A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose Escalation and Expansion Study of Gilteritinib (ASP2215) Combined With Chemotherapy in Children, Adolescents and Young Adults With FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)
Phase: PHASE1
Conditions: Acute Myeloid Leukemia (AML), Acute Myeloid Leukemia With FMS-like Tyrosine Kinase 3 (FLT3) Mutation / Internal Tandem Duplication (ITD)
Sponsor: Astellas Pharma Global Development, Inc.

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 1 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose 
Escalation and Expansion Study of Gilteritinib (ASP2215) 
Combined with Chemotherapy in Children, Adolescents and 
Young Adults with FMS-like Tyrosine Kinase 3 (FLT3)/Internal 
Tandem Duplication (ITD) Positive Relapsed or Refractory Acute 
Myeloid Leukemia (AML)  
 
ISN/Protocol 2215-CL-0603 
Version 8.0 
Incorporating Substantial Amendment 7 
 
22 Jul 2022 
 
IND 117548 
EudraCT 2018-002301-61 
Pediatric Investigational Plan EMEA-002064-PIP01-16 
 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
 
Protocol History: 
Version 1.0 Original [02 Jul 2018] 
Version 2.0 Incorporating Substantial Amendment 1 [24 May 2019] 
Version 3.0 [UK] Incorporating Country-specific Substantial Amendment 2 [02 August 2019] 
Version 4.0 [CA] Incorporating Country-specific Substantial Amendment 3 [15 August 2019] 
Version 5.0 [DE] Incorporating Country-specific Substantial Amendment 4 [31 October 2019] 
Version 6.0 Incorporating Substantial Amendment 5 [17 Feb 2021] 
Version 7.0 Incorporating Substantial Amendment 6 [07 Sep 2021] 
 
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 participant; 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.   

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 2 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Table of Contents 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ································
········  9 
I. 
SIGNATURES ································
································
·····················
 15 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ····························
 17 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················
 18 
IV. 
SYNOPSIS ································
································
··························
 22 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································
· 39 
1 
INTRODUCTION ································
································
·················
 44 
1.1 
Background ································
································
····················
 44 
1.2 
Nonclinical and Clinical Data ································
·······························
 45 
1.3 
Summary of Key Safety Information for Study Drugs ································
···  45 
1.3.1 
Gilteritinib (ASP2215) Data ································
···························
 45 
1.3.1.1 
Gilteritinib Nonclinical Data ································
·····················
 45 
1.3.1.2 
Gilteritinib Clinical Data ································
··························
 46 
1.3.2 
Co-administered Chemotherapy Regimens ································
··········
 46 
1.4 
Risk Benefit Assessment ································
································
·····  46 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ································
··  48 
2.1 
Study Objective(s) ································
································
············
 48 
2.1.1 
Primary Objective ································
································
·······  48 
2.1.2 
Secondary Objectives ································
································
···  48 
2.1.3 
Exploratory Objectives ································
································
· 49 
2.2 
Study Design and Dose Rationale ································
···························
 49 
2.2.1 
Study Design ································
································
·············
 49 
2.2.2 
Dose Rationale ································
································
···········
 56 
2.3 
Endpoints ································
································
·······················
 57 
2.3.1 
Primary Endpoints ································
································
·······  57 
2.3.2 
Definition of Dose-limiting Toxicity (DLT) ································
·········  57 
2.3.2.1 
DLT Observation Period ································
··························
 58 
2.3.2.2 
DLT Criteria ································
································
········  58 
2.3.3 
Secondary Endpoints ································
································
····  58 
2.3.4 
Exploratory Endpoints ································
································
··  59 
3 
STUDY POPULATION ································
································
··········
 59 
3.1 
Selection of Study Population ································
·······························
 59 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 3 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
3.2 
Inclusion Criteria ································
································
··············
 59 
3.3 
Exclusion Criteria ································
································
·············
 61 
4 
TREATMENT(S) ································
································
··················
 63 
4.1 
Identification of Investigational Product(s) ································
················
 63 
4.1.1 
Study Drug(s) ································
································
············
 63 
4.1.2 
Co-administered Chemotherapy Regimen ································
············
 63 
4.2 
Packaging and Labeling ································
································
······  64 
4.3 
Study Drug Handling ································
································
·········  64 
4.4 
Blinding ································
································
························
 65 
4.5 
Assignment and Allocation ································
································
··  65 
5 
TREATMENTS AND EVALUATION ································
························
 65 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················
 65 
5.1.1 
Dose/Dose Regimen and Administration Period ································
····  65 
5.1.1.1 
Gilteritinib (ASP2215) ································
····························
 65 
5.1.1.2 
Co-administered Chemotherapy Drugs ································
·········  67 
5.1.2 
Interruption or Reduction in Dose of the Study Drug ·······························
 67 
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ································
································
··················
 69 
5.1.4 
Treatment Compliance ································
································
··  70 
5.1.5 
Criteria for Continuation of Treatment ································
···············
 70 
5.1.6 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation ······  70 
5.2 
Demographics and Baseline Characteristics ································
···············
 71 
5.2.1 
Demographics ································
································
············
 71 
5.2.2 
Medical History ································
································
··········
 71 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
(Optional for Healthy Volunteer Studies) ································
············
 71 
5.2.3.1 
Disease History ································
································
····  71 
5.2.3.2 
FMS-like Tyrosine Kinase (FLT3) Mutation Status ···························
 72 
5.2.3.3 
Performance Status ································
································
 72 
5.3 
Efficacy Assessments ································
································
·········  73 
5.3.1 
Response Definitions ································
································
···  73 
5.3.1.1 
Complete Remission ································
······························
 73 
5.3.1.2 
Complete Remission with Incomplete Platelet Recovery ·····················
 73 
5.3.1.3 
Complete Remission with Incomplete Hematologic Recovery ··············
 73 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 4 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.3.1.4 
Composite Complete Remission ································
·················
 73 
5.3.1.5 
Complete Remission with Partial Hematologic Recovery ····················
 74 
5.3.1.6 
Partial Remission ································
································
··  74 
5.3.1.7 
Not Evaluable/No Response ································
······················
 74 
5.3.1.8 
Relapse ································
································
··············
 74 
5.3.1.9 
Best Response ································
································
······  74 
5.3.1.10 
Complete Remission Rate ································
························
 74 
5.3.1.11 
Composite Complete Remission Rate ································
···········
 74 
5.3.1.12 
Complete Remission with Partial Hematologic Recovery Rate ··············
 75 
5.3.1.13 
Complete Remission and Complete Remission with Partial 
Hematologic Recovery Rate ································
······················
 75 
5.3.2 
Survival Time, Duration and Other Efficacy Endpoints ····························
 75 
5.3.2.1 
Overall Survival ································
································
····  75 
5.3.2.2 
Event-free Survival ································
································
 75 
5.3.2.3 
Leukemia-free Survival ································
···························
 75 
5.3.2.4 
Duration of Remission ································
····························
 75 
5.3.2.5 
Transplantation Rate ································
······························
 76 
5.3.3 
Bone Marrow Aspiration and/or Biopsy ································
··············
 76 
5.3.4 
Survival Status and Subsequent Antileukemic Treatments and Their 
Outcomes ································
································
·················
 76 
5.4 
Safety Assessment ································
································
············
 77 
5.4.1 
Vital Signs ································
································
················
 77 
5.4.2 
Laboratory Assessments ································
································
 77 
5.4.3 
Physical Examination ································
································
···  79 
5.4.4 
Electrocardiogram ································
································
·······  79 
5.4.5 
Imaging ································
································
···················
 80 
5.4.5.1 
Chest X-ray or Computed Tomography Scan ································
··  80 
5.4.5.2 
Multigated Acquisition Scan (MUGA) or Echocardiogram (ECHO) ·······  80 
5.4.6 
Order of Assessments ································
································
···  80 
5.5 
Adverse Events and Other Safety Aspects ································
·················
 81 
5.5.1 
Definition of Adverse Events ································
··························
 81 
5.5.1.1 
Abnormal Laboratory Findings ································
··················
 81 
5.5.1.2 
Potential Cases of Drug-Induced Liver Injury ································
· 81 
5.5.1.3 
Disease Progression and Study Endpoints ································
······  82 
5.5.2 
Definition of Serious Adverse Events (SAEs) ································
·······  82 
5.5.3 
Criteria for Causal Relationship to Study Drug ································
······  83 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 5 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ····························
 84 
5.5.4.1 
Reporting of Serious Adverse Events (SAEs) ································
··  84 
5.5.5 
Follow-up of Adverse Events ································
··························
 86 
5.5.6 
Monitoring of Common Serious Adverse Events ································
···  86 
5.5.7 
Special Situations ································
································
········  87 
5.5.7.1 
Pregnancy ································
································
···········
 87 
5.5.7.2 
Medication Error, Overdose and “Off-Label Use” ····························
 88 
5.5.7.3 
Misuse/Abuse ································
································
······  88 
5.5.7.4 
Occupational Exposure ································
···························
 88 
5.5.7.5 
(Suspicion of) Transmission of Infectious Agent ······························
 89 
5.5.7.6 
Suspected Drug-Drug Interaction ································
················
 89 
5.5.8 
Supply of New Information Affecting the Conduct of the Study ··················
 89 
5.5.9 
Urgent Safety Measures ································
································
 90 
5.5.10 
Reporting Urgent Safety Measures ································
····················
 90 
5.6 
Test Drug Concentration ································
································
·····  90 
5.7 
Other Measurements, Assessments or Methods ································
···········
 91 
5.7.1 
Blood Sample for Banked Pharmacogenomic (PGx) Sample Analysis 
(Optional) ································
································
·················
 91 
5.7.2 
Exploratory Biomarker Analysis ································
······················
 91 
5.7.3 
Clinical Outcome Assessment ································
·························
 92 
5.8 
Total Amount of Blood ································
································
·······  92 
6 
DISCONTINUATION ································
································
············
 92 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment ·······················
 92 
6.1.1 
Lost to Follow-up································
································
········  93 
6.2 
Discontinuation of the Site ································
································
···  93 
6.3 
Discontinuation of the Study································
································
· 93 
7 
STATISTICAL METHODOLOGY ································
···························
 94 
7.1 
Sample Size ································
································
····················
 94 
7.1.1 
Phase 1 ································
································
····················
 94 
7.1.2 
Phase 2 ································
································
····················
 94 
7.2 
Analysis Sets ································
································
···················
 95 
7.2.1 
Full Analysis Set (FAS) ································
································
 95 
7.2.2 
Safety Analysis Set (SAF) ································
······························
 95 
7.2.3 
Pharmacokinetic Analysis Set (PKAS) ································
···············
 95 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 6 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
7.2.4 
Pharmacodynamic Analysis Set (PDAS) ································
·············
 96 
7.2.5 
Minimal Residual Disease (MRD) Analysis Set (MAS) ···························
 96 
7.3 
Demographics and Baseline Characteristics ································
···············
 96 
7.3.1 
Subject Disposition ································
································
······  96 
7.3.2 
Previous and Concomitant Medications ································
··············
 96 
7.3.3 
Medical History ································
································
··········
 96 
7.3.4 
Treatment Compliance ································
································
··  96 
7.3.5 
Extent of Exposure ································
································
······  96 
7.4 
Analysis of Efficacy ································
································
··········
 97 
7.4.1 
Analysis of Primary Endpoint ································
·························
 97 
7.4.2 
Analysis of Secondary Endpoints ································
·····················
 97 
7.4.3 
Analysis of Exploratory Endpoints ································
····················
 98 
7.5 
Analysis of Safety ································
································
·············
 98 
7.5.1 
Adverse Events ································
································
··········
 98 
7.5.2 
Laboratory Assessments ································
································
 98 
7.5.3 
Vital Signs ································
································
················
 99 
7.5.4 
Physical Examination ································
································
···  99 
7.5.5 
12-lead Electrocardiograms ································
····························
 99 
7.5.6 
Concentration-Response Relationship Analysis ································
·····  99 
7.6 
Analysis of Pharmacokinetics ································
·······························
 99 
7.6.1 
Estimation of Pharmacokinetic Parameters ································
··········
 99 
7.6.2 
Statistical Analysis of Pharmacokinetic Parameters ································
 99 
7.7 
Analysis of Pharmacodynamics ································
···························
 100 
7.8 
Analysis of Biomarkers································
································
·····  100 
7.9 
Palatability and Acceptability Assessment ································
···············
 100 
7.10 
Major Protocol Deviations and Other Analyses ································
·········  100 
7.11 
Interim Analysis (and Early Discontinuation of the Clinical Study) ··················
 100 
7.12 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·······  100 
8 
OPERATIONAL CONSIDERATIONS ································
·····················
 101 
8.1 
Data Collection ································
································
··············
 101 
8.2 
Screen Failures ································
································
··············
 101 
8.3 
Major Protocol Deviations ································
································
· 101 
9 
END OF TRIAL ································
································
·················
 102 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 7 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
10 
STUDY ORGANIZATION ································
································
····  102 
10.1 
Dose Escalation Committee (DEC) ································
·······················
 102 
11 
REFERENCES ································
································
··················
 103 
12 
APPENDICES ································
································
···················
 105 
12.1 
Ethical, Regulatory, and Study Oversight Considerations ·····························
 105 
12.1.1 
Ethical Conduct of the Study ································
·························
 105 
12.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) ································
·················
 105 
12.1.3 
Protocol Amendment and/or Revision ································
··············
 105 
12.1.4 
Financial Disclosure (Optional) ································
·····················
 106 
12.1.5 
Informed Consent of Subjects ································
·······················
 106 
12.1.5.1 
Subject Information and Consent ································
··············
 106 
12.1.5.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ···························
 106 
12.1.6 
Source Documents ································
································
····  107 
12.1.7 
Record Retention ································
································
······  107 
12.1.8 
Subject Confidentiality and Privacy/Data Protection ·····························
 109 
12.1.9 
Arrangement for Use of Information and Publication of the Clinical Study ···  109 
12.1.10 
Insurance of Subjects and Others (UNIQUE to JP/Studies enrolling 
subjects in EU) ································
································
·········  110 
12.1.11 
Signatory Investigator for Clinical Study Report ································
··  110 
12.2 
Procedure for Clinical Study Quality Control ································
···········
 111 
12.2.1 
Clinical Study Monitoring ································
····························
 111 
12.2.2 
Direct Access to Source Data/Documents ································
··········
 111 
12.2.3 
Data Management ································
································
·····  111 
12.2.4 
Quality Assurance ································
································
·····  111 
12.3 
Contraception Requirements ································
·······························
 112 
12.4 
List of Excluded Concomitant Medications································
··············
 115 
12.5 
Liver Safety Monitoring and Assessment ································
················
 120 
12.6 
Common Serious Adverse Events ································
·························
 123 
12.7 
Pharmacogenomic (PGx) Analysis With Banked Sample (Optional) ················
 125 
12.8 
Definitions of Line of Therapy and Tools to Determine Study Eligibility ···········
 127 
12.9 
Clinical Study Continuity ································
································
··  128 
13 
SPONSOR’S SIGNATURES ································
································
··  133 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 8 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
List of In-text Tables 
Table 1 
Schedule of Assessments for Phase 1, Phase 2 and Long-term Treatment (LTT) ·····  40 
Table 2 
Dose Levels ································
································
····················
 50 
Table 3 
Dose Escalation Rules during the DLT Observation Period ·····························
 50 
Table 4 
Safety Monitoring Rules for Phase 2 ································
·······················
 54 
Table 5 
Treatment Plan for Cycle 1 and Cycle 2 of Phases 1 and 2 ······························
 55 
Table 6 
Test Drug (Gilteritinib Tablets) ································
·····························
 63 
Table 7 
Co-administered Drug Products Supplied by the Sponsor ·······························
 64 
Table 8 
Dose Levels in Phase 1 with Correlation to Maximum Dose per Day ··················
 66 
Table 9 
Guidelines for Gilteritinib (ASP2215) Dose Interruption or Reduction ················
 68 
Table 10 
Karnofsky Performance Status ································
······························
 72 
Table 11 
Lansky Play-Performance Scale for Children ································
·············
 73 
Table 12 
Laboratory Tests Performed During the Conduct of the Study ··························
 77 
Table 13 
NCI-CTCAE Version 5.0 ································
································
····  84 
Table 14 
Estimated Total Volume of Blood Collected in Phase 1 or Phase 2 ····················
 92 
Table 15 
Alternative Approaches/Measures Permissible for Protocol Assessments ···········
 130 
 
List of In-text Figures 
Figure 1 
Study Flow Chart ································
································
··············
 39 
Figure 2 
Schematic Representation of Dose Assignments of Each Dose Level in the 3 + 3 
Design ································
································
··························
 52 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 9 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
DOCUMENT HISTORY 
Document 
Date 
Version 7.0 Incorporating Substantial Amendment 6 
07 Sep 2021 
Version 6.0 Incorporating Substantial Amendment 5 
17 Feb 2021 
Version 5.0 [DE] Incorporating Country-specific Substantial Amendment 4 
31 Oct 2019 
Version 4.0 [CA] Incorporating Country-specific Substantial Amendment 3 
15 Aug 2019 
Version 3.0 [UK] Incorporating Country-specific Substantial Amendment 2 
02 Aug 2019 
Version 2.0 Incorporating Substantial Amendment 1 
24 May 2019 
Version 1.0 Original 
02 Jul 2018 
Amendment 7 [Substantial] 22 Jul 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and 
the Council of the European Union and applicable national laws and regulations because it potentially significantly impacts the safety or physical/mental 
integrity of participants or the scientific value of the study. 
Overall Rationale for the Amendment: 
The overall rationale for this amendment is based on regulatory feedback. 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 10 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Summary of Changes 
Substantial Changes 
Section 
Number 
Description of Change 
Brief Rationale 
IV, 2.2.1 
For a dose to be considered biologically active, at least 7 of 9 subjects at the RP2D dose in 
each group must demonstrate CR, a high degree of gilteritinib biologic activity (as measured 
by PIA), or a combination of both with the following conditions for PIA:  
• 
Subjects that complete 2 induction cycles must achieve PIA of > 90% for at least 3 of 4 
trough time points; or 
• 
Subjects that complete only 1 induction cycle must achieve PIA of > 90% at 2 of 2 
trough time points. 
The original intent of the study was for 
subjects to receive 2 cycles of treatment. 
However, subjects who achieve 
response after 1 cycle and have an 
available transplant donor, have 
proceeded to transplant. This 
modification will allow subjects who 
receive 1 cycle to be evaluable for 
biological activity based on CR, PIA or 
a combination of both and such subjects 
will not need to be replaced in RP2D 
determination. 
IV, V, 
2.1.1, 3.1, 
3.2, 12.8 
Update the phase 2 primary objective and inclusion criterion #4 for the phase 2 portion of the 
study to clarify that a subject must be refractory to or at the first hematologic relapse after 
first-line remission induction AML therapy (up to 2 induction cycles).  Definition of line of 
therapy is added to Appendix 12.8. 
The AML eligibility is updated for the 
phase 2 portion of the study to align 
with entry criteria for the phase 3 
gilteritinib program; the flow chart for 
line of therapy is added to ensure clarity 
and understanding of the therapy 
definitions. 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 11 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Section 
Number 
Description of Change 
Brief Rationale 
IV, 2.3.1 
The primary phase 1 endpoint for determination of MTD and/or RP2D is updated to remove 
the following text: “…based on the DLT and biologic activity according to PIA.” 
 
 
 
 
 
One of the primary endpoints for phase 2 (i.e., CR rates after 2 cycles of therapy) is updated 
to specify that the CR rate will be further described by the duration of CR (only for USA). 
The MTD and/or RP2D determination 
will be based on the combination of 
both safety and efficacy data; this 
change also aligns with the updated 
definition of biological activity. 
 
To provide additional information 
regarding CR rate based on regulatory 
feedback. 
IV, 2.3.2.2 
DLT criteria are updated to clarify that nonhematologic DLT will be defined as grade 3 
nonhematologic toxicity at least possibly related to protocol therapy that persists for > 48 
hours without resolution to grade ≤ 2 or grade 4 nonhematologic toxicity, regardless of 
duration, at least possibly related to protocol therapy. Hy’s law (as defined in [Section 12.5]) 
or treatment-related deaths will be considered as a DLT. Exceptions for the following 
toxicities commonly seen with intensive AML reinduction regimens are revised: grade 4 
elevation in hepatic transaminases is removed; grade 4 fever with neutropenia, with or 
without infection, is removed; grade 4 infection is replaced with grade 4 infections expected 
as direct complication of cytopenia due to active underlying leukemia; and grade 4 mucositis 
is removed. Hematologic DLT will be evaluated at day 42 from the start of cycle 1 day 1. 
To ensure subject safety. 
IV, 3.2 
Remove serum creatinine from inclusion criterion #8, but retain estimated glomerular 
filtration rate of > 60 mL/min/1.73 m2. 
To describe the minimal renal function 
criterion in terms of creatinine clearance 
or estimated glomerular filtration rate 
alone. 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 12 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Section 
Number 
Description of Change 
Brief Rationale 
IV, 3.3 
Update exclusion criterion #6 to exclude subjects who have active clinically significant 
GVHD or are on treatment with immunosuppressive drugs for treatment of active GVHD, 
with the exception of subjects being weaned from systemic corticosteroids where the subject 
is receiving ≤ 0.5 mg/kg of prednisone (or equivalent) daily dose for prior GVHD. Subjects 
who have received calcineurin inhibitors within 4 weeks prior to screening, unless used as 
GVHD prophylaxis. 
To ensure subject safety. 
2.2.1, 11 
Safety monitoring rules are clarified. A Bayesian posterior probability for safety monitoring 
will be used for phase 2. Subjects in phase 2 will be continued to be monitored for ≥ grade 3 
non-hematologic AEs considered at least possibly related to protocol therapy, and AEs of any 
grade leading to treatment discontinuation or death considered at least possibly related to 
protocol therapy. The event rate will be reviewed for the first 6 evaluable subjects at the end 
of cycle 1. After that, the event rate will be reviewed continuously. The estimated event rate 
based on the Bayesian beta-binomial model will be provided for safety monitoring. If the 
event rate is ≥ 20% with a posterior probability of at least 80%, then the enrollment to phase 
2 will be paused and safety will be reassessed by the DEC. With a non-informative prior 
Beta(1,1) distribution, the numbers of subjects with event for certain evaluable subjects, 
which trigger the enrollment pause for safety review, are listed in [Table 4]. The algorithm 
for differentiation syndrome based on the [Montesinos et al, 2009] criteria, in addition to the 
preferred term of ‘acute promyelocytic leukemia differentiation syndrome’, will be used to 
search for potential cases of differentiation syndrome in every 6 subjects in phase 2. 
To ensure subject safety. 
 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 13 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Nonsubstantial Changes 
Section 
Number 
Description of Change 
Brief Rationale 
II, 13 
Update clinical research contact identity, medical monitor/study physician 
information, and senior data science and statistical manager identity (sponsor’s 
signature page). 
To provide updated contact information. 
IV 
Planned study period is updated to end 3Q2026. 
To update period based on current study 
enrollment projections. 
IV, 2.2.1 
Clarify that, in addition to pharmacokinetic parameters and biological activity, 
response assessment will also be evaluated during cycle 1 and/or cycle 2. 
To clarify that response assessment is part of 
the data that will be considered when 
determining the optimal dose. 
IV, V, 2.2.1, 
5.1.1.1.3, 5.1.5 
LTT is updated to clarify that subjects completing 1 or 2 treatment cycles of phase 
1 or 2 will have the option to participate in LTT and that subjects receiving 
clinical benefit during phase 1 or 2 may initiate LTT only after discussion and 
approval from the Astellas medical monitor. Criteria clarifying clinical benefit is 
updated for all sites as follows: 
 
a) Completed 1 or 2 treatment cycles of phase 1 or 2. 
b) Subject did not develop intolerable or unacceptable toxicity. 
c) Subject has achieved remission, stable or improved disease, or symptom 
improvement, or decreased transfusion dependence. 
d) Any other reason that the investigator judges will benefit the subject from 
continued treatment with gilteritinib, must be reviewed and approved by 
the Astellas medical monitor. 
 
During the LTT period, subjects will receive gilteritinib once daily starting from 
day 1 through day 28 of a 28-day cycle at the same dose received during phase 1 
or 2. 
To provide a clear definition of clinical benefit 
to qualify for LTT. 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 14 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Section 
Number 
Description of Change 
Brief Rationale 
IV, 2.2.1, 7.1.2 
Operationally, 22 response evaluable subjects will be needed during the first stage, 
with 4 CR responders or 9 CRc responders after 1 or 2 cycles of therapy required 
to continue to a total of 52 response evaluable subjects. If there are less than 4 CR 
responders in stage 1, the enrollment will be stopped in the USA and the study 
will not proceed to stage 2 in the USA. 
USA-specific response requirements are 
clarified based on regulatory feedback. 
IV, 2.2.1, 11 
In addition to safety data through the DLT observation period, the DEC will 
review response data and gilteritinib biologic activity (as measured by PIA) 
through the cycle 1 and/or cycle 2 of the evaluable subjects. The algorithm for 
differentiation syndrome based on the [Montesinos et al, 2009] criteria, in addition 
to the preferred term of ‘acute promyelocytic leukemia differentiation syndrome’, 
is added to search for potential cases of differentiation syndrome at every dose 
level in phase 1. The RP2D and/or MTD will be selected based on the DEC’s 
review of all available data at each dose level, including safety data, 
pharmacokinetic data (if available), response data and gilteritinib biologic activity 
data, and the RP2D will become the minimum safe and biologically effective dose 
level. 
To ensure subject safety. 
5.5.2.1 
This section describing “Always Serious Adverse Events” is removed. 
This section described a sponsor process that 
is now obsolete and replaced with an updated 
process. As this is a sponsor process that does 
not impact reporting by the investigator site, it 
is removed from the protocol. 
10.1 
The responsibilities of the DEC are clarified and will also include previous IDMC 
responsibilities formerly described in Section 10.2. 
A separate IDMC will not be utilized in this 
study; the DEC will fulfill the independent 
safety monitoring requirements. 
Throughout 
Minor editorial changes incorporated as necessary. 
 
 
Document history and protocol amendment summary of changes are placed at the 
beginning of the protocol. 
Minor editorial changes incorporated to 
improve clarity. 
 
