs) 
WAS: 
Name and Use:  
[Phase 1 part] 
ASP2215 
study drug 
Cytarabine 
concomitant chemotherapy drug 
Idarubicin 
concomitant chemotherapy drug 
[Phase 2 part] 
ASP2215 
study drug 
AS3329381/Cytarabine 
study drug and/or concomitant 
chemotherapy drug (based on the local 
regulation) 
Idarubicin 
concomitant chemotherapy drug 
 
IS AMENDED TO: 
Name and Use:  
[Phase 1 part] 
ASP2215 
study drug 
Cytarabine 
concomitant chemotherapy drug 
Idarubicin 
concomitant chemotherapy drug 
[Phase 2 part] 
ASP2215 
study drug 
AS3329381/Cytarabine 
study drug and/or concomitant 
chemotherapy drug (based on the local 
regulation) 
Idarubicin 
concomitant chemotherapy drug 


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1 Protocol Summary 
1.1 Synopsis, Treatment Discontinuation Criteria 
WAS: 
Discontinuation Criteria from Post-Treatment Follow-up for Individual Subjects: 
• Subject declines further study participation (i.e., withdrawal of consent). 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
• Death. 
• The study meets the criteria to complete the long term follow-up (i.e., Duration of 
long-term follow-up is until 3 years after the last subject first treatment or completion 
of 30-day follow-up of the last subject, whichever is longer.) 
 
IS AMENDED TO: 
Discontinuation Criteria from Post-Treatment Follow-up for Individual Subjects: 
• Subject declines further study participation (i.e., withdrawal of consent). 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
• Death. 
[Only applies to Phase 2 part] 
• The study meets the criteria to complete the long-term follow-up (i.e., During the 
long-term follow-up period, the subject will be followed for Duration of long term 
follow up is until 3 years after the last subject’s first treatment or completion of 30-day 
follow-up of the last subject, whichever is longer.) 
 
1 Protocol Summary 
1.3 Schedule of Assessments, Table 7 [Phase 2 part], Induction Therapy 
WAS: 
Response Assessment 
xx Eligibility criteria laboratory tests can be confirmed by the local lab. The values used 
for eligibility evaluation should be entered in eCRF and the central sample at the same 
timing of local lab tests should be submitted. 
 
IS AMENDED TO: 
Response Assessment (including extramedullary leukemia) 
xx Eligibility criteria laboratory tests can be confirmed by the local lab. The values used 
for eligibility evaluation should be entered in eCRF and the central sample at the same 
timing of local lab tests should be submitted. Lab values prior to informed consent 


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may be collected in the eCRF in case the local bone marrow assessment result 
before. 
 
1 Protocol Summary 
1.3 Schedule of Assessments, Table 7 [Phase 2 part], Consolidation Therapy 
WAS: 
Assessments 
D1 
Response Assessment 
X 
Bone Marrow Aspiration/Biopsy pp, qq, bbb 
 
IS AMENDED TO: 
Assessments 
D1 
Response Assessment (including extramedullary 
leukemia)  
Xbbb 
Bone Marrow Aspiration/Biopsy pp, qq, bbb 
 
1 Protocol Summary 
1.3 Schedule of Assessments, Table 7 [Phase 2 part], Maintenance Therapy 
WAS: 
Assessments 
Cycle 1 
Day 1 
Cycle 1 
Day 15 
Cycle 2 
Day 1 
Cycle 2 
Day 15 
Cycle X 
Day 1 a 
Response Assessment 
X 
 
 
 
 
Bone Marrow Aspiration/Biopsy pp, qq 
X iii 
X jjj 
 
IS AMENDED TO: 
Assessments 
Cycle 1 
Day 1 
Cycle 1 
Day 15 
Cycle 2 
Day 1 
Cycle 2 
Day 15 
Cycle X 
Day 1 a 
Response Assessment (including 
extramedullary leukemia) 
X 
X iii 
X jjj 
Bone Marrow Aspiration/Biopsy pp, qq 
 
1 Protocol Summary 
1.3 Schedule of Assessments, Table 7 [Phase 2 part], End of Treatment 
WAS: 
Assessments 
Pre-HSCT Visit  
EOT Visit m 
30-Day 
Follow-Up 
mmm 
Long-term 
Follow-Up nnn 
Visit window 
 
+/- 7 days 
+/- 7 days 
Response Assessment 
X rrr 
 
X sss 
Bone Marrow Aspiration/Biopsy pp, qq 


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nnn Duration of long-term follow-up is until 3 years after the last subject first treatment or 
completion of 30-day follow-up of the last subject, whichever is longer. The first 
follow-up will be performed 3 months after the 30-day follow-up visit. On site visit 
assessment will be performed at the timing of relapse. 
rrr Does not need to be repeated if collected at a regularly scheduled visit within 7 days of 
the End of Treatment Visit. If bone marrow aspirate is unobtainable (e.g., dry tap), the 
whole blood sample will be used. 
 
IS AMENDED TO: 
Assessments 
Pre-HSCT Visit  
EOT Visit m 
30-Day 
Follow-Up 
mmm 
Long-term 
Follow-Up nnn 
Visit window 
 
+/  + 7 days 
+/- 7 days 
Response Assessment (including 
extramedullary leukemia) 
X rrr 
 
X sss 
Bone Marrow Aspiration/Biopsy pp, qq 
nnn Duration of During the long-term follow-up period, the subject will be followed for 
is until 3 years after the last subject’s first treatment or completion of 30-day follow-up 
of the last subject, whichever is longer. The first follow-up will be performed 3 months 
after the 30-day follow-up visit. On site visit assessment will be performed at the timing 
of relapse. 
rrr Does not need to be repeated if collected at a regularly scheduled visit within 7 days of 
the Pre-HSCT visit or End of Treatment Vvisit. If bone marrow aspirate is 
unobtainable (e.g., dry tap), the whole blood sample will be used. 
 
2 Introduction 
2.1.1.2 Safety Pharmacology and Toxicology 
WAS: 
In juvenile rats (dosing from postnatal day [PND] 4 to 42), no mortality was noted at 5 
mg/kg per day, but 1 animal was moribund sacrificed at 2.5 mg/kg per day. The cause of 
moribundity was considered to be deteriorated general conditions due to the unexpectedly 
high exposure. In the preliminary non-Good Laboratory Practice (GLP) dose range finding 
study (dosing from PND 4 to 21), gastrointestinal bleeding detected as abnormal stool 
color (dark red) was noted at 10 mg/kg per day and higher. Gastrointestinal bleeding was 
suggested to be a target organ at 10 mg/kg per day or higher as in adult rats in the 13-week 
dose study (2215-TX-0002). The minimum lethal dose level of 2.5 mg/kg per day in 
juvenile rats was lower than that in adult rats in the 13-week dose study (20 mg/kg per 
day). 
 
IS AMENDED TO: 
In juvenile rats (dosing from postnatal day [PND] 4 to 42), no mortality was noted at 5 
mg/kg per day, but 1 animal was moribund sacrificed at 2.5 mg/kg per day. The cause of 
moribundity was considered to be deteriorated general conditions due to the unexpectedly 


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high exposure. In the preliminary non-Good Laboratory Practice (GLP) dose range finding 
study (dosing from PND 4 to 21), gastrointestinal bleeding detected as abnormal stool 
color (dark red) was noted at 10 mg/kg per day and higher. Gastrointestinal tract was 
suggested to be a target organ of toxicity at doses of 10 mg/kg per day or higher in 
juvenile rats, as well as in adult rats Gastrointestinal bleeding was suggested to be a 
target organ at 10 mg/kg per day or higher as in adult rats in the 13-week dose study 
(2215-TX-0002). The minimum lethal dose level of 2.5 mg/kg per day in juvenile rats was 
lower than that in adult rats in the 13-week dose study (20 mg/kg per day). 
 
2 Introduction 
2.1.2 Summary of Key Safety Information for Investigational Product(s) 
WAS: 
2.1.2 
Summary of Key Safety Information for Investigational Product(s) 
 
IS AMENDED TO: 
2.1.2 
Summary of Key Safety Information for Study DrugInvestigational Product(s) 
 
1 Protocol Summary and 3 Study Objective(s) and Endpoint(s) 
1.1 Synopsis, Table 8 Study Objective(s) and Endpoints [Phase 1 part] 
WAS: 
Exploratory 
● 
Evaluate the efficacy of ASP2215 
concomitant with induction and 
consolidation chemotherapy 
● 
CR (Complete Remission) 
● 
CRp (CR with incomplete platelet 
recovery) 
● 
CRi (CR with incomplete 
hematologic recovery) 
● 
PR (Partial Remission) 
● 
CRc (Composite CR): CR + CRp + 
CRi 
● 
Overall response rate: CRc + PR 
 
IS AMENDED TO: 
Exploratory 
● 
Evaluate the efficacy of ASP2215 
concomitant with induction and 
consolidation chemotherapy 
● 
CR (Complete Remission) 
● 
CRp (CR with incomplete platelet 
recovery) 
● 
CRi (CR with incomplete 
hematologic recovery) 
● 
PR (Partial Remission) 
● 
CRc (Composite CR): CR + CRp + 
CRi 


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● 
Overall response rate: CRc + PR 
● 
Duration of response 
 
1 Protocol Summary and 3 Study Objective(s) and Endpoints  
1.1 Synopsis, Table 8 Study Objective(s) and Endpoints [Phase 2 part] 
WAS: 
● 
Evaluate the safety and efficacy of 
ASP2215 in combination with induction 
and consolidation therapy followed by 
maintenance therapy 
● 
Overall survival (OS) 
● 
Event free survival (EFS) 
● 
Relapse free survival (RFS) 
● 
CR rate after each treatment therapy 
● 
CR rate without MRD after each 
treatment therapy 
● 
Complete remission with partial 
hematological recovery (CRh) rate 
after each treatment therapy 
● 
CRc rate after each treatment 
therapy 
● 
Duration of CR, CRh, CR/CRh and 
CRc 
● 
Adverse events (AEs), safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
 
IS AMENDED TO: 
● 
Evaluate the safety and efficacy of 
ASP2215 in combination with induction 
and consolidation therapy followed by 
maintenance therapy 
● 
Overall survival (OS) 
● 
Event free survival (EFS) 
● 
Relapse free survival (RFS) 
● 
CR rate after each treatment therapy 
● 
CR rate without minimal residual 
disease (MRD) after each treatment 
therapy 
● 
Complete remission with partial 
hematological recovery (CRh) rate 
after each treatment therapy 
● 
Composite complete remission 
(CRc) rate after each treatment 
therapy 
● 
CR/CRh rate after each treatment 
therapy 
● 
Duration of CR, CRh, CR/CRh and 
CRc 


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● 
Duration of response 
● 
Adverse events (AEs), safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
 
1 Protocol Summary and 4 Study Design and Dose Rationale 
1.1 Synopsis, Study Design Overview, 4.1 Study Design 
WAS: 
[Phase 2 part] 
After achieving of objectives of the Phase 1 part, the Phase 2 part can be initiated. Subjects 
will receive ASP2215 at the recommended dose established in Phase 1 part. The target 
population will be limited to newly diagnosed FLT3-mutated AML and the sample size is 
approximately 80 subjects. An evaluable sample size of 70 subjects in Phase 2 part 
provides more than 80% power to detect a 15% increase in CR rate from 55% (historical 
benchmark) to 70% at one-sided significance level of 0.05.  
Interim analysis for futility stopping of the Phase 2 part will be performed at the timing 
when 35 subjects are evaluable for the primary endpoint of CR rate after induction therapy 
period. Predictive probability that 46 or more subjects will achieve CR at the final analysis 
of 70 evaluable subjects will be calculated as futility criteria. 
 
IS AMENDED TO: 
[Phase 2 part] 
After achieving theof objectives of the Phase 1 part, the Phase 2 part can be initiated. 
Subjects will receive ASP2215 at the recommended dose established in the Phase 1 part. 
The primary objective of the Phase 2 part is to evaluate the efficacy of ASP2215 in 
combination with induction therapy in newly diagnosed FLT3-mutated AML 
subjects. The target population will be limited to newly diagnosed FLT3-mutated AML. 
The primary analysis for the primary endpoint of the CR rate will be conducted 
when all registered subjects complete the induction therapy period and the sample size 
is approximately 80 subjects. An evaluable sample size of 70 subjects in Phase 2 part 
provides more than 80% power to detect a 15% increase in CR rate from 55% (historical 
benchmark) to 70% at one sided significance level of 0.05.  
Interim analysis for futility stopping of the Phase 2 part will be performed at the timing 
when 35 subjects are evaluable for the primary endpoint of CR rate after induction therapy 
period. Predictive probability that 46 or more subjects will achieve CR at the final analysis 
of 70 evaluable subjects will be calculated as futility criteria. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, 
after which the subjects will enter the long-term follow-up period for collection of 
subsequent AML treatment, remission status, relapse and survival (cause and date of 
death). During the long-term follow-up period, the subject will be followed for 3 years 
after the last subject’s first treatment or completion of 30-day follow-up of the last 
subject, whichever is longer. 
 


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4 Study Design and Dose Rationale 
4.3 End of Study Definition 
WAS: 
Study completion is defined as the conclusion of data collection for the defined study 
primary endpoints. The study may be closed within a participating country per local 
regulations once the study has been completed and if all subjects enrolled in the country 
are no longer receiving IP. Study will continue until all long-term follow-ups are 
completed. 
 
IS AMENDED TO: 
Study completion is defined as the conclusion of data collection for the defined study 
primary endpoints. The study may be closed within a participating country per local 
regulations once the study has been completed and if all subjects enrolled in the country 
are no longer receiving study drugIP. Study will continue until all long-term follow-ups 
are completed. 
 
5 Study Population 
5.4.1 Rescreening 
WAS: 
[Phase 1 part] 
Results of screening assessments that do not meet the parameters required by eligibility 
criteria (e.g., clinical laboratory tests, ECG, etc.) may be repeated within the 7-day 
screening period without the need to register the subject as a screen failure. If more than 7 
days elapse from the date of signing the ICF, the subject must be documented as a screen 
failure. In order to re-screen, a new ICF must be signed and the subject entered into 
screening with a new subject identification number. 
 
IS AMENDED TO: 
[Phase 1 part] 
Not applicable Results of screening assessments that do not meet the parameters required 
by eligibility criteria (e.g., clinical laboratory tests, ECG, etc.) may be repeated within the 
7 day screening period without the need to register the subject as a screen failure. If more 
than 7 days elapse from the date of signing the ICF, the subject must be documented as a 
screen failure. In order to re screen, a new ICF must be signed and the subject entered into 
screening with a new subject identification number. 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
 
WAS: 
6 INVESTIGATIONAL PRODUCTS (STUDY DRUGS AND CONCOMITANT 
CHEMOTHERAPY DRUGS)  
6.1 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs)  
Table 10 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 


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Use 
Study drug 
Study 
drug/Concomitant 
chemotherapy drug 
(based on the local 
regulation) 
Concomitant 
chemotherapy drug 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding preparation, handling and storage of the IP and concomitant chemotherapy 
drugs. 
 