Changes incorporated per update to Astellas 
Global Protocol Format V11.0. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 15 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
I. SIGNATURES 
1. SPONSOR’S SIGNATURES 
Required signatures (e.g., Protocol authors and contributors, etc.) are located in [Section 13 
Sponsor’s Signatures].  
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 16 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
2. INVESTIGATOR’S SIGNATURE 
A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose Escalation and 
Expansion Study of Gilteritinib (ASP2215) Combined with Chemotherapy in 
Children, Adolescents and Young Adults with FMS-like Tyrosine Kinase 3 
(FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory 
Acute Myeloid Leukemia (AML) 
ISN/Protocol 2215-CL-0603 
Version 8.0, Incorporating Substantial Amendment 7 
22 Jul 2022 
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 subinvestigator(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: 
 
 
Printed Name:-----------------------------------------------------------------------
- 
Date (DD Mmm YYYY) 
<Insert name and qualification of the Investigator> 
Address: 
 
 
 
 
 
 
 
 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 17 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
24h-Contact for Serious 
Adverse Events (SAEs) 
 
See [Section 5.5.4.1 Reporting of 
Serious Adverse Events] for SAE 
Fax Number and Email 
 
, Oncology Medical Science 
Astellas Pharma Global Development 
1 Astellas Way, Northbrook, Illinois, USA- 60062 
 
 
Please fax or email the SAE Worksheet to: 
Astellas Pharma Global Development, Inc. 
Pharmacovigilance 
North America Fax Number: 888-396-3750 
(North America Alternate Fax: 847-317-1241) 
International Fax Number: +44 800 471 5263 
Email: safety-us@astellas.com 
Investigational sites in Japan: 
Astellas Pharma Inc. – Japan 
Pharmacovigilance 
Fax Number: +81-3-3243-5747 
Email: rk-safety-jp@astellas.com 
PAREXEL International 
Global Monitoring Operations 
Fax: +81 36888 5377 
Medical Monitor/Study 
Physician: 
 
, Oncology Medical Science 
Astellas Pharma Global Development 
1 Astellas Way, Northbrook, Illinois, USA 60062 
 
 
Clinical Research Contacts 
(Global): 
 
 
 
Astellas Pharma Global Development, Inc. 
1 Astellas Way, Northbrook, Illinois, USA 60062 
 
 
Clinical Research Contacts 
(Japan): 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan 
Phone No.:  
+81-3-3244-1097 
Fax:  
 
+81-3-3243-5737 
Contact details for nonbusiness hours and emergency: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 18 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
5HT2B 
serotonin 5 hydroxytryptamine 2B 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
AXL 
AXL tyrosine kinase 
BCRP 
breast cancer resistance protein 
Cmax 
maximum concentration 
CNS 
central nervous system 
CA 
Competent Authorities 
cEC 
concerned Ethics Committee 
CL/F 
oral clearance 
COA 
clinical outcome assessment 
CR 
complete remission 
CRc 
composite complete remission 
CRh 
complete remission with partial hematological recovery 
CRF 
case report form 
CRi 
complete remission with incomplete hematologic recovery 
CRO 
contract research organization 
CRp 
complete remission with incomplete platelet recovery 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DEC 
Dose Escalation Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EFS 
event-free survival 
EOT 
end of treatment 
ERK 
extracellular signal-regulated kinase 
FAS 
full analysis set 
FLAG 
fludarabine, cytarabine and granulocyte colony-stimulating factor 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 19 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Abbreviations 
Description of abbreviations 
FLT3 
FMS-like tyrosine kinase 3 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GVHD 
graft-versus-host disease 
HEK293 
human embryonic kidney 293 
hERG 
human ether-à-go-go-related gene 
HRT 
hormone replacement therapy 
HSCT 
hematopoietic stem cell transplant 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
 
 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISN 
international study number 
ITD 
internal tandem duplication 
LA-CRF 
liver abnormality case report form 
LFT 
liver function tests 
LLN 
lower limit of normal 
LTK 
leukocyte receptor tyrosine kinase 
LTT 
long-term treatment 
MedDRA 
medical dictionary for regulatory activities 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
OATP 
organic anion transporting polypeptide 
OS 
overall survival 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PIA 
plasma inhibitory activity 
PKAS 
pharmacokinetic analysis set 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 20 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Abbreviations 
Description of abbreviations 
PND 
postnatal day 
PRES 
posterior reversible encephalopathy syndrome 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
RP2D 
recommended phase 2 dose 
R/R 
relapsed/refractory 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
terminal elimination half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TKD 
tyrosine kinase domain 
tmax 
time of maximum concentration  
ULN 
upper limit of normal 
USM 
urgent safety measure 
Vd/F 
apparent volume of distribution 
WBC 
white blood cell 
XRT 
X-ray treatment 
  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 21 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
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. 
Enroll 
To register or enter a subject into a clinical study. NOTE: Once a subject has 
received the study drug or placebo, the clinical study protocol applies to the 
subject.  
Intervention 
The drug, device, therapy or process under investigation in a clinical study 
that is believed to have an effect on outcomes of interest in a study (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Randomization 
The process of assigning study subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
study. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for 
participation in a study. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Subject/ Participant 
An individual who participates in a clinical trial either as a recipient of the 
investigational product(s) or as a control. 
The term “subject” is part of the federal regulation and may be used 
interchangeably with participant. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 22 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
IV. 
SYNOPSIS 
Date and Version No of Protocol Synopsis: 
22 Jul 2022/Version 8.0 
Sponsor:  
Astellas Pharma Global Development Inc. (APGD) 
Protocol Number:  
2215-CL-0603 
Name of Study Drug:  
Gilteritinib (ASP2215) 
Phase of Development:  
Phase 1/2 
Title of Study: 
A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose Escalation and Expansion Study of 
Gilteritinib (ASP2215) Combined with Chemotherapy in Children, Adolescents and Young Adults 
with FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or 
Refractory Acute Myeloid Leukemia (AML)  
Planned Study Period:  
From 3Q2020 to 3Q2026 
Study Objective(s):  
Primary Objectives: 
The primary objectives are: 
• 
Phase 1 (Dose Escalation Phase):  
To determine the maximum tolerated dose (MTD) and/or optimally safe and biologically active 
recommended phase 2 dose (RP2D) of gilteritinib given in sequential combination with 
fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) in children, 
adolescents and young adults with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 
(FLT3) [internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD)] acute 
myeloid leukemia (AML). 
• 
Phase 2 (Dose Expansion Phase):  
To determine complete remission (CR) rates and composite complete remission (CRc) rates 
after 2 cycles of gilteritinib in sequential combination with FLAG in children, adolescents and 
young adults with FLT3 (ITD) AML who are refractory to or at the first hematologic relapse 
after first-line remission induction AML therapy (up to 2 induction cycles).  
Secondary Objectives: 
The secondary objectives are: 
● 
To assess the safety, tolerability and toxicities of gilteritinib when given in sequential 
combination with FLAG in children, adolescents, and young adults with R/R FLT3/ITD AML.  
● 
To evaluate FLT3 inhibition due to gilteritinib treatment 
● 
To characterize gilteritinib pharmacokinetics. 
● 
To perform serial measurements of minimal residual disease (MRD) and examine the 
relationship with study endpoints. 
● 
To obtain preliminary estimates of 1-year event-free survival (EFS) and overall survival (OS) 
rate. 
● 
To assess the acceptability and palatability of the formulation. 
Exploratory Objectives: 
The exploratory objectives are: 
● 
To relate the clinical responses to gilteritinib therapy with FLT3 plasma inhibitory activity 
(PIA). 
● 
To evaluate relationship between FLT3 ligand levels and clinical response. 
● 
To assess the mechanisms of innate and acquired resistance to gilteritinib. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 23 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Planned Total Number of Study Centers and Location(s):  
Approximately 30 sites in North America, Europe and Asia 
Study Population:  
Phase 1 (Dose Escalation Phase): Male and female children, adolescents and young adults from 
6 months to less than 21 years of age with R/R FLT3 (ITD and/or TKD) AML.  
Phase 2 (Dose Expansion Phase): Male and female children, adolescents and young adults from 
6 months to less than 21 years of age with FLT3 (ITD) AML who are refractory to or at the first 
hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles).  
Number of Subjects to be Enrolled/Randomized: 
Up to 97* total subjects from 6 months to less than 21 years of age can be enrolled in the study. 
Subject enrollment distribution during each phase of the study is outlined below:  
● Phase 1 (Dose Escalation Phase):  
Group 1: 
Subjects from 2 years to less than 21 years of age: minimum 5 subjects from 2 years to 
18 years, up to 15* subjects 
Group 2: 
Subjects from 1 year to less than 2 years of age: minimum 2 subjects, up to 15* subjects 
Group 3: 
Subjects from 6 months to less than 1 year of age: minimum 2 subjects, up to 15* subjects. 
*The number of subjects enrolled in phase 1 will depend on the number of dose levels 
evaluated, evaluation of biological activity, and the availability of time points for PIA 
assessments. 
● Phase 2 (Dose Expansion Phase):  
Fifty-two (52) evaluable subjects from 6 months to less than 21 years of age can be enrolled 
with: 
o at least 2 subjects from 6 months to less than 6 years of age,  
o at least 6 subjects from 6 years to less than 12 years of age, and  
o at least 10 subjects from 12 years to less than 18 years of age. 
Study Design Overview:  
This study is an open-label, single-arm, phase 1/2 study to evaluate the safety, pharmacokinetics, 
and anti-leukemic activity of gilteritinib in children, adolescents and young adults with AML. 
The study will consist of 2 phases:  
• Phase 1 (Dose Escalation Phase) 
• Phase 2 (Dose Expansion Phase) 
One cycle is defined as 28 days of treatment. A subject completing 1 or 2 treatment cycles in phase 
1 or 2 will have the option to participate in long-term treatment (LTT) with gilteritinib (for up to 
2 years). The study treatment will continue until 1 of the discontinuation criteria is met. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 24 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Phase 1 (Dose Escalation Phase):  
The primary objective of phase 1 will be to establish an optimally safe and biologically active 
RP2D and/or to determine MTD for gilteritinib in combination with FLAG. The RP2D will be a 
dose, which is safe (i.e., has an acceptable dose limiting toxicity [DLT] profile) and demonstrates 
CR, a high degree of gilteritinib biologic activity (as measured by PIA), or a combination of both. 
Dose Escalation in phase 1 will be performed in 3 groups based on the age of the subject: 
• Group 1: Dose Escalation in subjects from 2 years to less than 21 years of age 
• Group 2: Dose Escalation in subjects from 1 year to less than 2 years of age 
• Group 3: Dose Escalation in subjects from 6 months to less than 1 year of age 
Induction therapy in this phase will consist of 2 cycles of gilteritinib plus FLAG. During each 
cycle, FLAG (cycle 1 and 2) chemotherapy will be administered on days -1 to 5 and gilteritinib 
will be administered once per day on days 8 to 21 at the assigned dose levels below:  
Level 
Dose 
-1 
1 mg/kg/day (maximum 60 mg/day) # 
1 
2 mg/kg/day (maximum 120 mg/day) * 
2 
3 mg/kg/day (maximum 180 mg/day) ** 
* Starting dose of gilteritinib for Group 1; # Starting dose of gilteritinib for Groups 2 and 3 
** To be evaluated only if there is lack of toxicity or acceptable DLT profile combined with the lack of 
sufficient gilteritinib activity observed at the Dose Level 1 (2 mg/kg/day). Not applicable for sites in USA. 
DLT assessment will occur during the first cycle only. Pharmacokinetic parameters, response 
assessment and biological activity will be evaluated during cycle 1 and/or cycle 2.  
Dose Escalation Rules 
Dose escalation, stay, or de-escalation between the dose levels in Groups 1, 2 and 3 will be guided 
by the 3 + 3 design.  
Dose escalation rules during the DLT Observation Period are as follows: 
Number of Subjects with 
DLT at the Given Dose  
Escalation Decision Rules 
0 of 3 or ≤ 1 of 6 subjects 
Escalate and enter up to 3 subjects at the next dose level, if the next 
higher dose level is available 
1 of 3 subjects 
Enter up to 3 subjects at the same dose level 
≥ 2 subjects 
De-escalate, if the next lower dose level is available or stop escalating 
Intra-subject dose escalation is not allowed during the study. Guidance for intra subject dose 
interruption or reduction for gilteritinib is outlined in [Section 5.1.2 Interruption or Reduction in 
Dose of the Study Drug]. 
The Dose Escalation Committee (DEC) will review safety data through the DLT observation 
period for 3 evaluable subjects at each dose level. In addition to safety data through the DLT 
observation period, the DEC will review response data and gilteritinib biologic activity (as 
measured by PIA) through the cycle 1 and/or cycle 2 of the evaluable subjects. The algorithm for 
differentiation syndrome based on the [Montesinos et al, 2009] criteria, in addition to the preferred 
term of ‘acute promyelocytic leukemia differentiation syndrome’, will be used to search for 
potential cases of differentiation syndrome at every dose level in phase 1. The decision will be 
made by the DEC to escalate to the next planned dose level, remain at the same dose level, 
de-escalate to the dose level below or stop escalation. The RP2D and/or MTD will be selected 
based on the DEC’s review of all available data at each dose level, including safety data, 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 25 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
pharmacokinetic data (if available), response data and gilteritinib biologic activity data, and the 
RP2D will become the minimum safe and biologically effective dose level. 
• 
Group 1:  
Three subjects will be enrolled in the initial cohort starting at Dose Level 1 (2 mg/kg/day).  
• 
Groups 2 and 3:  
Three subjects will be enrolled in the initial cohort starting at Dose Level -1 (1 mg/kg/day). 
Enrollment of subjects in Groups 2 and 3 will be initiated following the decision by the 
DEC on the Dose Level 1 (2 mg/kg/day) evaluated in Group 1.  
Escalation to Dose Level 1 (2 mg/kg/day) in Groups 2 and 3 will not be performed if de-
escalation to Dose Level -1 (1 mg/kg/day) has been performed in Group 1 or Dose Level -
1 has been established as the MTD in Group 1. 
Additional subjects will be accrued as needed at the RP2D of each group (Groups 1, 2 and 3) to 
ensure that gilteritinib activity is assessable in at least 9 subjects in the respective age group.  
For the dose to be considered biologically active, at least 7 of 9 subjects at the RP2D dose in each 
group must demonstrate CR, a high degree of gilteritinib biologic activity (as measured by PIA), or 
a combination of both with the following conditions for PIA:  
• 
Subjects that complete 2 induction cycles must achieve PIA of > 90% for at least 3 of 4 
trough time points; or 
• 
Subjects that complete only 1 induction cycle must achieve PIA of > 90% at 2 of 2 trough 
time points. 
Alternative dose levels can be explored in the following cases: 
● 
A higher Dose Level 2 (3 mg/kg/day) in the event there is lack of toxicity or acceptable 
DLT profile combined with the lack of sufficient gilteritinib activity at the Dose Level 1 
(2 mg/kg/day), after discussion with the DEC. Dose Level 2 (3 mg/kg/day) will not be 
evaluated in subjects enrolled in USA. 
● 
A lower Dose Level than Dose Level -1 (1 mg/kg/day) in the event the Dose Level -1 
(1 mg/kg/day) demonstrates sufficient gilteritinib activity but DLTs are observed. 
Exploration of dose level lower that Dose Level -1 will be performed via an amendment to 
the current study protocol, after discussion with the DEC. 
Continued participation in phase 2 portion of the study for each age group will be 
dependent on the determination of RP2D in Groups 1, 2 and 3, respectively. 
Dose-limiting Toxicity (DLT) Observation Period 
The DLT observation period will be 28 days from the start of cycle 1 day 1, i.e., for the first cycle 
only. 
Dose-limiting Toxicity (DLT) Criteria 
Nonhematologic Dose-limiting Toxicity will be defined as grade 3 nonhematologic toxicity at 
least possibly related to protocol therapy that persists for > 48 hours without resolution to grade ≤ 2 
or grade 4 nonhematologic toxicity, regardless of duration, at least possibly related to protocol 
therapy. Hy’s law (as defined in [Section 12.5]) or treatment-related deaths will be considered as a 
DLT. Gilteritinib dosing will be interrupted if nonhematologic DLT occurs. Exceptions will 
include the following toxicities commonly seen with intensive AML reinduction regimens: 
• 
Alopecia, anorexia or fatigue. 
• 
Grade 3 vomiting or diarrhea that resolves (with or without supportive care) to ≤ grade 2 
within 48 hours 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 26 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
• 
Grade 3 nausea that resolves (with or without supportive care) to ≤ grade 2 within 7 days 
• 
Grade 3 elevation in total bilirubin (TBL) that is asymptomatic and that returns to ≤ grade 2 
elevation within 7 days 
• 
Grade 3 elevation in hepatic transaminases (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST] and gamma-glutamyl transferase [GGT]) or alkaline phosphatase 
(ALP) that returns to ≤ grade 2 elevation within 14 days  
• 
Grade 3 fever with neutropenia, with or without infection 
• 
Grade 3 infection or grade 4 infections expected as direct complication of cytopenia due to 
active underlying leukemia 
• 
Grade 3 mucositis 
Hematologic Dose-limiting Toxicity will be defined as failure to recover a peripheral absolute 
neutrophil count (ANC) > 500/µL and non-transfusion dependent platelet count > 20000/µL due to 
documented bone marrow aplasia/hypoplasia at day 42 from the start of cycle 1 day 1.  
Failure to recover peripheral counts due to disease involvement of the bone marrow will not be 
considered dose-limiting toxicity. 
Subject Replacement (Only for Phase 1 Dose Escalation) 
A subject meeting fulfilling the inclusion/exclusion criteria and receiving 80% of the intended dose 
of the study treatment regimen (FLAG and gilteritinib) during the DLT observation period will be 
considered evaluable for DLT. 
A subject that receives less than 80% of the intended dose of the study treatment regimen (for 
reasons other than a DLT) during the DLT observation period will not be evaluable for DLT and 
will be replaced by another subject in the dose level. 
In addition, if after enrollment any subject is found not to fulfill any inclusion/exclusion criteria 
that would adversely affect safety or efficacy evaluation of that subject or are not evaluable for 
DLT, they may be replaced after discussion with the DEC. 
Subjects without adequate sampling time points to assess biological activity for RP2D 
determination can be replaced. 
Phase 2 (Dose Expansion Phase): 
The phase 2 part of this study is the dose expansion phase, which will be initiated upon 
establishment of the optimally safe and biologically effective RP2D and/or MTD dose from Group 
1 of phase 1.  
Enrollment of subjects from 6 months to less than 2 years in phase 2 will depend upon the RP2D 
established in the respective age group (Groups 2 and 3) during the phase 1 portion of the study.  
Applicable only for sites in Germany: Enrollment of subjects in phase 2 will be initiated in sites in 
Germany only after a positive assessment on the phase 1 data of each age group (Group 1, 2 or 3) 
is received from the competent authority of the country. 
Phase 2 will be a single-arm, 2-stage, open-label design with 52 response evaluable subjects from 
6 months to less than 21 years of age, with: 
• 
at least 2 subjects from 6 months to less than 6 years of age, 
• 
at least 6 subjects from 6 years to less than 12 years of age, and 
• 
at least 10 subjects from 12 years to less than 18 years of age.  
Induction therapy in this phase will consist of 2 cycles of gilteritinib plus FLAG. During each cycle 
(1 and 2), FLAG chemotherapy will be administered on days -1 to 5 and gilteritinib will be 
administered once per day on days 8 to 21 at the assigned dose. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 27 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Subjects are response evaluable if  
1. they are confirmed FLT3/ITD mutation positive,  
2. they receive at least 1 dose of gilteritinib, and  
3. they are disease progression/recurrence free during cycle 1 and 2 of FLAG + gilteritinib and 
have the required bone marrow evaluations or have died of disease progression during the first 
2 cycles.  
Initially, 22 response evaluable subjects will be needed during the first stage, with 9 CRc 
responders or 4 CR responders after 1 or 2 cycles of therapy required to continue to a total of 52 
response evaluable subjects.  
Applicable only for sites in USA: If there are less than 4 CR responders in stage 1, the enrollment 
will be stopped in the USA and the study will not proceed to stage 2 in the USA. 
Treatment Plan (Phases 1 and 2): 
An overview of the treatment plan for cycle 1 and cycle 2 is presented below: 
Cycle 1 & Cycle 2 
Day 
 -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 & 7 
Day 
8 to 21 
Day 
28 
Fludarabine  
 
 
 
 
 
 
 
 
Disease evaluation 
Cytarabine  
 
 
 
 
 
 
 
 
G-CSF 
 
 
 
 
 
 
 
 
Gilteritinib 
 
 
 
 
 
 
 
 
IT Cytarabine* 
 
 
 
 
 
 
 
 
G-CSF: granulocyte-colony stimulating factor; IT: induction therapy. 
* Subject may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional 
standards. 
Criteria to Begin Cycle 2 (Phases 1 and 2): 
Subjects should receive a second cycle of gilteritinib plus FLAG when all non-hematologic grade 3 
and 4 toxicities have resolved to ≤ grade 2. It is suggested but not required that cycle 2 begin when 
ANC > 1000/µL and platelets are > 100000/µL in responding subjects. 
Any subject who is unable to initiate cycle 2 after 50 days from the start of cycle 1 day 1 will be 
evaluated for participation in cycle 2 and/or replacement. 
Response Assessment (Phases 1 and 2): 
The end of cycle 1 bone marrow analysis will be performed upon count recovery but no later than 
day 28. For subjects whose response assessment is not evaluable due to hypocellularity, a repeat 
bone marrow analysis should be performed at least every 14 days until response determination is 
possible. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 28 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
Long-term Treatment (LTT) (Phase 1 and 2):  
In the event the principal investigator feels that a subject is receiving clinical benefit from 
treatment with gilteritinib in phase 1 or phase 2, subjects having completed 1 or 2 treatment cycles 
of phase 1 or 2 will have the option to participate in LTT with gilteritinib for up to 2 years (~26 
cycles). LTT for any subject may only be initiated after discussion with the medical monitor. 
Subjects receiving clinical benefit during phase 1 or 2 may initiate LTT after discussion and 
approval from Astellas medical monitor. Clinical benefit is defined as follows: 
 
a) Completed 1 or 2 treatment cycles of phase 1 or 2. 
b) Subject did not develop intolerable or unacceptable toxicity . 
c) Subject has achieved remission, stable or improved disease, or symptom improvement, or 
decreased transfusion dependence.  
d) Any other reason that the investigator judges will benefit the subject from continued 
treatment with gilteritinib, must be reviewed and approved by the Astellas medical 
monitor.  
During the LTT period, subjects will receive gilteritinib once daily starting from day 1 through day 
28 of a 28-day cycle at the same dose received during phase 1 or 2.  
End of Treatment (EOT) Visit:  
An end of treatment (EOT) visit will be performed 7 days after last dose of gilteritinib, or prior to 
initiation of another anticancer therapy, whichever occurs earlier. 
EOT1 Visit (C2D28 for phase 1 or phase 2) will be performed for any subject participating in phase 
1 or 2 and indicates the end of the respective phase.  
EOT2 will be performed for any subject participating in LTT phase and indicates the end of the 
LTT phase. 
28-Day Follow-up Visit:  
A follow-up visit will be performed 28 days following the EOT visit of phase 1 and phase 2 (i.e., 
EOT1), in the event the subject is not eligible to continue for LTT. In the event it is determined that 
the subject is eligible to participate in the LTT, then a follow-up visit will only be performed 28 
days following the LTT EOT visit (i.e., EOT2). 
Survival Follow-up:  
Survival follow-up will be performed every 3 months for up to 2 years from the 28-day follow-up 
visit. Survival follow-up will include collection of data on subsequent anti-leukemic 
treatments/outcomes received by the subject, remission status and survival (cause of death and date 
of death) of the subject. In the event that the subject is not available for a clinic visit, follow-up via 
telephone or e-mail correspondence is acceptable. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 29 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
Inclusion/Exclusion Criteria: 
Inclusion: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed 
consent and privacy language as required per national regulations (e.g., Health Insurance 
Portability and Accountability Act Authorization for USA sites) must be obtained from the 
subject or subject’s parent or legal guardian and if required child assent prior to any study-
related procedures (including withdrawal of prohibited medication, if applicable). 
2. Phase 1: Subject is positive for FLT3 (ITD and/or TKD) mutation in bone marrow or blood as 
determined by the local institution. 
Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as 
determined by the local institution.  
3. Subject is aged ≥ 6 months and < 21 years of age* at the time of signing informed consent 
and/or assent, as applicable.  
* For phase 2: Enrollment of subjects from 6 months to less than 1 year (Group 3) and 1 year to less 
than 2 years (Group 2) will be dependent on the establishment of RP2D in the respective for age 
groups during phase 1. 
4. Subject has a diagnosis of AML according to The French–American–British (FAB) 
classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease 
(except subjects with active central nervous system [CNS] leukemia). 
a) In the phase 1 portion of the study, subject must be in first or greater relapse or refractory 
to induction therapy with no more than 1 attempt at remission induction (up to 2 
induction cycles). 
b) For the phase 2 portion of the study, subject must be in first relapse or refractory to 
induction therapy with no more than 1 attempt at remission induction (up to 2 induction 
cycles) (see definition of line of therapy in Appendix 12.8). 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 30 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5. Subject has fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study. 
• 
Myelosuppressive chemotherapy: 
o 
For subject who relapses while receiving cytotoxic therapy, at least 21 days must 
have elapsed since the completion of cytotoxic therapy and prior to screening, unless 
based on investigator’s judgment the subject has recovered earlier than 21 days. 
o 
Cytoreduction with the following can be initiated and continued for up to 24 hours 
prior to the start of systemic protocol therapy (cycle 1 day -1) as determined by the 
investigator: 
● 
hydroxyurea, 
● 
low dose cytarabine (100 mg/m2 per dose once daily for 5 days) or 
● 
other low dose/maintenance therapies as per local site practice. 
o 
Subject who has received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib, etc) is 
eligible for this study. 
• 
Hematopoietic growth factors: at least 7 days must have elapsed since the completion of 
therapy with a growth factor and prior to screening. 
• 
Biologic (anti-neoplastic agent): at least 7 days must have elapsed since the completion 
of therapy with a biologic agent and prior to screening. For agents that have known 
adverse events (AEs) occurring beyond 7 days after administration, this period must be 
extended beyond the time during which AEs are known to occur. The duration of this 
interval must be discussed with the medical monitor. 
• 
X-ray treatment (XRT):  
o 
14 days must have elapsed for local palliative XRT for CNS chloromas and prior to 
screening; no washout period is necessary for other chloromas; 
o 
Prior to screening, 90 days must have elapsed if the subject had a prior traumatic 
brain injury or has received craniospinal XRT. 
6. For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must have 
elapsed since HSCT and subject must not have active graft-versus-host disease (GVHD). 
7. Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score of 
≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if related to the subject’s 
leukemia in the investigator’s judgment. 
8. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
• 
Serum AST and ALT ≤ 3.0 x upper limit normal (ULN) for age 
• 
Total serum bilirubin ≤ 1.5 x ULN for age 
• 
Estimated glomerular filtration rate of  
> 60 mL/min/1.73 m2.  
9. A female subject is eligible to participate if she is not pregnant (see [Appendix 12.3 
Contraception Requirements]) and at least 1 of the following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 
Contraception Requirements] 
OR 
b) WOCBP who agrees to follow the contraceptive guidance as defined in [Appendix 12.3 
Contraception Requirements] throughout the treatment period and for at least 180 days 
after the final study drug administration. 
10. 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.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 31 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
11. Female subject must not donate ova starting at Screening and throughout the study, and for 
180 days after the final study drug administration. 
12. A male subject with female partner(s) of childbearing potential must agree to use contraception 
as detailed in [Appendix 12.3 Contraception Requirements] during the treatment period and for 
at least 180 days after the final study drug administration. 
13. A male subject must not donate sperm during the treatment period and for at least 120 days 
after the final study drug administration. 
14. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a 
condom for the duration of the pregnancy or time partner is breastfeeding throughout the study 
period and for 180 days after the final study drug administration. 
15. Subject and subject’s parent(s) or legal guardian agrees not to participate in another 
interventional study while on treatment.  
16. Live Vaccines: At least 6 weeks must have elapsed since the administration of the last dose of a 
live vaccine and prior to initiation of study treatment (cycle 1 day -1). 
Waivers to the inclusion criteria will NOT be allowed. 
Exclusion Criteria:  
1. Subject has active CNS leukemia. 
2. This criterion has been removed. 
3. Subject has uncontrolled or significant cardiovascular disease, including: 
• 
Diagnosed or suspected congenital long QT syndrome or any history of clinically 
significant ventricular arrhythmias (such as ventricular tachycardia, ventricular 
fibrillation, or torsades de pointes); any history of arrhythmia will be discussed with the 
sponsor’s medical monitor prior to subject’s entry into the study 
• 
Prolonged QTcF interval on pre-entry electrocardiogram (ECG) (≥ 450 ms) 
• 
Any history of second- or third-degree heart block (may be eligible if the subject 
currently has a pacemaker) 
• 
Heart rate < 50 beats/minute on pre-entry ECG 
• 
Uncontrolled hypertension 
• 
Complete left bundle branch block 
4. Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing 
signs/symptoms related to the infection without improvement despite appropriate antibiotics or 
other treatment. The subject needs to be off pressors and have negative blood cultures for 
48 hours. 
5. Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or 
immunotherapy other than as specified in the protocol. 
6. Subject has active clinically significant GVHD or is on treatment with immunosuppressive 
drugs for treatment of active GVHD, with the exception of subjects being weaned from 
systemic corticosteroids where the subject is receiving ≤ 0.5 mg/kg of prednisone (or 
equivalent) daily dose for prior GVHD. Subject has received calcineurin inhibitors within 4 
weeks prior to screening, unless used as GVHD prophylaxis. 
7. Subject has active malignant tumors other than AML. 
8. Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that 
would compromise subject safety or compliance; interfere with consent, study participation, 
follow-up or interpretation of study results. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 32 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
9. Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below 
institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels 
during the screening period is allowed.  
10. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 
(CYP)3A/P-glycoprotein (P-gp). 
11. Subject is known to have human immunodeficiency virus infection. 
12. Subject has active hepatitis B or C, or other active hepatic disorder. 
● 
Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA 
are not eligible. 
● 
Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B 
surface antibody will be eligible if hepatitis B DNA is undetectable. 
● 
Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is 
undetectable. 
13. This criterion has been removed.  
14. Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent 
and before starting gilteritinib.  
15. Subject has known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, G-CSF 
or any components of the formulations used. 
Waivers to the exclusion criteria will NOT be allowed. 
Investigational Product(s): 
Gilteritinib tablets containing 40 mg of active ingredient and mini-tablets containing 10 mg of 
active ingredient.  
Dose(s):  
● 
Phase 1 (Dose Escalation Phase):  
Gilteritinib will be administered once daily starting from day 8 through day 21 of a 28-day 
cycle starting at 2 mg/kg per day for Group 1. For Groups 2 and 3, the starting dose is Dose 
Level -1 (1 mg/kg/day).  
Level 
Dose (by body weight) 
-1 
1 mg/kg/day (for a maximum dose of 60 mg/day) # 
1 
2 mg/kg/day (for a maximum dose of 120 mg/day) * 
2 
3 mg/kg/day (for a maximum dose of 180 mg/day) ** 
* Starting dose of gilteritinib for Group 1; # Starting dose of gilteritinib for Groups 2 and 3 
** To be evaluated only if there is lack of toxicity or acceptable DLT profile combined with the lack of 
sufficient gilteritinib activity observed at the Dose Level 1 (2 mg/kg/day). Not applicable for sites in 
USA. 
Weight-based dosing (rounding to the nearest 10 mg) is proposed to be used in pediatric subjects 
up to a body weight of 60 kg. At weights of 60 kg and greater, a flat dose will be given (i.e., the 
maximum dose for the particular dose level).  
Gilteritinib daily dose for any subject ≤ 5 kg weight will be discussed and approved by Astellas 
medical monitor. 
● 
Phase 2 (Dose Expansion Phase): 
Gilteritinib will be administered once daily starting from day 8 through day 21 of a 28-day 
cycle at the RP2D or MTD established by phase 1 for the respective age groups. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 33 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
Long-term Treatment Period:  
Gilteritinib will be administered once daily starting from day 1 through day 28 of a 28-day 
cycle at the same dose the subject received during phase 1 or 2 for a period of up to 2 years. 
Mode of Administration: 
Gilteritinib will be administered orally. 
Co-administered Drugs: 
The co-administered drugs during phase 1 and phase 2 are as follows: 
Cycle 1 and 2: FLAG on days -1 to 5 
Dose(s): 
Fludarabine: 30 mg/m2 per day 
Cytarabine: 2000 mg/m2 per day 
G-CSF: 5 µg/kg per day 
Subject may receive prophylactic intrathecal cytarabine at the start of the cycle as per institutional 
standards.  
FLAG dosage calculation per institutional practice (such as mg/kg/dose) for subjects less than 
2 years of age, or below a certain weight or body surface area, is allowed. 
Mode of Administration: 
Intravenous 
Duration of Treatment:  
Treatment Period for Phase 1 and Phase 2:  
Up to 2 cycles of 28 days each. 
Cycle 1 and 2: FLAG on days -1 to 5 and gilteritinib on days 8 to 21. 
Treatment Period for Long-term Treatment:  
LTT with gilteritinib for up to 2 years (~ 26 cycles) may continue only after discussion with the 
medical monitor.  
Concomitant Medication Restrictions or Requirements: 
The following is allowed during the course of the study: 
● 
Local practice for prophylaxis of conjunctivitis caused by high-dose cytarabine 
The following are prohibited during the course of the study: 
● 
Treatment with strong inducers of CYP3A/P-gp. 
● 
Therapies to treat AML including, but not limited to: 
● 
Chemotherapy 
● 
Surgery 
● 
Immunotherapy, cellular therapy or vaccines 
o Exceptions: Hydroxyurea (up to 5 g daily for up to 2 weeks to keep the absolute blast 
count below 50 x 109/L), intrathecal chemotherapy, cranial irradiation, localized radiation 
for palliation and leukapheresis are allowed. 
● 
Vaccination with live vaccines (the prohibited duration starts from 6 weeks prior to the first 
dose of FLAG regimen and lasts until 6 weeks after the last dose of FLAG regimen) 
● 
Any other investigational agent for AML. 
● 
Participation in another interventional study while on treatment 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 34 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Caution is advised when considering the concomitant use of the following medications:  
● 
Treatment with Medications known to prolong QT or QTcF intervals. For concomitant drugs 
that have the potential to prolong QT or QTc intervals, a cardiology consult should be obtained 
as medically indicated. 
● 
Strong inhibitors of P-gp and concomitant drugs that target serotonin 5 hydroxytryptamine 2B 
(5HT2B) receptor or sigma nonspecific receptor are to be avoided with the exception of drugs 
that are considered absolutely essential for the care of the subject.  
● 
Treatment with concomitant drugs that are strong inhibitors of CYP3A should be avoided with 
the exception of antibiotics, antifungals and antivirals that are used as standard of care to 
prevent or treat infections. If CYP3A inhibitors are used concomitantly, subjects should be 
closely monitored for AEs. 
● 
Precaution should be used in treatment of gilteritinib with concomitant drugs that are substrates 
of P-gp (e.g., digoxin, dabigatran etexilate), BCRP (e.g., mitoxantrone, rosuvastatin) and OCT1 
(e.g., metformin), since these transporters have been shown to be inhibited by gilteritinib in 
vitro. 
Formal Stopping Rules:  
Discontinuation Criteria 
• 
Subject and/or parent(s) or legal guardian declines further study participation (i.e., withdrawal 
of consent) 
• 
Subject develops an intolerable or unacceptable toxicity 
• 
Investigator determines that continuation of the study treatment will be detrimental to the 
subject 
• 
Subject has no response or progressive disease with no clinical benefit as defined by the 
investigator 
• 
Subject becomes pregnant 
• 
Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment 
• 
Subject is found to have significantly deviated from any 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 receives any antileukemic therapy other than the assigned treatment, with the exception 
of hydroxyurea up to 5 g daily for up to 2 weeks, prophylactic intrathecal chemotherapy, 
cranial irradiation, localized radiation for palliation or leukapheresis.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 35 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation (HSCT) 
Pre-HSCT preparation: 
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 if they have completed 
cycle 1 of phase 1 or 2. However, gilteritinib should be stopped for at least 1 week prior to start of 
the preparative regimen and a pre-HSCT visit should be performed prior to starting the 
conditioning regimen for HSCT.  
Resumption of Treatment After HSCT: 
Subjects returning to the study post HSCT can resume gilteritinib at the same dose prior to HSCT if 
the following conditions are met: 
• 
Subject is between 30 to 90 days post HSCT 
• 
Subject has had successful engraftment as demonstrated by ANC ≥ 500 /µL and platelets 
≥ 20000/µL without transfusions 
• 
Subject does not have ≥ grade 2 acute GVHD 
• 
Subject is in CRc (CR, complete remission with incomplete hematologic recovery [CRi], or 
complete remission with incomplete platelet recovery [CRp]) 
For subjects resuming gilteritinib treatment, subjects will follow the procedures listed under 
subsequent visits (day 1) in the Schedule of Assessments [Table 1]. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 36 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
Endpoints for Evaluation:  
Primary: 
The primary endpoints are: 
• 
Phase 1: Determination of MTD and/or RP2D  
• 
Phase 2:  
o CRc rates (overall best response) after 2 cycles of therapy.  
o CR rates after 2 cycles of therapy; CR rate will be further described by the duration of CR 
(only for USA). 
Secondary: 
The secondary endpoints are: 
• 
Inhibition of phosphorylated FLT3 (pFLT3) measured by PIA assay 
• 
Gilteritinib plasma concentration 
• 
Pharmacokinetic parameters (e.g., oral clearance [CL/F], apparent volume of distribution 
[Vd/F], maximum concentration [Cmax], time of maximum concentration [tmax], area under 
the concentration-time curve [AUC]) of gilteritinib  
• 
Safety, tolerability and toxicity assessments of gilteritinib when given in combination with 
FLAG 
• 
EFS rate 
• 
OS rate 
• 
MRD assessment 
• 
Acceptability and palatability assessment of the formulation 
Exploratory: 
The exploratory endpoints are: 
• 
Correlation of clinical responses to gilteritinib therapy with FLT3 PIA levels 
• 
Correlation of FLT3 PIA levels and clinical responses to gilteritinib therapy with FLT3 ligand 
levels before and after exposure to FLAG chemotherapy 
• 
Assessment of mechanisms of innate and acquired resistance to gilteritinib 
Statistical Methods:  
Sample size justification:  
Phase 1 
Group 1: 
Three subjects will be enrolled in a cohort at 1 of a series of doses of gilteritinib with a starting 
dose of 2 mg/kg/day according to the 3 + 3 design. Additional subjects will be accrued as needed to 
ensure that gilteritinib activity is assessable in at least 9 subjects.  
The RP2D will be a safe dose of gilteritinib that demonstrates sufficient activity. 
The number of subjects enrolled will depend on the number of dose levels evaluated, evaluation of 
biological activity, and the availability of time points for PIA assessments.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 37 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
Groups 2 and 3: 
Three subjects will be enrolled in a cohort at one of a series of doses of gilteritinib with a starting 
dose of 1 mg/kg/day according to the 3 + 3 design.  
Additional subjects will be accrued as needed to ensure that gilteritinib activity is assessable in at 
least 9 subjects.  
The RP2D will be a safe dose of gilteritinib that demonstrates sufficient activity. 
The number of subjects enrolled will depend on the number of dose levels evaluated, evaluation of 
biological activity, and the availability of time points for PIA assessments.  
Phase 2 
The phase 2 portion of this study will be a single-arm, 2-stage, open-label design with a total of 
52 response evaluable subjects. Subjects are response evaluable if (1) they are confirmed 
FLT3/ITD mutation positive, (2) they receive at least 1 dose of gilteritinib, and (3) they are 
progression/recurrence free during the first 2 cycles of FLAG + gilteritinib and have the required 
bone marrow evaluations or have died of disease progression during the first 2 cycles. Subjects 
who die during treatment will be counted as nonresponders for purposes of analysis.  
In the available dataset (COG AAML 06P1, 1-BFM AML 2001-01, Costa dataset), there are 26 
CRc responders out of 73 subjects (a CRc rate of about 35%). With a 1-sided Type 1 error rate of 
2.5%, there will be about 80% power to detect a 30% CR rate (i.e., a 16% increase in CR rate from 
the null hypothesis value of 14%). The 52 response evaluable subjects will provide about 90% 
power to detect a 56% CRc rate (i.e., a 21% increase in CRc rate from the null hypothesis value of 
35%), with 1-sided Type error rate of 5%. Operationally, 22 response evaluable subjects will be 
needed during the first stage, with 4 CR responders or 9 CRc responders after 1 or 2 cycles of 
therapy required to continue to a total of 52 response evaluable subjects. If there are less than 4 CR 
responders in stage 1, the enrollment will be stopped in the USA and the study will not proceed to 
stage 2 in the USA. Ultimately, 13 or more CR responders or 24 CRc responders will be required 
to meet the efficacy threshold of FLAG + gilteritinib. The sample size was calculated in East 
Version 6.4 for CR. 
Efficacy:  
The rates of CRc, CR, OS, and EFS will be summarized using descriptive statistics. The survival 
curve and median for time-to-event variables and EFS and OS rates at 6 months/1 year/2 years will 
be estimated using the Kaplan-Meier method and will be reported along with the corresponding 
95% confidence interval. 
Pharmacokinetics:  
Gilteritinib plasma concentrations will be summarized by dose levels, study day and sample 
collection window using descriptive statistics, including number of subjects, mean, standard 
deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the 
mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. If 
warranted, plasma concentrations for active metabolites will also be summarized in a similar 
manner. 
Gilteritinib pharmacokinetic parameters (e.g., CL/F, Vd/F) will be estimated using population 
pharmacokinetic analysis. Simulation will be performed to predict pharmacokinetic parameters 
such as Cmax, tmax and AUC. Pharmacokinetic parameters will be summarized by phase of the study 
and dose levels using descriptive statistics, including number of subjects, mean, standard deviation, 
minimum, median, maximum, geometric mean, and CV of the mean and geometric mean. If 
warranted, pharmacokinetic parameters for active metabolites will also be summarized in a similar 
manner. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 38 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Pharmacodynamics:  
A PIA assay will be employed to determine FLT3 inhibition relative to baseline FLT3 levels. Data 
will be summarized by phase of the study and dose levels using descriptive statistics, including 
number of subjects, mean, standard deviation, minimum, median, maximum, geometric mean, and 
coefficient of variation (CV) of the mean and geometric mean. 
Safety:  
Safety analyses will include all subjects who receive at least 1 dose of the treatment regimen. 
Safety analyses will consist of data summaries of AEs, DLTs, and other safety parameters. The 
number and percent of subjects experiencing 1 or more AE(s) will be summarized by the phase of 
the study and dose levels. The relationship to study drug and severity of AE will also be 
summarized. AEs will be coded to system organ class and preferred term using Medical Dictionary 
for Regulatory Activities (MedDRA) terminology and will be graded by the investigator using the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
severity grade (version 5.0).  
Laboratory parameters will be summarized by the phase of the study, dose levels and visits using 
descriptive statistics for shifts in change from baseline, and will be presented in listings of 
clinically significant abnormalities. Descriptive statistics will be used to summarize vital sign 
results and changes from baseline by phase of the study and dose level and visit. The 12-lead ECG 
results will be summarized by phase of the study, dose levels, visits and time points using 
descriptive statistics. 
Interim Analyses:  
The phase 2 portion of this study will be a 2-stage design [See Section 7.1.2]. No other formal 
interim analysis is planned. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 39 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Figure 1 
Study Flow Chart 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 40 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Table 1 
Schedule of Assessments for Phase 1, Phase 2 and Long-term Treatment (LTT) 
Assessments 
Screening 
PHASE 1/PHASE 2 
LTT  
EOT2/ 
Pre-
HSCT 
Visit v 
28-day 
Follow-
upw 
 
Survival 
Follow-
upx 
 
 
Cycle 1a  
 
Cycle 2a 
 
Cycle 1 & 
Subsequent 
Cycles 
Cycle Day → 
Days 
-28 to -2 
Day 
-1 
Day 
1 
Day 
4 
Day 
8 
Day 
15 
Day 
21 
Day 
28 
Day 
-1 
Day 
1 
Day 
4 
Day 
8 
Day 
15 
Day 
21 
Day 28 
/EOT1v 
Day 
1 
Visit Window (days) → 
 
 
 
± 1 
± 1 
± 2 
± 2 
± 2 
 
 
± 1 
± 1 
± 2 
± 2 
± 2 
± 2 
± 2 
+ 7 
± 7 
Informed consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Karnofsky/Lansky 
performance status  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
Physical examinationd 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy test for WOCBPe 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
Chest x-ray (or chest CT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf  
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Clinical laboratory tests 
(chemistry, hematology, 
coagulation, urinalysis) g 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Thyroid function testsh 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
MUGA or ECHOi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
PK sample collectionj 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
PGxk  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Inhibitory Assay 
(PIA) & FLT3 Ligand l 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
FLT3 mutational statusm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biopsy and MRD 
analysisn, o 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Gilteritinib dispensingp 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
FLAG administrationq 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
DLT assessmentr 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 41 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Assessments 
Screening 
PHASE 1/PHASE 2 
LTT  
EOT2/ 
Pre-
HSCT 
Visit v 
28-day 
Follow-
upw 
 
Survival 
Follow-
upx 
 
 
Cycle 1a  
 
Cycle 2a 
 
Cycle 1 & 
Subsequent 
Cycles 
Cycle Day → 
Days 
-28 to -2 
Day 
-1 
Day 
1 
Day 
4 
Day 
8 
Day 
15 
Day 
21 
Day 
28 
Day 
-1 
Day 
1 
Day 
4 
Day 
8 
Day 
15 
Day 
21 
Day 28 
/EOT1v 
Day 
1 
Visit Window (days) → 
 
 
 