IS AMENDED TO: 
6 INVESTIGATIONAL PRODUCTS (STUDY DRUGS AND CONCOMITANT 
CHEMOTHERAPY DRUGS)  
6.1 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs)  
Table 10 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
Use 
Study drug 
Study 
drug/Concomitant 
chemotherapy drug 
(based on the local 
regulation) 
Concomitant 
chemotherapy drug 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding preparation, handling and storage of the study drugIP and concomitant 
chemotherapy drugs. 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.1.1 Dose/Dose Regimen and Administration Period 
WAS: 
[Phase 2 part] 
Concomitant chemotherapy drugs 
 
IS AMENDED TO: 
[Phase 2 part] 
Concomitant chemotherapy drugs 
 


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6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.2.1 Packaging and Labeling 
WAS: 
All IPs supplied by the Sponsor in this study will be prepared, packaged and labeled under 
the responsibility of qualified personnel at API or sponsor’s designee in accordance with 
API or sponsor’s designee standard operating procedures (SOPs), Good Manufacturing 
Practice (GMP) guidelines, International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines and applicable local laws/regulations. 
Each IP will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug. 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding packaging and labeling of the IP and concomitant chemotherapy. 
 
IS AMENDED TO: 
All study drugsIPs supplied by the Ssponsor in this study will be prepared, packaged and 
labeled under the responsibility of qualified personnel at API or sponsor’s designee in 
accordance with API or sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines and applicable local laws/regulations. 
Each study drugIP will bear a label conforming to regulatory guidelines, GMP and local 
laws and regulations that identifies the contents as investigational drug. 
Refer to the pharmacy manual, product label and package insert for detailed information 
regarding packaging and labeling of the study drugIP and concomitant chemotherapy. 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.2.1.1 ASP2215 
WAS: 
• Study title 
 
IS AMENDED TO: 
• Study numbertitle 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.2.1.2 Concomitant Chemotherapy Drugs (Idarubicin, Cytarabine) 
WAS: 
6.2.1.2 Concomitant Chemotherapy Drugs (Idarubicin, Cytarabine) 
 


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IS AMENDED TO: 
6.2.1.2 Concomitant Chemotherapy Drugs (Idarubicin, Cytarabine) 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.2.2 Handling, Storage and Accountability 
WAS: 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all IP received and any discrepancies are reported 
and resolved before use of the IP. 
2. Only subjects enrolled in the study may receive IP and only authorized study site 
personnel may supply or administer IP. Only IP with appropriate expiry/retest dating 
may be dispensed. 
3. All IP must be stored in a secure, environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions and access must be 
limited to the investigator and authorized study site personnel. 
4. The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).  
5. Further guidance and instruction on final disposition of used and unused IP is provided 
in the pharmacy manual. 
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the IP and concomitant chemotherapy. 
 
IS AMENDED TO: 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study drugIP received and any discrepancies are 
reported and resolved before use of the study drugIP. 
2. Only subjects enrolled in the study may receive study drugIP and only authorized 
study site personnel may supply or administer study drugIP. Only study drugIP with 
appropriate expiry/retest dating may be dispensed. 
3. All study drugIP must be stored in a secure, environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions and 
access must be limited to the investigator and authorized study site personnel. 
4. The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).  
5. Further guidance and instruction on final disposition of used and unused study drugIP 
is provided in the pharmacy manual. 
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the study drugIP and concomitant chemotherapy. 
 


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6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.3 Randomization and Blinding 
WAS: 
This is an open-label study. For Phase 2 part, subject enrollment and dispensation of IP and 
concomitant chemotherapy will be performed via the interactive response technology 
(IRT) system. Specific IRT procedures will be described in the respective study manual. 
 
IS AMENDED TO: 
This is an open-label study. For Phase 2 part, subject enrollment and dispensation of study 
drugIP and concomitant chemotherapy will be performed via the interactive response 
technology (IRT) system. Specific IRT procedures will be described in the respective study 
manual. 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.4 Investigational Product and Concomitant Chemotherapy Drug Compliance 
WAS: 
6.4 Investigational Product and Concomitant Chemotherapy Drug Compliance 
 
IS AMENDED TO: 
6.4 Study DrugInvestigational Product and Concomitant Chemotherapy Drug Compliance 
 
6 Investigational Products (Study Drugs and Concomitant Chemotherapy Drugs) 
6.6 Dose Modification 
WAS: 
[Phase 2 part] 
ASP2215: 
Table 15 Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 2) 
Myelosuppression (Maintenance therapy only) 
Grade 4 neutropenia and 
thrombocytopenia 
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. 
 
IS AMENDED TO: 
[Phase 2 part] 
ASP2215: 
Table 15 should be followed if the specified events occurred during the ASP2215 
dosing period. If the events occurred outside the ASP2215 dosing period, reduction of 
ASP2215 dosing may be determined upon the investigator’s discretion. 
Table 15 Guidelines for ASP2215 Dose Interruption or Reduction Event (for Phase 2) 
Myelosuppression (Maintenance therapy only) 


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Grade 4 neutropenia and/or 
thrombocytopenia 
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. 
 
7 Study Procedures and Assessments 
7.1.3 Survival Time, Duration and Other Efficacy Endpoints 
WAS: 
Follow-up will continue until the final database lock, which is estimated to occur when the 
last subject enrolled reaches the 30-day follow-up visit. 
 
IS AMENDED TO: 
For the Phase 1 part, Ffollow-up will continue until the final database lock, which is 
estimated to occur when the last subject enrolled reaches the 2830-day follow-up visit. For 
the Phase 2 part, follow-up will continue until 3 years after the last subject’s first 
treatment or completion of 30-day follow-up of the last subject, whichever is longer. 
 
7 Study Procedures and Assessments 
7.1.3.3 Relapse-free Survival 
WAS: 
[Phase 2 part] 
Relapse-free survival (RFS) is defined as time from the date of achievement of remission 
until relapse or death from any cause, whichever comes first. For a subject who is not 
known to have relapsed or died, RFS is censored on the date of last relapse-free disease 
assessment date. 
 
IS AMENDED TO: 
[Phase 2 part] 
Relapse-free survival (RFS) is defined as time from the date of achievement of first 
CRcremission until relapse or death from any cause, whichever comes first. For a subject 
who is not known to have relapsed or died, RFS is censored on the date of last relapse-free 
disease assessment date. 
 
7 Study Procedures and Assessments 
7.1.3.4 Transplantation rate 
WAS: 
Transplantation rate is defined as the percentage of subjects undergoing HSCT during the 
study period. 
 


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IS AMENDED TO: 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Transplantation rate is defined as the percentage 
 
7 Study Procedures and Assessments 
7.1.3.5 Duration of Response 
WAS: 
Duration of response is defined as the period from the first day of achieving CR, CRh, 
CRp, CRi, or PR to the first day of confirmed relapse. 
 
IS AMENDED TO: 
Duration of response is defined as the period from the first day of achieving CR, CRh, 
CRp, CRi, or PR to the first day of confirmed relapse. 
 
7 Study Procedures and Assessments 
7.2.2 Laboratory Assessments 
WAS: 
[Phase 2 part] 
Measurements will be performed centrally for both scheduled and unscheduled visits. 
Local lab assessments can be performed. The local hematology assessment will be 
recorded in the eCRF if the central assessment was not evaluable. 
 
IS AMENDED TO: 
[Phase 2 part] 
Measurements will be performed centrally for both scheduled and unscheduled visits. 
Local lab assessments can be performed. The local hematology assessment will be 
recorded in the eCRF if the central assessment was not evaluable. 
 
7 Study Procedures and Assessments 
7.3.1 Time Period for Collecting Adverse Event and Serious Adverse Event Information 
WAS: 
[Phase 2 part] 
In order to identify any events that may be associated with study procedures and could lead 
to a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received IP. 
 


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IS AMENDED TO: 
[Phase 2 part] 
In order to identify any events that may be associated with study procedures and could lead 
to a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drugIP. 
 
7 Study Procedures and Assessments 
7.3.4 Follow-up of Adverse Events 
WAS: 
If after the protocol-defined AE collection period, an AE progresses to an SAE, or the 
investigator learns of any (S)AE including death, where he/she considers there is 
reasonable possibility it is related to the IP or study participation, the investigator must 
promptly notify the sponsor. 
 
IS AMENDED TO: 
If after the protocol-defined AE collection period, an AE progresses to an SAE, or the 
investigator learns of any (S)AE including death, where he/she considers there is 
reasonable possibility it is related to the study drugIP or study participation, the 
investigator must promptly notify the sponsor. 
 
7 Study Procedures and Assessments 
7.3.6 Disease-related Events and/or Disease-related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events 
WAS: 
• Disease progression: events including defined study endpoints that are clearly 
consistent with the expected pattern of progression of the underlying disease are not to 
be recorded as AEs. These data will be captured as efficacy assessment data. If there is 
any uncertainty as to whether an event is due to anticipated disease progression and/or 
if there is evidence suggesting a causal relationship between the IP and the event, it 
should be reported as an (S)AE. All deaths up to 30 days after the final administration 
of study drugIP must be reported as an SAE, even if attributed to disease progression. 
 
IS AMENDED TO: 
• Disease progression: events including defined study endpoints that are clearly 
consistent with the expected pattern of progression of the underlying disease are not to 
be recorded as AEs. These data will be captured as efficacy assessment data. If there is 
any uncertainty as to whether an event is due to anticipated disease progression and/or 
if there is evidence suggesting a causal relationship between the study drugIP and the 
event, it should be reported as an (S)AE. All deaths up to 30 days after the final 
administration of study drugIP must be reported as an SAE, even if attributed to 
disease progression. 
 


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7 Study Procedures and Assessments 
7.3.7 Special Situations 
WAS: 
[Phase 2 part] 
Certain special situations observed in association with the IP, such as incorrect 
administration (e.g., wrong dose of IP or background therapy) are collected in the eCRF, as 
protocol deviation or may require special reporting, as described below. These special 
situations are not considered AEs, but do require to be communicated to Astellas as per the 
timelines defined below. 
 
IS AMENDED TO: 
[Phase 2 part] 
Certain special situations observed in association with the study drugIP, such as incorrect 
administration (e.g., wrong dose of study drugIP or background therapy) are collected in 
the eCRF, as protocol deviation or may require special reporting, as described below. 
These special situations are not considered AEs, but do require to be communicated to 
Astellas as per the timelines defined below. 
 
7 Study Procedures and Assessments 
7.6.1 FLT3 Mutation Assessment 
WAS: 
[Phase 2 part] 
FLT3 mutation status will be assessed from bone marrow samples taken at the screening 
visit and end-of-treatment and may be assessed from bone marrow or blood samples at 
other time points during the study. 
 
IS AMENDED TO: 
[Phase 2 part] 
FLT3 mutation status will be assessed from bone marrow samples taken at the screening 
visit and end of treatment and may be assessed from bone marrow or blood samples at 
other time points during the study. 
 
8 Discontinuation 
8.1 Discontinuation of Individual Subject(s) From Study Treatment, 8.2 Discontinuation of 
Individual Subject(s) From Study 
WAS: 
8.1 Discontinuation of Individual Subject(s) From Study Treatment 
[Phase 2 part] 
Discontinuation Criteria from Post-Treatment Follow up for Individual Subjects: 
• Subject declines further study participation (i.e., withdrawal of consent). 


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• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
• Death. 
• The study meets the criteria to complete the long term follow-up (i.e. Duration of long-
term follow-up is until 3 years after the last subject first treatment or completion of 30-
day follow-up of the last subject, whichever is longer.). 
8.2 Discontinuation of Individual Subject(s) From Study 
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in Schedules of 
Assessments. The only exception to this is when the subject specifically withdraws consent 
for any further contact with him/her or persons previously authorized by the subject to 
provide this information. 
All subjects who discontinue study treatment are to be followed for survival status until 
completion of the study. 
 
IS AMENDED TO: 
8.1 Discontinuation of Individual Subject(s) From Study Treatment 
[Phase 2 part] 
Discontinuation Criteria from Post Treatment Follow up for Individual Subjects: 
• Subject declines further study participation (i.e., withdrawal of consent). 
• Subject is lost to follow up despite reasonable efforts by the investigator to locate the 
subject. 
• Death. 
• The study meets the criteria to complete the long term follow up (i.e. Duration of long
term follow up is until 3 years after the last subject first treatment or completion of 30
day follow up of the last subject, whichever is longer.). 
8.2 Discontinuation of Individual Subject(s) From Study 
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in Schedules of 
Assessments. The only exception to this is when the subject specifically withdraws consent 
for any further contact with him/her or persons previously authorized by the subject to 
provide this information. 
For the Phase 2 part, Aall subjects who discontinue study treatment are to be followed 
for survival status until completion of the study. 
Discontinuation Criteria from Post-Treatment Follow up for Individual Subjects: 
• Subject declines further study participation (i.e., withdrawal of consent). 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate 
the subject. 
• Death. 
[Only applies to Phase 2 part] 
• The study meets the criteria to complete the long-term follow-up (i.e., During the 
long-term follow-up period, the subject will be followed for 3 years after the last 


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subject’s first treatment or completion of 30-day follow-up of the last subject, 
whichever is longer.). 
 
8 Discontinuation 
8.2.1 Lost to Follow-up 
WAS: 
Every reasonable effort is to be made to contact any subject lost to follow up during the 
course of the study to complete study related assessments, record outstanding data and 
retrieve IP. 
 
IS AMENDED TO: 
Every reasonable effort is to be made to contact any subject lost to follow up during the 
course of the study to complete study related assessments, record outstanding data and 
retrieve study drugIP. 
 
9 Statistical Methodology 
9.2.2 Per Protocol Set (PPS) 
DELETED: 
9.2.2 
Per Protocol Set (PPS) 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
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 non adherence to the protocol, in a 
manner that might reasonably impact the primary analysis, and will be defined in the SAP. 
The PPS will be a secondary analysis set for efficacy analyses. Selected demographic and 
baseline characteristics may also be summarized for the PPS. 
 
9 Statistical Methodology 
9.2.5 Pharmacodynamic Analysis Set (PDAS) 
WAS: 
9.2.5 Pharmacodynamic Analysis Set (PDAS)  
[Phase 2 part] 
Subjects who received the study drug, from whom samples for pharmacodynamic 
assessment have been collected for at least 1-time point after the study drug administration, 
and from whom pharmacodynamic measurement has been obtained will be included. 
Exploratory biomarker analysis of MRD will be performed using PDAS. 
 
IS AMENDED TO: 


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9.2.49.2.5 Pharmacodynamic Analysis Set (PDAS)  
[Phase 2 part] 
Not applicable.Subjects who received the study drug, from whom samples for 
pharmacodynamic assessment have been collected for at least 1 time point after the study 
drug administration, and from whom pharmacodynamic measurement has been obtained 
will be included. Exploratory biomarker analysis of MRD will be performed using PDAS. 
 
9 Statistical Methodology 
 
ADDED: 
9.2.6 
MRD Analysis Set (MAS) 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
The MRD Analysis Set (MAS) consists of all subjects who were enrolled and received 
at least 1 dose of study drug, were centrally confirmed as FLT3-ITD positive and had 
a baseline and at least post-baseline sample with MRD data. 
 
9 Statistical Methodology 
9.3.1 Demographics 
WAS: 
Descriptive statistics will include number of subjects, mean, standard deviation, minimum, 
Q1, median, Q3 and maximum for continuous endpoints and frequency and percentage for 
categorical endpoints. The analyses will be performed in the FAS, PPS, SAF, PKAS, and 
PDAS. 
 
IS AMENDED TO: 
Descriptive statistics will include number of subjects, mean, standard deviation, minimum, 
Q1, median, Q3 and maximum for continuous endpoints and frequency and percentage for 
categorical endpoints. The analyses will be performed in the FAS, PPS, SAF, PKAS, and 
MASPDAS. 
 
9 Statistical Methodology 
9.3.2 Subject Disposition 
WAS: 
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all subjects who received IP. 
Similar tables for screening disposition, investigational period disposition and follow-up 
disposition will also be presented for all subjects who received IP. All disposition details 
and dates of first and last evaluations for each subject will be listed. 


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IS AMENDED TO: 
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all subjects who received IP. 
Similar tables for screening disposition, investigational period disposition and follow-up 
disposition will also be presented for all subjects who received IP. All disposition details 
and dates of first and last evaluations for each subject will be listed. 
 
9 Statistical Methodology 
9.3.5 Investigational Product Exposure 
WAS: 
9.3.5 
Investigational Product Exposure 
The number and percentage of subjects exposed to IP will be summarized. 
All IP exposure data will be listed. 
 
IS AMENDED TO: 
9.3.5 
Study DrugInvestigational Product Exposure 
The number and percentage of subjects exposed to study drugIP will be summarized. 
All study drugIP exposure data will be listed. 
 
9 Statistical Methodology 
9.4.1.2 Sensitivity Analysis of Primary Endpoint 
DELETED: 
9.4.1.2 Sensitivity Analysis of Primary Endpoint 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
The same analysis of the primary endpoint as described in Section 9.4.1 will be conducted 
using the PPS. 
 
9 Statistical Methodology 
9.4.2 Analysis of Secondary Endpoints 
WAS: 
[Phase 2 part] 
The statistical analyses on secondary efficacy endpoints include the following descriptive 
analyses for ASP2215 in combination with induction and consolidation therapy followed 
by maintenance therapy: 


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● 
Kaplan-Meier method for time-to-event endpoints including OS, EFS, RFS, duration 
of CR, CRh, CR/CRh, and CRc. 
● 
The two-sided 95% exact confidence interval of the binary endpoints including CR 
rate, CRh rate, CR/CRh rate, and CRc rate. 
For each of the secondary responder endpoints, analyses are conducted are analyzed after 
each treatment therapy. 
 
IS AMENDED TO: 
[Phase 2 part] 
The statistical analyses on secondary efficacy endpoints include the following descriptive 
analyses for ASP2215 in combination with induction and consolidation therapy followed 
by maintenance therapy: 
● 
Kaplan-Meier method for time-to-event endpoints including OS, EFS, RFS, duration 
of CR, CRh, CR/CRh, and CRc and response. 
● 
The two-sided 95% exact confidence interval of the binary endpoints including CR 
rate, CRh rate, CR/CRh rate, and CRc rate. 
For each of the secondary responder endpoints, analyses are conducted are analyzed after 
each treatment therapy. 
 
9 Statistical Methodology 
9.4.3 Analysis of Exploratory Endpoints 
WAS: 
[Phase 1 part] 
Not applicable.  
[Phase 2 part] 
Exploratory biomarker analysis of MRD will be performed using PDAS. 
 
IS AMENDED TO: 
[Phase 1 part] 
Not applicable. The statistical analyses on exploratory endpoints include the following 
descriptive analyses for ASP2215 in combination with induction and consolidation 
therapy followed by maintenance therapy: 
• 
Kaplan-Meier method for time-to-event endpoints duration of response, CR 
and CRc. 
• 
The 2-sided 95% exact confidence interval of the binary endpoints CR rate, 
CRp rate, CRi rate, PR rate, CRc rate and response rate. 
[Phase 2 part] 
Exploratory biomarker analysis of MRD will be performed using MASPDAS. 
 


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9 Statistical Methodology 
9.5.2 Adverse Events 
WAS: 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
graded using NCI-CTCAE. A treatment-emergent adverse event (TEAE) is defined as an 
AE observed after starting administration of the IP and within 30 days (for phase 1 part, 28 
days) after the last administration of IP. An IP-related TEAE is defined as any TEAE with 
a causal relationship assessed as YES by the investigator. 
The number and percentage of subjects with TEAEs, IP-related TEAEs, serious TEAEs, 
IP-related serious TEAEs, TEAEs leading to withdrawal of treatment and IP-related 
TEAEs leading to withdrawal of treatment will be summarized by System Organ Class 
(SOC), Preferred Term (PT). The number and percentage of TEAEs by severity will also 
be summarized. 
 
IS AMENDED TO: 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
graded using NCI-CTCAE. A treatment-emergent adverse event (TEAE) is defined as an 
AE observed after starting administration of the study drugIP and within 30 days (for 
phase 1 part, 28 days) after the last administration of study drugIP. An drugIP-related 
TEAE is defined as any TEAE with a causal relationship assessed as YES by the 
investigator. 
The number and percentage of subjects with TEAEs, drugIP-related TEAEs, serious 
TEAEs, drugIP-related serious TEAEs, TEAEs leading to withdrawal of treatment and 
drugIP-related TEAEs leading to withdrawal of treatment will be summarized by System 
Organ Class (SOC), Preferred Term (PT). The number and percentage of TEAEs by 
severity will also be summarized. 
 
9 Statistical Methodology 
9.7 Analysis of Pharmacodynamics | Immunogenicity 
WAS: 
[Phase 2 part] 
Not applicable. (PDAS is used for exploratory biomarker analysis of MRD.) 
 
IS AMENDED TO: 
[Phase 2 part] 
Not applicable. (PDAS is used for exploratory biomarker analysis of MRD.) 
 


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9 Statistical Methodology 
9.9 Major Protocol Deviations 
WAS: 
Major protocol deviations as defined in Section 10.3 will be summarized for all subjects 
who received IP by study site. 
 
IS AMENDED TO: 
Major protocol deviations as defined in Section 10.3 will be summarized for all subjects 
who received study drugIP by study site. 
 
10 Operational Considerations 
10.1.1 Data Collection 
WAS: 
The investigator or site designee will enter data using an Electronic Data Capture (EDC) 
system. The investigator is responsible for ensuring that all data in the electronic Case 
Report Forms (eCRFs) and queries are accurate and complete and that all entries are 
verifiable with source documents. The source documents should be appropriately 
maintained by the site. 
The monitor should verify the data in the eCRF with the source documents and confirm 
that there are no inconsistencies between them. 
 
IS AMENDED TO: 
The investigator or site designee will enter data using an Electronic Data Capture (EDC) 
system. The investigator is responsible for ensuring that all data in the electronic Case 
Report Forms (eCRFs) and queries are accurate and complete and that all entries are 
verifiable with source documents. The source documents should be appropriately 
maintained by the site. 
The monitor should verify the data in the eCRF with the source documents and confirm 
that there are no inconsistencies between them. 
 
10 Operational Considerations 
10.2.2 Medical History and Concurrent diseases 
WAS: 
Medical history is any disease from which the subject has recovered before the start of 
investigation product administration. 
Any medical conditions from which the subject has not recovered before the start of 
investigational product administration should also be collected as concurrent diseases in 
the eCRF. 
 


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IS AMENDED TO: 
Medical history is any disease from which the subject has recovered before the start of 
investigation productstudy drug administration. 
Any medical conditions from which the subject has not recovered before the start of study 
druginvestigational product administration should also be collected as concurrent diseases 
in the eCRF. 
 
11 References 
 
ADDED: 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. 
Diagnosis and management of AML in adults: 2017 ELN recommendations 
from an international expert panel. Blood. 2017;129:424-47. 
 
12 Appendices 
12.1.6 Record Retention 
WAS: 
[UNIQUE to JP Region] 
4. Records of control for IP and other duties related to the study. Procedure for controlling 
the IP, drug inventory and accountability record, vouchers for the receipt and return of 
the IP, and the prescriptions for concomitant medications. 
 
IS AMENDED TO: 
[UNIQUE to JP Region] 
4. Records of control for study drugIP and other duties related to the study. Procedure for 
controlling the study drugIP, drug inventory and accountability record, vouchers for 
the receipt and return of the study drugIP, and the prescriptions for concomitant 
medications. 
 
12 Appendices 
12.2.1 Study Monitoring 
WAS: 
The sponsor or delegated CRO is responsible for monitoring the study to ensure that the 
rights, safety and well-being of subjects are protected, the study is properly conducted in 
adherence to the current protocol and GCP and the study data reported by the investigators 
are accurate, complete and verifiable with the source. The sponsor is responsible for 
assigning the study monitor(s) to this study for proper monitoring. They will monitor the 
study in accordance with planned monitoring procedures. 
 


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IS AMENDED TO: 
The sponsor or delegated CRO is responsible for monitoring the study to ensure that the 
rights, safety and well-being of subjects are protected, the study is properly conducted in 
adherence to the current protocol and GCP and the study data reported by the investigators 
are accurate, complete and verifiable with the source. The sponsor is responsible for 
assigning the study monitor(s) to this study for proper monitoring. They will monitor the 
study in accordance with planned monitoring procedures. 
 
12 Appendices 
12.3 Contraception Requirements 
WAS: 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time 
of signing the ICF and until the end of relevant systemic exposure, defined as 180 days 
after the final IP administration.a 
 
IS AMENDED TO: 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time 
of signing the ICF and until the end of relevant systemic exposure, defined as 180 days 
after the final study drugIP administration.a 
 
12 Appendices 
12.4.1 Definition of Adverse Events 
WAS: 
An AE is any untoward medical occurrence in a subject administered an investigational 
product (IP), and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of IP whether or not considered related to the IP. 
 
IS AMENDED TO: 
An AE is any untoward medical occurrence in a subject administered an study 
druginvestigational product (IP), and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study drugIP whether or not considered related to 
the study drugIP. 
 


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12 Appendices 
12.4.3 Criteria for Causal Relationship to Investigational Product 
WAS: 
Criteria for Causal Relationship to Investigational Product 
A medically qualified investigator is obligated to assess the relationship between IP and 
each occurrence of each (S)AE. This investigator will use medical judgment as well as the 
reference safety information to determine the relationship. The causality assessment is 1 of 
the criteria used when determining regulatory reporting requirements. 
The investigator is requested to provide an explanation for the causality assessment for 
each (S)AE and must document in the medical notes that he/she has reviewed the (S)AE 
and has provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?” For this 
study, causality of with each IP (ASP2215, cytarabine, and idarubicin) should be 
determined and reported by investigator. 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the IP (rather than a relationship cannot be ruled 
out) or if there is evidence to reasonably deny a causal relationship: 
• Has the subject been administered IP? 
Table 21 Criteria for Determining Causal Relationship with the Investigational Product 
 
IS AMENDED TO: 
Criteria for Causal Relationship to Study DrugInvestigational Product 
A medically qualified investigator is obligated to assess the relationship between study 
drug/concomitant chemotherapyIP and each occurrence of each (S)AE. This investigator 
will use medical judgment as well as the reference safety information to determine the 
relationship. The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
The investigator is requested to provide an explanation for the causality assessment for 
each (S)AE and must document in the medical notes that he/she has reviewed the (S)AE 
and has provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the study 
drug/concomitant chemotherapyIP and each (S)AE will be assessed by answering “yes” 
or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the study drug/concomitant chemotherapyIP?” For this 
study, causality of with each study drug/concomitant chemotherapyIP (ASP2215, 
cytarabine, and idarubicin) should be determined and reported by investigator. 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the study drug/concomitant chemotherapyIP 
(rather than a relationship cannot be ruled out) or if there is evidence to reasonably deny a 
causal relationship: 


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• Has the subject been administered study drug/concomitant chemotherapyIP? 
Table 21 Criteria for Determining Causal Relationship with the Study DrugInvestigational 
Product 
 
12 Appendices 
12.4.5 Reporting Procedures for Serious Adverse Events 
WAS: 
[UNIQUE to JP Region] 
In the case of a SAE, the investigator must report to the head of the study site and must 
contact the delegated CRO by fax or email immediately (within 24 hours of awareness).  
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the appropriate regulatory 
authorities to the delegated CRO by fax or email immediately (within 24 hours of 
awareness) and to the head of the hospital.  
 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE/special situations worksheet 
to: 
Sponsor Contact: 
Astellas Pharma Inc., Development, Japan-Asia Clinical Development 1 
Location: 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan 
TEL: 03- 3244-1097 
FAX: 03-3243-5737 
 
Contract Research Organizer (CRO) Contact: 
 
IS AMENDED TO: 
[UNIQUE to JP Region] 
In the case of a SAE, the investigator must report to the head of the study site and must 
contact the sponsor via the delegated CRO by fax or email immediately (within 24 hours 
of awareness).  
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the appropriate regulatory 
authorities to the sponsor via the delegated CRO by fax or email immediately (within 24 
hours of awareness) and to the head of the hospital.  
 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE/special situations worksheet 
to: 
Sponsor Contact: 
Astellas Pharma Inc., Development, Japan-Asia Clinical Development 1 


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Location: 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan 
TEL: 03- 3244-1097 
FAX: 03 3243 5737 
 
Sponsor Contact [Contract Research Organizer (CRO) Contact]: 
 
12 Appendices 
12.7 List of Excluded Concomitant Medications 
WAS: 
For strong CYP3A inhibitors and strong CYP3A inducers, refer to the below link for 
details. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-
interaction-studies-study-design-data-analysis-and-clinical-implications-guidance 
 
IS AMENDED TO: 
For strong CYP3A inhibitors and strong CYP3A inducers, refer to the below link for 
details. 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers https://www.fda.gov/regulatory
information/search fda guidance documents/clinical drug interaction studies study
design data analysis and clinical implications guidance 
 
12 Appendices 
12.9 Acceptable Range of Schedule of Assessments 
WAS: 
[Phase 2 part] 
The definitions for windows to be used for analyses by visit will be outlined in the SAP. 
 
IS AMENDED TO: 
[Phase 2 part] 
The definitions for windows to be used for analyses by visit will be outlined in Table 7 
(Schedule of Assessments [Phase 2 Part])the SAP. 
 
12 Appendices 
 
ADDED: 
12.11 Clinical Study Continuity 
INTRODUCTION 


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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 subject level during any crisis (e.g., natural 
disaster, pandemic).  
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study subjects 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 schedules of assessments [Table 6 and Table 7] unless the 
site principal investigator discusses the need with the Astellas medical monitor to 
implement the alternate measures.  
The approach outlined within this appendix defines which assessments are required 
to maintain a favorable benefit/risk to the subject, 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 as 
described in [Section 7 Study Procedures and Assessments] due to a crisis. 
INFORMED CONSENT 
Subjects 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 subject to provide written consent prior to implementation, the 
principal investigator or designee will obtain oral agreement from the subject 
followed by written documentation as soon as feasible. A separate addendum to the 
study informed consent will be provided to document the subject’s consent of the 
changes. 
SUBJECT PROCEDURES ASSESSMENT 
Sites with subjects 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 subject 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 subject with respect to time and travel. 
• Subject(s) have temporarily relocated from the current study site to an alternate 
study site to avoid placing a burden on the subject with respect to travel. 
• Subject(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. 
• Subject has risk factors for which traveling to the site poses an additional risk to 
the subject’s health and safety. 


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Adherence to the original protocol as reflected in the schedules of assessments [Table 
6 and Table 7] is expected, where plausible, in the case of a crisis. The alternate 
measures as noted in [Table 37] 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 study drug and 
maintaining critical safety and efficacy assessments for subjects in the study at a time 
of crisis. 
If one or more of the alternate measures noted below is implemented for a subject, 
the site should document in the subject’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). 
 