± 1 
± 1 
± 2 
± 2 
± 2 
 
 
± 1 
± 1 
± 2 
± 2 
± 2 
± 2 
± 2 
+ 7 
± 7 
Clinical Outcome 
Assesments 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
AE/SAE assessmentt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and concomitant 
medicationsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subsequent anti-leukemic 
treatments/outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AE: adverse event; C: cycle; COA: clinical outcome assessment; CT: computed tomography; D: day; DLT; dose limiting toxicity; ECG: electrocardiogram; ECHO: echocardiogram; 
EOT: end of treatment; FLAG: fludarabine, cytarabine, and granulocyte colony-stimulating factor;  FLT3: FMS-like tyrosine kinase 3; HSCT: hematopoietic stem cell transplant; 
ICF: informed consent form; LTT: long-term treatment; MRD: minimal residual disease; MUGA: multigated acquisition; PGx: pharmacogenomics; PIA: plasma inhibitory assay; 
PK: pharmacokinetic; SAE: serious adverse event; WOCBP: women of childbearing potential 
Note: The day after day -1 is day 1. There is no day 0. 
a. Visits for each cycle should be based upon day 1 of that cycle. Unscheduled visits may be performed at any time during the study whenever necessary to assess for or follow-up 
AEs or if deemed necessary by the investigator. Unscheduled visits will include assessment of AEs; additional assessments (e.g., laboratory testing) that may be performed as 
deemed appropriate by the investigator. Cycle 2 can begin once the subject meets the “Criteria to Begin Cycle 2 (Phases 1 and 2)” as outlined in [Section 2.2.1 Study Design]. 
b. ICF must be obtained prior to performing any study-specific procedures with the exception of procedures that are performed within the protocol specified windows as part of 
routine patient management. 
c. Vital signs (includes blood pressure, respiratory rate, O2 saturation, pulse rate and temperature) should be collected pre-dose as applicable. All vital sign measures will be obtained 
with the subject in the sitting or supine position. 
d. A complete physical exam will be completed at screening and will be directed towards subject-reported symptoms and areas of disease, as per investigator judgment. Brief physical 
exams can be completed thereafter and must be obtained predose. Physical examination also includes measurements of height and weight. Weight and height will be collected at 
screening, day 1 of each cycle and EOT1 (C2D28 for phase 1/phase 2).  
e. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 72 hours prior to the start 
of each cycle. 
Footnotes continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 42 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
f. ECG assessment is required at screening. During treatment period, pre-dose ECG must also be obtained within 1 hour prior to dosing. The 12-lead ECGs will be recorded in 
triplicate (3 separate ECGs with 10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and transmitted electronically for central reading. Triplicate ECGs 
must also be obtained within 1 hour prior to obtaining the time-matched PK samples, for a particular visit.  
g. Laboratory tests performed will include hematology, serum chemistries, liver function, coagulation, urinalysis and uric acid.  
Coagulation and urinalysis: Screening only 
Uric acid: C1D1, C1D4, C1D8 and C1D15 only 
h. For phase 1/phase 2: Thyroid function tests will be performed during screening, C1D1, C2D1 and C2D28 visit.  
For LTT: Thyroid function tests will be performed on C1D1 and repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1, etc.). 
i. MUGA scans or ECHO (per local standard of care) are to be performed at screening and C2D28/EOT1 visit. Note: MUGA scans are not applicable to Germany.  
j. PK samples will be collected in cycle 1 and cycle 2 at the following time points: 
● C1D8 - Predose 
● C1D15 (± 2 days) – Predose 
● C1D21 (± 2 day) – Predose and 4 to 6 hours 
● C2D15 (± 2 days) – Predose 
Predose samples should be collected within 1 hour prior to dosing. 
k. Whole blood and buccal swab collected at C1D -1 (predose) for optional PGx study. Sample should be collected prior to the administration of induction chemotherapy. 
l. PIA and FLT3 Ligand samples will be collected on C1D8 (predose), C1D15 (predose) and C1D21 (predose), C1D21 (4-6 hours post dose), C2D8 (predose), C2D15 (predose) and 
C2D21 (predose). Samples should be collected at or near the same time as PK samples. Predose samples should be collected within 1 hour prior to dosing. 
m. Subjects is positive for the FLT3/ITD mutation in bone marrow or blood as determined by the local institution. A bone marrow aspirate or blood sample must be sent to the central 
laboratory for FLT3 mutational analysis during the screening period. 
n. If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of whole blood should be collected instead. Bone marrow aspirate is required, and bone marrow 
biopsy is preferred. In case of inadequate aspirate, bone marrow biopsy is required.  
Bone marrow samples are required during screening and end of each cycle (C1D28 and C2D28) for phase 1/phase 2.  
For LTT: Bone marrow assessments will be performed on C1D1 and repeated after every 3 cycles until 1 year of LTT, followed by every 6 cycles until 2 years of LTT (i.e., C1D1, 
C4D1, C7D1, C10D1, C13D1, C19D1, etc.). Bone marrow samples are also required at the end of treatment visit and as clinically indicated. Bone marrow assessments do not need 
to be performed on C1D1 of LTT and EOT2, if a bone marrow assessment was performed within 2 weeks during the previous study visit. 
o. For subjects whose response assessment is not evaluable due to hypocellularity, a repeat bone marrow analysis should be performed at least every 14 days until response 
determination is possible. 
p. For phase 1/phase 2: Gilteritinib will be dispensed on day 8 of each cycle and will be taken daily by the subject from day 8 to day 21 of each cycle. 
For LTT: Gilteritinib bottles will be dispensed on day 1 of each cycle and will be taken by the subject once daily for the 28-day cycle. 
Footnotes continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 43 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
q. FLAG will be administered on days -1 to 5 of cycle 1 and cycle 2. Refer to Table 5 Treatment Plan for cycle 1 and cycle 2 of phases 1 and 2 for detailed scheduled of FLAG 
administration. 
r. DLT assessment is performed in cycle 1 of phase 1 only.  
s. Clinical outcome assessment (COA) should be collected immediately after the administration of the study drug on that visit day. For LTT: COA will be collected only on C1D1 
visit. 
t. AE collection begins after the signing of the informed consent and will be collected until the 28-day Follow-up visit of the subject or the subject is determined to be a screen failure. 
For subjects who plan to proceed to HSCT and resume gilteritinib treatment after HSCT, AE collection will continue until the start of the HSCT conditioning regimen and AE 
collection will resume upon the resumption of gilteritinib treatment until 30 days after the last dose of study drug. For subjects who do not plan to resume gilteritinib treatment after 
HSCT, AE collection will continue until the start of the HSCT conditioning regimen or 30 days after the last dose of study drug, whichever comes first.  
u. Includes medications taken within 28 days prior Screening. 
v. An EOT visit [EOT1 or EOT2] will be performed 7 days after last dose of gilteritinib, or prior to initiation of another anticancer therapy, whichever occurs earlier. EOT1 visit 
(C2D28 for phase 1/phase 2) will be performed for any subject participating in phase 1 or 2 and indicates the end of the respective phase. EOT2 visit will be performed for any 
subject participating in LTT phase and indicates the end of LTT. For subjects who will undergo HSCT and plan to resume gilteritinib treatment after HSCT, a pre-HSCT visit will 
be performed. 
w. A follow-up visit will be performed 28 days following the C2D28/EOT1 visit in the event the subject is not participating in the LTT phase. In the event the subject is participating 
in LTT, then the follow-up visit will be performed 28 days following the EOT2 visit. 
x. Survival follow-up will be performed every 3 months for up to 2 years after the 28-day follow-up visit. In the event that the subject is not available for a clinic visit, telephone or e-
mail correspondence is acceptable.  
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 44 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
1 
INTRODUCTION 
1.1 
Background 
Acute myeloid leukemia (AML) is a group of biologically heterogeneous diseases that comprise 
20% of pediatric and 80% of adult acute leukemias. It is estimated that 19940 people in the 
United States will be diagnosed with AML in 2020, and 11180 of these patients will die from 
AML [American Cancer Society, 2020]. While outcomes for children with de novo AML have 
improved over the past several decades, event-free survival (EFS) and overall survival (OS) 
remain suboptimal at approximately 60 and 70%, respectively. Relapsed disease and poor 
response to salvage therapy remain significant hurdles in achieving cure [Sexauer & Tasian, 
2017].  
FMS-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase (RTK) 
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 [Schlenk & Döhner, 2009].  
Mutations in FLT3 are one of the most common genetic alterations in AML and are associated 
with high rates of relapse in adults and children. Activating FLT3 mutations are classified into 
2 types [Sexauer & Tasian, 2017]:  
1. internal tandem duplication (FLT3–ITD) mutations, which are 3 to 400 bp in-frame 
duplications located in the juxtamembrane domain and  
2. activating point mutations, which are found in the tyrosine kinase domain (FLT3-TKD) 
and most often involve residue D835.  
ITD and TKD mutations occur in approximately 25% and 10% of adult AML cases, 
respectively. Recent studies have reported similar incidence of ITD and activating TKD 
mutations in childhood AML. Numerous clinical studies have demonstrated inferior clinical 
outcomes in patients with FLT3-ITD AML [Sexauer & Tasian, 2017]. 
Children with FLT3–ITD AML treated on Children’s Cancer Group and Pediatric Oncology 
Group studies fared similarly poorly with 30% 4-year EFS when treated with conventional 
multi-agent chemotherapy. Higher mutant-to-wild-type FLT3 allelic ratios have also been 
associated with increasingly inferior outcomes in children treated on Dutch Children’s 
Oncology Group and Children’s Oncology Group studies [Sexauer & Tasian, 2017].  
Given the significant negative prognostic effects of FLT3–ITD mutations in AML and the 
relative frequency of these alterations, therapeutic targeting of aberrant FLT3 signaling has 
been a major research focus with goals of decreasing relapse and improving survival 
[Sexauer & Tasian, 2017].  
AXL tyrosine kinase (AXL), an RTK, has been detected in AML and has been shown to play 
a role in mediating migration and invasiveness of cancer cells. Inhibition of AXL has been 
shown to increase apoptosis and inhibit proliferation of FLT3-ITD and FLT3 wild-type AML 
cell lines and primary AML cells in vitro and reduced tumor burden and prolonged survival 
in mouse models [Janning et al, 2015]. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 45 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
ASP2215 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). 
Gilteritinib 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, gilteritinib inhibited the 
growth of cells expressing FLT3-ITD, FLT3-D835Y or FLT3-ITD-D835Y.  
The efficacy of gilteritinib as monotherapy has been demonstrated in adult patients with R/R 
AML. Phase 1 and phase 2 studies of gilteritinib in combination with chemotherapy in newly 
diagnosed patients with AML are currently ongoing. A phase 2 maintenance study with 
gilteritinib in newly diagnosed patients with AML after first CR is ongoing. A phase 3 study 
of gilteritinib in comparison with azacitidine in newly diagnosed FLT3-mutated AML 
patients is ongoing, but was recently closed to enrollment post interim analysis.  
Two phase 3 studies, one of gilteritinib compared with chemotherapy in FLT3-mutated 
patients with R/R AML and one of gilteritinib compared with placebo as a maintenance 
therapy following HSCT in patients with FLT3/ITD AML in first CR, are also ongoing. 
XOSPATA (gilteritinib) tablets have been approved by the FDA, EMA, MHLW, Health 
Canada and other health authorities for the treatment of adult patients who have relapsed or 
refractory AML with an FLT3 mutation. 
1.2 
Nonclinical and Clinical Data 
A detailed description of the chemistry, pharmacology, efficacy and safety of gilteritinib is 
provided in the current version of the [ASP2215 Investigator’s Brochure]. 
1.3 
Summary of Key Safety Information for Study Drugs 
1.3.1 
Gilteritinib (ASP2215) Data 
The nonclinical and clinical studies that are referred to in this section are described in more 
detail in the current version of the [ASP2215 Investigator’s Brochure]. 
1.3.1.1 Gilteritinib Nonclinical Data 
Major findings in the safety pharmacology studies were vomiting, positive fecal occult blood 
and increased/decreased blood calcium ion 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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 46 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Gilteritinib has a potential to induce genotoxicity in vivo. Gilteritinib showed teratogenic 
potential and embryo-fetal deaths in the embryo-fetal development study in rats. Gilteritinib 
showed no potential to induce phototoxicity in cultured mammalian cells. 
When gilteritinib was dosed to juvenile rats from PND 4 to 42, the minimum lethal dose level 
was 2.5 mg/kg per day and this dose level was lower than that (20 mg/kg per day) in adult 
rats in the 13-week dose study. In the preliminary (non-GLP) dose range finding study 
(dosing from PND 4 to 21), gastrointestinal bleeding 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. It 
should be noted that gilteritinib exposure, i.e., Cmax and AUC24, decreased after repeated 
dosing, which may be due to maturation of CYP450 isozymes over time; however, a 
definitive conclusion cannot be made as it has not been determined if and which rat-specific 
CYP isozymes are involved with gilteritinib metabolism. 
Compared to adult rats treated with gilteritinib, juvenile rats treated with the same dose were 
exposed to higher gilteritinib levels, and juvenile rats at similar exposure (i.e., at 10 mg/kg 
per day in juvenile vs 20 mg/kg per day in adult rats) exhibited mortality and moribundity 
earlier during the treatment period. 
1.3.1.2 Gilteritinib Clinical Data 
Data from clinical studies 2215-CL-0101, 2215-CL-0102, 2215-CL-0103 and 2215-CL-0301 
demonstrated efficacy in FLT3-mutation positive patients with R/R AML, with a tolerable 
safety profile. 
Expected serious adverse drug reactions for gilteritinib include (by preferred term) pericardial 
effusion, pericarditis, cardiac failure, diarrhea, nausea, fatigue, asthenia, anaphylactic 
reaction, increased blood creatine phosphokinase, increased ALT, increased AST, ECG QT 
prolonged, arthralgia, posterior reversible encephalopathy syndrome, acute kidney injury, 
differentiation syndrome, dyspnea, cough, and hypotension [ASP2215 Investigator’s 
Brochure; Section 5.2.3 and Appendix 1]. 
1.3.2 
Co-administered Chemotherapy Regimens 
Detailed information on the toxicities and common AEs associated with the co-administered 
chemotherapy regimens can be found within the Package Insert, Summary of Product 
Characteristics or local product information. 
1.4 
Risk Benefit Assessment 
As in adults, the prognosis for children with R/R FLT3/ITD AML is particularly poor, even 
with the current standard of care.  
The current standard of care for children with FLT3-ITD mutations is intensive induction 
chemotherapy followed by hematopoietic stem cell transplantation (HSCT) [Cooper et al, 
2016; Brown and Small, 2004]. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 47 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
The FLAG (fludarabine, cytarabine and filgrastim) regimen is a non-anthracycline based 
chemotherapy and has been reported as effective and well tolerated in newly diagnosed as 
well as in resistant or relapsing AML patients [Montillo et al, 1998; Estey et al, 1993]. 
FLAG chemotherapy without an anthracycline (liposomal daunorubicin/idarubicin) is a 
relatively effective and well-tolerated regimen in children with relapsed or refractory AML 
[Kaspers et al, 2013; Lee et al, 2009]. 
The use of FLAG chemotherapy has allowed intensive post-remission therapy including 
HSCT in such patients [Lee et al, 2009]. 
Children with acute myeloid leukemia and internal tandem duplication mutations in the FLT3 
receptor tyrosine kinase have a poor prognosis despite intensive chemotherapy and 
hematopoietic stem cell transplantation. FLT3 inhibition represents a promising therapeutic 
strategy for improving survival in this high-risk patient population [Cooper, 2016; Brown and 
Small, 2004]. 
Gilteritinib is a third-generation oral FLT3 inhibitor that has been approved by FDA and 
PMDA for the treatment of adult patients who have relapsed or refractory AML with an 
FLT3 mutation. 
In an adult population (Study 2215-CL-0101), gilteritinib has resulted in CRc in over 40% of 
patients receiving 80 mg or higher dose in FLT3 mutation-positive patients. The majority of 
patients in the study received multiple treatments prior to receiving gilteritinib. Furthermore, 
gilteritinib was well tolerated at the proposed doses in this study. Refer to the current version 
of the [ASP2215 Investigator’s Brochure] for further details. 
Since the clinical progression of FLT3/ITD AML appears to be similar in children and adults, 
it is expected that the clinical benefit with inclusion of gilteritinib in pediatric FLT3/ITD 
AML should be similar to that demonstrated in adult studies.  
An efficacious and safe dose of gilteritinib in pediatric patients has not yet been determined. 
This is a first-in-child phase 1/2 study of gilteritinib and the primary objective of this study is 
to determine a safe and biologically active dose of gilteritinib given in sequential 
combination with FLAG chemotherapy regimen in in children, adolescents and young adults 
with R/R FLT3/ITD AML. 
In the juvenile animal studies in rats (2215-TX-0015 and 2215-TX-0016), changes 
suggesting effects on the development of reproductive system, nervous system, kidney, lung, 
immune system, skeletal system and gastrointestinal system, which undergo significant 
postnatal development, were not observed. Based on the difference in the development of 
heart in humans and rats, effects on the cardiac development could not be investigated in the 
juvenile animal studies in rats, therefore, infants younger than 6 months will not be involved 
in this study [Hew & Keller, 2003]. 
The juvenile toxicity data suggest that the safety profile in children less than 2 years may 
differ from older children. Further, there may be differences in safety profiles for children 
between 6 months to less than 1 year old compared with 1 year to less than 2 year-old 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 48 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
children based on CYP450 ontogeny. Therefore, the phase 1 portion of the clinical study will 
have a separate sub-group focusing on the age group from 6 months to less than 2 years to 
establish the recommended phase 2 dose (RP2D) in this age group. The approach will 
provide evidence for safe dosing in this age group of children.  
Subjects enrolled in this study may experience AEs, including previously unknown AEs 
related to study drug or may experience procedural complications, e.g., light skin irritation 
from the adhesive on the ECG electrodes. While the proposed dose regimen was established 
to minimize the number of subjects reaching exposures associated with increased toxicity in 
adults, some pediatric subjects could reach exposures that resulted in transaminase elevation 
and gastrointestinal (GI)-type adverse effects in adults. Subjects with prolonged QTcF are 
excluded from participation in this study. Pediatric subjects enrolled in this study will be 
closely monitored for AEs, especially for liver toxicity.  
It is unknown if pediatric subjects participating in this clinical study will benefit from 
administration of gilteritinib. Overall, based on the target population selected for this study 
(children, adolescents and young adults with R/R FLT3-ITD AML), the exclusion criteria and 
the proposed dose regimen, which is expected to match adult efficacious exposures, the benefit 
and risk assessment associated with the participation of study population is worth exploring. 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objective(s) 
2.1.1 
Primary Objective 
The primary objectives are: 
● 
Phase 1 (Dose Escalation Phase):  
To determine the MTD and/or optimally safe and biologically active RP2D of gilteritinib 
given in sequential combination with FLAG in children, adolescents and young adults 
with R/R FLT3 (ITD and/or TKD) AML. 
● 
Phase 2 (Dose Expansion Phase):  
To determine CR rates and CRc rates after 2 cycles of gilteritinib in sequential 
combination with FLAG in children, adolescents and young adults with FLT3 (ITD) 
AML who are refractory to or at the first hematologic relapse after first-line remission 
induction AML therapy (up to 2 induction cycles). 
2.1.2 
Secondary Objectives  
The secondary objectives are: 
● 
To assess the safety, tolerability and toxicities of gilteritinib when given in sequential 
combination with FLAG in children, adolescents, and young adults with R/R FLT3/ITD 
AML  
● 
To evaluate FLT3 inhibition due to gilteritinib treatment 
● 
To characterize gilteritinib pharmacokinetics  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 49 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
To perform serial measurements of minimal residual disease (MRD) and examine the 
relationship with study endpoints 
● 
To obtain preliminary estimates of 1-year event-free survival (EFS) and overall survival 
(OS) rate 
● 
To assess the acceptability and palatability of the formulation. 
2.1.3 
Exploratory Objectives 
The exploratory objectives are: 
● 
To relate the clinical responses to gilteritinib therapy with FLT3 PIA. 
● 
To evaluate relationship between FLT3 ligand levels and clinical response. 
● 
To assess the mechanisms of innate and acquired resistance to gilteritinib. 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This study is an open-label, single-arm, phase 1/2 study to evaluate the safety, 
pharmacokinetics, and anti-leukemic activity of gilteritinib in children, adolescents and 
young adults with AML.  
The study will consist of 2 phases:  
● 
Phase 1 (Dose Escalation Phase) 
● 
Phase 2 (Dose Expansion Phase) 
One cycle is defined as 28 days of treatment. A subject completing 1 or 2 treatment cycles in 
phase 1 or 2 will have the option to participate in long-term treatment (LTT) with gilteritinib 
(for up to 2 years). The study treatment will continue until 1 of the discontinuation criteria is 
met. 
Phase 1 (Dose Escalation Phase):  
The primary objective of phase 1 will be to establish an optimally safe and biologically active 
RP2D and/or to determine MTD for gilteritinib in combination with FLAG.  
The RP2D will be a dose, which is safe (i.e., has an acceptable DLT profile) and 
demonstrates CR, a high degree of gilteritinib biologic activity (as measured by PIA), or a 
combination of both.  
Dose Escalation during phase 1 will be performed in 3 groups based on the age of the subject: 
● 
Group 1: Dose Escalation in subjects from 2 years to less than 21 years of age 
● 
Group 2: Dose Escalation in subjects from 1 year to less than 2 years of age 
● 
Group 3: Dose Escalation in subjects from 6 months to less than 1 year of age 
Induction therapy in this phase will consist of 2 cycles of gilteritinib plus FLAG. During each 
cycle, FLAG chemotherapy will be administered on days -1 to 5 and gilteritinib will be 
administered once per day on days 8 to 21 at the assigned dose levels as outlined in below:  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 50 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Table 2 
Dose Levels 
Level 
Dose 
-1 
1 mg/kg/day (maximum 60 mg/day) # 
1 
2 mg/kg/day (maximum 120 mg/day) * 
2  
3 mg/kg/day (maximum 180 mg/day) ** 
* Starting dose of gilteritinib for Group 1; # Starting dose of gilteritinib for Groups 2 and 3 
** To be evaluated only if there is lack of toxicity or acceptable DLT profile combined with the lack of 
sufficient gilteritinib activity observed at the Dose Level 1 (2 mg/kg/day). Not applicable for sites in USA. 
DLT assessment will occur during the first cycle only. Pharmacokinetic parameters, response assessment and 
biological activity will be evaluated during cycle 1 and/or cycle 2.  
Dose Escalation Rules 
Dose escalation, stay, or de-escalation between the dose levels in Groups 1, 2 and 3 will be 
guided by the 3 + 3 design.  
Dose escalation rules to be followed during the DLT Observation Period are outlined in 
Table 3.  
Table 3 
Dose Escalation Rules during the DLT Observation Period 
Number of Subjects with DLT at the Given Dose  
Escalation Decision Rules 
0 of 3 or ≤ 1 of 6 subjects 
Escalate and enter up to 3 subjects at the next dose 
level, if the next higher dose level is available. 
1 of 3 subjects 
Enter up to 3 subjects at the same dose level 
≥ 2 subjects 
De-escalate, if the next lower dose level is available or 
stop escalating 
DLT: dose-limiting toxicity 
Intra-subject dose escalation is not allowed during the study. Guidance for intra subject dose 
interruption or reduction for gilteritinib is outlined in [Section 5.1.2 Interruption or Reduction 
in Dose of the Study Drug].   
The Dose Escalation Committee (DEC) will review safety data through the DLT observation 
period for 3 evaluable subjects at each dose level. In addition to safety data through the DLT 
observation period, the DEC will review response data and gilteritinib biologic activity (as 
measured by PIA) through the cycle 1 and/or cycle 2 of the evaluable subjects. The algorithm 
for differentiation syndrome based on the [Montesinos et al, 2009] criteria, in addition to the 
preferred term of ‘acute promyelocytic leukemia differentiation syndrome’, will be used to 
search for potential cases of differentiation syndrome at every dose level in phase 1. The 
decision will be made by the DEC to escalate to the next planned dose level, remain at the 
same dose level, de-escalate to the dose level below or stop escalation. The RP2D and/or 
MTD will be selected based on the DEC’s review of all available data at each dose level, 
including safety data, pharmacokinetic data (if available), response data and gilteritinib 
biologic activity data, and the RP2D will become the minimum safe and biologically 
effective dose level.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 51 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
Group 1:  
Three subjects will be enrolled in the initial cohort starting at Dose Level 1 
(2 mg/kg/day). 
● 
Groups 2 and 3:  
Three subjects will be enrolled in the initial cohort starting at Dose Level -1 
(1 mg/kg/day). Enrollment of subjects in Groups 2 and 3 will be initiated following 
the decision by the DEC on the Dose Level 1 (2 mg/kg/day) evaluated in Group 1.  
Escalation to Dose Level 1 (2 mg/kg/day) in Groups 2 and 3 will not be performed if 
de-escalation to Dose Level -1 (1 mg/kg/day) has been performed in Group 1 or Dose 
Level -1 has been established as the MTD in Group 1. 
Additional subjects will be accrued as needed at the RP2D of each group (Groups 1, 2 and 3) 
to ensure that gilteritinib activity is assessable in at least 9 subjects in the respective age 
group.  
For the dose to be considered biologically active, at least 7 of 9 subjects at the RP2D dose in 
each group must demonstrate CR, a high degree of gilteritinib biologic activity (as measured 
by PIA), or a combination of both with the following conditions for PIA:  
● Subjects that complete 2 induction cycles must achieve PIA of > 90% for at least 3 of 
4 trough time points; or 
● Subjects that complete only 1 induction cycle must achieve PIA of > 90% at 2 of 
2 trough time points. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 52 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Figure 2 
Schematic Representation of Dose Assignments of Each Dose Level in the 
3 + 3 Design  
 
DLTs: dose-limiting toxicities; MTD: maximum tolerated dose 
 
Alternative dose levels can be explored in the following cases: 
● 
A higher Dose Level 2 (3 mg/kg/day) in the event there is lack of toxicity or acceptable 
DLT profile combined with the lack of sufficient gilteritinib activity at the Dose Level 1 
(2 mg/kg/day), after discussion with the DEC. Dose Level 2 (3 mg/kg/day) will not be 
evaluated in subjects enrolled in USA. 
● 
A lower dose level than Dose Level -1 (1 mg/kg/day) in the event the Dose Level -1 
(1 mg/kg/day) demonstrates sufficient gilteritinib activity but DLTs are observed. 
Exploration of dose level lower that Dose Level -1 will be performed via an amendment 
to the current study protocol, after discussion with the DEC. 
Continued participation in phase 2 portion of the study for each age group will be dependent 
on the determination of RP2D in Groups 1, 2 and 3, respectively.  
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 53 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
Subject Replacement (Only For Phase 1 -Dose Escalation) 
A subject meeting fulfilling the inclusion/exclusion criteria and receiving 80% of the 
intended dose of the study treatment regimen (FLAG and gilteritinib) during the DLT 
observation period will be considered evaluable for DLT. 
A subject that receives less than 80% of the intended dose of the study treatment regimen (for 
reasons other than a DLT) during the DLT observation period will not be evaluable for DLT 
and will be replaced by another subject in the dose level. 
In addition, if after enrollment any subject is found not to fulfill any inclusion/exclusion 
criteria that would adversely affect safety or efficacy evaluation of that subject or are not 
evaluable for DLT, they may be replaced after discussion with the DEC.  
Subjects without adequate sampling time points to assess biological activity for RP2D 
determination can be replaced.  
Phase 2 (Dose Expansion Phase): 
The phase 2 part of this study is the dose expansion phase, which will be initiated upon 
establishment of the optimally safe and biologically effective RP2D and/or MTD dose from 
Group 1 of phase 1.  
Enrollment of subjects from 6 months to less than 2 years in phase 2 will depend upon the 
RP2D established in the respective age group (Groups 2 and 3) during the phase 1 portion of 
the study.  
Applicable only for Germany: Enrollment of subjects in phase 2 will be initiated in sites in 
Germany only after a positive assessment on the phase 1 data of each age group (Group 1, 2 
or 3) is received from the competent authority of the country. 
Phase 2 will be a single-arm, 2-stage, open-label design with at least 52 response evaluable 
subjects from 6 months to less than 21 years of age, with: 
● 
at least 2 subjects from 6 months to less than 6 years of age, 
● 
at least 6 subjects from 6 years to less than 12 years of age, and 
● 
at least 10 subjects from 12 years to less than 18 years of age.  
Subjects are response evaluable if  
1. they are confirmed FLT3/ITD mutation positive 
2. they receive at least 1 dose of gilteritinib, and  
3. they are disease progression/recurrence free during the first 2 cycles of FLAG + 
gilteritinib and have the required bone marrow evaluations, or have died of disease 
progression during the first 2 cycles.  
Induction therapy in this phase will consist of 2 cycles of gilteritinib plus FLAG. During each 
cycle, FLAG chemotherapy will be administered on days -1 to 5 and gilteritinib will be 
administered once per day on days 8 to 21 at the assigned dose (RP2D). 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 54 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Initially, 22 response evaluable subjects will be needed during the first stage, with 9 CRc 
responders or 4 CR responders after 1 or 2 cycles of therapy required to continue to a total of 
52 response evaluable subjects.  
Applicable only for USA: If there are less than 4 CR responders in stage 1, the enrollment 
will be stopped in the USA and the study will not proceed to stage 2 in the USA. 
A Bayesian posterior probability for safety monitoring will be used for phase 2. Subjects 
in phase 2 will be continued to be monitored for ≥ grade 3 non-hematologic AEs considered 
at least possibly related to protocol therapy, and AEs of any grade leading to treatment 
discontinuation or death considered at least possibly related to protocol therapy. The event 
rate will be reviewed for the first 6 evaluable subjects at the end of cycle 1. After that, the 
event rate will be reviewed continuously. The estimated event rate based on the Bayesian 
beta-binomial model will be provided for safety monitoring. If the event rate is ≥ 20% with a 
posterior probability of at least 80%, then the enrollment to phase 2 will be paused and safety 
will be reassessed by the DEC. With a non-informative prior Beta(1,1) distribution, the 
numbers of subjects with event for certain evaluable subjects, which trigger the enrollment 
pause for safety review, are listed in [Table 4]. The algorithm for differentiation syndrome 
based on the [Montesinos et al, 2009] criteria, in addition to the preferred term of ‘acute 
promyelocytic leukemia differentiation syndrome’, will be used to search for potential cases 
of differentiation syndrome in every 6 subjects in phase 2. 
Table 4 
Safety Monitoring Rules for Phase 2 
Number of Evaluable Participants 
Minimum Number of Subjects with Event to Pause 
Enrollment 
6 
2 
7-10 
3 
11-14 
4 
15-19 
5 
20-23 
6 
24-27 
7 
28-31 
8 
32-36 
9 
37-40 
10 
41-45 
11 
46-49 
12 
50-52 
13 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 55 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Treatment Plan (Phases 1 and 2): 
An overview of the treatment plan is presented below. 
Table 5 
Treatment Plan for Cycle 1 and Cycle 2 of Phases 1 and 2 
Cycles 1 and 2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 & 7 
Day 
8 to 21 
Day 
28 
Fludarabine  
 
 
 
 
 
 
 
 
Disease 
evaluation 
Cytarabine  
 
 
 
 
 
 
 
 
G-CSF 
 
 
 
 
 
 
 
 
Gilteritinib 
 
 
 
 
 
 
 
 
IT Cytarabine* 
 
 
 
 
 
 
 
 
G-CSF: granulocyte-colony stimulating factor; IT: induction therapy 
* Subject may receive intrathecal cytarabine at the start of the cycle, as per institutional standards.  
Criteria to Begin Cycle 2 (Phases 1 and 2): 
Subjects should receive a second cycle of gilteritinib plus FLAG when all non-hematologic 
grade 3 and 4 toxicities have resolved to ≤ grade 2. It is suggested, but not required, that cycle 2 
begin when absolute neutrophil count (ANC) > 1000/µL and platelets are > 100000/µL in 
responding subjects.  
Any subject who is unable to initiate cycle 2 after 50 days from the start of cycle 1 day 1 will 
be evaluated for participation in cycle 2 and/or replacement.  
Response Assessment (Phases 1 and 2): 
The end of cycle 1 bone marrow analysis will be performed upon count recovery but no later 
than day 28. For subjects whose response assessment is not evaluable due to hypocellularity, 
a repeat bone marrow analysis should be performed at least every 14 days until response 
determination is possible. 
Long-term Treatment (LTT) (Phases 1 and 2): 
In the event the principal investigator feels that a subject is receiving clinical benefit from 
treatment with gilteritinib in phase 1 or phase 2, subjects having completed 1 or 2 treatment 
cycles of phase 1 or 2 will have the option to participate in LTT with gilteritinib for up to 2 
years (~ 26 cycles). Subjects receiving clinical benefit during phase 1 or 2 may initiate LTT 
after discussion and approval from  the Astellas medical monitor. Clinical benefit (see 
[Section 5.1.5]) is defined as follows: 
a) Completed 1 or 2 treatment cycles of phase 1 or 2. 
b) Subject did not develop intolerable or unacceptable toxicity. 
c) Subject has achieved remission, stable or improved disease, or symptom 
improvement, or decreased transfusion dependence.  
d) Any other reason that the investigator judges will benefit the subject from continued 
treatment with gilteritinib, must be reviewed and approved by the Astellas medical 
monitor.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 56 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
During the LTT period, subjects will receive gilteritinib once daily starting from day 1 
through day 28 of a 28-day cycle at the same dose received during phase 1 or 2.  
End of Treatment (EOT) Visit (Phase 1, Phase 2 and LTT):  
An end of treatment (EOT) visit will be performed 7 days after last dose of gilteritinib, or 
prior to initiation of another anticancer therapy, whichever occurs earlier. 
EOT1 Visit (C2D28 for phase 1 or phase 2) will be performed for any subject participating in 
phase 1 or 2 and indicates the end of the respective phase.  
EOT2 will be performed for any subject participating in LTT phase and indicates the end of 
the LTT phase. 
28-day Follow-up Visit:  
A follow-up visit will be performed 28 days following the EOT visit of phase 1 and phase 2 
(i.e., EOT1), in the event the subject is not eligible to continue for LTT. In the event it is 
determined that the subject is eligible to participate in the LTT, then a follow-up visit will 
only be performed 28 days following the LTT EOT visit (i.e., EOT2). 
Survival Follow-up Visit:  
Follow-up for survival will be performed every 3 months for up to 2 years from the 28-day 
follow-up visit. Survival follow-up visit will include collection of data on subsequent 
anti-leukemic treatments/outcomes received by the subject, remission status and survival 
(cause of death and date of death) of the subject. In the event that the subject is not available 
for a clinic visit, follow-up via telephone or e-mail correspondence is acceptable. 
2.2.2 
Dose Rationale 
Gilteritinib has been evaluated in relapsed and refractory AML subjects in the USA (clinical 
study 2215-CL-0101) and Japan (clinical study 2215-CL-0102) at doses from 20 mg to 
450 mg. Clinical efficacy data supports doses of 120 mg and greater to ensure efficacy in 
FLT3-mutation positive subjects. PIA has shown substantial reduction of phospho-FLT3, 
with > 90% inhibition at doses of 80 mg or greater. 
The adult phase 1/2 study 2215-CL-0101 determined that daily doses of 80 and 120 mg of 
gilteritinib are expected to result in adequate drug exposure for clinical efficacy for adult 
patients with FLT3-mutation-positive R/R AML while providing and acceptable safety 
profile without the need for dose adjustment in patients receiving concomitant treatment with 
strong or moderate CYP3A4 inhibitors.  
In study 2215-CL-0101 (USA) study, the MTD was determined to be 300 mg, and in study 
2215-CL-0102 (Japan), the MTD was determined to be 200 mg; however, 120 mg was 
selected as the recommended phase 2/3 dose based on comparable efficacy, effective 
inhibition of target, and lower DLT rate. This dose is being used in all ongoing phase 3 
studies.  
Overall, 120 mg provides a good balance of ensuring effective drug levels for virtually all 
adult subjects with a low incidence of safety concerns.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 57 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Pediatric pharmacokinetic simulation was performed using the adult population PK model 
based on data from healthy volunteers and AML patient studies. The data indicate that 
pediatric daily dose of 3 mg/kg is predicted to result in comparable gilteritinib exposure 
observed to adults administered 120 mg once daily. Hence the pediatric starting dose for 
children from 2 years to less than 21 years of age is 2 mg/kg (1 dose level less than the RP3D 
for adults) to provide initial safety margin given the lack of clinical data in adults for the 
combination of gilteritinib and FLAG. 
Based on the toxicology data in juvenile rats, the safety profile in children less than 2 years 
may differ from older children. Therefore, the phase 1 portion of the clinical study will have a 
separate sub-group focusing on the age group from 6 months to less than 2 years to establish 
the RP2D in this age group. The starting dose for children from 6 months to less than 2 years 
of age will be dependent on the tolerability observed in older children (2 years and above). 
This may be re-evaluated during the course of the phase 1 portion of the study depending on 
the safety response observed in children from 2 years to less than 21 years of age.  
Weight-based dosing (rounding to the nearest 10 mg) is proposed to be used in pediatric 
subjects up to a body weight of 60 kg. At weights of 60 kg and greater, a flat dose will be 
given (i.e., the maximum dose for the particular dose level). 
For Group 1: One dose de-escalation to 1 mg/kg (maximum of 60 mg) will be allowed.  
For Groups 2 and 3: One dose escalation to 2 mg/kg (maximum of 120 mg) will be allowed, 
provided the dose level of 2 mg/kg/day has been established to be safe in Group 1. 
Dose Level 2 (3 mg/kg/day) will be explored if there is lack of toxicity or acceptable DLT 
profile combined with the lack of sufficient gilteritinib activity observed at the Dose Level 1 
(2 mg/kg/day). This would not apply for sites in the USA. 
2.3 
Endpoints  
2.3.1 
Primary Endpoints 
The primary endpoints are: 
● 
Phase 1: Determination of MTD and/or RP2D. 
● 
Phase 2:  
o CRc rates (overall best response) after 2 cycles of therapy.  
o CR rates after 2 cycles of therapy; CR rate will be further described by the duration 
of CR (only for USA). 
2.3.2 
Definition of Dose-limiting Toxicity (DLT) 
A DLT is defined as any of the events meeting the DLT criteria that occur during the DLT 
observation period and that is considered to be possibly or probably related to protocol 
therapy.   