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Alternative Schedule of Assessments in Response to a Crisis [Phase 2 part] 
Assessments 
Alternate Approach(es) 
Treatment phase 
EOT/Pre-HSCT 
Follow-up 
(30-day and Long-term) 
Screening 
/Induction 
Consolidation 
Maintenance 
Informed consent 
Not applicable 
X 
 
 
 
 
Eligibility criteria 
Not applicable 
X 
 
 
 
 
Medical and disease 
history 
Not applicable 
X 
 
 
 
 
Vital Signs 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within the 
induction treatment period and 
consolidation treatment period. 
• For the remaining visits including 
maintenance phase, this exam can be 
performed at a local clinic per SOC 
and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
 
Height and Weight 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within the 
induction treatment period and 
consolidation treatment period. 
• For the remaining visits including 
maintenance phase, this exam can be 
performed at a local clinic per SOC 
and results can be submitted to PI 
for evaluation. 
X 
X 
X 
 
 
ECOG Performance 
Status 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within the 
X 
X 
X 
X 
 


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induction treatment period and 
consolidation treatment period. 
• For the remaining visits including 
maintenance phase, this exam can be 
performed at a local clinic per SOC 
and results can be submitted to PI 
for evaluation. 
Physical 
examination 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within the 
induction treatment period and 
consolidation treatment period. 
• For the remaining visits including 
maintenance phase, this exam can be 
performed at a local clinic per SOC 
and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
X 
Pregnancy test for 
WOCBP (serum) 
• No alternative approach during 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within 
consolidation treatment period. 
• For the maintenance phase, these 
exams can be performed at a local 
clinic per SOC and results can be 
submitted to PI for evaluation. 
X 
 
X 
 
 
Pregnancy test for 
WOCBP (urine) 
• No alternative approach during 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within 
consolidation treatment period. 
• For the maintenance phase, these 
exams can be performed at a local 
clinic per SOC and results can be 
submitted to PI for evaluation. 
X 
 
X 
 
 


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Chest x-ray (or 
chest CT) 
No alternative approach 
X 
 
 
 
 
12-lead ECG 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within the 
induction treatment period and 
consolidation treatment period. 
• For the remaining visits including 
maintenance phase, this exam can be 
performed at a local clinic per SOC 
and results can be submitted to PI 
for evaluation. 
X 
X 
X 
X 
 
Clinical laboratory 
tests (chemistry, 
hematology, 
coagulation, 
urinalysis) 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within induction 
treatment period and consolidation 
treatment period. 
• For the remaining visits including 
maintenance phase, these exams can 
be performed at a local clinic per 
SOC and results can be submitted to 
PI for evaluation. 
X 
X 
X 
X 
X 
Thyroid function 
tests 
• No alternative approach during the 
screening period and both 
cytarabine and idarubicin/HIDAC 
treatment period within the 
consolidation treatment period. 
• For the maintenance phase, these 
exams can be performed at a local 
clinic per SOC and results can be 
submitted to PI for evaluation. 
X 
X 
X 
X 
 
MUGA or ECHO 
No alternative approach 
X 
 
 
 
 
PK Sample 
Collection 
No alternative approach 
X 
X 
 
 
 


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PGx 
No alternative approach 
X 
 
 
 
 
FLT3 mutational 
status 
No alternative approach 
X 
 
 
 
 
Bone marrow 
aspirate/biopsy and 
MRD analysis 
• No alternative approach during the 
screening period and HIDAC 
treatment period within the 
consolidation treatment period. 
• For the remaining visits including 
maintenance phase, these exams can 
be performed at a local clinic per 
SOC and results can be submitted to 
PI for evaluation. 
X 
X 
X 
X 
X 
AE/SAE assessment 
Remote/Virtual/Telemedicine Visits 
allowed for non-dosing visits. Please 
refer to protocol schedule of 
assessments. 
X 
X 
X 
X 
X 
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 
Subsequent anti-
leukemic 
treatments/outcomes 
Remote/Virtual/Telemedicine Visits 
allowed 
 
 
 
 
X 
Survival  
Remote/Virtual/Telemedicine Visits 
allowed 
 
 
 
 
X 
Cytarabine 
administration 
No alternative approach  
X 
X 
 
 
 
Idarubicin 
administration 
No alternative approach  
X 
 
 
 
 
ASP2215 
administration 
If necessary, ASP2215 could be 
delivered from the hospital to the 
patient 
X 
X 
X 
 
 
AE: adverse event; CT: computed tomography; ECG: electrocardiogram; ECHO: echocardiogram; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; HIDAC: high-dose 
cytarabine; HSCT: hematopoietic stem cell transplant; PGx: pharmacogenomic; MRD: minimal residual disease; MUGA: multigated acquisition; PI: principal investigator; 
PK: pharmacokinetic; SAE: serious adverse event; SOC: standard of care; WOCBP: woman of childbearing potential. 


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STUDY DRUG SUPPLY 
If any of the conditions outlined above in the Subjects Procedures Assessment are 
met, one or all of the following mitigating strategies will be employed, as needed, to 
ensure continuity of study drug supply to the subjects: 
• Increase stock of study drug on site to reduce number of shipments required, if 
site space will allow. 
• Direct-to-Subject shipments of study drug from the site to the subject’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 subject 
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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Version 8.0 Incorporating Substantial Amendment 7 
14 
SPONSOR SIGNATURE 
 

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc. 
SAP Final Version 1.00 
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16-Nov-2021 
Astellas 
Page 1 of 52 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Final Version 1.00, dated 16-Nov-2021 
 
A Phase 1/2 Study of ASP2215 in Combination with Induction and Consolidation 
Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia 
 
 
 
 
ISN: 2215-CL-0104 
 
 
 
 
 
Sponsor: Astellas Pharma Inc. (API) 
 
 
 
 
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 Inc. 
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Astellas 
Page 2 of 52 
Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 4 
1 
INTRODUCTION ································
································
··················
 8 
2 
FLOW CHART AND VISIT SCHEDULE ································
····················
 8 
3 
STUDY OBJECTIVE(S) AND DESIGN ································
·······················
 8 
3.1 
Study Objective(s) ································
································
·············
 8 
3.1.1 
Primary objectives ································
································
········  8 
3.1.2 
Secondary objectives ································
································
·····  8 
3.1.3 
Exploratory objectives ································
································
···  9 
3.2 
Study Design ································
································
····················
 9 
3.3 
Randomization································
································
·················
 10 
4 
SAMPLE SIZE ································
································
····················
 10 
4.1.1 
Target Sample Size ································
································
······  10 
4.1.2 
Justification of Sample Size ································
····························
 11 
5 
ANALYSIS SETS ································
································
·················
 11 
5.1 
Full Analysis Set (FAS) ································
································
······  11 
5.2 
Safety Analysis Set (SAF) ································
································
···  11 
5.3 
Dose-Determining Analysis Set (DDAS) ································
··················
 12 
5.4 
Pharmacokinetics Analysis Set (PKAS) ································
····················
 12 
5.5 
Pharmacodynamic Analysis Set (PDAS) ································
···················
 12 
5.6 
MRD Analysis Set (MAS) ································
································
···  12 
6 
ANALYSIS VARIABLES ································
································
·······  13 
6.1 
Efficacy Endpoints ································
································
············
 13 
6.1.1 
Response Definition ································
································
·····  13 
6.1.2 
Primary Efficacy Endpoint ································
·····························
 14 
6.1.3 
Secondary Efficacy Endpoints ································
·························
 14 
6.1.4 
Exploratory Efficacy Endpoints ································
·······················
 16 
6.2 
Safety Variables ································
································
···············
 17 
6.3 
Pharmacokinetic Variables ································
································
···  18 
6.4 
Pharmacodynamic Variables ································
································
 18 
6.5 
Other Variables ································
································
················
 18 
7 
STATISTICAL METHODOLOGY ································
···························
 21 


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7.1 
General Considerations ································
································
·······  21 
7.2 
Study Population ································
································
··············
 21 
7.2.1 
Disposition of Subjects ································
································
· 21 
7.2.2 
Protocol Deviations ································
································
·····  22 
7.2.3 
Demographic and Other Baseline Characteristics ································
···  23 
7.2.4 
Previous and Concomitant Medications ································
··············
 24 
7.2.5 
Previous and Concomitant Transfusions ································
·············
 25 
7.2.6 
Non-Medication Therapy ································
·······························
 25 
7.3 
Study Drugs ································
································
····················
 25 
7.3.1 
Exposure ································
································
··················
 25 
7.4 
Analysis of Efficacy ································
································
··········
 25 
7.5 
Analysis of Safety ································
································
·············
 26 
7.5.1 
DLT (Phase 1 part only) ································
································
 27 
7.5.2 
Adverse Events (AEs) ································
································
··  27 
7.5.3 
Clinical Laboratory Evaluation ································
························
 30 
7.5.4 
Vital Signs ································
································
················
 31 
7.5.5 
Electrocardiograms (ECGs) ································
····························
 32 
7.5.6 
ECOG Performance Status ································
·····························
 33 
7.6 
Analysis of PK································
································
·················
 33 
7.6.1 
Pharmacokinetic ASP2215 Parameters ································
···············
 33 
7.6.2 
Change from the Protocol ································
······························
 33 
7.7 
Analysis of PD································
································
·················
 34 
7.7.1 
Change from the Protocol ································
······························
 34 
7.8 
Subgroups of Interest ································
································
·········  34 
7.9 
Other Analyses ································
································
················
 34 
7.9.1 
FLT3 Mutation Test ································
································
·····  34 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 35 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········  35 
7.11.1 
Missing Data ································
································
·············
 35 
7.11.2 
Outliers ································
································
···················
 36 
7.11.3 
LLOQ ································
································
·····················
 36 
7.11.4 
BLQ data ································
································
·················
 36 
7.11.5 
Visit Windows ································
································
···········
 36 
8 
DOCUMENT REVISION HISTORY ································
·························
 49 


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9 
REFERENCES ································
································
····················
 49 
10 
APPENDICES ································
································
·····················
 50 
10.1 
Appendix 1: Signature ································
································
········  50 
10.2 
Appendix 2: Search Strategy for Adverse Events of Interest ····························
 51 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
AESI 
Adverse events of special safety interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AML 
Acute Myeloid Leukemia 
API 
Astellas Pharma Inc. 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical Classification 
AUC 
Area under the plasma concentration-time curve 
AUC24 
Area under plasma concentration-time curve from time 0 to 24 
AUCinf 
AUC from the time of dosing extrapolated to time infinity 
AUClast 
AUC from the Time of Dosing to the Last Measurable Concentration 
AXL 
AXL receptor tyrosine kinase 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CID 
Cumulative Incidence of Death 
CIR 
Cumulative Incidence of Relapse 
CL/F 
Oral clearance 
Cmax 
Maximum concentration 
CR 
Complete Remission 
CR1 
1st Complete Remission 
CRc 
Composite Complete Remission 
CRF 
Case Report Form 
CRh 
Complete Remission with Partial Hematological Recovery 
CRi 
Complete Remission with Incomplete Hematological Recovery 
CRM 
Continual Reassessment Method 
CRp 
Complete Remission with Incomplete Platelet Recovery 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DDAS 
Dose-Determining Analysis Set 
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EFS 
Event Free Survival 


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Abbreviations 
Description of abbreviations 
ELN 
European LeukemiaNet 
ESS 
Effective Sample Size 
FAB 
French-American-British 
FAS 
Full Analysis Set 
FLT3 
FMS-like tyrosine kinase-3 
FLT3-ITD 
FLT3- Internal Tandem Duplication 
FLT3-TKD 
FLT3- Tyrosine Kinase Domain 
GM 
Geometric Mean 
HLT 
High Level Term 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
Lambda z 
Terminal elimination rate constant 
LLOQ 
Lower Limit of Quantification 
LVEF 
Left Ventricular Ejection Fraction 
MAS 
MRD Analysis Set 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Molecular Response 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple Gate Acquisition 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NR 
No Response 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PD 
Pharmacodynamic 
PDAS 
Pharmacodynamic Analysis Set 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetics Analysis Set 
PR 
Partial Remission 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PT 
Preferred Term 
QTc 
Corrected Q-T Interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s factor 
RBC 
Red Blood Cell 
RED 
Recommended Expansion Dose 
RFS 
Relapse Free Survival 
RR 
Interval between 2 consecutive r waves on an ECG 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS  
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
t1/2 
Apparent terminal elimination half-life 
TLF 
Tables, Listings and Figures 
tmax 
Time of the Maximum concentration 
TTE-FAS 
Time-to-Event Full Analysis Set 


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Abbreviations 
Description of abbreviations 
ULN 
Upper Limit of Normal 
Vz/F 
Apparent Volume of Distribution During the Terminal Elimination Phase 
after Oral Dosing 
WHO 
World Health Organization 
WHODD 
WHO Drug Dictionary 
WHODD(B2) 
WHO Drug Dictionary (B-2 Format) 
WHODD(B3) 
WHO Drug Dictionary (B-3 Format) 
WOCBP 
Women of childbearing potential 
 
 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline 
Last available assessments of subjects as they enter a study before they 
receive any treatment. 
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a study.  
Note: Not all endpoints are themselves assessments since certain 
endpoints might apply to populations or emerge from analysis of results. 
That is, endpoints might be facts about assessments (e.g., prolongation of 
survival). 
Investigational period 
Period of time where major interests of protocol objectives are observed, 
and where the test product or comparative drug (sometimes without 
randomization) is given to a subject and continues until the last 
assessment after completing administration of the test product or 
comparative drug. 
Registration failure 
A subject who signed the ICF and met the pre-registration criteria but did 
not meet all inclusion and exclusion criteria by day 8. These subjects 
received chemotherapy but never received ASP2215. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
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 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 database lock for primary analysis for the primary 
endpoint.  
This statistical analysis is coordinated by the responsible biostatistician of Development API 
(Global Development, API). Any changes from the analyses planned in the SAP will be 
justified in the CSR. 
2 
FLOW CHART AND VISIT SCHEDULE 
Details of the schedule of clinical assessments are available in the protocol. 
3 
STUDY OBJECTIVE(S) AND DESIGN 
3.1 
Study Objective(s) 
3.1.1 
Primary objectives 
[Phase 1 part] 
● 
To determine the maximum tolerated dose (MTD) and/or recommended expansion dose 
(RED) of ASP2215 concomitant with cytarabine/idarubicin as induction chemotherapy 
based on the status of the onset of dose-limiting toxicity (DLT). 
● 
To evaluate the safety and tolerability of ASP2215 concomitant with 
cytarabine/idarubicin as induction chemotherapy and high-dose cytarabine as 
consolidation chemotherapy. 
● 
To evaluate the safety and tolerability of ASP2215 in maintenance therapy after 
induction and consolidation therapy. 
[Phase 2 part] 
● 
To evaluate the efficacy of ASP2215 in combination with induction therapy in newly 
diagnosed FLT3 (FMS-like tyrosine kinase-3) -mutated AML (Acute Myeloid 
Leukemia) subjects. 
3.1.2 
Secondary objectives 
[Phase 1 part] 
● 
To characterize the pharmacokinetic (PK) parameters of ASP2215 concomitant with 
induction and consolidation chemotherapy. 
● 
To evaluate the PK parameters of cytarabine concomitant with ASP2215. 
[Phase 2 part] 
● 
To characterize the PK parameters of ASP2215 concomitant with induction and 
consolidation chemotherapy. 
● 
To evaluate the safety and efficacy of ASP2215 in combination with induction and 
consolidation therapy followed by maintenance therapy 




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following criteria will be considered unevaluable for DLT and will be replaced by another 
subject in the cohort. 
● 
A subject that receives less than 80% of the assigned dose of ASP2215 during DLT 
assessment period specified in each part (e.g., subject in dose assessment part who 
misses ≥ 3 daily doses during DLT assessment period of dose evaluation part and 
interrupts the study for a reason other than a DLT) 
● 
Unable to assess the safety adequately during DLT assessment period specified in each 
part such as due to the lack of required safety assessment(s) 
 
The decision of whether or not to proceed to the next dose of ASP2215 will be made through 
discussion among the sponsor, principal investigators, and medical advisor with reference to 
the recommended dose level calculated using Bayesian-CRM, the safety data, etc., and after 
review by the sponsor’s responsible person. The MTD is defined as the highest dose of 
ASP2215 at which the posterior mean of the DLT incidence during Cycle 1 of induction 
therapy is estimated to be closest to 33%. 
[Phase 2 part] 
After achieving the objectives of the Phase 1 part, the Phase 2 part can be initiated. Subjects 
will receive ASP2215 at the recommended dose established in the Phase 1 part. The primary 
objective of the Phase 2 part is to evaluate the efficacy of ASP2215 in combination with 
induction therapy in newly diagnosed FLT3-mutated AML subjects. The target population 
will be limited to newly diagnosed FLT3-mutated AML. The primary analysis for the 
primary endpoint of the CR rate will be conducted when all registered subjects complete the 
induction therapy period.  
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, relapse and survival (cause and date of death). Duration of 
long-term follow-up is until 3 years after the last subject first treatment or completion of 30-
day follow-up of the last subject, whichever is longer. 
3.3 
Randomization  
Randomization is not performed in this study since this is an open-label, uncontrolled study. 
4 
SAMPLE SIZE 
4.1.1 
Target Sample Size 
[Phase 1 part] 
6 subjects 
Dose-evaluation part: At least 3 subjects per cohort (which may be changed according to the 
status of the onset of DLT and the number of cohorts) 
Expansion part: At least 3 subjects 


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[Phase 2 part] 
Approximately 80 subjects 
4.1.2 
Justification of Sample Size 
[Phase 1 part: Dose-evaluation part] 
To assess MTD and RED of ASP2215 as induction therapy concomitant with 
cytarabine/idarubicin in newly diagnosed AML subjects, 3 DLT evaluable subjects per dose 
level for 1 dose level were assumed.  The sample size may increase depending on the 
occurrence of toxicities. 
[Phase 1 part: Expansion part] 
The sample size was set to 3 subjects to further assess the safety and efficacy of ASP2215 at 
the dose tested in the expansion part. 
[Phase 2 part] 
A sample size of 70 subjects in Phase 2 part provides more than 80% power to detect a 15% 
increase in CR rate from 55% (historical benchmark based on the RATIFY study, Stone et al, 
2017.) to 70% at one-sided significance level of 0.05. To account for several subjects 
dropping out from the study, 80 subjects will be enrolled. 
5 
ANALYSIS SETS 
In accordance with ICH recommendations in guidelines E3 and E9, the following analysis 
sets will be used for the analyses. 
5.1 
Full Analysis Set (FAS) 
[Phase 1 part] 
Subjects who meet all of the following criteria will be included: 
• 
Received at least 1 dose of study drug 
• 
Assessed for at least 1 efficacy variable after study drug administration 
[Phase 2 part] 
Subjects who meet all of the following criteria will be included: 
• 
Received at least 1 dose of study drug 
• 
Had at least one post-baseline bone marrow assessment 
 
For the statistical analysis of some Time-to-Event efficacy variables, TTE-FAS will be used. 
TTE-FAS is defined similarly as the FAS, however, the criterion for bone marrow 
assessment is removed. 
5.2 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the SAF will be used. 


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[Phase 1 part] 
All subjects who received at least 1 dose of study drug will be included. 
[Phase 2 part] 
The SAF will be defined as the same as Phase 1 part. 
5.3 
Dose-Determining Analysis Set (DDAS) 
[Phase 1 part] 
Subjects who do not fall under any of the following criteria will be included: 
• 
Received less than 80% of the intended dose of ASP2215 during DLT assessment period 
specified in each part (e.g., subject in dose evaluation part who misses ≥ 3 daily doses 
during DLT assessment period and interrupts the study for a reason other than a DLT) 
• 
Unable to assess safety adequately during DLT assessment period specified in each part 
such as due to the lack of required safety assessment(s). 
[Phase 2 part] 
Not applicable. 
5.4 
Pharmacokinetics Analysis Set (PKAS) 
Subjects who received the study drug, from whom samples for drug concentration 
measurement have been collected for at least 1 time-point after the study drug administration, 
and from whom drug concentration measurement has been obtained will be included. 
5.5 
Pharmacodynamic Analysis Set (PDAS) 
[Phase 1 part] 
Subjects who received the study drug, from whom samples for pharmacodynamic assessment 
have been collected for at least 1-time point after the study drug administration, and from 
whom pharmacodynamic measurement has been obtained will be included. 
[Phase 2 part] 
Not applicable. 
5.6 
MRD Analysis Set (MAS) 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Subjects who received at least one dose of study drug, were centrally confirmed as FLT3-
ITD positive at screening and had a baseline and at least one post-baseline sample with MRD 
data. 


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6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
6.1.1 
Response Definition 
Antitumor response will be assessed on the days of bone marrow sampling based on the bone 
marrow findings, and peripheral blast count, neutrophil count, and platelet count. Preferably, 
samples from both bone marrow aspiration and biopsy should be obtained, but if the bone 
marrow aspiration was determined to be sufficient, biopsy may be omitted. 
Antitumor response is defined per modified Cheson criteria (2003) or modified ELN 
recommendations (2017) as outlined below [Döhner et al, 2017; Cheson et al, 2003].  
[Phase 1 part] 
The assessment will be performed by the investigator. The results of bone marrow findings 
and peripheral blast count will be entered into the eCRF.  
[Phase 2 part] 
Bone marrow aspiration and/or biopsy samples and hematology samples are evaluated both 
centrally and locally. If bone marrow samples were obtained for unscheduled visits, those 
samples along with hematology samples should be submitted for central assessment. 
Definitions 
Complete Remission (CR): 
CR is defined as a morphologically leukemia-free state at the post-baseline visit, having a 
neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow 
myeloblasts < 5%. There must be no evidence of Auer rods and no evidence of 
extramedullary leukemia. The blast counts in peripheral blood must be ≤ 2%. 
Complete Remission with Partial Hematologic Recovery (CRh): 
CRh is defined as a condition at the post baseline visit, having bone marrow myeloblasts < 
5%, partial hematologic recovery neutrophil count≥ 500/mm3 and platelet count ≥ 
50,000/mm3, no evidence of extramedullary leukemia and cannot be classified as CR. The 
blast counts in peripheral blood must be ≤ 2%. 
Complete Remission with Incomplete Platelet Recovery (CRp): 
CRp is defined as a condition that meets all of the CR criteria at the post-baseline visit, 
except for the unrecovered platelet count (< 100,000/mm3). 
Complete Remission with Incomplete Hematological Recovery (CRi): 
CRi is defined as a condition that meets all of the CR criteria at the post-baseline visit, except 
for the unrecovered neutrophil count (< 1,000/mm3) whether or not having unrecovered 
platelet counts). 
Partial Remission (PR): 


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At a post-baseline visit, PR is defined as a condition with regeneration of normal 
hematopoietic cells in the bone marrow.  
If bone marrow myeloblasts between 5% and 25% and a decrease from baseline of at least 
50% in the marrow myeloblasts, no detectable (or trace of residual) blasts, and no evidence 
of extramedullary leukemia, the response is classified as PR.  
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 done, the response will be classified as 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% myeloblasts in the bone marrow 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 myeloblasts in the bone marrow to > 25% or >2% 
blast in peripheral blood 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 
PR will be classified as non-responders. 
6.1.2 
Primary Efficacy Endpoint 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
● 
CR rate after induction therapy period 
Defined as the number of subjects who achieve the best response of CR divided by the 
number of subjects in the analysis population during induction therapy period. Subjects with 
unknown or missing response, or who provide no information on response will be treated as 
non-responders and will be included in the denominator when calculating rates. 
6.1.3 
Secondary Efficacy Endpoints 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 


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● 
Overall survival (OS) 
OS is defined as the time from start date of the first treatment until the date of death due to 
any cause. For a subject who is not known to have died by the end of long-term follow-up, 
OS is censored at the date of last known alive. 
As a sensitivity analysis, OS is defined similarly as the above, however, subjects who 
undergo HSCT will be censored at the time of HSCT. 
● 
Event free survival (EFS) 
The time from the date of start date of the first treatment until the date of documented relapse 
after CR, treatment failure or death from any cause, whichever occurs first. For a subject with 
none of these events, EFS is censored at the date of last disease assessment. Subject without 
post-treatment disease assessment will be censored at the start date of the treatment. 
Treatment failure includes those subjects who failed to achieve CRc by the end of 
consolidation period, or who discontinued the treatment due to “lack of efficacy” without a 
previous response. 
Treatment failure date refers to the end of treatment date for subjects with treatment failure. 
● 
Relapse free survival (RFS)  
The time from the date of achievement of first CRc until relapse or death from any cause, 
whichever comes first for subjects who achieve CRc. For a subject who is not known to have 
relapsed or died, RFS is censored on the date of last relapse-free disease assessment date. 
Last relapse-free disease assessment date refers to the subject’s last disease assessment date. 
● 
CR rate after each treatment therapy 
Defined as the number of subjects who achieve the best response of CR divided by the 
number of subjects in the analysis population after each treatment therapy period. 
Subjects with unknown or missing response, or who provide no information on response will 
be treated as non-responders and will be included in the denominator when calculating rates. 
● 
CR rate without MRD after each treatment therapy 
Defined similarly as CR rate after each treatment therapy. Responders achieve that the best 
response is CR and MRD status is negative. CRc rate without MRD after each treatment 
therapy will also be defined similarly. 
● 
CRh rate after each treatment therapy 
Defined similarly as CR rate after each treatment therapy. 
● 
CRc (Composite CR) rate after each treatment therapy 
CRc: CR + CRp + CRi 
Defined similarly as CR rate after each treatment therapy. 
● 
CR/CRh rate after each treatment therapy 
CR/CRh: CR or CRh. 
Defined similarly as CR rate after each treatment therapy.  
● 
Duration of CR, CR/CRh, CRh, CRc, response 
Duration of CR is defined as the time from the date of achieving first CR until the date of 
first documented relapse for subjects who achieve CR. Subjects who die without report of 


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relapse are considered non-events and censored at their last relapse-free disease assessment 
date. Subjects who come off the study for HSCT will be considered non-events and censored 
at the time of HSCT. Other subjects who do not relapse on study are considered non-events 
and censored at the last relapse-free assessment date. Duration of CRh, Duration of CR/CRh, 
Duration of CRc and Duration of response are defined similarly as Duration of CR. 
6.1.4 
Exploratory Efficacy Endpoints 
[Phase 1 part] 
● 
CR rate 
Defined as the number of subjects with CR divided by the number of subjects in the 
analysis population. Subjects with unknown or missing response, or who provide no 
information on response at the end of study will be treated as non-responders and will be 
included in the denominator when calculating rates. 
● 
CRp rate 
Defined similarly as CR rate. 
● 
CRi rate 
Defined similarly as CR rate. 
● 
CRc rate 
Defined similarly as CR rate. 
● 
PR rate 
Defined similarly as CR rate. 
● 
Overall response rate: CRc + PR 
Defined similarly as CR rate. 
● 
Duration of response – Duration of response is defined as the period from the first date 
of achieving CR, CRp, CRi, or PR to the first date of documented relapse for subjects 
who achieve CR, CRp, CRi, or PR. Subjects who die without report of relapse are 
considered non-events and censored at their last relapse-free disease assessment date. 
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 is defined similarly as duration of response for subjects who achieved 
CR. 
● 
Duration of CRc is defined similarly as duration of response for subjects who achieved 
CRc. 
[Phase 2 part] 
● 
Transplantation rate 
Transplantation rate is defined as the percentage of subjects undergoing HSCT during the 
study period. 
● 
Cumulative incidence of relapse (CIR) after 1st CR (CR1) 
Defined as the time from the date of achieving CR1 until relapse. When calculating this 
variable, only subjects who achieved CR1 are included. Subjects alive without relapse will be 
censored on the date of last relapse-free disease assessment date. Although subjects who died 
without relapse should be treated as the subjects who occurred competing event, those 


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subjects will be censored at the date of death. 
● 
Cumulative incidence of death (CID) after CR1 
Defined as the time from the date of achieving CR1 until death. When calculating this 
variable, only subjects who achieved CR1 are included. Subjects who are alive without death 
will be censored at the date of last known alive. 
● 
Time to hematopoietic recovery after each treatment cycle 
Defined as the time from the date of start date of the treatment until the date of having a 
neutrophil count of ≥ 1,000/ mm3 and platelet count of ≥ 100,000/ mm3. Subjects with none 
of these events are censored at the date of last assessment within each treatment cycle. 
● 
MRD 
MRD is defined as binary endpoint, negative or positive. More detail of the definition is in 
Section 6.5. MRD rate is defined as the percentage of subjects whose MRD is negative. 
● 
MR 
MR is defined as binary endpoint, MR or no MR. More detail of the definition is in Section 
6.5. MR rate is defined as the percentage of subjects who achieve MR. 
● 
MRD-negative CR rate after induction 
Defined as the number of subjects who achieve the best response of CR and whose MRD is 
negative during induction period divided by the number of subjects in the analysis population 
during induction therapy period. Subjects with unknown or missing response, or who provide 
no information on response will be treated as non-responders and will be included in the 
denominator when calculating rates. 
● 
Overall MRD-negative CR rate for any treatment period 
Defined as the number of subjects who achieve the best response of CR and at least one post-
baseline MRD is negative divided by the number of subjects in the analysis population. If 
subjects have multiple MRD samples collected across different timepoints, the overall MRD 
status is negative if there is at least one MRD sample is negative and the overall MRD status 
is positive if all available MRD samples are positive. Subjects with unknown or missing post-
baseline MRD status, or who provide no information on post-baseline MRD status will be 
treated as MRD positive and will be included in the denominator when calculating rates. 
6.2 
Safety Variables  
Safety will be assessed by evaluation of the following variables:  
● 
Occurrence of DLTs (Phase 1 part only) 
● 
Adverse events (AEs) 
A treatment-emergent adverse event (TEAE) is defined as an AE observed after starting 
administration of the study drug. If the adverse event occurs on first administration date of 
the study drug and the onset check box is marked “Onset after first ASP2215 taken” or the 
onset check box is left blank, then the adverse event will be considered treatment emergent. 
If the adverse event occurs on first administration date of the study drug and the onset check 
box is marked “Onset before first ASP2215 taken”, then the adverse event will not be 
considered treatment emergent. If a subject experience an event both before starting 
administration of the study drug and after starting administration of the study drug, the event 
will be considered as TEAE only if it has worsened in severity (i.e. it is reported with a new 


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start date). All adverse events collected that begin within 30 days after taking the last dose of 
the 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 drug 
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 drug or 
30 days after the last dose of study drug. Missing or partial AE onset date will be imputed per 
Section 7.11.1. 
ASP2215-related TEAE is defined as any TEAE with at least possible relationship (possibly 
or probably related) to ASP2215 as assessed by the investigator or with missing assessment 
of the causal relationship 
A regimen-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.  
● 
Laboratory parameters 
● 
Vital signs 
● 
12-lead ECG: including QT assessment 
6.3 
Pharmacokinetic Variables  
● 
Plasma concentration of ASP2215 and Cytarabine 
● 
Pharmacokinetic parameters of ASP2215 
6.4 
Pharmacodynamic Variables 
[Phase 1 part] 
● 
Total FLT3 concentration 
● 
Total AXL concentration 
[Phase 2 part] 
Not applicable. 
6.5 
Other Variables 
● 
FLT3-ITD mutation status 
● 
FLT3-TKD mutation status 
● 
FLT3 mutation status 
Either of FLT3-ITD mutation status or FLT3-TKD mutation status is positive, this 
variable shows positive. 
● 
MRD 
MRD negative is defined as summed FLT3-ITD signal ratio of any post-baseline sample 
≤10−4. MRD positive is defined as summed FLT3-ITD signal ratio of any post-baseline 
sample> 10−4. 