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 58 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
2.3.2.1 DLT Observation Period 
The DLT observation period will be 28 days from the start of cycle 1 day 1; for the first cycle 
only. 
2.3.2.2 DLT Criteria 
Nonhematologic Dose-limiting Toxicity will be defined as grade 3 nonhematologic toxicity at 
least possibly related to protocol therapy that persists for > 48 hours without resolution to grade 
≤ 2 or grade 4 nonhematologic toxicity, regardless of duration, at least possibly related to 
protocol therapy. Hy’s law (as defined in [Section 12.5]) or treatment-related deaths will be 
considered as a DLT. Gilteritinib dosing will be interrupted if nonhematologic DLT occurs. 
Exceptions include the following toxicities commonly seen with intensive AML reinduction 
regimens: 
● Alopecia, anorexia or fatigue. 
● Grade 3 vomiting or diarrhea that resolves (with or without supportive care) to ≤ grade 2 
within 48 hours 
● Grade 3 nausea that resolves (with or without supportive care) to ≤ grade 2 within 7 days 
● Grade 3 elevation in total bilirubin (TBL) that is asymptomatic and that returns to ≤ grade 
2 elevation within 7 days 
● Grade 3 elevation in hepatic transaminases (ALT/SGPT, AST/SGOT and gamma-
glutamyl transferase [GGT]) or ALP that returns to ≤ grade 2 elevation within 14 days  
● Grade 3 fever with neutropenia, with or without infection 
● Grade 3 infection or grade 4 infections expected as direct complication of cytopenia due 
to active underlying leukemia 
● Grade 3 mucositis  
Hematologic Dose-limiting Toxicity will be defined as failure to recover a peripheral ANC 
> 500/µL and non-transfusion dependent platelet count > 20000/µL due to documented bone 
marrow aplasia/hypoplasia at day 42 from the start of cycle 1 day 1.  
Failure to recover peripheral counts due to disease involvement of the bone marrow will not 
be considered as a DLT.  
2.3.3 
Secondary Endpoints  
The secondary endpoints are: 
● Inhibition of phosphorylated FLT3 (pFLT3) measured by PIA assay 
● Gilteritinib plasma concentration 
● Pharmacokinetic parameters (e.g., oral clearance [CL/F], apparent volume of distribution 
[Vd/F], Cmax, tmax, AUC) of gilteritinib  
● Safety, tolerability and toxicity assessments of gilteritinib when given in combination 
with FLAG 
● EFS rate 
● OS rate 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 59 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● MRD assessment 
● Acceptability and palatability assessment of the formulation 
2.3.4 
Exploratory Endpoints 
The exploratory endpoints are: 
● Correlation of clinical responses to gilteritinib therapy with FLT3 PIA levels 
● Correlation of FLT3 PIA levels and clinical responses to gilteritinib therapy with FLT3 
ligand levels before and after exposure to FLAG chemotherapy 
● Assessment of mechanisms of innate and acquired resistance to gilteritinib 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
Phase 1 (Dose Escalation Phase): Male and female children, adolescents and young adults 
from 6 months to less than 21 years of age with R/R FLT3 (ITD and/or TKD) AML. 
Phase 2 (Dose Expansion Phase): Male and female children, adolescents and young adults 
from 6 months to less than 21 years of age with FLT3 (ITD) who are refractory to or at the 
first hematologic relapse after first-line remission induction AML therapy (up to 2 induction 
cycles). 
Re-screening is allowed, with a limit of 2 re-screenings for any potential subject. Enrollment 
of a re-screened subject into the study will be permissible as long as they are re-consented to 
the most current version of the informed consent form (ICF) applicable at the site, fulfill all 
inclusion and exclusion criteria and the screening procedures are performed as per the 
Schedule of Assessments and within the protocol-defined timeframe. 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved 
informed consent and privacy language as required per national regulations (e.g., Health 
Insurance Portability and Accountability Act Authorization for USA sites) must be 
obtained from the subject or subject’s parent or legal guardian and if required child 
assent prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable). 
2. Phase 1: Subject is positive for FLT3 (ITD and/or TKD) mutation in bone marrow or 
blood as determined by the local institution. 
Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as 
determined by the local institution. 
3. Subject is aged ≥ 6 months and < 21 years of age* at the time of signing informed 
consent and/or assent, as applicable.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 60 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
* For phase 2: Enrollment of subjects from 6 months to less than 1 year (Group 3) and 
1 year to less than 2 years (Group 2) will be dependent on the establishment of RP2D 
in the respective age groups during phase 1. 
4. Subject has a diagnosis of AML according to The French–American–British (FAB) 
classification with ≥ 5% blasts in the bone marrow, with or without extramedullary 
disease (except subjects with active CNS Leukemia). 
a) In the phase 1 portion of the study, subject must be in first or greater relapse or 
refractory to induction therapy with no more than 1 attempt at remission induction 
(up to 2 induction cycles). 
b) For the phase 2 portion of the study, subject must be refractory to or at the first 
hematologic relapse after first-line remission induction AML therapy (up to 
2 induction cycles) (see definition of line of therapy in Appendix 12.8). 
5. Subject has fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study.  
● Myelosuppressive chemotherapy: 
o 
For subject who relapses while receiving cytotoxic therapy, at least 21 days 
must have elapsed since the completion of cytotoxic therapy and prior to 
screening, unless based on investigator’s judgment the subject has recovered 
earlier than 21 days. 
o 
Cytoreduction with the following can be initiated and continued for up to 
24 hours prior to the start of systemic protocol therapy (cycle 1 day -1) as 
determined by the investigator:  
● 
hydroxyurea, 
● 
low dose cytarabine (100 mg/m2 per dose once daily for 5 days) or 
● 
other low dose/maintenance therapies as per local site practice. 
o 
Subject who has received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib, 
etc.) is eligible for this study. 
● Hematopoietic growth factors: at least 7 days must have elapsed since the 
completion of therapy with a growth factor prior to screening. 
● Biologic (antineoplastic agent): at least 7 days must have elapsed since the 
completion of therapy with a biologic agent prior to screening. For agents that have 
known AEs occurring beyond 7 days after administration, this period must be 
extended beyond the time during which AEs are known to occur. The duration of this 
interval must be discussed with the medical monitor. 
● X-ray treatment (XRT):  
o 
14 days must have elapsed for local palliative XRT for CNS chloromas and 
prior to screening; no washout period is necessary for other chloromas; 
o 
Prior to screening, 90 days must have elapsed if the subject had a prior traumatic 
brain injury or has received craniospinal XRT. 
6. For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must 
have elapsed since HSCT and subject must not have active GVHD.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 61 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
7. Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score 
of ≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if related to the 
subject’s leukemia in the investigator’s judgment.  
8. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
● Serum AST and ALT ≤ 3.0 x upper limit normal (ULN) for age 
● Total serum bilirubin ≤ 1.5 x ULN for age 
● Estimated glomerular filtration rate of > 60 mL/min/1.73 m2 
9. A female subject is eligible to participate if she is not pregnant (see [Appendix 12.3 
Contraception Requirements]) and at least 1 of the following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 
Contraception Requirements] 
OR 
b) WOCBP who agrees to follow the contraceptive guidance as defined in 
[Appendix 12.3 Contraception Requirements] throughout the treatment period and 
for at least 180 days after the final study drug administration. 
10. 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. 
11. Female subject must not donate ova starting at Screening and throughout the study, and 
for 180 days after the final study drug administration. 
12. A male subject with female partner(s) of childbearing potential must agree to use 
contraception as detailed in [Appendix 12.3 Contraception Requirements] during the 
treatment period and for at least 180 days after the final study drug administration. 
13. A male subject must not donate sperm during the treatment period and for at least 
120 days after the final study drug administration. 
14. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent 
or use a condom for the duration of the pregnancy or time partner is breastfeeding 
throughout the study period and for 180 days after the final study drug administration. 
15. Subject and subject’s parent(s) or legal guardian agrees not to participate in another 
interventional study while on treatment. 
16. Live Vaccines: At least 6 weeks must have elapsed since the administration of the last 
dose of a live vaccine and prior to initiation of study treatment (cycle 1 day -1). 
Waivers to the inclusion criteria will NOT be allowed. 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. Subject has active CNS leukemia. 
2. This criterion has been removed. 
3. Subject has uncontrolled or significant cardiovascular disease, including: 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 62 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
Diagnosed or suspected congenital long QT syndrome or any history of clinically 
significant ventricular arrhythmias (such as ventricular tachycardia, ventricular 
fibrillation, or torsades de pointes); any history of arrhythmia will be discussed with 
the sponsor’s medical monitor prior to subject’s entry into the study 
● 
Prolonged QTcF interval on pre-entry ECG (≥ 450 ms) 
● 
Any history of second or third degree heart block (may be eligible if the subject 
currently has a pacemaker) 
● 
Heart rate < 50 beats/minute on pre-entry ECG 
● 
Uncontrolled hypertension 
● 
Complete left bundle branch block 
4. Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing 
signs/symptoms related to the infection without improvement despite appropriate 
antibiotics or other treatment. The subject needs to be off pressors and have negative 
blood cultures for 48 hours. 
5. Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or 
immunotherapy other than as specified in the protocol. 
6. Subject has active clinically significant GVHD or is on treatment with 
immunosuppressive drugs for treatment of active GVHD, with the exception of subjects 
being weaned from systemic corticosteroids where the subject is receiving ≤ 0.5 mg/kg 
of prednisone (or equivalent) daily dose for prior GVHD. Subject has received 
calcineurin inhibitors within 4 weeks prior to screening, unless used as GVHD 
prophylaxis. 
7. Subject has active malignant tumors other than AML. 
8. Subject has any significant concurrent disease, illness, psychiatric disorder or social issue 
that would compromise subject safety or compliance, interfere with consent, study 
participation, follow-up or interpretation of study results. 
9. Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below 
institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels 
during the screening period is allowed.  
10. Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP)3A/P-gp. 
11. Subject is known to have human immunodeficiency virus infection. 
12. Subject has active hepatitis B or C, or other active hepatic disorder. 
• Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis 
B DNA are not eligible. 
• Subjects with negative HBsAg, positive hepatitis B core antibody and negative 
hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable. 
• Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is 
undetectable. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 63 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
13. This criterion has been removed.  
14. Subject must wait for at least 5 half-lives after stopping therapy with any investigational 
agent and before starting gilteritinib. 
15. Subject has known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, 
G-CSF or any components of the formulations used. 
Waivers to the exclusion criteria will NOT be allowed.  
4 
TREATMENT(S) 
4.1 
Identification of Investigational Product(s) 
4.1.1 
Study Drug(s) 
The study drug is gilteritinib (ASP2215) available as a tablet containing 40 mg of active 
ingredient and mini-tablet containing 10 mg of active ingredient.  
The tablets are packaged in a high-density polyethylene bottle. The study centers will be 
provided bottles of gilteritinib, each containing 30 tablets. The study site personnel will fill 
out the label to indicate the dispensing date, subject's gilteritinib dose and the corresponding 
number of tablets that need to be taken each day. The total dose must be dispensed using the 
tablet strength as appropriate for the child (e.g., a dose of 50 mg/day could be dispensed as 
one 40 mg tablet and one 10 mg tablet or five 10 mg tablets, as determined appropriate by the 
investigator). The gilteritinib product information is listed in Table 6. 
Table 6 
Test Drug (Gilteritinib Tablets) 
Test Drug 
Gilteritinib Tablets 
Code name 
ASP2215 
Active ingredient 
Chemical name: (C29H44N8O3)2·C4H4O4 
Composition and 
dosage form 
40 mg Tablet: One tablet contains 40 mg of gilteritinib in free form. 
Gilteritinib tablets are round light-yellow film-coated tablets. 
10 mg Mini-tablet: One tablet contains 10 mg of gilteritinib in free form. Gilteritinib 
mini tablets are round pale-yellow film-coated tablets. 
Storage 
Bottled gilteritinib should be stored according to labeled storage instructions. Store in 
original container. 
 
4.1.2 
Co-administered Chemotherapy Regimen  
The co-administered drugs consist of induction therapy with FLAG regimen from day -1 to day 
5 for cycle 1 and cycle 2 for both phase 1 and phase 2. The FLAG regimen will be administered 
per institutional guidelines for chemotherapy product preparation and administration. All cycles 
will be 28 days. The co-administered chemotherapy regimen will be supplied by the responsible 
site pharmacy of each investigational site or by the sponsor if applicable [Table 7].  
Sites are permitted to use generic chemotherapy drug that is approved by the respective 
regulatory authority (e.g., FDA, European Commission or each country regulatory agency). 
Refer to the approved package insert, summary of product characteristics or local product 
information for co-administered chemotherapy drug product information and storage 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 64 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
condition supplied by the manufacturers. In the situation when co-administered 
chemotherapy products are supplied by the sponsor, co-administered chemotherapy products 
used in this study will be packaged by the manufacturer, but labeled and repackaged into 
white cartons (secondary packaging) under the responsibility of Astellas Pharma Global 
Development, Inc. (APGD)-Astellas United States Technologies (AUST) in accordance with 
APGD-AUST Standard Operating Procedures (SOPs), Good Manufacturing Practice (GMP) 
guidelines, International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines and applicable local laws/regulations. 
Table 7 
Co-administered Drug Products Supplied by the Sponsor 
FLAG Induction Chemotherapy 
Fludarabine for IV use 
Fludarabine Powder for Solution for Infusion 
Cytarabine for IV use 
Cytarabine Solution for Infusion 
Cytarabine for IT use 
Cytarabine Solution for Injection 
G-CSF Filgrastim for SC/IV use 
Filgrastim Solution for Injection or Infusion  
Co-administered drug products supplied by sponsor can vary by brand and strength depending on market 
availability. 
FLAG: fludarabine, cytarabine and granulocyte colony-stimulating factor;  
G-CSF: granulocyte-colony stimulating factor; IV: intravenous; SC: subcutaneous. 
4.2 
Packaging and Labeling 
Gilteritinib used in this study will be prepared, packaged and labeled under the responsibility 
of qualified staff at APGD-AUST or sponsor’s designee in accordance with APGD-AUST or 
sponsor’s designee SOPs, GMP guidelines, ICH GCP guidelines and applicable local 
laws/regulations. 
Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations, which identifies the contents as investigational drug. A qualified person of 
Astellas Pharma Europe B.V. or sponsor’s designee will perform the final release of the 
medication according to Directive 2003/94/EC annex 13. 
In the situation when co-administered products are supplied by the sponsor, co-administered 
products used in this study will be labeled and repackaged into white cartons under the 
responsibility of APGD-AUST in accordance with APGD-AUST SOPs, GMP guidelines, 
ICH GCP guidelines and applicable local laws/regulations. 
4.3 
Study Drug Handling  
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator/or designee and that: 
● 
Such deliveries are recorded, 
● 
Study drug is handled and stored according to labeled storage conditions, 
● 
Study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 65 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
Any unused study drug is returned to the sponsor. 
Study drug inventory and accountability records will be maintained by the investigator or 
designee. Study drug accountability throughout the study must be documented and 
reconciled.  
The following guidelines are therefore pertinent: 
● 
The investigator or designee agrees not to supply study drug(s) to any persons except the 
eligible subjects in this study in accordance with the protocol. 
● 
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs. 
● 
The investigator or designee will store and take accountability of the study drug(s) in 
conforming to the procedures for handling the study drugs written by the sponsor. 
● 
The investigator or designee will prepare and retain records of the study drug's receipt, 
the inventory at the study site, the use by each subject, and the return to the sponsor or 
alternative disposal of unused study drug(s) if approved by sponsor. These records 
should include dates, quantities, batch/serial numbers, expiration dates (if applicable), 
and the unique code numbers assigned to the study drugs and subjects. 
● 
At the conclusion or termination of this study, the investigator, or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned/disposal of medication. Any discrepancies must be accounted for 
and documented. Appropriate forms of deliveries and returns/disposal must be signed by 
the site staff delegated this responsibility. 
● 
The site must return used and unused gilteritinib and unused co-administered 
chemotherapy drugs supplied by sponsor, back to the sponsor or designee at the end of 
the study or upon expiration. 
4.4 
Blinding 
This section is not applicable as this is an open-label study. 
4.5 
Assignment and Allocation 
Enrollment and study drug assignment will be performed via Interactive Response Technology.  
5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other 
Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
5.1.1.1 Gilteritinib (ASP2215) 
Gilteritinib is an oral tablet that subjects will take. Subjects will be instructed to take the daily 
gilteritinib dose with water as close to the same time each morning as possible. Gilteritinib 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 66 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
can be taken without regard to food. Gilteritinib [40 mg and/or 10 mg tablet] will be 
self-administered at home when subjects are not scheduled for clinic visits.  
● 
Gilteritinib 40 mg tablet cannot be crushed, chewed or compounded. They must be 
swallowed intact 
● 
Gilteritinib 10 mg tablet cannot be crushed or chewed. They must be also be 
swallowed intact. Alternatively, they can be dissolved in white grape juice or water to 
form a suspension (liquid formulation) to drink. The compounding instructions will 
be available in the pharmacy manual of the study.  
If a dose of gilteritinib is missed or not taken at the usual time: 
● 
Administer the dose as soon as possible on the same day, and at least 12 hours prior to 
the next scheduled dose 
● 
Return to the normal schedule the following day 
● 
Do not administer 2 doses within 12 hours 
If vomiting occurs after dosing, the subject should not receive another dose, but just wait 
until the next morning to dose. 
Gilteritinib will be self-administered at home when subjects are not scheduled for clinic 
visits. 
5.1.1.1.1 
Phase 1 (Dose Escalation Phase) 
Gilteritinib will be administered once daily starting from day 8 through day 21 of a 28-day 
cycle starting at 2 mg/kg per day for Group 1 [Table 8]. For Groups 2 and 3, the starting dose 
is Dose Level -1 (1 mg/kg/day).  
Table 8 
Dose Levels in Phase 1 with Correlation to Maximum Dose per Day 
Dose Level 
Dose (by body weight) 
-1 
1 mg/kg/day (for a maximum dose of 60 mg/day) # 
1 
2 mg/kg/day (for a maximum dose of 120 mg/day) * 
2 
3 mg/kg/day (for a maximum dose of 180 mg/day)** 
* Starting dose of gilteritinib for Group 1; # Starting dose of gilteritinib for Groups 2 and 3. 
** To be evaluated only if there is lack of toxicity or acceptable DLT profile combined with the lack of 
sufficient gilteritinib activity observed at the Dose Level 1 (2 mg/kg/day). Not applicable for sites in USA. 
Weight-based dosing (rounding to the nearest 10 mg) is proposed to be used in pediatric 
subjects up to a body weight of 60 kg. At weights of 60 kg and greater, a flat dose will be 
given (i.e., the maximum dose for the particular dose level as per Table 8).  
Gilteritinib daily dose for any subject ≤ 5 kg weight will be discussed and approved by 
Astellas medical monitor.  
5.1.1.1.2 
Phase 2 (Dose Expansion Phase) 
Gilteritinib will be administered once daily starting from day 8 through day 21 of a 28-day 
cycle at the RP2D or MTD established by phase 1 for the respective age groups. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 67 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.1.1.1.3 
Long-term Treatment Period 
Gilteritinib will be administered once daily starting from day 1 through day 28 of a 28-day 
cycle at the same dose the subject received during phase 1 or 2 for a period of up to 2 years.  
5.1.1.2 Co-administered Chemotherapy Drugs 
The co-administered chemotherapy drugs during each cycle of phase 1 (Dose Escalation 
Phase) and phase 2 (Dose Expansion Phase) are as follows: 
● Cycle 1 and 2:  
FLAG on days -1 to 5 
o Fludarabine 30 mg/m2 per day will be administered intravenously for 5 days (from 
day 1 to day 5). 
o Cytarabine 2000 mg/m2 per day will be administered intravenously for 5 days 
(from day 1 to day 5). 
o G-CSF filgrastim 5 µg/kg per day will be administered by SC/intravenous for 
6 days (from day -1 to day 5). 
o Subject may receive prophylactic intrathecal cytarabine at the start of the cycle as 
per site institutional standards.  
FLAG dosage calculation per institutional practice (such as mg/kg/dose) for 
subjects less than 2 years of age, or below a certain weight or body surface area, is 
allowed. 
5.1.2 
Interruption or Reduction in Dose of the Study Drug  
Intra subject dose reduction or interruption, during any phase of the study, is as follows: 
● Phase 1: 
During the DLT observation period, the assigned dose levels of gilteritinib are not 
allowed to change. Any subject requiring dose reduction in cycle 1 may be considered for 
replacement. The gilteritinib dose may be reduced for subjects after cycle 1. 
● Phase 2: 
For the phase 2 portion of the study, dose reduction is allowed in cycle 1 or 2. 
● LTT: 
For LTT portion of the study, dose reductions are allowed in any cycle. 
The guidance outlined in Table 9 should be followed for gilteritinib dose interruption or 
reduction. Dose interruption or reduction for any other reason other than that outlined in 
Table 9 must be discussed with the medical monitor. Note that dose reductions should occur 
in a step-wise manner, following the dose levels outlined in Table 9. After the initial dose 
reduction, additional dose reductions may occur unless stated otherwise. If no further dose 
reductions are available (below 1 mg/kg per day), study treatment will be discontinued. 
Any subject who has been off treatment for more than 14 days, other than for HSCT, can 
only resume treatment only after discussion with the medical monitor. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 68 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Intra-subject dose escalation is not allowed in phase 1, 2 or LTT. 
Table 9 
Guidelines for Gilteritinib (ASP2215) Dose Interruption or Reduction  
QTc Prolongation 
QTcF > 500 ms 
(based on central or 
local reading) 
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). Cardiology consult will be obtained as medically 
indicated. If the repeat ECG confirms a mean of the triplicate QTcF > 500 ms, 
dosing of gilteritinib 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. 
If QTcF resolves to ≤ 480 ms within 14 days, the subject may resume dosing but at a 
reduced dose as long as they are not currently receiving 1 mg/kg.  
If QTcF does not resolve to ≤ 480 ms within 14 days, treatment with gilteritinib will 
be discontinued and an EOT visit should be performed.  
Nonhematological Events 
Grade 3 clinically 
significant related to 
gilteritinib 
Dosing will be interrupted for up to 14 days. 
If the AE resolves to ≤ grade 1 within 14 days, the subject may resume dosing but at 
a reduced dose as long as they are not currently receiving 1 mg/kg. 
If the AE does not resolve to ≤ grade 1 within 14 days, treatment with gilteritinib will 
be discontinued and an EOT visit should be performed.  
Grade 4 clinically 
significant toxicity  
related to gilteritinib 
Treatment with gilteritinib will be discontinued. 
Posterior reversible 
encephalopathy 
syndrome (PRES) 
Treatment with gilteritinib will be discontinued for subjects diagnosed with PRES 
Differentiation 
Syndrome 
If differentiation syndrome is suspected, initiate corticosteroids and hemodynamic 
monitoring until improvement. Taper corticosteroids after resolution of symptoms. 
Symptoms of differentiation syndrome may recur with premature discontinuation of 
corticosteroid treatment.  
If severe signs and/or symptoms of differentiation syndrome persist for more than 
48 hours after initiation of corticosteroids, interrupt gilteritinib until signs and 
symptoms are no longer severe.  
Treatment with gilteritinib can be resumed at the same dose when signs and 
symptoms improve to Grade 2 or lower. 
Myelosuppression  
CRp or CRi 
Dose may be reduced without interruption if the following criteria are met: 
• 
Subject has received a minimum of 2 cycles of gilteritinib 
• 
Platelets < 25 x 109/L and/or ANC ≤ 0.5 x 109/L; 
• 
Marrow blasts < 5%; 
• 
No evidence of extramedullary disease; 
Further stepwise dose reduction is permitted if dosing 1 full cycle at the reduced dose 
has not resulted in the desired hematologic recovery.  
AE: adverse event; ANC: absolute neutrophil count;  
CRi: complete remission with incomplete hematologic recovery;  
CRp: complete remission with incomplete platelet recovery ECG: electrocardiogram; EOT: end of treatment;  
LTT: long-term treatment; PRES: posterior reversible encephalopathy syndrome; QTcF: Fridericia-corrected 
QT interval 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 69 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication Therapy) 
All medications and concomitant treatments administered from 28 days prior to screening 
must be recorded in the Case Report Form (CRF). Concomitant medications should be 
collected for reported AE/serious adverse events (SAEs) through 30 days post dose for 
subjects who have discontinued. For subjects who undergo HSCT, concomitant medications 
should be collected for reported AE/SAEs through start of conditioning treatment or 30 days 
post dose, whichever comes first. 
The following is allowed during the course of the study: 
● Local practice for prophylaxis of conjunctivitis caused by high-dose cytarabine 
The following are prohibited during the course of the study: 
● Treatment with strong inducers of CYP3A/P-gp. 
● Therapies to treat AML including, but not limited to: 
a) Chemotherapy 
b) Surgery 
c) Immunotherapy, cellular therapy or vaccines 
Exceptions: Hydroxyurea (up to 5 g daily for up to 2 weeks to keep the absolute blast 
count below 50 x 109/L), intrathecal chemotherapy, cranial irradiation, localized radiation 
for palliation and leukapheresis are allowed. 
● 
Vaccination with live vaccines (the prohibited duration starts from 6 weeks prior to the 
first dose of FLAG regimen and lasts until 6 weeks after the last dose of FLAG regimen) 
● Any other investigational agent for AML. 
● Participation in another interventional study while on treatment 
Caution is advised when considering the concomitant use of the following medications:  
● Treatment with Medications known to prolong QT or QTcF intervals. For concomitant 
drugs that have the potential to prolong QT or QTc intervals, a cardiology consult should 
be obtained as medically indicated. 
● Strong inhibitors of P-gp and concomitant drugs that target serotonin 5HT2B receptor or 
sigma nonspecific receptor are to be avoided with the exception of drugs that are 
considered absolutely essential for the care of the subject.  
● Treatment with concomitant drugs that are strong inhibitors of CYP3A should be avoided 
with the exception of antibiotics, antifungals and antivirals that are used as standard of 
care to prevent or treat infections. If CYP3A inhibitors are used concomitantly, subjects 
should be closely monitored for AEs. 
● 
Precaution should be used in treatment of gilteritinib with concomitant drugs that are 
substrates of P-gp (e.g., digoxin, dabigatran etexilate), BCRP (e.g., mitoxantrone, 
rosuvastatin) and OCT1 (e.g., metformin), since these transporters have been shown to 
be inhibited by gilteritinib in vitro. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 70 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Common CYP3A inhibitors, CYP3A inducers, drugs targeting the serotonin receptor, P-gp 
inhibitors or inducers, and drugs known to prolong QT or QTc intervals are listed in 
[Appendix 12.4]. The investigator should consult individual labels for all drugs that the 
subject is taking to evaluate if they fall into any of the above-named categories.  
5.1.4 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with study 
treatment. Investigator or designee should ensure that study subjects meet this goal 
throughout the study period. When study treatment is administered at the research facility, it 
will be administered under the supervision of study personnel. 
Compliance of the study drug (gilteritinib) will be monitored by the accounting of unused 
medication returned by the subject at visits. Compliance will be documented. 
If compliance is 80% or less, the investigator or designee is to counsel the subject and ensure 
steps are taken to improve compliance.  
In phase 1 portion of the study, subjects who are less than 80% compliant with the study 
treatment regimen will not be evaluable for DLT and may be replaced. 
Treatment compliance should be monitored closely and deviation in compliance should be 
reported to the sponsor.  
5.1.5 
Criteria for Continuation of Treatment  
A subject completing 1 or 2 treatment cycles of phase 1 or 2 will have the option to 
participate in LTT with gilteritinib for up to 2 years (~ 26 cycles), in the event the principal 
investigator feels that a subject is receiving clinical benefit from treatment with gilteritinib in 
phase 1 or phase 2. 
Subjects receiving clinical benefit during phase 1 or 2 may initiate LTT with gilteritinib for 
up to 2 years only after discussion and approval from the Astellas medical monitor. Clinical 
benefit is defined as follows: 
a) Completed 1 or 2 treatment cycles of phase 1 or 2. 
b) Subject did not develop intolerable or unacceptable toxicity. 
c) Subject has achieved remission, stable or improved disease, or symptom 
improvement, or decreased transfusion dependence.  
d) Any other reason that the investigator judges will benefit the subject from continued 
treatment with gilteritinib, must be reviewed and approved by the Astellas medical 
monitor.  
5.1.6 
Resumption of Treatment After Hematopoietic Stem Cell Transplantation  
Pre-HSCT preparation: 
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 if they 
have completed cycle 1 of phase 1 or 2. However, gilteritinib should be stopped for at least 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 71 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
1 week prior to start of the preparative regimen and a pre-HSCT visit should be performed 
prior to starting the conditioning regimen for HSCT.  
Resumption of Treatment after HSCT: 
Subjects returning to the study post HSCT can resume gilteritinib at the same dose prior to 
HSCT if the following conditions are met: 
● 
Subject is between 30 to 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 (CR, complete remission with incomplete hematologic recovery [CRi], 
complete remission with incomplete platelet recovery [CRp]) 
For subjects resuming gilteritinib treatment, subjects will follow the procedures listed under 
subsequent visits (day 1) in the Schedule of Assessments [Table 1]. 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be collected for all subjects and will include age, sex, race and 
ethnicity.  
5.2.2 
Medical History 
Medical history includes all significant medical conditions other than AML that have 
resolved prior to informed consent. Conditions that are ongoing at the time of consent will be 
collected as baseline condition on the Medical History Electronic Case Report Form (eCRF). 
Details that will be collected include the onset date and recovery date and NCI-CTCAE 
grade, if applicable for ongoing conditions. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease (Optional for 
Healthy Volunteer Studies) 
5.2.3.1 Disease History 
AML diagnosis and studies related to AML subtype classification will be collected and will 
include date and method of diagnosis, bone marrow evaluations, histopathology, 
cytogenetics, immunophenotyping and cytochemistry, FLT3 mutation status performed using 
institutional assay, lumbar puncture results if performed (red blood cell [RBC], WBC and 
differential, cytospin results) and related genetic syndromes. Dates for diagnostic procedures 
will be collected. 
Prior HSCT and AML therapy including induction, consolidation and maintenance 
chemotherapy will be collected. Response to HSCT and AML therapy, as well as the duration 
of the response will also be collected.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 72 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.2.3.2 FMS-like Tyrosine Kinase (FLT3) Mutation Status 
Only for subjects who have R/R AML and have not received chemotherapy within 1 month 
prior to screening, FLT3 mutation status obtained within 1 month as part of routine patient 
management prior to obtaining informed consent in the study may be used if documentation 
is available for eligibility assessment.  
5.2.3.3 Performance Status 
The Karnofsky Performance Score (KPS) [Karnofsky and Burchenal, 1949] will be used to 
assess performance status [Table 10] of a subject ≥ 16 years of age while and the Lansky 
play-performance scale [Lansky et al, 1987] will be used to assess performance status 
[Table 11] of a subject < 16 years of age.  
Performance status will be obtained and recorded according to the Schedules of Assessments 
[Table 1]. 
Table 10 
Karnofsky Performance Status  
Index 
Specific criteria 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity, minor signs or symptoms of disease 
80 
Normal activity with effort, some signs or symptoms of disease 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization is indicated although death not imminent.  
20 
Hospitalization necessary, very sick, active supportive treatment necessary.  
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 73 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Table 11 
Lansky Play-Performance Scale for Children 
Index 
Specific criteria 
100 
fully active, normal 
90 
minor restrictions in physically strenuous activity 
80 
active, but tires more quickly 
70 
both greater restriction of, and less time spent in, active play 
60 
up and around, but minimal active play; keeps busy with quieter activities 
50 
gets dressed, but lies around much of the day; no active play; able to participate in all quiet 
play and activities 
40 
mostly in bed; participates in quiet activities 
30 
in bed; needs assistance even for quiet play 
20 
often sleeping; play entirely limited to very passive activities 
10 
no play: does not get out of bed 
0 
unresponsive 
 