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● 
MR 
MR is defined as summed FLT3-ITD signal ratio of any post-baseline sample ≤10−2. 
No MR is defined as summed FLT3-ITD signal ratio of any post-baseline sample>
10−2. 
● 
FLT3-ITD signal ratio 
FLT3-ITD signal ratio is defined as the ratio of FLT3-ITD sequence reads divided by the 
total number of FLT3 sequence reads. This is being calculated by central laboratory. For 
subjects with more than one FLT3-ITD variant, the FLT3-ITD signal ratio will be 
summed at each timepoint. 
● 
Duration of exposure (days) 
Duration of exposure to each treatment will be calculated in days, using the following 
formula: 
○ 
Duration of exposure for each treatment cycle is defined as Last dose date – First 
dose date + 1 – (on-study HSCT period for subjects undergo on-study HSCT) for 
each cycle. For Phase1 part, last dose date of study drug exposure = (initial dose 
date of the cycle + 14 – 1) if last dose date of the cycle is not captured on dosing 
CRF. 
○ 
Duration of exposure for each treatment period is calculated as sum of the duration 
of exposure for each treatment cycle. 
○ 
Duration of exposure during study for study drug =  
(Duration of exposure for Induction period) + (Duration of exposure for 
Consolidation period) + (Duration of exposure for Maintenance period). 
When the last date of exposure is beyond cutoff date, the cutoff date will be used as the 
last date of exposure. When the start or stop date is missing, then the exposure will be 
treated as missing. 
● 
Number of dosing days (days) 
Defined as number of days with non-zero dosing. 
Number of dosing days is calculated for each treatment period. 
● 
Cumulative dose (mg or g) 
Defined as total amount of drug given to a patient, which calculated as follows: 
○ 
ASP2215: Sum of (actual dose level * number of dosing days within each dose 
level) 
○ 
Chemotherapy: Sum of actual dose across the days when administered. 
Actual dose is calculated as: 
(Actual volume administered / Total volume prepared)* Intended dose * Body 
surface area. 


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If number of doses taken is unknown, it will be treated as missing. 
Cumulative dose is calculated for each treatment period. 
● 
Average of daily dose (mg/day or g/day) 
Defined as cumulative dose divided by number of dosing days. 
Average of daily dose is calculated for each treatment period. 
● 
Dose intensity (mg/day or g/day) 
Represents unit of dose given to a patient per unit of time, calculated as cumulative dose 
divided by duration of exposure. 
Dose intensity is calculated for each treatment period. 
● 
Relative dose intensity (%) 
Defined as dose intensity divided by planned dose intensity * 100%.  
Relative dose intensity is calculated for each treatment period. 
Where planned dose intensity (mg/day or g/day) will be calculated as follows: 
○ 
ASP2215: 120 mg 
○ 
Cytarabine, Induction for Phase 1 part: Calculated Dose in mg on CRF 
○ 
Cytarabine, Induction for Phase 2 part: 100 mg/m^2 * BSA 
○ 
Cytarabine, Consolidation for Phase 1 part: Calculated Dose (sum of Infusion 1 
and 2) in g on CRF 
○ 
Cytarabine, Consolidation for Phase 2 part: 1.5 g/m^2 * BSA * 2 times 
○ 
Idarubicin for Phase 1 part: Calculated Dose in mg on CRF 
○ 
Idarubicin for Phase 2 part: 12 mg/m^2 * BSA 
Average of BSA and Calculated Dose across the days when administered will be used 
in the calculation of planned dose intensity. 
● 
Previous and concomitant medication 
The period of evaluation for previous medications is as follows:  
o 
28 days before Day 1 of induction period – before Day 1 of induction period. 
Concomitant medication is defined as medication used between Day 1 of induction 
period and the last dose of treatment. For subjects who 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 Day1 of induction period and 
the start of the HSCT conditioning regimen, or between resumption of ASP2215 and the 
last dose of the study drug. 
● 
Previous and concomitant transfusion 


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Previous transfusion is defined as transfusion received before Day 1 of induction period, 
i.e. transfusion completed before Day 1 of induction period. 
Concomitant transfusion is defined as transfusion received between Day 1 of induction 
period and the last dose of treatment. For subjects who undergo HSCT without leaving 
the study and plan to resume ASP2215 treatment after HSCT, concomitant transfusion is 
defined as transfusion received between Day1 of induction period and the start of the 
HSCT conditioning regimen, or between resumption of ASP2215 and the last dose of the 
study drug. 
7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
● 
For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation, minimum, Q1, median, Q3 and maximum. When needed, the 
use of other percentiles (e.g.10% and 90%) will be mentioned in the relevant Section. 
● 
For continuous PK parameters, the coefficient of variation will be calculated, and for 
Cmax and AUCs, the geometric mean will also be calculated. GM will not be calculated if 
at least one value is the BLQ. 
● 
tmax will be summarized using median and range.  
● 
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%. 
● 
All data processing, summarization, and analyses will be performed using SAS (ver. 9.4) 
or higher on Red Hat Enterprise Linux. 
● 
Specifications for Table, Figures, and data listing formats can be found in the TLF 
specifications for this study. 
● 
MedDRA (version 23.0) will be used as the coding dictionary for adverse event and 
medical history. 
● 
WHODD(B2) (V2016Sep) for Phase 1 part and WHODD(B3) (V2018Mar) for Phase 2 
part will be used as the coding dictionary for previous and concomitant medications. 
● 
The assessments impacted by COVID-19 will be listed and sensitivity analyses to assess 
the impact of COVID-19 for some efficacy may be performed if needed. 
● 
[Phase 1 part] All analysis will be presented by the dose-evaluation part, expansion part 
and overall, unless specifically stated otherwise. 
● 
[Phase 1 part] The data of a subject who was allocated to ASP2215 40 mg per day will 
be used only for listings. 
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
[Phase 1 part] 
The following subject data will be presented: 


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● 
Number and percentage of subjects with informed consent, discontinued before 
allocation to the treatment, allocated to the treatment (overall only). 
● 
Number and percentage of subjects who were included/excluded in each analysis set. 
● 
Number and percentage of subjects excluded from each analysis set by reason. 
● 
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation for subjects allocated to the treatment. 
● 
Number and percentage of subjects completed and discontinued the post-study, by 
primary reason for post-study discontinuation for subjects allocated to the treatment. 
[Phase 2 part] 
● 
Number and percentage of subjects with informed consent, discontinued before pre-
registration to the study, allocation to the treatment, discontinued before registration to 
the study and allocation to study drug. 
● 
Number and percentage of subjects completed and discontinued the pre-registration 
period, by primary pre-registration status. 
● 
Number and percentage of subjects completed and discontinued the registration period, 
by primary registration status. 
● 
Number and percentage of subjects who were included/excluded in each analysis set. 
● 
Number and percentage of subjects excluded from each analysis set by reason. 
● 
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation for subjects allocated to the treatment. 
● 
Number and percentage of subjects completed and discontinued the follow-up, by 
primary reason for follow-up discontinuation for subjects allocated to the treatment. 
● 
Number and percentage of subjects completed and discontinued the long-term follow-up, 
by primary reason for long-term follow-up discontinuation for subjects allocated to the 
treatment. 
7.2.2 
Protocol Deviations 
[Phase 1 part] 
Not applicable. 
[Phase 2 part] 
Protocol deviations as defined in the study protocol (Section 10.3 Major Protocol Deviations) 
will be assessed for all subjects who received treatment. The number and percentage of 
subjects meeting any criteria will be summarized for each criterion and overall, 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, 


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PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment.   
7.2.3 
Demographic and Other Baseline Characteristics 
[Phase 1 part] 
Analysis set: SAF, FAS, DDAS, PKAS, PDAS 
Demographic and other baseline characteristics will be summarized by descriptive statistics 
or categorical analysis.  
The following demographic variables will be summarized and presented. 
Table 1.1. Demographic Variables and Analysis Methods for all analysis sets 
Item 
Classification 
Analysis Methods 
Age (years) 
Measurement value 
<65 years, >=65 years 
Descriptive statistics 
Categorical analysis 
Height [Screening](cm) 
Measurement value 
Descriptive statistics 
Weight (kg) 
Measurement value 
Descriptive statistics 
BMI (kg/m^2) 
BMI (kg/m^2) = Weight (kg) / (Height 
(cm) / 100)^2 
Descriptive statistics 
BSA (m^2) 
BSA (m^2) = Weight (kg) ^ 0.425 x 
Height (cm) ^ 0.725 x 0.007184 
Descriptive statistics 
Subject ECOG Status 
0, 1, 2, 3, 4 
Categorical analysis 
Sex 
Male, Female, Unknown 
Categorical analysis 
Race 
White, Black or African American, 
Asian, American Indian or Alaska 
Native, Native Hawaiian or Other 
Pacific Islander, Other 
Categorical analysis 
BMI: Body Mass Index, BSA: Body Surface Area, ECOG: Eastern Cooperative Oncology Group 
[Phase 2 part] 
Analysis set: SAF, FAS, PKAS, MAS 
Demographic and other baseline characteristics will be summarized by descriptive statistics 
or categorical analysis. 
The following demographic variables will be summarized and presented. 


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Table 1.2. Demographic Variables and Analysis Methods for all analysis sets 
Item 
Classification 
Analysis Methods 
Age (years) 
Measurement value 
<65 years, >=65 years 
Descriptive statistics 
Categorical analysis 
Height [Screening](cm) 
Measurement value 
Descriptive statistics 
Weight [Screening] (kg) 
Measurement value 
Descriptive statistics 
BMI (kg/m^2) 
BMI (kg/m^2) = Weight (kg) / 
(Height (cm) / 100)^2 
Descriptive statistics 
BSA (m^2) 
BSA (m^2) = Weight (kg) ^ 0.425 x 
Height (cm) ^ 0.725 x 0.007184 
Descriptive statistics 
Subject ECOG Status 
0, 1, 2, 3, 4 
Categorical analysis 
Sex 
Male, Female, Unknown 
Categorical analysis 
Race 
White, Black or African American, 
American Indian or Alaska Native, 
Asian Indian, Chinese, Filipino, 
Japanese, Korean, Taiwanese, 
Vietnamese, Other Asian, Native 
Hawaiian, Guamanian or Chamorro, 
Samoan and Other Pacific Islander 
Categorical analysis 
Region 
Japan, Korea, Taiwan 
Categorical analysis 
BMI: Body Mass Index, BSA: Body Surface Area, ECOG: Eastern Cooperative Oncology Group 
 
Analysis set: SAF 
Frequency tabulations for AML disease history including AML subtype as classified by 
WHO classification and FAB classification, risk status with specific cytogenetic patterns, 
antecedent hematological disorder (Phase 1 part only), central nervous system leukemia 
(Phase 1 part only), FLT3-ITD mutation status (Phase 1 part only), FLT3 point mutation 
status (Phase 1 part only) will be presented. 
Medical history other than AML will be coded in MedDRA and summarized by SOC and PT 
as well as by PT alone. 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 
the treatment. For ongoing medical conditions, CTCAE grade will be provided in listing. 
Result from MUGA scan or ECHO, if performed, will be provided in listing. 
7.2.4 
Previous and Concomitant Medications  
Analysis set: SAF 
Previous medications are coded with WHODD and will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO 
name. 
As with previous medication, concomitant medication will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO 
name. 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. 


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Concomitant medication will also be summarized by preferred WHO name, and presented in 
decreasing order of frequency based on the total number of subjects took each medication. 
7.2.5 
Previous and Concomitant Transfusions 
Analysis set: SAF 
Frequency tabulations of subjects received transfusions and blood product will be presented for 
previous transfusion and concomitant transfusion. Descriptive statistics will be presented for 
number of transfusion unit received per subject for each type of blood product. 
7.2.6 
Non-Medication Therapy 
Analysis set: SAF 
Frequency tabulations of subjects with non-medication therapy and reason for use will be 
presented. Number of non-medication therapy received per subject will be summarized using 
descriptive statistics. 
7.3 
Study Drugs 
7.3.1 
Exposure 
Analysis set: SAF 
The following information on ASP2215 exposure will be presented: 
● 
Descriptive statistics for cumulative dose of the treatment subject was exposed to, 
number of dosing days, average of daily dose, dose intensity, and relative dose intensity; 
and  
● 
Number and percent of subject with dose reduction and interruption. 
Duration of exposure will be summarized in two ways: 
● 
Descriptive statistics will be presented. 
● 
Exposure time will be categorized according to the following categories (study drug 
only): 
○ less than 14 days 
○ at least 14 days, less than 42 days  
○ at least 42 days, less than 84 days  
○ at least 84 days, less than 168 days 
○ 168 days or more 
○ Unknown. 
Number and percentage of subjects in each of these categories will be summarized. 
Listing of subjects with dose reduction and interruption will also be provided. 
7.4 
Analysis of Efficacy 
[Phase 1 part] 
The efficacy analysis will be performed on the FAS. 


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For response variables, best response after each treatment therapy period will be summarized. 
The number and percentage of subjects in each category will be presented together with two-
sided exact 95% CIs based on binomial distribution. Swimmer’s plot will be presented for 
response variables. 
For time-to-event variables efficacy analysis will be summarized using descriptive statistics. 
The survival curve and the median will be estimated using the Kaplan-Meier method and will 
be reported along with the corresponding 95% CIs. 
[Phase 2 part] 
The efficacy analysis will be performed on the FAS and TTE-FAS. The interpretation of 
statistical results will be based on the FAS. The TTE-FAS will be used to analyze OS and 
EFS. Analysis of MRD and MR will be performed using MAS. 
Primary efficacy variable 
For primary efficacy variable, CR rate after induction therapy period, the two-sided 90% 
exact CI by Clopper-Pearson method will be calculated. The lower limit will be used to 
compare with the benchmark of CR rate of 55%. The number and percentage of subjects in 
each category and swimmer’s plot will also be presented. As a supportive analysis, CR rate 
after induction therapy period reported by Day 60 and CR rate after induction therapy period 
not being dependent on RBC and platelet transfusion (No Transfusion of RBC and Platelet 
within 1 week prior to disease assessment) will also be calculated. 
Other efficacy variables 
For other efficacy variables, analysis method will be described as follows: 
Categorical variables: 
The number and percentage of subjects in each category will be presented together with two-
sided exact 95% CIs based on binomial distribution. Swimmer’s plot will be presented for 
response variables. 
For response assessment variables, best response rate after each treatment therapy will be 
summarized. The number and percentage of subjects in each category will be presented 
together with two-sided exact 95% CIs based on binomial distribution. For subjects who 
undergo HSCT, any response assessment data after HSCT will not be used (i.e. for those 
subjects, only response assessment data before HSCT will be used). 
As a sensitivity analysis, response assessment will be defined similarly as the above analysis, 
however, all response assessment data will be used even if there were subjects who undergo 
HSCT (i.e. response assessment data after HSCT will also be used). 
 
Time-to-event variables: 
For time-to-event variables efficacy analysis will be summarized using descriptive statistics. 
The survival curve and the median will be estimated using the Kaplan-Meier method and will 
be reported along with the corresponding 95% CIs. Kaplan-Meier plot will be presented. 
7.5 
Analysis of Safety 
Some analyses that do not depend on the measurement time point such as the summary of 
TEAEs will be performed for not only Phase 1 part and Phase 2 part separately but also 
Phase 1/Phase 2 part totally. The details are described in the following Sections. 


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7.5.1 
DLT (Phase 1 part only) 
Analysis set: DDAS 
The following data will be summarized for the DDAS. 
● 
For DLT incidence, the number and percentage of subjects will be summarized. 
● 
The posterior mean of the DLT rate will be estimated from the Bayesian-CRM using the 
following statistical models. 
The dose-response relationship against DLT occurrence assumes power model, as shown 
below. 
The occurrence of DLTs for each patient should follow the Bernoulli distribution. 
Power model: 
Pr(𝑌𝑖𝑘= 1|𝑑𝑜𝑠𝑒= 𝑑𝑘) = 𝜋(𝑥𝑘, 𝛼) = 𝑥𝑘
exp(𝛼) 
where α is the model parameter, 𝑥𝑘 is the skeleton of DLT incidence probability in the dose 
for number k used in the statistical model, 𝑑𝑘 is the administered dose level of number k, 𝑌𝑖𝑘 is 
the presence/absence of DLT in subject i and dose level of number k (1 is present) and π(•) is 
the probability of DLT occurrence under given conditions. 
Prior distribution of parameters assumed a normal distribution with the mean as 0 and 
variance as 1.26. Using the ESS, the variance of the prior distribution of a parameter α was 
set so that the information content of prior distribution in the power model is approximately 1 
subject.  
The skeletons to be used in the statistical model are 𝑥1 = 0.08 and 𝑥2 = 0.17. 
7.5.2 
Adverse Events (AEs) 
[Phase 1 part, Phase 2 part, Phase 1/Phase 2 part] 
Analysis set: SAF 
AEs will be coded using MedDRA and graded using NCI-CTCAE (V4.0). All AE recorded 
on treatment including within 30 days after the last administration will be summarized. 
TEAEs will be graded using National Cancer Institute’s Common Terminology Criteria for 
AEs (NCI-CTCAE). 
An overview table will include the following details: 
● 
Number and percentage of subjects with TEAEs 
● 
Number and percentage of subjects with ASP2215-related TEAEs 
● 
Number and percentage of subjects with regimen-related TEAEs 
● 
Number and percentage of subjects with serious TEAEs 
● 
Number and percentage of subjects with ASP2215-related serious TEAEs 
● 
Number and percentage of subjects with regimen-related serious TEAEs 
● 
Number and percentage of subjects with TEAEs leading to dose reduction of ASP2215 
● 
Number and percentage of subjects with ASP2215-related TEAEs leading to dose 
reduction of ASP2215 


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● 
Number and percentage of subjects with regimen-related TEAEs leading to dose 
reduction of ASP2215 
● 
Number and percentage of subjects with TEAEs leading to dose interruption of 
ASP2215 
● 
Number and percentage of subjects with ASP2215-related TEAEs leading to dose 
interruption of ASP2215 
● 
Number and percentage of subjects with regimen-related TEAEs leading to dose 
interruption of ASP2215 
● 
Number and percentage of subjects with TEAEs leading to withdrawal of treatment 
● 
Number and percentage of subjects with ASP2215-related TEAEs leading to withdrawal 
of treatment 
● 
Number and percentage of subjects with regimen-related TEAEs leading to withdrawal 
of treatment 
● 
Number and percentage of subjects with TEAEs leading to death 
● 
Number and percentage of subjects with ASP2215-related TEAEs leading to death 
● 
Number and percentage of subjects with regimen-related TEAEs leading to death 
● 
Number and percentage of subjects with grade 3 or higher TEAEs 
● 
Number and percentage of subjects with ASP2215-related grade 3 or higher TEAEs 
● 
Number and percentage of subjects with regimen-related grade 3 or higher TEAEs 
● 
Number and percentage of subjects with deaths 
● 
Number of TEAEs 
● 
Number of ASP2215-related TEAEs 
● 
Number of regimen-related TEAEs 
● 
Number of serious TEAEs 
● 
Number of ASP2215-related serious TEAEs 
● 
Number of regimen-related serious TEAEs 
● 
Number of TEAEs leading to dose reduction of ASP2215 
● 
Number of ASP2215-related TEAEs leading to dose reduction of ASP2215 
● 
Number of regimen-related TEAEs leading to dose reduction of ASP2215 
● 
Number of TEAEs leading to dose interruption of ASP2215 
● 
Number of ASP2215-related TEAEs leading to dose interruption of ASP2215 
● 
Number of regimen-related TEAEs leading to dose interruption of ASP2215 
● 
Number of TEAEs leading to withdrawal of treatment 
● 
Number of ASP2215-related TEAEs leading to withdrawal of treatment 
● 
Number of regimen-related TEAEs leading to withdrawal of treatment 
● 
Number of TEAEs leading to death 
● 
Number of ASP2215-related TEAEs leading to death 
● 
Number of regimen-related TEAEs leading to death 
● 
Number of grade 3 or higher TEAEs 
● 
Number of ASP2215-related grade 3 or higher TEAEs 
● 
Number of regimen-related grade 3 or higher TEAEs 
 


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The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized. Summaries will be provided for: 
● 
TEAEs 
● 
ASP2215-related TEAEs 
● 
Regimen-related TEAEs 
● 
Serious TEAEs 
● 
ASP2215-related serious TEAEs 
● 
Regimen-related serious TEAEs 
● 
TEAEs leading to dose reduction of ASP2215 
● 
ASP2215-related TEAEs leading to dose reduction of ASP2215 
● 
Regimen-related TEAEs leading to dose reduction of ASP2215 
● 
TEAEs leading to dose interruption of ASP2215 
● 
ASP2215-related TEAEs leading to dose interruption of ASP2215 
● 
Regimen-related TEAEs leading to dose interruption of ASP2215 
● 
TEAEs leading to withdrawal of treatment 
● 
ASP2215-related TEAEs leading to withdrawal of treatment 
● 
Regimen-related TEAEs leading to withdrawal of treatment 
● 
TEAEs leading to death 
● 
ASP2215-related TEAEs leading to death 
● 
Regimen-related TEAEs leading to death 
● 
Grade 3 or higher TEAEs 
● 
ASP2215-related grade 3 or higher TEAEs 
● 
Regimen-related grade 3 or higher TEAEs 
● 
Common (>=10%) TEAEs excluding serious adverse events 
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.   
The number and percentage of subjects with TEAEs, as classified by SOC and PT will also 
be summarized by NCI-CTCAE severity grade and by relationship to ASP2215 and regimen. 
In the subject count, if a subject has multiple TEAEs with the same SOC or PT, but with 
differing severity grade or relationship, then the subject will be counted only once with the 
worst severity grade and highest degree of relationship, however, if any of the severity grade 
or relationship values are missing then the subject will be counted only once with missing 
severity grade or relationship. 
AESI are defined in the Safety Review Plan for ASP2215 as specified in (Appendix 2). 
The number and percentage of subjects with TEAE of special safety interest, as classified by 
AESI category and PT will be summarized for the followings: 
● 
TEAEs with special safety interest 
● 
Grade 3 or higher TEAEs with special safety interest 


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● 
ASP2215-related Grade 3 or higher TEAEs with special safety interest 
● 
Regimen-related Grade 3 or higher TEAEs with special safety interest 
All AEs, deaths, SAEs and withdrawals due to AEs will be displayed in listings. 
7.5.3 
Clinical Laboratory Evaluation 
Analysis set: SAF 
All clinical laboratory evaluations including hematology and bone marrow, biochemistry, 
coagulation and urinalysis will be performed locally (for Phase 2 par, both centrally and 
locally).  
The baseline visit is the last measurement taken prior to initial treatment. 
 Quantitative clinical laboratory variables, i.e. hematology, biochemistry, coagulation and 
urinalysis will be summarized using mean, standard deviation, minimum, maximum and 
median by measurement time point. 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 L, N, or H by measurement time point 
according to supplied reference ranges. SI unit will be used for display. Summary shifts in 
each laboratory test result will be presented by measurement time point. 
The number and percentage of subjects below and above reference range will be summarized 
by measurement time point. 
Frequency tabulations of qualitative clinical laboratory variable (urinalysis) will be presented 
by measurement time point. 
For hematology and biochemistry two types of shift tables will be presented:  
● 
Shift tables of reference range changes from baseline to each treatment visit (low, 
normal, high), and 
● 
Summary shifts of reference range changes from baseline to each treatment visit (shift 
from normal or high to low, shift from normal or low to high, categorized increase [shift 
from low to normal or from normal to high], categorized no change [value stays in the 
same reference range], categorized decrease [shift from high to normal or from normal to 
low]). 
 
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. NCI-CTCAE grade of laboratory 
evaluations will be summarized by number and percentage of subjects by measurement time 
point. Shift tables of NCI-CTCAE grade change from baseline to worst post-baseline grade 
will also be presented. 
Bone marrow results will be listed only. 


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7.5.3.1 Liver function tests  
The following potentially clinically significant criteria in liver function tests for ALP, ALT, 
AST and their combination are defined. The subject’s highest value during the investigational 
period will be used.  
 
Parameter 
 
 
 
 
Criteria 
ALT 
  
 
 
 
 
> 3xULN 
 
  
 
 
 
 
> 5xULN 
 
  
 
 
 
 
> 8xULN 
 
  
 
 
 
 
> 10xULN 
 
  
 
 
 
 
> 20xULN 
AST 
 
 
 
 
 
> 3xULN 
 
  
 
 
 
 
> 5xULN 
 
  
 
 
 
 
> 8xULN 
 
  
 
 
 
 
> 10xULN 
 
 
 
 
 
 
> 20xULN 
ALT or AST   
 
 
 
> 3xULN 
 
  
 
 
 
 
> 5xULN 
 
  
 
 
 
 
> 8xULN 
 
  
 
 
 
 
> 10xULN 
 
  
 
 
 
 
> 20xULN 
Total Bilirubin  
 
 
 
> 2xULN 
ALP 
 
 
  
 
 
> 1.5xULN 
ALT and/or AST AND Total Bilirubin(*) 
(ALT and/or AST > 3xULN) and  
total bilirubin > 2xULN 
ALT and/or AST AND  
Alkaline Phosphatase AND   
 
ALT and/or AST > 3xULN AND Alkaline  
Total Bilirubin(*) 
 
 
 
Phosphatase < 2xULN 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 for Phase 1 
part, Phase 2 part and Phase 1/Phase 2 part totally. 
 
7.5.4 
Vital Signs 
Analysis set: SAF 
The baseline visit is the last measurement taken prior to initial treatment. 
Vital signs (systolic blood pressure, diastolic blood pressure, pulse and body temperature) 
will be summarized using mean, standard deviation, minimum, maximum and median by 
measurement time point. Additionally, a within-subject change will be calculated per 


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measurement time point as the post-baseline measurement minus the baseline measurement 
and summarized by measurement time point. 
Tables for potentially clinically significant vital signs will be generated using baseline value 
and highest value obtained during treatment for each subject for Phase 1 part, Phase 2 part 
and Phase 1/Phase 2 part totally. 
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 
≥120 bpm AND ≥15 bpm change from baseline 
DBP: Diastolic Blood Pressure; SBP: Systolic Blood Pressure 
 
7.5.5 
Electrocardiograms (ECGs) 
Analysis set: SAF 
The 12-lead ECG will be measured at the scheduled time points. 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. 
ECG variables will be summarized using mean, standard deviation, minimum, maximum and 
median for each measurement time point, including changes from baseline. 
Number and percentage of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the overall 
interpretation of 12 lead ECG will be tabulated by measurement time point. A shift analysis 
table showing shift in overall ECG interpretation from baseline to each time point will be 
provided. The worst of the three overall ECG interpretations will be used as the time-specific 
overall ECG interpretation for a subject. 
The QT interval corrected for heart rate by Fridericia’s formula, QTcF, is defined as: QTc (F) 
= QT/(RR)0.33. 
The QTcF interval variables will be summarized by the frequencies of subjects with 
following categories for each measurement time point. 
 
QTc Interval Criteria Value (msec) 
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450 to ≤ 480 
> 480 to ≤ 500 
> 500 
QTc: Corrected Q-T Interval 
The change from baseline of QTcF interval variables will be summarized by the frequencies 
of subjects with following categories for each measurement time point. 


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Variable 
Change from Baseline 
QTc Interval (msec) 
<0  
≥ 0 to ≤ 30  
> 30 to ≤ 60  
> 60  
QTc: Corrected Q-T Interval 
7.5.6 
ECOG Performance Status 
Analysis set: SAF 
Number and percentage of subjects for each category of the ECOG performance status at 
each assessment time will be provided. Negative change scores indicate an improvement and 
positive scores indicate a decline in performance. 
ECOG scores will also be summarized using shift table from baseline to post-baseline score 
by visit. 
7.6 
Analysis of PK 
The pharmacokinetic analysis will be performed on the PKAS. For plasma concentrations of 
ASP2215 and Cytarabine, descriptive statistics will be calculated by time and treatment 
period.  
The PK parameters will be calculated using WinNonlin software (Pharsight Corp, Mountain 
View, California, US) version 8.0. Non-compartmental methods will be used to derive the 
values of the PK parameters.  
7.6.1 
Pharmacokinetic ASP2215 Parameters 
 The following PK parameters will be estimated in both induction and consolidation period, 
using plasma concentrations of ASP2215 and actual elapsed times from dosing, provided 
enough data are available for accurate estimations. Exclusion of PK parameter estimates from 
the descriptive statistics will be considered by the pharmacokineticist on a case-by-case basis. 
 