5.3 
Efficacy Assessments 
5.3.1 
Response Definitions 
Response to treatment will be defined per modified criteria [Cheson et al, 2003] as outlined 
below. 
5.3.1.1 Complete Remission 
For subjects to be classified as being in CR at a post-baseline visit, they must have bone 
marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free 
state and must have an ANC ≥ 1 x 109/L and platelet count ≥ 100 x 109/L and normal marrow 
differential with < 5% blasts, and they will be RBC and platelet transfusion independent 
(defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There 
should be no evidence of extramedullary leukemia. 
5.3.1.2 Complete Remission with Incomplete Platelet Recovery 
For subjects to be classified as being in CRp at a post-baseline visit, they must achieve CR 
except for incomplete platelet recovery (< 100 x 109/L). 
5.3.1.3 Complete Remission with Incomplete Hematologic Recovery 
For subjects to be classified as being in CRi at a post-baseline visit, they must fulfill all the 
criteria for CR except for incomplete hematological recovery with residual neutropenia 
< 1 x 109/L with or without complete platelet recovery. RBC and platelet transfusion 
independence is not required. 
5.3.1.4 Composite Complete Remission 
For subjects to be classified as being in CRc at a post-baseline visit, they must achieve CR, 
CRp or CRi at the visit.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 74 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Overall best response is defined as CRc after 2 cycles of therapy.  
5.3.1.5 Complete Remission with Partial Hematologic Recovery 
At a post-baseline visit, subjects will be classified as CRh if they have marrow blasts < 5%, 
partial hematologic recovery ANC ≥ 0.5 x 109/L and platelets ≥ 50 x 109/L, no evidence of 
extramedullary leukemia and cannot be classified as CR. 
5.3.1.6 Partial Remission 
For subjects to be classified as being in PR at a post-baseline visit, they must have bone 
marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with 
no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the 
percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% 
and 25%. A value of less or equal than 5% blasts is also considered a PR if Auer rods are 
present. 
5.3.1.7 Not Evaluable/No Response 
In the situation where no bone marrow assessments are performed or myeloblast value is 
missing, blast value from peripheral blood is missing or ≤ 2%, and extramedullary leukemia 
is missing or not done, the response will be classified as not evaluable (NE). In any case 
response cannot be categorized as CR, CRp, CRi, PR or NE, it will be categorized as NR. 
5.3.1.8 Relapse 
Relapse after CR, CRh, CRp or CRi is defined as a reappearance of leukemic blasts in the 
peripheral blood or ≥ 5% blasts in the bone marrow aspirate not attributable to any other 
cause or reappearance or new appearance of extramedullary leukemia. 
Relapse after PR is similarly defined with reappearance of significant numbers of peripheral 
blasts and an increase in the percentage of blasts in the bone marrow aspirate to > 25% not 
attributable to any other cause or reappearance or new appearance of extramedullary 
leukemia. 
5.3.1.9 Best Response 
Best response is defined as the best measured response to treatment for all visits (in the order 
of CR, CRp, CRi, PR, NR and NE) post-baseline. Subjects with best responses of CR, CRp, 
CRi or PR will be considered responders. Subjects who do not achieve at least a best 
response of PR will be considered nonresponders. 
5.3.1.10 Complete Remission Rate 
CR rate is defined as the number of subjects who achieve the best response of CR divided by 
the number of subjects in the analysis population. 
5.3.1.11 Composite Complete Remission Rate 
CRc rate is defined as the number of subjects who achieve the best response of CRc (CR, 
CRp or CRi) divided by the number of subjects in the analysis population.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 75 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.3.1.12 Complete Remission with Partial Hematologic Recovery Rate 
CRh rate is defined as the number of subjects who achieve CRh at any of the post-baseline 
visits and do not have best response of CR divided by the number of subjects in the analysis 
population. 
5.3.1.13 Complete Remission and Complete Remission with Partial Hematologic 
Recovery Rate 
CR/CRh rate is defined as the number of subjects who achieve either CR or CRh at any of the 
post-baseline visits divided by the number of subjects in the analysis population. 
5.3.2 
Survival Time, Duration and Other Efficacy Endpoints 
5.3.2.1 Overall Survival 
OS is defined as the time from the date of enrollment until the date of death from any cause. 
For a subject who is not known to have died by the end of study follow-up, OS is censored at 
the date of last contact. 
Date of last contact is the latest date the subject is known to be alive by the cutoff date.  
5.3.2.2 Event-free Survival 
EFS is defined as the time from the date of enrollment until the date of documented relapse 
(excluding relapse after PR), treatment failure or death, whichever occurs first. If a subject 
experiences relapse or death, the subject is defined as having EFS event related to either 
“relapse” or “death”, and the event date is the date of relapse or death. If a subject fails to 
achieve any of the response of CR, CRp, CRi or PR during the treatment period, the subject 
is defined as having EFS event related to treatment failure, and the event date is the 
enrollment date. For a subject who is not known to have had a relapse or treatment failure or 
death event, EFS is censored at the date of last relapse-free disease assessment. Subject is not 
censored at HSCT. 
5.3.2.3 Leukemia-free Survival 
LFS is defined as the time from the date of first CRc until the date of documented relapse or 
death for subjects who achieve CRc. For a subject who is not known to have relapsed or died, 
LFS is censored on the date of last relapse-free disease assessment date.  
5.3.2.4 Duration of Remission 
Duration of Remission 
Duration of remission includes duration of CRc, duration of CR/CRh, duration of CRh, 
duration of CR, duration of CRi, duration of CRp and duration of response (CRc + PR). 
Duration of CRc 
Duration of CRc is defined as the time from the date of first CRc until the date of 
documented relapse for subjects who achieve CRc. Subjects who die without report of 
relapse are considered nonevents and censored at their last relapse-free disease assessment 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 76 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
date. Other subjects who do not relapse on study are considered nonevents and censored at 
the last relapse-free disease assessment date. 
Duration of CR/CRh, CRh, CR, CRp, CRi 
Duration of CR/CRh, CRh, CR, CRp, CRi is defined similarly as duration of CRc. 
Duration of Response 
Duration of response is defined as the time from the date of either first CRc or PR until the 
date of documented relapse of any type for subjects who achieve CRc or PR. Subjects who 
die without report of relapse are considered nonevents and censored at their last relapse-free 
disease assessment date. Other subjects who do not relapse on study are considered 
nonevents and censored at the last relapse-free assessment date. 
5.3.2.5 Transplantation Rate 
Transplantation rate is defined as the percentage of subjects undergoing HSCT during the 
study period. 
5.3.3 
Bone Marrow Aspiration and/or Biopsy 
Bone marrow samples are required during screening and end of each cycle (C1D28 and 
C2D28) for phase 1 and phase 2.  
For subjects whose response assessment is not evaluable due to hypocellularity, a repeat bone 
marrow analysis should be performed at least every 14 days until response determination is 
possible. 
For LTT, bone marrow assessments will be performed on C1D1 and repeated after every 
3 cycles until 1 year of LTT, followed by after every 6 cycles until 2 years of LTT (i.e., 
C1D1, C4D1, C7D1, C10D1, C13D1, C19D1 etc.). Bone marrow samples are also required 
at the pre-HSCT/end of treatment visit and as clinically indicated. Bone marrow assessments 
on LTT C1D1 and EOT2 can be avoided if the last bone marrow sample in the study was 
collected within 2 weeks of the visit.  
If bone marrow aspirate is unobtainable (e.g., dry tap), an additional EDTA tube of whole 
blood should be collected instead. Bone marrow aspirate is required, and bone marrow biopsy 
is preferred. In case of inadequate aspirate, bone marrow biopsy is required.  
5.3.4 
Survival Status and Subsequent Antileukemic Treatments and Their Outcomes 
Information on survival status, subsequent antileukemic treatments and outcomes will be 
collected for all subjects. 
The first survival status will occur at the 28 day follow-up visit where telephone contact with 
the subject is sufficient unless any assessment must be repeated for resolution of 
treatment-related AEs.  
After the 28 day follow-up visit, the subject or caregiver will continue to be contacted via 
telephone by site personnel for follow-up every 3 months for up to 2 years. Data may be 
supplemented by site records when available at the time of the contact (e.g., treatment 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 77 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
records, outcomes). Follow-up will continue until the final database lock, which is estimated 
to be up to 2 years of follow-up post completion of treatment.  
If a subject death occurs during the SAE reporting period or if the death occurs after the SAE 
reporting period, but is determined by the investigator to be possibly related to study drug, 
then the associated AE with outcome of death will also be reported on the CRF and SAE 
form. If a subject death does not meet the criteria of an SAE, then death and antileukemic 
treatment and outcome up through the date of death should be collected and entered in CRF.  
5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Vital signs, including systolic and diastolic blood pressures (mmHg), radial pulse rate (beats 
per minute), respiratory rate, O2 saturation and temperature will be obtained and recorded at 
the times specified in the Schedule of Assessments [Table 1]. All vital sign measurements 
will be obtained with the subject in the sitting or supine position. 
If clinically significant vital sign changes from baseline (pretreatment) are noted, the changes 
will be documented as AEs on the AE page of the eCRF. Clinical significance will be defined 
as a variation in vital signs, which has medical relevance that could result in an alteration in 
medical care. The investigator will continue to monitor the subject until the parameter returns 
to grade ≤ 1 or to the baseline (pretreatment) value or until the investigator determines that 
follow-up is no longer medically necessary. 
5.4.2 
Laboratory Assessments 
The laboratory tests that will be performed during the conduct of the study are described 
below [Table 12]. Safety assessments will be obtained using local laboratories. See Schedule 
of Assessments [Table 1] for study visit involving sample collection. Clinical significance of 
out-of-range laboratory findings is to be determined and documented by the investigator/sub-
investigator who is a qualified physician. 
Table 12 
Laboratory Tests Performed During the Conduct of the Study 
Panel/Assessment 
Parameters to be Analyzed 
Estimated sample volume 
Hematology 
White Blood Cell Count (WBC) 
WBC Differential 
Red Blood Cell Count (RBC) 
Hemoglobin (Hgb) 
Hematocrit (Hct) 
Mean Corpuscular Volume 
Platelet Count 
MCHC 
MCH 
1.0 mL of whole blood1 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 78 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Panel/Assessment 
Parameters to be Analyzed 
Estimated sample volume 
Biochemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Glomerular filtration rate 
Uric acid2 
Glucose 
Calcium 
Phosphate 
Magnesium 
Albumin 
Total Protein 
Alkaline Phosphatase 
Lactate Dehydrogenase 
Creatine Phosphokinase 
Triglycerides 
Total Cholesterol 
Liver Function Tests including: 
Total Bilirubin 
Alanine Aminotransferase 
Aspartate Aminotransferase 
1.1 mL of whole blood1 
Thyroid Function 
Tests 
TSH 
Free T4 
2.5 of whole blood2 
Serum Pregnancy 
Test 
Human Chorionic Gonadotropin or 
alternatively pregnancy dipstick can be 
used 
1.4 ml of whole blood2 
Coagulation Profile 
INR (with PT if reported) 
aPTT 
Fibrinogen (Screening Only) 
D-dimer (Screening Only) 
2.0 mL of whole blood2 
Urinalysis  
Color 
Appearance 
Specific Gravity 
pH 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
Protein 
Urobilinogen 
Dipstick 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 79 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Panel/Assessment 
Parameters to be Analyzed 
Estimated sample volume 
Bone Marrow 
Blast Count and Cell Counts 4 
Flow Cytometry for Blasts 
MRD 
Aspirate 1 to 3 mL in EDTA tube.  
If aspirate is unavailable, then biopsy and 
whole blood is required.  
2 to 3 bedside smear slides in addition to 
the sample (aspirate/biopsy and whole 
blood). 
Peripheral Blood 
Disease Assessment for Blast Count and 
Manual Differential 
Peripheral blood 2 mL and 2 to 3 bedside 
peripheral blood smear slides 
Bone Marrow 
Aspirate and/or 
Blood3 
FLT3 Mutation Analysis 
Bone marrow aspirate 0.25 mL to 
0.75 mL in a Sodium Heparin tube or 1 
to 3 mL of peripheral blood in a Sodium 
Heparin tube 
PIA & FLT3 
Ligand 
FLT3 inhibition (PIA) 
FLT3 Ligand 
2 mL of whole blood 
PK 
Gilteritinib 
1 mL of whole blood 
PGx 
Pharmacogenomics Analysis 
3 mL of whole blood and a buccal swab 
sample 
aPTT: activated partial thromboplastin time; eCRF: Electronic Case Report Form; FLT3: FMS-like tyrosine 
kinase; INR: international normalization ratio; MRD: minimal residual disease; PK: pharmacokinetics; PGx: 
Pharmacogenomics; PIA: plasma inhibitory assay; PT: prothrombin time; T4: thyroxin; TSH: thyroid 
stimulating hormone. 
1 
Estimated volumes are provided since local laboratories will be used for these assessments and the volume 
may vary depending on the site institutional practice. 
2 
On days 1, 4, 8 and 15 in cycle 1 of phase 1 or phase 2. 
3 
Screening only. 
4 
In addition to the central read of these values, available local results will also be entered into the electronic 
case report form. 
5.4.3 
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 exam are to be 
performed only if clinically indicated. Physical examinations will be conducted at visits as 
outlined in the Schedule of Assessments. Each physical examination will include the 
observation and review of body system, weight and height at Screening and on day 1 of each 
cycle. If clinically significant worsening of findings from predose (day 1) is noted at any study 
visit, the changes will be documented as AEs on the Adverse-Event page of the CRF. Clinical 
significance is defined as any variation in physical findings, which has medical relevance that 
could result in an alteration in medical care. The investigator will continue to monitor the 
subject until the parameter returns to grade ≤ 1, or to the baseline (pretreatment) condition, or 
until the investigator determines that follow up is no longer medically necessary. 
5.4.4 
Electrocardiogram  
A 12-lead ECG will be performed as outlined in the Schedule of Assessment [Table 1] using 
a central ECG reading laboratory. Predose assessments should be taken within 1 hour prior to 
study drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs, 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 80 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and 
transmitted electronically for central reading. The mean of the triplicate ECG from central 
read should be used for all final treatment decisions and AE reporting. 
If the mean triplicate QTcF is > 500 ms at any time point, the ECG will be repeated (within 
2 hours if identified on machine read or as soon as possible if identified from central read). 
Cardiology consult will be obtained as medically indicated. If QTcF > 500 ms is confirmed, 
then the investigator will interrupt and reduce gilteritinib per the interruption or reduction 
guidelines in [Section 5.1.2]. 
Triplicate ECGs must also be obtained within 1 hour prior to obtaining the time-matched 
pharmacokinetic samples, for a particular visit. For phase 1 and 2, all visits have a predose 
pharmacokinetic sample with the exception of the cycle 1 day 21 visit, where there is a 
predose and 4 to 6 hours post dose pharmacokinetic samples are collected. Thus, a triplicate 
ECG will be obtained within 1 hour of the predose pharmacokinetic sample and 4 to 6 hours 
post dose pharmacokinetic sample for cycle 1 day 21. 
5.4.5 
Imaging  
5.4.5.1 Chest X-ray or Computed Tomography Scan 
Local chest X-ray or computed tomography (CT) scan is to be performed at screening. A 
chest X- ray (or CT of chest) performed as part of routine patient management within 
2 weeks prior to start of screening can be used if available.  
5.4.5.2 Multigated Acquisition Scan (MUGA) or Echocardiogram (ECHO) 
A local MUGA scan or ECHO is to be performed as outlined in the Schedule of Assessment 
[Table 1], i.e., at screening and EOT1 for each subject. Additional MUGA scans or ECHO 
will be performed while on gilteritinib treatment when clinically indicated.  
5.4.6 
Order of Assessments  
Predose assessments: 
Predose indicates dosing prior to gilteritinib or chemotherapy. The following sequence order 
for study activities is recommended during cycle 1 and 2 of phase 1 or 2:  
● Vitals signs 
● Triplicate ECGs (within 1 hour prior to dosing) 
● Any type of blood draw (includes clinical laboratory tests, thyroid function test, 
pharmacokinetic sample, PIA/FLT3 Ligand sample, Pregnancy test) 
Postdose assessments: 
The post dose assessments includes  
● 
Pharmacokinetic samples and  
● 
ECG: Triplicate ECGs are to be obtained within 1 hour prior to the time-matched 
pharmacokinetic sample during cycle 1 and 2 of phase 1 or 2. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 81 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
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 a medicinal 
product whether or not considered related to the medicinal product. 
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 treatment. AE collection begins after the signing of the informed consent 
and will be collected until 28 days after the last dose of study drug (or until the 28-day 
follow-up visit of the subject, whichever is later) or the subject is determined to be a screen 
failure.  
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. 
5.5.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, clinical chemistry, or urinalysis) or 
other safety assessment (e.g., ECGs, radiographic scans, vital signs measurements, physical 
examination), 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. 
5.5.1.2 Potential Cases of Drug-Induced Liver Injury 
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on Drug Induced Liver Injury (DILI). Abnormal values in AST and/or ALT concurrent or 
with abnormal elevations in TBL that meet the criteria outlined in [Appendix 12.5 Liver 
Safety Monitoring and Assessment], in the absence of other causes of liver injury, are 
considered potential cases of DILI (potential Hy’s Law cases) and are always to be 
considered important medical events and reported per [Section 5.5.4.1 Reporting of Serious 
Adverse Events].  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 82 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5.1.3 Disease Progression and Study Endpoints 
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 as outlined in 
[Section 7.4 Analysis of Efficacy]. Progressive Disease should not be reported as an 
AE/SAE unless the disease progression is the cause of death. 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 last dose of study drug must 
be reported as an SAE, even if attributed to disease progression.  
● 
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic, or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical study. These procedures are collected per the eCRFs Completion Guidelines. 
5.5.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
● 
Results in death 
● 
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death) 
● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
● 
Results in congenital anomaly, or birth defect 
● 
Requires 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). Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious.  
● 
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 1 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.  
  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 83 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5.3 
Criteria for Causal Relationship to Study Drug 
A medically qualified investigator is obligated to assess the relationship between each study 
drug and each occurrence of each (S)AE. This medically qualified investigator will use 
medical judgment, as well as the Reference Safety Information 1.3 Summary of Key Safety 
Information for Study Drugs to determine the relationship. The causality assessment is 1 of 
the criteria used when determining regulatory reporting requirements. 
The medically qualified 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 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”. 
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 (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship: 
● 
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug?  
● 
Plausibility; i.e., could the event been caused by the study drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and clinical study data, etc. 
● 
Dechallenge/Dose reduction/Rechallenge:  
o Did the (S)AE resolve or improve after stopping or reducing the dose of the 
suspect drug? Also consider the impact of treatment for the event when evaluating 
a dechallenge experience.  
o 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 study drug (e.g., based on values pre-, during 
and post-treatment) 
● 
Available alternative explanations independent of study drug 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 
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/designee. However, it is very 
important that the medically qualified investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to sponsor/designee. With 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 84 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
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.  
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the NCI-CTCAE 
guidelines (Version 5.0) [Table 13]. The items that are not stipulated in the NCI-CTCAE 
Version 5.0 will be assessed according to the criteria below and entered into the eCRF. 
Table 13 
NCI-CTCAE Version 5.0 
Grade 
Assessment Standard 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A Semi-colon indicates ‘or’ within the description of the grade. A single dash (-) indicates a grade is not 
available. Not all grades are appropriate for all AEs. 
Activities of Daily Living (ADL) 
*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. 
5.5.4.1 Reporting of Serious Adverse Events (SAEs) 
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue until the 28-day Follow-up visit of the subject or until the 
subject is determined to be a screen failure.  
In the case of a SAE, the investigator must complete and submit an SAE worksheet 
containing all information that is required by local and/or regional regulations to sponsor or 
designee by email or fax 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 as well as the investigator causality assessment including the explanation for the 
causality assessment.   

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 85 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Specific for study sites in Japan: 
In the case of a SAE, the investigator or subinvestigator must report to the head of the study 
site and must contact the sponsor/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/delegated CRO by fax or email immediately (within 24 hours of 
awareness) and to the head of the hospital. 
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE/Special Situations Worksheet to: 
Astellas Pharma Global Development – United States 
North American Fax number: 888-396-3750 
(North America Alternate Fax: 847-317-1241) 
International Fax number: +44-800-471-5263 
Email: safety-us@astellas.com  
Specific for study sites in JAPAN: 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE/special situations worksheet to: 
Astellas Pharma Inc. – Japan 
Pharmacovigilance 
Fax number 81-3-3243-5747 
Email: rk-safety-jp@astellas.com 
PAREXEL International 
Global Monitoring Operations 
Fax: +81 36888 5377 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's medical monitor/study physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel].  
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification and for sites in Japan - 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 (e)CRF.  
The following minimum information is required:  
● 
International Study Number (ISN)/Study number,  
● 
Subject number, sex and age, 
● 
The date of report, 
● 
A description of the SAE (event, seriousness criteria),  
● 
Causal relationship to the study drug (including reason), and 
● 
The drug provided  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 86 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
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., Suspected Unexpected Serious Adverse Reaction [SUSAR] 
reporting) according to current local/regional regulatory requirements in participating 
countries. The sponsor or sponsor's designee will submit expedited safety reports (e.g., IND 
Safety Reports, SUSAR, CIOMS-I [Council for International Organizations of Medical 
Sciences]) to Competent Authorities (CA) and concerned Ethics Committee (cEC) per 
current local regulations and will inform the investigators of such regulatory reports as 
required. Investigators must submit safety reports as required by their IRB/local IEC within 
timelines set by regional regulations (e.g., EMA, FDA) where required. Documentation of the 
submission to and receipt by the IRB/local IEC of expedited safety reports should be retained 
by the site. 
The sponsor or designee will notify all investigators responsible for ongoing clinical studies 
with the study drug of all SUSARs, which require submission per local requirements. 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor. 
The investigators may contact the sponsor’s medical monitor/expert for any other problem 
related to the safety, welfare, or rights of the subject.  
5.5.5 
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 [see Section 5.5.1 Definition of Adverse 
Event], an AE progresses to a 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 treatment 
or study participation, the investigator must promptly notify the sponsor. 
5.5.6 
Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in [Appendix 12.6 Common 
Serious Adverse Events] for reference. The list does NOT change the investigator’s reporting 
obligations, nor his obligations to perform a causality assessment, or prevent the need to 
report an AE meeting the definition of an SAE as detailed above. The purpose of this list is to 
alert the investigator that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common SAEs” as specified in 
[Appendix 12.6 Common Serious Adverse Events]. The sponsor will monitor these events 
throughout the course of the study for any change in frequency. Any changes to this list will 
be communicated to the participating investigational sites. Investigators must report 
individual occurrences of these events as stated in [Section 5.5.4.1 Reporting of Serious 
Adverse Events].  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 87 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5.7 
Special Situations  
Certain Special Situations observed in association with the study drug(s), such as incorrect 
administration (e.g., wrong dose of study drug, comparator, or background therapy) are 
collected in the eCRF, as Protocol Deviation per [Section 8.3 Major Protocol Deviations] 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 eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.5.4.1 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the SAE worksheet. 
The Special Situations are: 
● 
Pregnancy  
● 
Medication Error, Overdose and “Off-label use” 
● 
Misuse/abuse 
● 
Occupational exposure 
● 
(Suspicion of) Transmission of infectious agent  
● 
Suspected Drug-Drug interaction 
5.5.7.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 180 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 5.5.4.1 Reporting of Serious Adverse Events] using the 
Pregnancy Reporting Form 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 or within 120 days from 
the discontinuation of dosing and report the information to sponsor according to the timelines 
in [Section 5.5.4.1 Reporting of Serious Adverse Events] using the Pregnancy Reporting 
Form.  
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 
study subject as an AE in the eCRF or SAE per [Section 5.5.4.1 Reporting of Serious 
Adverse Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are 
to be reported via the Pregnancy Reporting Form.  
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below:  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 88 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
“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 study drug. 
● 
If an infant dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug 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. (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. 
5.5.7.2 Medication Error, Overdose and “Off-Label Use” 
If a Medication Error, Overdose or “Off-Label Use” (i.e., use outside of what is stated in the 
protocol) is suspected, refer to [Section 8.3 Major Protocol Deviations]. 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 5.5.4.1 Reporting of Serious Adverse Events] 
together with the details of the medication error, overdose and/or “Off-Label Use”. 
In the event of suspected gilteritinib overdose, the subject should receive supportive care and 
monitoring. The medical monitor/expert should be contacted as applicable. 
In the event of suspected overdose for FLAG regimen, refer to the approved Package Insert, 
Summary of Product Characteristics, or local product information supplied by the 
manufacturer for each agent.  
5.5.7.3 Misuse/Abuse 
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to the sponsor 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 a SAE, the SAE is also to be reported as described in [Section 5.5.4.1 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s). 
5.5.7.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the study drug(s) of site staff whilst 
preparing it for administration to the patient) to the study drug(s) occurs, the investigator 
must forward the Special Situation worksheet to the sponsor by fax or email immediately 
(within 24 hours of awareness). Any associated (S)AEs occurring to the individual associated 
with or resulting from the Special Situation are to be reported on the Special Situations 
worksheet. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 89 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5.7.5 (Suspicion of) Transmission of Infectious Agent  
If transmission of an infectious agent associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to the sponsor by fax or email 
immediately (within 24 hours of awareness) and any associated (S)AEs are to be reported in 
the e-CRF. If the AE meets the definition of a SAE, the SAE is also to be reported as 
described in [Section 5.5.4.1 Reporting of Serious Adverse Events] together with the details 
of the suspected transmission of infectious agent. 
5.5.7.6 Suspected Drug-Drug Interaction 
If a suspected drug-drug interaction associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to the sponsor 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 5.5.4.1 Reporting of Serious Adverse Events] together with details of the 
suspected drug-drug interaction. 
5.5.8 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the clinical study.  
Specific to Japan: 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the 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 
[Appendix 12.1.5.2 Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information]. 
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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 90 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.5.9 
Urgent Safety Measures  
An Urgent Safety Measure (USM) is an intervention which 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 CA, IRB/IEC, where applicable, in order to protect study subjects from any 
immediate hazard to their health and/or safety. Either the investigator or the sponsor can 
initiate an USM. The cause of an USM can be safety, product or procedure related.  
5.5.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the Astellas Study Physician 
(Specific to Japan: and/or 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 CA and cEC within the 
timelines required per current local regulations, and will inform the investigators as required. 
When required, investigators must notify their IRB/IEC within timelines set by regional 
regulations. 
5.6 
Test Drug Concentration 
Plasma concentrations of gilteritinib will be evaluated for the escalation (phase 1) and 
expansion (phase 2) phases as outlined in Schedule of Assessments [Table 1].  
For phase 1 and phase 2, pharmacokinetic samples will be collected in cycle 1 and cycle 2 at 
the following time points: 
● Cycle 1 day 8 – Predose 
● Cycle 1 day 15 (±2 days) – Predose 
● Cycle 1 day 21 (±2 day) – Predose and 4 to 6 hours  
● Cycle 2 day 15 (±2 days) – Predose 
Predose samples should be collected within 1 hour prior to dosing. For each sample, 1.0 mL 
of blood will be collected and processed. 
Plasma samples may also be used for metabolite profiling of gilteritinib. The reports for the 
metabolite profiling and identification will not be incorporated to the clinical study report. 
Blood sampling, processing, storage and shipment instructions will be provided in the Lab 
manual. Samples will be shipped to and analyzed by a sponsor designated analytical 
laboratory. 
Please refer to the Laboratory Manual for more detailed information on this topic. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 91 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.7 
Other Measurements, Assessments or Methods 
5.7.1 
Blood Sample for Banked Pharmacogenomic (PGx) Sample Analysis (Optional) 
Pharmacogenomic (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. After 
enrollment (see Schedule of Assessments [Table 1]), a 3 mL sample of whole blood and 
buccal swab sample for possible retrospective PGx analysis will be collected from subjects 
who consent. Samples will be shipped to a sponsor designated banking contract research 
organization (CRO). 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual. 
See [Appendix 12.7, Retrospective PGx Sub-study] for further details on the banking 
procedures.  
5.7.2 
Exploratory Biomarker Analysis  
Bone marrow samples: 
Samples will be analyzed for MRD at the time points defined in the schedule of assessments 
[Table 1] and may be analyzed for MRD at other time points. Samples will be analyzed for 
FLT3 mutational status at screening/baseline and EOT1 for phase 1 and phase 2, and may be 
analyzed for FLT3 mutational status at other time points. Samples may be analyzed for 
mutations in AML related genes and changes in proteins in relation to treatment effects at 
screening/baseline and EOT1 for phase 1 and phase 2, and may be analyzed for mutations in 
AML related genes and changes in proteins in relation to treatment effects at other time 
points. Samples may be used for method development or validation of diagnostic assays 
related to study treatment. 
Blood samples: 
Samples will be analyzed for PIA and FLT3 ligand assay in relation to dose and clinical 
response. Samples may be analyzed for MRD at any time point. Samples may be analyzed for 
FLT3 mutational status at screening/baseline and EOT1 for phase 1 and phase 2, and may be 
analyzed for FLT3 mutational status at other time points. Samples may be analyzed for 
mutations in AML related genes and changes in proteins in relation to treatment effects at 
screening/baseline and EOT1 for phase 1 and phase 2, and may be analyzed for mutations in 
AML related genes and changes in protein expression in relation to treatment effects at other 
time points.  
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. Samples 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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 92 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
5.7.3 
Clinical Outcome Assessment 
A clinical outcome assessment (COA) using a 5-point Facial Hedonic scale will be used 
during the study period to report palatability and the acceptability of the study drug 
formulation. 
The COA measure should be collected immediately after administration of the study drug on 
that visit day. 
5.8 
Total Amount of Blood 
The estimated total blood volume to be collected for the entire phase of the study (phase 1 or 
phase 2) should not be more than 71.5 mL [Table 14]. 
Table 14 
Estimated Total Volume of Blood Collected in Phase 1 or Phase 2 
Parameter 
Screening 
(mL) 
Cycle 1  
(mL) 
Cycle 2 
(mL) 
Approximate total volume 
per parameter (mL) 
Hematology 
1# 
6# 
6# 
13# 
Chemistry 
1.1# 
6.6# 
6.6# 
14.3# 
Thyroid Function 
2.5# 
2.5# 
5# 
10# 
Coagulation  
2# 
0# 
0# 
2# 
Pregnancy† 
1.4# 
1.4# 
1.4# 
4.2# 
PK 
0 
4 
1 
5 
FLT3 Ligand/PIA 
0 
8 
6 
14 
Disease Assessment 
2 
2 
2 
6 
PGx 
0 
3 
0 
3 
Approximate total volume  
10 
33.5 
28 
71.5 
FLT3: FMS-like tyrosine kinase 3; PGx: pharmacogenomics; PIA: plasma inhibitory activity; PK: 
pharmacokinetics 
# Estimated volumes are provided since local laboratories will be used for these assessments and the volume 
may vary depending on the site institutional practice. 
† Applicable for WOCBP or alternatively pregnancy dipstick can be used 
The estimated total blood volume to be collected during each visit of the LTT phase should 
not be more than 8 mL. 
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment  
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason. The reason for discontinuation from 
study treatment must be documented in the subject’s medical records. 
A subject must discontinue study treatment for any of the following reasons: 
● Subject and/or parent(s) or legal guardian declines further study participation 
(i.e., withdrawal of consent) 
● Subject develops an intolerable or unacceptable toxicity 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 93 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● Investigator determines that continuation of the study treatment will be detrimental to the 
subject 
● Subject has no response or progressive disease with no clinical benefit (see 
[Section 5.1.5]) as defined by the investigator 
● Subject becomes pregnant 
● Subject is noncompliant with the protocol based on the investigator or medical monitor 
assessment 
● Subject is found to have significantly deviated from any of the inclusion or exclusion 
criteria after enrollment (subjects having clinical benefit [Section 5.1.5] may be kept in 
the study after discussion with the medical monitor) 
● Subject receives any antileukemic therapy other than the assigned treatment, with the 
exception of hydroxyurea up to 5 g daily for up to 2 weeks, prophylactic intrathecal 
chemotherapy, cranial irradiation, localized radiation for palliation or leukapheresis.  
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 Schedule of 
Assessments [Table 1]. 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 
participant to provide this information. If a subject is discontinued from the study with an 
ongoing AE or an unresolved laboratory result that is significantly outside of the reference 
range, the investigator will attempt to provide follow-up until the condition stabilizes or no 
longer is clinically significant. 
All subjects who discontinue study treatment are to be followed for up to 2 years after their 
28-day Follow-up Visit, death or the final analysis whichever occurs first per Schedule of 
Assessments. 
6.1.1 
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.  
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. 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor (Specific to Japan: and the head of the study site). 
6.3 
Discontinuation of the Study 
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 94 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.  
7 
STATISTICAL METHODOLOGY 
A statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the clinical study report (CSR). 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
SD, minimum, median and maximum) for continuous endpoints, and frequency and 
percentage for categorical endpoints, unless otherwise specified. Percentages by categories 
will be based on the number of subjects with no missing data, i.e., will add up to 100%. 
Baseline will be defined as the last observation prior to first dose, unless otherwise specified. 
7.1 
Sample Size 
7.1.1 
Phase 1 
Group 1:  
Three subjects will be enrolled in a cohort at one of a series of doses of gilteritinib with a 
starting dose of 2 mg/kg/day according to the 3 + 3 design. Additional subjects will be 
accrued as needed at the determined RP2D of Group 1 to ensure that gilteritinib activity is 
assessable in at least 9 subjects.  
The RP2D will be a safe dose of gilteritinib that demonstrates sufficient activity. 
The number of subjects enrolled will depend on the dose levels evaluated, evaluation of 
biological activity, and the availability of time points for PIA assessments.  
Groups 2 and 3:  
Three subjects will be enrolled in a cohort at one of a series of doses of gilteritinib with a 
starting dose of 1 mg/kg/day according to the 3 + 3 design.  
Additional subjects will be accrued as needed to ensure that gilteritinib activity is assessable 
in at least 9 subjects.  
The RP2D will be a safe dose of gilteritinib that demonstrates sufficient activity. 
The number of subjects enrolled will depend on the dose levels evaluated, evaluation of 
biological activity, and the availability of time points for PIA assessments.  
7.1.2 
Phase 2 
The phase 2 portion of this study will be a single-arm, 2-stage, open-label design with a total 
of 52 response evaluable subjects. Subjects are response evaluable if (1) they are confirmed 
FLT3/ITD mutation positive; (2) they receive at least 1 dose of gilteritinib; and (3) they are 
progression/recurrence free during the first 2 cycles of FLAG + gilteritinib and have the 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 95 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
required bone marrow evaluations, or have died of disease progression during the first 
2 cycles. Subjects who die during treatment will be counted as nonresponders for purposes of 
analysis.  
In the available dataset (COG AAML 06P1, 1-BFM AML 2001-01, Costa dataset), there are 
26 CRc responders out of 73 subjects (a CRc rate of about 35%). With a 1-sided Type 1 error 
rate of 2.5%, there will be about 80% power to detect a 30% CR rate (i.e., a 16% increase in 
CR rate from the null hypothesis value of 14%). The 52 response evaluable subjects will 
provide about 90% power to detect a 56% CRc rate (i.e., a 21% increase in CRc rate from the 
null hypothesis value of 35%), with 1-sided Type error rate of 5%. Operationally, 
22 response evaluable subjects will be needed during the first stage, with 4 CR responders or 
9 CRc responders after 1 or 2 cycles of therapy required to continue to a total of 52 response 
evaluable subjects. If there are less than 4 CR responders in stage 1, the enrollment will be 
stopped in the USA and the study will not proceed to stage 2 in the USA. Ultimately, 13 or 
more CR responders or 24 CRc responders will be required to meet the efficacy threshold of 
FLAG + gilteritinib. The sample size was calculated in East Version 6.4 for CR.  
7.2 
Analysis Sets 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.  
7.2.1 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all subjects who are enrolled and receive at least 
1 dose of the treatment regimen. This will be the primary analysis set for efficacy analyses. 
7.2.2 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) consists of all subjects who took at least 1 dose of the treatment 
regimen and will be used for safety analyses. 
For the statistical summary of the safety data, the SAF will be used. 
Note that the SAF and FAS are the same in this study. 
7.2.3 
Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least 
1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling is 
known. Additional subjects may be excluded from the PKAS at the discretion of the 
pharmacokineticist. Any formal definitions for exclusion of subjects or time-points from the 
PKAS will be documented in the in the Classification Specifications and determined the 
Classification Meeting.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 96 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
7.2.4 
Pharmacodynamic Analysis Set (PDAS)  
The PDAS consists of a subset of the SAF for which sufficient pharmacodynamic 
measurements were collected. Inclusion of subjects in the PDAS with missing data or major 
protocol deviations will be considered on a case-by-case basis. 
The PDAS will be used for all summaries and analyses of pharmacodynamic data. 
7.2.5 
Minimal Residual Disease (MRD) Analysis Set (MAS) 
The MRD Analysis Set (MAS) will consist of all subjects who were enrolled and received at 
least 1 dose of treatment regimen and had at least 1 post-baseline sample with MRD data. 
7.3 
Demographics and Baseline Characteristics  
Demographics and other baseline characteristics will be summarized by dose levels for the 
SAF. Descriptive statistics will include number of subjects, mean, standard deviation, 
minimum, median and maximum for continuous endpoints, and frequency and percentage for 
categorical endpoints.  
7.3.1 
Subject Disposition  
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all enrolled subjects and for 
subjects in the SAF by dose level and overall. Similar tables for screening disposition, 
investigational period disposition and follow-up disposition will also be presented for all 
enrolled subjects by dose level and overall. All disposition details and dates of first and last 
evaluations for each subject will be listed. 
7.3.2 
Previous and Concomitant Medications  
All previous and concomitant medications will be presented in a listing. 
7.3.3 
Medical History  
Medical history for each subject will be presented in a listing. 
7.3.4 
Treatment Compliance 
Treatment compliance is defined as the total number of study drug actually taken by the 
subject divided by the number of study drug expected to be taken during the study multiplied 
by 100. Descriptive statistics for study drug compliance will be presented by dose level for 
the entire study period for the SAF. 
7.3.5 
Extent of Exposure 
Exposure to treatment, measured by the duration of treatment in number of days will be 
summarized by dose level on SAF. Duration of exposure to a study drug is defined as: (the 
last date that subject took study drug – the first dose date + 1). Any duration of dose 
interruptions will be excluded from the exposure.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 97 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
The following will be tabulated: 
● the total dose administered 
● number of intra subject dose reductions 
● number and proportion of subjects with dose reductions 
7.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS. The interpretation of results from statistical 
tests will be based on the FAS.  
7.4.1 
Analysis of Primary Endpoint  
The CR rate and the CRc (CR + CRp + CRi) rate will be summarized using descriptive 
statistics with 90% and 95% confidence intervals. 
Hypothesis test for Phase 2 CR rate: 
The null hypothesis H0 for CR is that the true CR rate p0 is ≤ 0.14, and the alternative 
hypothesis H1 is that the true CR rate p1 is ≥ 0.30. 
H0: p0 ≤ 0.14 
H1: p1 ≥ 0.30 
Hypothesis test for Phase 2 CRc rate: 
The null hypothesis H0 for CRc is that the true CRc rate p0 is ≤ 0.35, and the alternative 
hypothesis H1 is that the true CRc rate p1 is ≥ 0.56. 
H0: p0 ≤ 0.35 
H1: p1 ≥ 0.56 
7.4.2 
Analysis of Secondary Endpoints  
MRD will be assessed in relation to the following efficacy variables: 
● CR rate  
● CRc rate 
● Overall survival (OS) 
MRD negative status will be defined as FLT3-ITD signal ratio ≤ 10-4. Other FLT3-ITD signal 
ratio cut points may be assessed.  
The time of OS and EFS will be summarized using descriptive statistics. The survival curve 
and median for time-to-event variables and EFS and OS rates at 6 months/1 year/2 years will 
be estimated using the Kaplan-Meier method and will be reported along with the 
corresponding 95% confidence interval. 
Acceptability and palatability of the formulation will be summarized. The analysis method 
will be detailed in the SAP of the study.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 98 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
7.4.3 
Analysis of Exploratory Endpoints  
FLT3 mutation status and the mutational status of other AML-related genes at 
screening/baseline, EOT (for patients who relapse) will be assessed in relation to clinical 
efficacy.  
Changes in FLT3 ligand levels as compared to baseline sampling will be summarized at each 
time point by dose levels. 
Plasma inhibitory assay as compared to baseline sampling will be summarized at each time 
point by dose levels. 
Further analyses may be performed to explore relationships between mutational status and 
changes in proteins in relation to pharmacodynamic parameters and clinical response. 
7.5 
Analysis of Safety 
Safety analyses will consist of data summaries of AEs, DLTs, and other safety parameters on 
the SAF.  
7.5.1 
Adverse Events  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment Emergent Adverse Event (TEAE) is defined as an adverse event observed after 
starting administration of the study treatment and 30 days after the last dose of study 
treatment. The number and percentage of subjects with treatment-emergent AEs, SAEs, AEs 
leading to withdrawal of treatment, and AEs related to study drug will be summarized by 
system organ class, preferred term and treatment group. The number and percentage of AEs 
by severity will also be summarized. All AEs will be listed. 
A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator. 
AEs will be coded using MedDRA. An AE with onset at any time from first dosing until last 
scheduled procedure will be classified as treatment-emergent for inclusion in the summary 
tabulations. 
The number and percent of subjects experiencing 1 or more AE(s) will be summarized by 
phase of the study and dose levels. The relationship to study drug and severity of AE will 
also be summarized. AEs will be coded to system organ class and preferred term using 
MedDRA terminology and will be graded by the investigator using the NCI-CTCAE severity 
grade (version 5.0). 
7.5.2 
Laboratory Assessments  
Laboratory parameters will be summarized by phase of the study, dose level and visit using 
descriptive statistics for shifts in change from baseline and will be presented in listings of 
clinically significant abnormalities.  
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF by phase of the study, dose level and 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 99 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
visit. Shifts relative to normal ranges from baseline to each time point during treatment 
period in lab tests will also be tabulated. Laboratory data will be displayed in listings. 
7.5.3 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF by phase of the study and dose level and visit.  
7.5.4 
Physical Examination  
Physical examination will be listed by phase of the study and dose level using descriptive 
statistics. 
All clinically significant abnormal findings will be recorded as medical history or AEs and 
graded using NCI-CTCAE guidelines. 
7.5.5 
12-lead Electrocardiograms 
The 12-lead ECG results will be summarized by phase of the study, dose levels, visits and 
time points using descriptive statistics. 
All ECG interpretations will be displayed in listings. 
7.5.6 
Concentration-Response Relationship Analysis  
An exploratory analysis of gilteritinib concentration and select pharmacodynamic and clinical 
response endpoints may be evaluated.  
7.6 
Analysis of Pharmacokinetics 
7.6.1 
Estimation of Pharmacokinetic Parameters  
Population pharmacokinetic analysis will be performed on the data to characterize gilteritinib 
pharmacokinetics in pediatric patients with R/R AML. Details of model development, 
validation and simulations will be reported separately.  
7.6.2 
Statistical Analysis of Pharmacokinetic Parameters  
Gilteritinib plasma concentrations will be summarized by study phase, dose levels, visit and 
sample collection window using descriptive statistics, including number of subjects, mean, 
standard deviation, minimum, median, maximum, geometric mean, and coefficient of 
variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be 
plotted as appropriate. If warranted, plasma concentrations for active metabolites will also be 
summarized in a similar manner. 
Gilteritinib pharmacokinetic parameters (e.g., CL/F, Vd/F) will be estimated using population 
pharmacokinetic analysis. Simulation will be performed to predict pharmacokinetic 
parameters such as Cmax, tmax and AUC. Pharmacokinetic parameters will be summarized by 
phase of the study and dose levels using descriptive statistics, including number of subjects, 
mean, standard deviation, minimum, median, maximum, geometric mean, and CV of the 
mean and geometric mean. If warranted, pharmacokinetic parameters for active metabolites 
will also be summarized in a similar manner. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 100 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
7.7 
Analysis of Pharmacodynamics  
A PIA assay will be employed to determine FLT3 inhibition relative to baseline FLT3 levels. 
Data will be summarized by phase of the study and dose levels using descriptive statistics, 
including number of subjects, mean, standard deviation, minimum, median, maximum, 
geometric mean, and CV of the mean and geometric mean. 
7.8 
Analysis of Biomarkers  
Associations between biomarkers [Section 5.7.2 Exploratory Biomarker Analysis] and 
clinical results (efficacy, safety, or, pharmacodynamic) may be performed on subjects in the 
SAF who have the necessary baseline and on-study measurements to provide interpretable 
results for specific parameters of interest. Biomarkers may be summarized graphically or 
descriptively as they relate to clinical measures, as applicable. Summary statistics may be 
tabulated. Additional post-hoc analyses not specified in the protocol, such as alternative 
modeling approaches, may be conducted. All analyses described in this section are based on 
availability of the data.  
7.9 
Palatability and Acceptability Assessment 
Scores from the COA will be summarized by phase of the study and dose level and visit. 
7.10 
Major Protocol Deviations and Other Analyses  
Major protocol deviations as defined in [Section 8.3 Major Protocol Deviations] will be 
summarized for all enrolled subjects by dose level and total as well as by site, and will be 
provided in a data listing by site and subject.  
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn,  
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
7.11 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
The phase-2 portion of this study will be a 2-stage design [see Section 7.1.2 Phase 2]. No 
other formal interim analysis is planned.  
7.12 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses by visit will be outlined in the SAP. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 101 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
8 
OPERATIONAL CONSIDERATIONS 
8.1 
Data Collection 
The investigator or site designee will enter data collected using an Electronic Data Capture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within 
5 days after the subject visit. 
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. The monitor should verify 
the data in the eCRFs with source documents and confirm that there are no inconsistencies 
between them. 
Laboratory tests are performed at local and central laboratory; depending of the assessment 
evaluated. Central laboratory data will be transferred electronically to the sponsor or designee 
at predefined intervals during the study. The laboratory will provide the sponsor or designee 
with a complete and clean copy of the data. 
ECG results are performed at a central ECG reading laboratory. Central ECG read data will 
be transferred electronically to the sponsor or designee at predefined intervals during the 
study. The central ECG laboratory will provide the sponsor or designee with a complete and 
clean copy of the data. 
All procedures conducted under the protocol must be documented.  
The investigator or designee will be responsible for eCRF completion and that all data and 
queries are accurate, complete and are verifiable with the source. The source should be 
appropriately maintained by the clinical unit. 
Electronic data sources and any supporting documents should be available for 
review/retrieval by the sponsor/designee at any given time.  
8.2 
Screen Failures 
For screen failures, the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
8.3 
Major Protocol Deviations 
A major protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 102 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited. Refer to [Section 7.10 
Major Protocol Deviations and Other Analyses] for the major protocol deviation criteria. 
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, 
efficacy and/or pharmacokinetic parameters of the subject to determine subject continuation 
in the study.  
If a major deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately.  
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file.  
9 
END OF TRIAL  
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 completed and if all subjects enrolled in the country are no longer receiving 
study treatment and have completed all the protocol required visits/assessments or have 
discontinued from the study for any reason. 
The end of the study is defined as the last visit or scheduled procedure shown in the Schedule 
of Assessments (including phase 1, phase 2 and LTT) for the last participant in the study. 
10 
STUDY ORGANIZATION 
10.1 
Dose Escalation Committee (DEC) 
A DEC comprising of the sponsor, principal investigators and, if appropriate, expert 
consultants will be setup for this study. The DEC will be responsible for the review of safety 
data at specified time points in phase 1 in order to provide an assessment of whether dose 
escalation or de-escalation between the dose levels and/or to determine when maximum 
tolerated dose and/or RP2D has been reached in a given dose level. At each meeting, 
individual subject data will be reviewed for dose escalation or de-escalation decisions. 
Additional details regarding responsibilities and membership requirements will be included 
in the Subject Enrollment and Dose Escalation Plan.  
The DEC will also be responsible for the review of subject safety data enrolled in the phase 2 
portion of the study, enrollment rates, response rates and event (death) rates during periodic 
review. The DEC may recommend terminating enrollment for subjects from investigational 
sites based on safety evaluation.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 103 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
11 
REFERENCES  
American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018. 
ASP2215 Investigator’s Brochure, Current edition. 
Astellas Pharma Inc. ISN: 2215-TX-0015. A preliminary 18-day oral repeated-dose dose range 
finding study of asp2215 hemifumarate in juvenile rats. Study No.: SBL500-627. 23 Feb 2018.  
Astellas Pharma Inc. ISN: 2215-TX-0016. A 39-day repeated-dose oral toxicity study of ASP2215 
hemifumarate in juvenile rats with a 28-day recovery period. Study No.: SBL500-628. 27 Aug 
2018. 
Brown P, Small D. FLT3 inhibitors: a paradigm for the development of targeted therapeutics for 
paediatric cancer. Eur J Cancer. 2004;40:707–21. 
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-9. 
Cooper TM, Cassar J, Eckroth E, Malvar J, Sposto R, Gaynon P, et al. A phase 1 study of quizartinib 
combined with chemotherapy in relapsed childhood leukemia: a therapeutic advances in 
childhood leukemia & lymphoma (TACL) study. Clin Cancer Res. 2016;22(16):4014-22. 
Estey E, Plunkett W, Gandhi V, Rios MB, Kantarjian H, Keating MJ. Fludarabine and 
arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk 
Lymphoma. 1993;9(4-5):343-50. 
Hew KW, Keller KA. Postnatal anatomical and functional development of the heart: a species 
comparison. Birth Defects Res B Dev Reprod Toxicol. 2003;68(4):309-20. 
Janning M, Ben-Batalla I, Loges S. Axl inhibition: a potential road to a novel acute myeloid leukemia 
therapy? Expert Rev Hematol. 2015;8:135-8. 
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In 
Evaluation of chemotherapeutic agents. Edited by MacLeod CM. New York: Columbia 
University Press. 1949:191-205. 
Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, et al. Improved 
outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on 
liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013;31(5):599-
607. doi: 10.1200/JCO.2012.43.7384. 
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in 
childhood cancer patients. Cancer. 1987;60(7):1651-6. 
Lee SR, Yang DH, Ahn JS, Kim YK, Lee JJ, Choi YJ, et al. The clinical outcome of FLAG 
chemotherapy without idarubicin in patients with relapsed or refractory acute myeloid 
leukemia. J Korean Med Sci. 2009;24(3):498-503. doi: 10.3346/jkms.2009.24.3.498. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 104 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Montesinos P, Bergua JM, Vellenga E, Rayón C, Parody R, de la Serna J, et al. Differentiation 
syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and 
anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 
2009;113:775-83.  
Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, et al. Fludarabine, cytarabine, and 
G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 
1998;58(2):105-9. 
Schlenk RF, Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol. 2009;16(2):98-104. 
Sexauer AN, Tasian SK. Targeting FLT3 Signaling in childhood acute myeloid leukemia. Front. 
Pediatr. 2017;5:248. doi: 10.3389/fped.2017.00248. 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 105 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
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 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  
12.1.2 Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) 
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) and any other necessary documents be reviewed 
by an IEC/IRB. The IEC/IRB will review the ethical, scientific and medical appropriateness 
of the study before it is conducted. IEC/IRB approval of the protocol, informed consent and 
subject information and/or advertising, as relevant, will be obtained prior to the authorization 
of drug shipment to a study site. 
Any substantial amendments to the protocol will require 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 site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
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, CA approval or notification may 
be required. The changes will become effective only after the approval of the sponsor, the 
investigator, the regulatory authority, and the IRB/IEC (if applicable).  
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 
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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 106 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor. An approved copy of the new informed consent must also be 
forwarded to the sponsor. 
12.1.4 Financial Disclosure (Optional)  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
12.1.5 Informed Consent of Subjects 
12.1.5.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject 
and/or parent(s) or legal guardian, and answer all questions regarding this study. Prior to any 
study-related screening procedures being performed on the subject, the IC statement/assent 
will be reviewed and signed (Unique to Japan: place a personal seal) and dated by the 
subject and/or parent(s) or legal guardian, the person who administered the IC/assent and any 
other signatories according to local requirements. A copy of the signed (Unique to Japan: or 
sealed) IC/assent form will be given to the subject and/or parent(s) or legal guardian 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 IC/assent was obtained prior to any study-
related procedures and that the subject and/or parent(s) or legal guardian received a signed 
copy. 
The signed consent/assent forms will be retained by the investigator and made available (for 
review only) to the study monitor, auditor(s), regulatory authorities and other applicable 
individuals upon request. 
12.1.5.2 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 and/or 
parent(s) or legal guardian orally whenever new information becomes available that may 
be relevant to the subject’s consent or may influence the subject’s willingness to 
continue to participate in the study (e.g., report of serious drug adverse drug reaction). 
The communication must be documented in the subject’s medical records and whether 
the subject and/or parent(s) or legal guardian is willing to remain in the study or not must 
be confirmed and documented.  
2. The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject and/or parent(s) or legal guardian on all updated ICFs throughout their 
participation in the study. The investigator or his/her designee must re-consent subjects 
with the updated ICF/assent even if relevant information was provided orally. The 
investigator or his/her representative who obtained the written informed consent/assent 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 107 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
and the subject and/or parent(s) or legal guardian should sign and date the ICF/assent 
(Specific to Japan: place a personal seal). A copy of the signed Specific to Japan: or 
sealed) ICF/assent will be given to the subject and/or parent(s) or legal guardian 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. 
12.1.6 Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are hand-written on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
achieved, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electric devices) as part of regulated clinical 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, adverse event 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 available for archive.  
12.1.7 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 (for USA sites, 2 years after 
approval of the NDA or discontinuation of the IND). The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued. The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records. The sponsor will archive and 
retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. 
The records to be retained at the study sites are the ones listed as essential documents in 
GCP. These records shall be retained by the head of the study site or the record keeper 
designated by the head until notice issued by the sponsor on completion of the retention 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 108 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
period is received. These documents are also subject to direct access and should be provided 
upon request from the sponsor or regulatory authorities. 
The head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until the 
date defined in 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. 
Specific to Japan: 
The following are the major documents to be retained at the study site. 
a) Source documents (clinical data, documents and records for preparing the eCRF) 
hospital records, medical records, test records, memoranda, subject diary or 
checklists for evaluation, administration records, data recorded by automatic 
measuring instruments, reproductions or transcripts verified as precise copies, 
microfiche, negative films, microfilms/magnetic media, X-ray films, subject files 
and study-related records kept at either a pharmacy, a laboratory, or medical 
technical office, as well as subject registration forms, laboratory test slips including 
central measurement, worksheets specified by the sponsor, records of clinical 
coordinators and records related to the study selected from those verified in other 
departments or hospitals.  
b) 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 subinvestigators, list of signatures and print of seals (copy) and 
eCRF (copy), etc.  
c) 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.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 109 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
d) 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.  
12.1.8 Subject Confidentiality and Privacy/Data Protection 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless otherwise 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 clinical 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 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 USA. 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 sponsor shall serve as the controller of such 
data, as defined by the European Union (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 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. 
12.1.9 Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the clinical study in connection with the development of the drug 
and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 110 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
investigator understands that he/she has an obligation to provide the sponsor with all data 
obtained during the study. 
Publication of the study results is discussed in the clinical study agreement. 
12.1.10 Insurance of Subjects and Others (UNIQUE to JP/Studies enrolling subjects in EU) 
The sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
investigator's file.  
Specific to Japan: 
If a subject suffers any study-related injury, the sponsor will compensate 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. 
12.1.11 Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 111 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.2 
Procedure for Clinical Study Quality Control 
12.2.1 Clinical Study Monitoring 
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
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 relevant 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 IRB/IEC, or regulatory 
authorities. The confidentiality of the subject's identities shall be well protected consistent 
with local and national regulations when the source documents are subject to direct access. 
12.2.3 Data Management 
Data Management will be coordinated by the Data Science or designee of the sponsor in 
accordance with the SOPs for data management. All study-specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and World Health Organization (WHO) Drug Dictionary, respectively. 
12.2.4 Quality Assurance 
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied. 
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 112 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.3 
Contraception Requirements 
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in the Schedule of Assessments. 
WOMEN OF CHILDBEARING POTENTIAL (WOCBP) DEFINITIONS AND 
METHODS OF CONTRACEPTION DEFINITIONS  
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile.  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) Documented bilateral oophorectomy 
● 
Postmenopausal 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
In case the time of last regular menstrual bleeding cannot be clearly determined, confirmation 
with repeated FSH measurements of at least > 40 IU/L (or higher per local institutional 
guidelines) is required. 
Females on hormone replacement therapy (HRT) 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.  
Documentation of any of these categories can come from the site personnel’s review of the 
female subject’s medical records, medical examination, or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING 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 administrationa 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 113 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
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 
a) Oral 
b) Intravaginal 
c) Transdermal 
● 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
a) Oral 
b) Injectable 
c) Implantable 
● 
Other combined (estrogen- and progesterone-containing) methods 
a) Vaginal ring 
b) Injectable 
c) Implantable 
d) Intrauterine hormone-releasing system or intrauterine device 
● 
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. 
Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method 
are not acceptable methods of contraception. 
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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 114 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) 
OF CHILD BEARING POTENTIAL. 
Male subjects with female partners of childbearing potential are eligible to participate if they 
agree to the following during treatment and until the end of relevant systemic exposure 
defined as 180 days after final drug administrationa 
● 
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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 115 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.4 
List of Excluded Concomitant Medications 
Strong CYP3A Inhibitors 
Treatment with concomitant drugs that are strong inhibitors of CYP3A should be avoided 
with the exception of antibiotics, antifungals and antivirals that are used as standard of care to 
prevent or treat infections.  
The following list describes medications and foods that are common strong inhibitors of 
CYP3A. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A. 
Drug Type 
Generic Drug Name 
Human Immunodeficiency Virus Protease 
Inhibitors 
Indinavir 
Nelfinavir 
Lopinavir/ritonavir 
Ritonavir 
Saquinavir 
Food/Juice 
Grapefruit juice 
Others 
Boceprevir 
Clarithromycin 
Conivaptan 
Itraconazole 
Ketoconazole 
Nefazodone 
Posaconazole 
Telaprevir 
Telithromycin 
Voriconazole 
CYP: cytochrome P450. 
Source: University of Washington Metabolism and Transport Drug Interaction Database (2021): 
http://www.druginteractioninfo.org/   