[Phase 1 part] 
Single dose period: AUC24, AUClast, Cmax, and tmax 
[Phase 2 part] 
Not applicable. 
7.6.2 
Change from the Protocol 
Note that ASP2215 has a longer half-life (> 24 hours) than the dosing interval thus the 
following parameters will not be evaluated due to lack of accuracy under the planned PK 
sampling scheme:  
AUCinf, CL/F, Lambda z, t1/2 and Vz/F 


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7.7 
Analysis of PD 
Not applicable for this study except for a subject who was allocated to 40 mg per day. The 
total concentrations of FLT3 and AXL of the subject will be used only for listings. 
7.7.1 
Change from the Protocol 
Inhibition of FLT3 phosphorylation and inhibition of AXL phosphorylation have not been 
measured. 
7.8 
Subgroups of Interest  
[Phase 1 part] 
For analysis of response variable, subgroup analysis will be conducted using the FAS. 
Subgroup is defined on the basis of the categorized variables listed below: 
Grouping variable 
Subgroups 
FLT3-ITD Mutation Status 
Positive 
Negative 
FLT3-TKD Mutation Status  
Positive 
 
 
 
 
 
Negative 
FLT3 Mutation Status  
 
Positive 
 
 
 
 
 
Negative 
[Phase 2 part] 
For primary efficacy analysis and OS analysis, subgroup analysis will be conducted using the 
TTE-FAS. Subgroups are defined on the basis of the categorized variables listed below: 
Grouping variable 
Subgroups 
Age group 
< 65 Years 
>=65 Years 
 
Sex 
Female 
Male 
 
Region 
Japan 
 
Korea 
 
Taiwan 
 
FLT3 Mutation Type 
FLT3-ITD Mutation Status is positive 
FLT3-TKD Mutation Status is positive 
FLT3-ITD Mutation Status and FLT3-TKD Mutation 
Status are positive 
7.9 
Other Analyses 
7.9.1 
FLT3 Mutation Test 
[Phase 1 part] 
Analysis set: SAF, FAS 


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The presence/absence of FLT3-ITD mutation status, FLT3-TKD mutation status, FLT3 
mutation status and FLT3-ITD mutation status/FLT3-TKD mutation status will be 
summarized by frequency at each visit. 
[Phase 2 part] 
Analysis set: SAF, FAS 
FLT3 mutation type will be assessed from bone marrow sample taken at the screening visit or 
at the visit prior to consent. If bone marrow sample is unavailable, the whole blood sample 
taken at the screening visit will be used. The presence of FLT3-ITD mutation status, FLT3-
TKD mutation status and both of them will be summarized by frequency. 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not applicable. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.11.1 Missing Data 
The detail of missing efficacy variable is in Section 6.1. 
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: 
○ If the month and year are present, then impute as the last day of that month.  
○ If only the year is present, impute as December 31 of that year. 
○ 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. 
7.11.2 Outliers 
All values will be included in the analyses. 
7.11.3 LLOQ 
● 
LLOQ for ASP2215 
The LLOQ of the plasma sample which was measured by inVentiv is 10 ng/mL when using 
0.050 mL of plasma.  
As for the plasma sample of P06101 which was measured by ARIA, the LLOQ of the plasma 
sample is 0.5 ng/mL when using 0.050 mL of plasma. 
● 
LLOQ for Cytarabine 
The LLOQ is 0.5 ng/mL when using 0.050 mL of plasma.     
7.11.4 BLQ data 
Plasma concentrations below the LLOQ will be presented as “<LLOQ” in listings while 
treated as zero in the analyses. 
7.11.5 Visit Windows 
 [Phase 1 part] 
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. 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. The baseline visit is the last measurement taken prior to 
initial treatment. 
⚫ Visit Windows for Laboratory Tests 


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Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 
1 day before dosing 
(Before dosing if the 
screening and Day 1 
of Cycle 1 overlap). 
Treatment on Day 1 may 
be started on the day 
informed consent is 
obtained when the 
investigator or 
subinvestigator judges 
that immediate treatment 
is required due to rapid 
proliferative disease 
progression.  In this 
case, among the test 
items specified in both 
screening and Day 1 of 
Cycle 1 are not required 
to be performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
Day 4 
Day 4 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
± 1 day  
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
Day 42 
Day 42 
Scheduled date 
+ 14 days 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
Day 4 
Day 4 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
− 1 day 
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
Cycle X Day 1 
Day 28 (X − 1) + 1 
Scheduled date 
± 3 days 
X = Cycle 2 and 
subsequent cycles 


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End of treatment (for 
any period) or at the 
end of Cycle 26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date 
+ 7 days 
If the scheduled tests at 
discontinuation have 
been performed after the 
final study drug 
administration, the tests 
do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 
⚫ Visit Windows for Vital Signs 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time 
range 
Remarks 
Screening 
— 
7 days before dosing 
–1 day before dosing 
(Before dosing if the 
screening and Day 1 
of Cycle 1 overlap). 
Treatment on Day 1 
may be started on the 
day informed consent is 
obtained when the 
investigator or 
subinvestigator judges 
that immediate 
treatment is required 
due to rapid 
proliferative disease 
progression.  In this 
case, among the test 
items specified in both 
screening and Day 1 of 
Cycle 1 are not required 
to be performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
± 1 day  
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 
Day 42 
Day 42 
Scheduled date 
+ 14 days 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time 
range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date 
 
Day 15 
Day 15 
Scheduled date 
− 1 day 
 
Day 28 
Day 28 
Scheduled date 
± 7 days 
 


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Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time 
range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
Cycle X Day 1 
Day 28 (X − 1) + 1 
Scheduled date 
± 3 days 
X = Cycle 2 and 
subsequent cycles 
End of treatment (for any 
period) or at the end of 
Cycle 26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date 
+ 7 days 
If the scheduled tests at 
discontinuation have 
been performed after the 
final study drug 
administration, the tests 
do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
 
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Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
QT interval assessments 
will not be performed at 
the central ECG 
laboratory 
Day 1  
pre-dose 
Day 1 
Scheduled date, within 30 minutes 
before dosing 
Performed prior to PK 
blood sampling 
Day 4  
pre-dose 
Day 4 
Scheduled date, within 30 minutes 
before dosing 
Day 4  
4 hours post-dose 
Day 4 
Scheduled date, within 
± 30 minutes of the scheduled 
time 
Day 11  
pre-dose 
Day 11 
Scheduled date, within 30 minutes 
before dosing 
Day 17  
pre-dose 
Day 17 
Scheduled date − 1 day, within 
30 minutes before dosing 
Day 17  
4 hours post-dose 
Day 17 
Scheduled date − 1 day, within 
± 30 minutes of the scheduled 
time 
Day 28  
Day 28 
Scheduled date ± 7 days 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1  
pre-dose 
Day 1 
Scheduled date, within 30 minutes 
before dosing 
Performed prior to PK 
blood sampling 
Day 1  
4 hours post-dose 
Day 1 
Scheduled date, within 
± 30 minutes of the scheduled 
time 
Day 2  
pre-dose 
Day 2 
Scheduled date, within 30 minutes 
before dosing 
Day 15  
 
Day 15 
 
Scheduled date − 1 day 
 
Performed prior to PK 
blood sampling.  If 
performed on Day 14 
within the allowed visit 
window [−1] for Day 15, 
12-lead ECG will be 
performed at pre-dose. 
End of treatment (for 
any period) or at the 
end of Cycle 26 of 
the maintenance 
period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
QT interval assessments 
will not be performed at 
the central ECG 
laboratory.  If the 
scheduled tests at 
discontinuation have 
been performed after the 
final study drug 
administration, the tests 
do not have to be 
repeated even if they 
were performed before 
the date of judgment of 
discontinuation. 
ECG: Electrocardiogram 
 


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⚫ Visit Windows for ECOG Performance Status 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
Treatment on Day 1 
may be started on the 
day informed consent 
is obtained when the 
investigator or 
subinvestigator judges 
that immediate 
treatment is required 
due to rapid 
proliferative disease 
progression.  In this 
case, among the test 
items specified in both 
screening and Day 1 
of Cycle 1 are not 
required to be 
performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
Day 8 
Day 8 
Scheduled date  
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
Day 8 
Day 8 
Scheduled date  
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
If the scheduled tests 
at discontinuation 
have been performed 
after the final study 
drug administration, 
the tests do not have to 
be repeated even if 
they were performed 
before the date of 
judgment of 
discontinuation. 
 
⚫ Visit Windows for ECHO or MUGA 


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Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
To be performed on 
patients with a history 
of congestive heart 
failure of NYHA class 
3 or 4 (however, not 
necessary to be 
repeated at screening 
if ECHO or MUGA 
performed within 3 
months prior to 
enrollment showed 
LVEF of ≥ 45%). 
ECHO: Echocardiogram; MUGA: Multiple Gate Acquisition; NYHA: New York Heart Association; LVEF: 
Left Ventricular Ejection Fraction 
 
⚫ Visit Windows for Chest X-Ray or Chest CT 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
 
Chest X-ray or chest CT at screening is not necessary if either was performed within 7 days 
before study enrollment even before obtaining consent.  During any treatment period, chest 
X-ray or chest CT will be performed whenever it is determined to be clinically necessary 
based on the subject’s clinical conditions. 
 
⚫ Visit Windows for Body Height/Weight 
Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
Height is measured 
only at screening. 
 
Treatment on Day 1 
may be started on the 
day informed consent 
is obtained when the 
investigator or 
subinvestigator judges 
that immediate 
treatment is required 
due to rapid 
proliferative disease 
progression.  In this 
case, among the test 
items specified in both 


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screening and Day 1 
of Cycle 1 are not 
required to be 
performed twice. 
Day 1 
Day 1 
Before dosing on the 
scheduled date 
Same as above 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
If the scheduled tests 
at discontinuation 
have been performed 
after the final study 
drug administration, 
the tests do not have to 
be repeated even if 
they were performed 
before the date of 
judgment of 
discontinuation. 
 
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Induction period 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date 
 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1 
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
If the scheduled tests 
at discontinuation 
have been performed 
after the final study 
drug administration, 
the tests do not have to 
be repeated even if 
they were performed 
before the date of 
judgment of 
discontinuation. 
 
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Induction period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
Not necessary to 
repeat if the test was 
performed within 
28 days prior to study 
enrollment even 
before obtaining 
consent.  
Day 28 
Day 28 
Scheduled date ± 7 days 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Day 1 of each 
cycle  
Start of treatment) 
Acceptable time range 
Remarks 
Day 1 
Day 1 
Scheduled date – 7 days 
Performed only at the 
start of Cycle 1 of 
consolidation period 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date – 7 days 
 
End of treatment 
(for any period) or 
at the end of Cycle 
26 of the 
maintenance period 
Date of judgment of 
discontinuation  
or  
Cycle 26 Day 28 of the 
maintenance period 
Scheduled date + 7 days 
If the scheduled tests 
at discontinuation 
have been performed 
after the final study 
drug administration, 
the tests do not have to 
be repeated even if 
they were performed 
before the date of 
judgment of 
discontinuation. 
 
During the maintenance period, the bone marrow test will be performed whenever it is 
determined to be clinically necessary. 
 
⚫ Visit Windows for Plasma PK Assessment for ASP2215 and Cytarabine 


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Induction period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1 
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
pre-dose 
Day 1 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
cytarabine 
Cycle 1 Day 3 
pre-dose 
Day 3 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
cytarabine 
Cycle 1 Day 4 
pre-dose 
Day 4 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215 
Cycle 1 Day 4 
1 hour post-dose 
Day 4 
Scheduled date, scheduled 
time ± 10 minutes 
Cycle 1 Day 4 
2 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 10 minutes 
Cycle 1 Day 4 
4 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 4 
6 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 4 
10 hours post-dose 
Day 4 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 4 
24 hours post-dose 
Day 5 
Scheduled date, scheduled 
time ± 60 minutes and prior 
to Day 5 dosing 
Cycle 1 Day 8 
pre-dose 
Day 8 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215 and 
cytarabine 
Cycle 1 Day 11 
pre-dose 
Day 11 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215 
Cycle 1 Day 17 
pre-dose 
Day 17 
Scheduled date − 1 day, 
within 30 minutes before 
dosing 
Cycle 1 Day 28 
Day 28 
Scheduled date ± 7 days 
 


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Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1 
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
pre-dose 
Day 1 
Scheduled date, within 30 
minutes before dosing 
Blood sampling for 
ASP2215  
Cycle 1 Day 1 
1 hour post-dose 
Day 1 
Scheduled date, scheduled 
time ± 10 minutes 
Cycle 1 Day 1 
2 hours post-dose 
Day 1 
Scheduled date, scheduled 
time ± 10 minutes 
Cycle 1 Day 1 
4 hours post-dose 
Day 1 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 1 
6 hours post-dose 
Day 1 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 1 
10 hours post-dose 
Day 1 
Scheduled date, scheduled 
time ± 20 minutes 
Cycle 1 Day 1 
24 hours post-dose 
Day 2 
Scheduled date, scheduled 
time ± 60 minutes and prior 
to Day 2 dosing 
Blood sampling for 
ASP2215 and 
cytarabine 
 
Cycle 1 Day 6 
pre-dose 
Day 6 
Scheduled date, within 30 
minutes before dosing 
Cycle 1 Day 15 
 
Day 15 
 
Scheduled date − 1 day 
Blood sampling for 
ASP2215.  If 
performed on Day 14 
within the allowed 
visit window [−1] for 
Day 15, blood 
sampling will be 
performed at pre-
dose. 
End of treatment (for 
any period) 
Date of judgment of 
discontinuation 
Scheduled date + 7 days 
Blood sampling for 
ASP2215 is strongly 
recommended if 
possible  
Both in the induction and consolidation periods, blood sampling for PK analysis is performed 
only during Cycle 1. 
 
⚫ Visit Windows for FLT3 Mutation Test 


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Induction period 
Assessment timing 
Scheduled date 
Acceptable time range 
Remarks 
Screening 
— 
7 days before dosing – 1 day 
before dosing 
(Before dosing if the screening 
and Day 1 of Cycle 1 overlap). 
 
 
Consolidation period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date + 7 days 
Performed only for 
Cycle 1 of 
consolidation period 
 
Maintenance period 
Assessment timing 
Scheduled date 
(Day 1: Cycle 1 Day 1  
Start of treatment) 
Acceptable time range 
Remarks 
Cycle 1 Day 1 
Day 1 
Scheduled date 
 
[Phase 2 part] 
All analyses except for the analysis based on central laboratory data will be based on CRF 
visit except for the baseline. The baseline visit is the last measurement taken prior to initial 
treatment. 
For the analysis based on central laboratory data, 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. The visit windows for assessments are 
described in the following table. 
 


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CRF visit 
Visit Window 
Induction Day 8 
Scheduled day 
Induction Day 15 
D15 ± 2 
Induction Day 21 
D21 ± 2 
Induction Day 28 
D28 + 7 
Induction Day 42 
D42 + 7 
Induction Day 56 
D56 + 7 
Consolidation Day 8 
Scheduled day 
Consolidation Day 15 
D15 ± 2 
Consolidation Day 21 
D21 + 7 
Maintenance Cycle 2 Day 1 
(Maintenance Cycle 1 Day 1+28) ± 7 
Maintenance Cycle 5 Day 1 
(Maintenance Cycle 1 Day 1+112) ± 7 
Maintenance Cycle 8 Day 1 
(Maintenance Cycle 1 Day 1+196) ± 7 
Maintenance Cycle 11 Day 1 
(Maintenance Cycle 1 Day 1+280) ± 7 
Maintenance Cycle 14 Day 1 
(Maintenance Cycle 1 Day 1+364) ± 7 
Maintenance Cycle 17 Day 1 
(Maintenance Cycle 1 Day 1+448) ± 7 
Maintenance Cycle 20 Day 1 
(Maintenance Cycle 1 Day 1+532) ± 7 
Maintenance Cycle 23 Day 1 
(Maintenance Cycle 1 Day 1+616) ± 7 
Maintenance Cycle 26 Day 1 
(Maintenance Cycle 1 Day 1+700) ± 7 
 
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. The baseline visit is the last measurement taken prior to initial 
treatment. 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. 
 
8 
DOCUMENT REVISION HISTORY  
Version 
Date 
Changes 
Comment/rationale for change 
1.00 
16-NOV-2021 
NA 
Document finalized 
9 
REFERENCES 
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Reporting Standards 
for Therapeutic Trials in Acute Myeloid, L. (2003). 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, 21(24), 4642-4649. doi: 10.1200/JCO.2003.04.036. 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert 
panel. Blood. 2017;129:424-47. 
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) 


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10 
APPENDICES 
10.1 
Appendix 1: Signature 


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Author and Approver Signatories 
(E-signatures are attached at end of document)  
 
, Data Science Department, Astellas Pharma Inc. was 
the study statistician for this study and the primary author of this Statistical Analysis Plan 
 
 
 was the Statistical Lead for this study and the biostatistics peer reviewer of 
this Statistical Analysis Plan  
 
 
This Statistical Analysis Plan was approved by: 
 
  
10.2 
Appendix 2: 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) 
PPD
PPD
PPD


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Differentiation Syndrome a 
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) 
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 
HLT: high level term; PRES: posterior reversible encephalopathy syndrome; PT: preferred term; SMQ: standard 
MedDRA queries 
a: Only adverse events occur within the first 90 days