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 116 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Strong CYP3A/P-gp Inducers 
Treatment with concomitant drugs that are strong inducers of CYP3A/P-gp are prohibited.  
The following list describes medications and foods that are common strong inducers of 
CYP3A/P-gp. This list should not be considered all inclusive. Consult individual drug labels 
for specific information on a compound’s propensity to induce CYP3A/P-gp. 
Drug Type 
Generic Drug Name 
Antiepileptic, Anticonvulsant 
Carbamazepine 
Phenytoin 
Antibiotic 
Rifampicin 
Food/Juice Supplement 
St. John’s Wort 
CYP: cytochrome P450. 
Source: University of Washington Metabolism and Transport Drug Interaction Database (2021): 
http://www.druginteractioninfo.org/   
 
Drugs Targeting Serotonin Receptors 
Treatment with concomitant drugs that target serotonin 5HT2B receptor are to be avoided 
with the exception of drugs that are considered absolutely essential for the care of the subject. 
The following list describes medications that target serotonin receptors. This list should not 
be considered all inclusive. Consult individual drug labels for specific information on 
whether a compound targets serotonin receptors. 
Drug Type 
Generic Drug Name 
Affinity or function to 5HT2B receptor 
Eletriptan Hydrobromide 
5HT2B: 5-hydroxytryptamine 2B 
P-gp Inhibitors  
Treatment with strong inhibitors of P-gp are to be avoided with the exception of drugs that 
are considered absolutely essential for the care of the subject. 
The following list describes medications and foods that are common inhibitors of P-gp. This 
list should not be considered all inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to inhibit P-gp. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 117 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Transporter  
Gene  
Inhibitor  
P-gp  
ABCB1  
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, 
conivaptan, diltiazem, dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir and ritonavir, quercetin, 
quinidine, ranolazine, verapamil 
P-gp: P-glycoprotein 
Source:  University of Washington Metabolism and Transport Drug Interaction Database (2021): 
http://www.druginteractioninfo.org/ 
 
Drugs Targeting Sigma (nonspecific) Receptor (sigma R) 
Treatment with concomitant drugs that target non-sigma specific receptor are to be avoided 
with the exception of drugs that are considered absolutely essential for the care of the subject. 
No list of drugs that target sigma nonspecific receptor is provided. Please consult individual drug 
labels for specific information on whether a compound targets sigma nonspecific receptors. 
Drugs That May Prolong QT or QTc 
For concomitant drugs that have the potential to prolong QT or QTc intervals, a cardiology 
consult should be obtained as medically indicated. 
The following list describes drugs that are known to prolong QT or QTc. This list should not 
be considered all inclusive. Consult individual drug labels for specific information on 
whether a compound is known to prolong QT or QTc. 
Drug Type 
Generic Drug Name 
Class IA antiarrhythmics 
Quinidine 
Procainamide 
Disopyramide 
Class IC antiarrhythmics 
Flecainide  
Propafenone  
Moricizine 
Class III antiarrhythmics  
Amiodarone 
Sotalol 
Bretylium 
Ibutilide 
Dofetilide 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 118 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Drug Type 
Generic Drug Name 
Antipsychotics 
Thioridazine 
Mesoridazine 
Chlorpromazine 
Prochlorperazine 
Trifluoperazine 
Fluphenazine 
Perphenazine 
Pimozide 
Risperidone 
Ziprasadone 
Haloperidol 
Antimanics 
Lithium 
Tricyclic/tetracyclic antidepressants  
Amitriptyline 
Desipramine 
Doxepin 
Dosulepin hydrochloride 
Imipramine 
Maprotiline 
Selective serotonin and norepinephrine reuptake 
inhibitors (SSNRIs) antidepressants  
Venlafaxine 
Macrolide antibiotics 
Azithromycin 
Erythromycin 
Clarithromycin 
Dirithromycin 
Roxithromycin 
Tulathromycin 
Fluoroquinolone antibiotics 
Moxifloxacin 
Gatifloxacin 
Azole antifungals  
Ketoconazole 
Fluconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 119 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Drug Type 
Generic Drug Name 
Antimalarials 
Amodiaquine 
Atovaquone 
Chloroquine 
Doxycycline 
Halofantrine 
Mefloquine  
Proguanil 
Primaquine 
Pyrimethamine 
Quinine 
Sulphadoxine 
Antiprotozoals 
Pentamidine 
Antiemetics 
Droperidol 
Dolasetron 
Granisetron 
Ondansetron 
Antiestrogens 
Tamoxifen 
Immunosuppressants 
Tacrolimus 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 120 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.5 
Liver Safety Monitoring and Assessment  
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 x ULN or bilirubin > 2 x ULN should undergo detailed 
testing for liver enzymes (including at least ALT, AST, ALP 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: 
 
ALT or AST 
 
Total Bilirubin 
Moderate 
> 3 x ULN  
or 
> 2 x ULN 
Severe 
> 3 x ULN 
and 
> 2 x ULN 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 x ULN. 
● 
ALT or AST > 5 x ULN for more than 2 weeks.  
● 
ALT or AST > 3 x ULN and International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated). 
● 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site staff is to complete the liver abnormality 
case report form (LA-CRF). Subjects with confirmed abnormal liver function testing should 
be followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 121 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
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 is to be recorded as “AEs” within the (e)CRF. 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 patients, 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, is to be entered in the (e)CRF. 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:  
a) 
Acute viral hepatitis (A, B, C, D, E or other infectious agents),  
b) Ultrasound or other imaging to assess biliary tract disease, 
c) 
Other laboratory tests including INR, direct bilirubin. 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Treatment Discontinuation 
In the absence of an explanation for increased LFTs, 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 x ULN. 
● 
ALT or AST > 5 x ULN for more than 2 weeks. 
● 
ALT or AST > 3 x ULN and TBL > 2 x ULN or INR > 1.5) (If INR testing is 
applicable/evaluated). 
● 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, 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).  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 122 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
The 2 “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in transaminase elevations higher 3 x ULN (“2 x ULN elevations are too 
common in treated and untreated patients to be discriminating”).  
2. Cases of increased bilirubin (at least 2 x ULN) with concurrent transaminase 
elevations at least 3 x ULN and no evidence of intra- or extra-hepatic bilirubin 
obstruction (elevated ALP) or Gilbert’s syndrome [Temple, 2006]. 
Briefly, Hy’s Law cases have the following three components: 
a. 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 (nonhepatotoxic) 
control drug or placebo. 
b. Among study subjects showing such AT elevations, often with ATs much greater than 
3 x ULN, 1 or more also show elevation of serum TBL to >2 x ULN, without initial 
findings of cholestasis (elevated serum ALP). 
c. 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 [FDA guidance, July 2009]. 
References 
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3. 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 123 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.6 
Common Serious Adverse Events 
The following is a list of SAEs that the sponsor considers to be associated with the disease 
state being studied. The list does NOT change the reporting obligations or prevent the 
need to report an AE meeting the definition of an SAE as detailed in [Section 5.5.2 
Definition of Serious Adverse Events]. The purpose of this list is to alert you that some 
events reported as SAEs may not require expedited reporting to the regulatory authorities 
based on the classification of “common SAEs.” Investigators are required to follow the 
requirements detailed in [Section 5.5.4.1, Reporting of Serious Adverse Events]. 
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicate they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA.  
Serious Adverse Events Caused by AML 
Grades Usually 
Observed with AML 
Hematologic AE 
Anemia 
0 - 4 
Bone marrow hypocellular 
0 - 4 
CD4 lymphocytes decreased 
0 - 4 
Disseminated intravascular coagulation 
0 - 3 
Leukocytosis 
0 - 4 
Lymphocyte count decreased 
0 - 4 
Lymphocyte count increased 
0 - 4 
Neutropenia 
0 - 4 
Neutrophil count decreased 
0 - 4 
Platelet count decreased 
0 - 4 
Purpura 
0 - 3 
Thrombocytopenia 
0 - 4 
White blood cell decreased 
0 - 4 
Infection-related AE 
Bacterial infection (regardless of organ-system involved or specific bacterial 
cause) 
0 - 3 
Chills 
0 - 3 
Cough 
0 - 3 
Fever 
0 - 5 
Flu-like symptoms 
0 - 3 
Fungal infections (regardless of organ-system involved or fungal cause) 
0 - 3 
Mucositis 
0 - 4 
Periodontal disease 
0 - 3 
Pneumonia 
0 - 5 
Sepsis/septicemia/bacteremia (all causes) 
0 - 5 
Sinusitis 
0 - 4 
Sore throat 
0 - 3 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 124 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Serious Adverse Events Caused by AML 
Grades Usually 
Observed with AML 
Psychiatric and Nervous System Related AE 
Anxiety 
0 - 2 
Cognitive disturbance 
0 - 3 
Confusion 
0 - 5 
Depressed level of consciousness 
0 - 5 
Depression 
0 - 3 
Libido decreased 
0 - 2 
Meningismus 
0 - 5 
Seizure 
0 - 5 
Somnolence 
0 - 5 
Syncope 
3 
Other AE 
Activated partial thromboplastin time prolonged 
0 - 2 
Alanine aminotransferase increased 
0 - 2 
Alkaline phosphatase increased 
0 - 2 
Anorexia 
0 - 2 
Abdominal pain 
0 - 2 
Aspartate aminotransferase increased 
0 - 2 
Blood bilirubin increased 
0 - 2 
Bone and/or joint pain 
0 - 2 
Bruising 
0 - 2  
Bleeding/hemorrhage 
0 - 5 
Constipation 
0 - 2 
Diarrhea 
0 - 3 
Dyspnea 
0 - 5 
Fatigue 
0 - 3 
Febrile neutropenia 
0 - 4 
Flushing 
0 - 2 
Gamma-glutamyltransferase increased 
0 - 1 
GVHD-acute and chronic 
0 - 2 
Hypertrophied gums 
0 - 1 
Hyperuricemia 
0 - 1 
Hypokalemia 
0 - 2 
Hypotension 
0 - 2 
Hypoxia 
0 - 3 
INR increased 
0 - 1 
Lactate dehydrogenase increased 
0 - 2 
Malaise 
0 - 2 
Multiorgan failure 
0 - 5 
Nausea 
0 - 2 
Oral dysesthesia 
0 - 2 
Petichiae 
0 - 2 
Pruritus 
0 - 3 
Skin and subcutaneous tissue disorders 
0 - 3 
Transient ischemic attacks 
0 - 2 
Tumor lysis syndrome 
3 - 5 
Vasculitis 
0 - 5 
Vomiting 
0 - 3 
Weight loss 
0 - 2 
AE: adverse event; AML: acute myeloid leukemia; GVHD: graft-versus-host disease; INR: international 
normalization ratio  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 125 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.7 
Pharmacogenomic (PGx) 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 issues. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity. 
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study will participate in this PGx substudy. 
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 1 tube of whole blood 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 kinetics, 
efficacy and/or safety.  
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
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. 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 126 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the clinical 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.  
 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 127 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
 
12.8 
Definitions of Line of Therapy and Tools to Determine Study 
Eligibility 
Schematic representation of AML treatment and eligible path for study participation after 
treatment with 1 line of therapy.  
 
 
Below are examples of the treatment paths that would qualify the patient to participate in the 
study: 
● 
First induction → Refractory  
● 
First induction → Refractory → Second Induction*→ Refractory 
● 
First induction → Refractory → Second Induction*→ Remission→ Relapse 
(*can include different treatment from first induction) 
● 
First induction → Remission → Consolidation/Maintenance with HSCT→ Relapse 
● 
First induction → Consolidation/Maintenance without HSCT → Relapse 
Please note: Induction with consolidation/maintenance followed by HSCT is considered as 
1 line of therapy. HSCT by itself and hydroxyurea are not considered to be lines of therapy.  
 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 128 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
12.9 
Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during the COVID-19 pandemic.  
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during the COVID-19 pandemic. The site is expected to 
follow the protocol and associated Schedule of Assessments [Table 1 and Table 5] unless the 
site Principal Investigator (PI) discusses the need with the Astellas medical monitor to 
implement the alternate measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed as described in [Section 5 
Treatments and Evaluation] due to the COVID-19 pandemic. 
INFORMED CONSENT AND/OR ASSENT  
Participants who need to follow any or all of the alternate measures outlined in this appendix 
will be required to provide informed consent, which explicitly informs them of the nature of 
and rationale for these changes and gain their agreement to continue participation in the study 
prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the principal investigator or designee will obtain oral 
agreement from the participant followed by written documentation as soon as is feasible. A 
separate addendum to the study informed consent will be provided to document the 
participant’s consent of the changes, in the event the ICF/Assent Form does not contain the 
details. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the COVID-19 pandemic: 
● 
Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
● 
Site facilities have been closed for clinical study conduct.  
● 
Site has been restricted to treating patients with conditions outside of the scope of 
the study.  
● 
Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel.  

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 129 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
● 
Participant(s) have temporarily relocated from the current study site to an alternate 
study site to avoid placing a burden on the participant with respect to travel.  
● 
Participant(s) have temporarily relocated from their home location and the new 
distances from the site would cause undue burden with respect to time and travel.  
● 
Participant has risk factors for which traveling to the site poses an additional risk to 
the participant’s health and safety.  
Adherence to the original protocol as reflected in the Schedule of Assessments [Table 1 and 
Table 5] is expected, where plausible, in the case of the COVID-19 pandemic. The alternate 
measures as noted in below are only permissible in the event of the COVID-19 pandemic, 
and after discussing the need with the Astellas medical monitor to implement the alternate 
measures. This is to allow for continuity of receiving Investigational Medicinal Product 
(IMP) and maintaining critical safety and efficacy assessments for patients participating in 
the study at a time of the COVID-19 pandemic. 
If one or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding time point(s). 
ALTERNATIVE SCHEDULE OF ASSESSMENTS IN RESPONSE TO A CRISIS 
No alternative measures are permissible for cycle 1 and cycle 2 of phase 1 or phase 2 as 
several assessments and dosing of FLAG and gilteritinib need to be performed on-site at the 
clinic. 
The table below provides the alternative measures that are permissible for each assessment 
and the visit days on which those assessments are performed for the LTT and Survival 
Follow-up period. For detailed guidance on the conduct of the study assessments, please refer 
to [Table 1] and its footnotes and [Section 5] of the study protocol.  
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 130 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Table 15 
Alternative Approaches/Measures Permissible for Protocol Assessments 
Assessments 
Alternate Approach(es)  
LTT Cycle 1 
& Subsequent 
Cycles 
EOT2/ Pre-
HSCT Visit 
28-day 
Follow-up 
Survival 
Follow-up 
Cycle Day (Visit Window in days) → 
Day 1 (± 2) 
(± 2) 
(+ 7) 
(± 7) 
Informed consent 
Not Applicable 
 
 
 
 
Eligibility criteria 
Not Applicable 
 
 
 
 
Medical and disease history 
Not Applicable 
 
 
 
 
Vital Signs 
Vitals are linked to whether patient can be dosed that day in clinic.  
For D1 of each cycle, if ASP2215 dosing is given in the clinic then vitals can be 
drawn in the clinic.  
If ASP2215 dosing is not performed in the clinic then the assessment performed 
at local facility is acceptable if results can be made available to investigative site. 
Most vital sign parameters may be assessed and captured via phone contact if a 
patient/parent/guardian has adequate monitoring instruments and is 
knowledgeable and able to obtain measurements. 
X 
X 
 
 
Karnofsky/Lansky 
performance status  
For D1 of each cycle, if ASP2215 dosing is given in the clinic then the 
assessment can be drawn in the clinic.  
If ASP2215 dosing is not performed in the clinic then the assessment can be 
performed remotely (Virtual/Telephone) by the investigator is acceptable if 
results are captured appropriately in the site source documents.  
X 
X 
 
 
Physical examination 
Physical exam is linked to whether patient can be dosed that day in clinic. 
Targeted exam would be acceptable. 
Weight is needed on D1 of each cycle when patient will be in clinic to determine 
the actual dose of gilteritinib to be taken for the cycle based on the weight of the 
participant. 
If ASP2215 dosing is not performed in the clinic then the weight and height 
measurement performed at local facility or patient home is acceptable if results 
can be made available to investigative site. 
X 
X 
 
 
Pregnancy test for WOCBP 
For D1 of each cycle, if ASP2215 dosing is given in the clinic then labs can be 
drawn in the clinic.  
If ASP2215 dosing is not performed in the clinic then the assessment performed 
at local facility is acceptable if results can be made available to investigative site. 
X 
X 
 
 
Chest x-ray (or chest CT) 
Not Applicable 
 
 
 
 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 131 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Assessments 
Alternate Approach(es)  
LTT Cycle 1 
& Subsequent 
Cycles 
EOT2/ Pre-
HSCT Visit 
28-day 
Follow-up 
Survival 
Follow-up 
Cycle Day (Visit Window in days) → 
Day 1 (± 2) 
(± 2) 
(+ 7) 
(± 7) 
12-lead ECG 
For D1 of each cycle, if ASP2215 dosing is given in the clinic then the 
assessment can be performed in the clinic. If the site is not allowed to use 
sponsor supplied ECG machine but can use site ECG machine, then ECG in 
triplicates performed using site machine is acceptable as long as it is uploaded 
for central read. 
If ASP2215 dosing is not performed in the clinic then ECG in triplicates 
performed in local facility is acceptable if results can be made available to 
investigative site.  
X 
X 
 
 
Clinical laboratory tests 
(chemistry, hematology, 
coagulation, urinalysis) 
For D1 of each cycle, if ASP2215 dosing is given in the clinic then the labs can 
be performed in the clinic. If ASP2215 dosing is not performed in the clinic then 
lab assessments performed at local facility is acceptable if results can be made 
available to investigative site. 
X 
X 
 
 
Thyroid function tests 
For D1 of each cycle, if ASP2215 dosing is given in the clinic then the labs can 
be performed in the clinic. If ASP2215 dosing is not performed in the clinic then 
lab assessments performed at local facility is acceptable if results can be made 
available to investigative site. 
X 
 
 
 
MUGA or ECHO 
Not Applicable 
 
 
 
 
PK Sample Collection 
Not Applicable 
 
 
 
 
PGx 
Not Applicable 
 
 
 
 
Plasma Inhibitory Assay 
(PIA) & FLT3 Ligand 
Not Applicable 
 
 
 
 
FLT3 mutational status 
Not Applicable 
 
 
 
 
Bone marrow aspirate/biopsy 
and MRD analysis 
For D1 of each cycle, if ASP2215 dosing is given in the clinic then the labs can 
be performed in the clinic. If ASP2215 dosing is not performed in the clinic then 
lab assessments performed at local facility is acceptable if results can be made 
available to investigative site. 
X 
X 
 
 
Gilteritinib dispensing  
For D1 of each cycle, it is preferred to have ASP2215 dosing provided to the 
participant in the clinic. If in-clinic visit is not possible, ASP2215 could be 
delivered from the hospital to the patient.  
X 
 
 
 
FLAG administration 
Not Applicable 
 
 
 
 
Table continued on next page 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 132 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
Assessments 
Alternate Approach(es)  
LTT Cycle 1 
& Subsequent 
Cycles 
EOT2/ Pre-
HSCT Visit 
28-day 
Follow-up 
Survival 
Follow-up 
Cycle Day (Visit Window in days) → 
Day 1 (± 2) 
(± 2) 
(+ 7) 
(± 7) 
DLT assessment 
Not Applicable 
 
 
 
 
Clinical Outcome Assessment 
Only required for C1D1 of LTT.  
For D1 of each cycle, if ASP2215 dosing is given in the clinic then the 
assessment can be performed in the clinic. If ASP2215 dosing is not performed 
in the clinic then Clinical Outcome Assessment worksheet completed by the 
participant, parent or observer remotely can be sent to the site. 
X 
 
 
 
AE/SAE assessment 
Remote/Virtual/Telemedicine Visits allowed if ASP2215 dosing is not 
performed in the clinic 
X 
X 
X 
 
Prior and concomitant 
medications 
Remote/Virtual/Telemedicine collection of the Visits allowed for non-dosing 
visits. 
X 
X 
X 
 
Subsequent anti-leukemic 
treatments/outcomes 
Remote/Virtual/Telemedicine Visits allowed 
 
 
X 
X 
Survival  
Remote/Virtual/Telemedicine Visits allowed 
 
 
X 
X 
AE: adverse event; C: cycle; CT: computed tomography; D: day; DLT; dose limiting toxicity; ECG: electrocardiogram; ECHO: echocardiogram; EOT: end of treatment; FLAG: 
fludarabine, cytarabine, and granulocyte colony-stimulating factor; FLT3: FMS-like tyrosine kinase 3; HSCT: hematopoietic stem cell transplant; ICF: informed consent form; LTT: 
long- term treatment; MRD: minimal residual disease; MUGA: multigated acquisition; PGx: pharmacogenomics; PIA: plasma inhibitory assay; PK: pharmacokinetic; SAE: serious 
adverse event; WOCBP: women of childbearing potential 
 
 

Sponsor: APGD 
ISN/Protocol 2215-CL-0603 
EudraCT 2018-002301-61 
 
- CONFIDENTIAL - 
22 Jul 2022 
Astellas 
Page 133 of 133 
Version 8.0 Incorporating Substantial Amendment 7 
13 
SPONSOR’S SIGNATURES 
 
Astellas Signatories 
(Electronic signatures are attached at the end of the document.)  
 
 
, Oncology 
 
Medical Science 
 
, Biostatistics 
Data Science 
 
 
PPD
PPD