Clinical trial NCT02927262
Conditions: Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) / Internal Tandem Duplication (ITD) Mutation
Keywords: Acute myeloid leukemia First Complete Remission gilteritinib FLT3/ITD AML ASP2215
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2017-01-10; Completion date: 2024-02-19
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to compare relapse-free survival (RFS) between participants with FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) and who were randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a two-year period.

Detailed description:
Participants in CR1 were approached for this study after induction/consolidation therapy was complete and a decision not to proceed with transplantation was made or a suitable donor could not be identified. Participants were randomized in a 2:1 ratio to receive gilteritinib or placebo. Participants entered the screening period up to 14 days prior to the start of treatment. Participants were administered treatment over continuous 28-day cycles. Gilteritinib or placebo was given daily for up to 2 years. After treatment discontinuation, participants had a 30-day follow-up visit for safety, after which the participants entered the long-term follow up period for collection of subsequent AML treatment, remission status, and survival (cause of death and date of death). Final database lock will occur when last subject last follow-up visit is reached, per protocol. Study drug was not provided during the follow-up period.

Arms: arm 1: Participants received gilteritinib 120 mg (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-specified discontinuation criterion was met. arm 2: Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-specified discontinuation criterion was met.
Interventions: intervention 1: Gilteritinib intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol documents:
Prot_000.pdf: 
Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
Astellas
Page 1 of 126
Version 3.0 Incorporating Substantial Amendment 2
A Phase 2 Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Trial of the FLT3 Inhibitor Gilteritinib 
(ASP2215) Administered as Maintenance Therapy Following 
Induction/Consolidation Therapy for Subjects with 
FLT3/ITD AML in First Complete Remission
Protocol for Phase 2 Study of ASP2215
ISN/Protocol 2215-CL-0302
Version 3.0
Incorporating Substantial Amendment 2 [See Section 13]
25 April 2019
IND 117,548
EudraCT 2016-001643-39
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [09Jun2016]
Version 1.1 [05Oct2016]
Version 1.2 [UK] [19Dec2016]
Version 1.3 [FR] [22Feb2017]
Version 2.0 [30Mar2017]
Version 2.1 [01May2017]
Version 2.2 [21Sep2017]
Investigator:  
Investigator information is on file at Astellas
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.
NCT02927262


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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25 Apr 2019
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Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································15
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································24
1
INTRODUCTION·················································································28
1.1
Background ····················································································28
1.2
Nonclinical and Clinical Data ·······························································29
1.2.1
Nonclinical Data·········································································29
1.2.1.1
Summary of In Vitro Pharmacology Studies ···································29
1.2.1.2
Summary of In Vivo Pharmacology Studies ···································30
1.2.1.3
Summary of Nonclinical Pharmacokinetics ····································31
1.2.1.4
Summary of Nonclinical Safety··················································31
1.2.2
Clinical Data ·············································································32
1.2.2.1
Clinical Pharmacokinetics and Pharmacodynamics ···························32
1.2.2.2
Studies Using Human Biomaterials ·············································34
1.2.2.3
Clinical Safety······································································34
1.2.2.4
Clinical Efficacy ···································································37
1.3
Summary of Key Safety Information for Study Drugs ···································37
1.3.1
Gilteritinib Data ·········································································37
1.3.2
Gilteritinib Nonclinical Data···························································37
1.3.3
Gilteritinib Clinical Data ·······························································38
1.4
Risk-Benefit Assessment·····································································38
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································39
2.1
Study Objectives ··············································································39
2.1.1
Primary Objective ·······································································39
2.1.2
Secondary Objectives ···································································39
2.1.2.1
Key Secondary Objective·························································39
2.1.2.2
Additional Secondary Objectives················································39
2.1.3
Exploratory Objectives ·································································39
2.2
Study Design and Dose Rationale···························································40
2.2.1
Study Design·············································································40


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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2.2.2
Dose Rationale···········································································40
2.3
Endpoints·······················································································40
2.3.1
Primary Endpoints·······································································40
2.3.2
Secondary Endpoints····································································41
2.3.3
Exploratory Endpoints ··································································41
3
STUDY POPULATION··········································································41
3.1
Selection of Study Population ·······························································41
3.2
Inclusion Criteria··············································································41
3.3
Exclusion Criteria ·············································································44
4
TREATMENT(S)··················································································45
4.1
Identification of Investigational Product(s) ················································45
4.1.1
Test Drug(s)··············································································45
4.1.2
Comparative Drug(s)····································································45
4.2
Packaging and Labeling ······································································45
4.3
Study Drug Handling ·········································································46
4.4
Blinding ························································································47
4.4.1
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································47
4.4.2
Breaking the Treatment Code by the Sponsor ·······································47
4.5
Assignment and Allocation ··································································48
5
TREATMENTS AND EVALUATION························································48
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················48
5.1.1
Dose/Dose Regimen and Administration Period ····································48
5.1.2
Interruption or Reduction in Dose of the Study Drug(s)····························48
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································50
5.1.4
Treatment Compliance··································································51
5.2
Demographics and Baseline Characteristics ···············································51
5.2.1
Demographics············································································51
5.2.2
Medical History··········································································51
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············52
5.2.3.1
Disease History ····································································52
5.2.3.2
FMS-like Tyrosine Kinase 3 Mutation Status··································52
5.2.3.3
Performance Status ································································52


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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5.3
Efficacy Assessment··········································································52
5.3.1
Bone Marrow Aspirate and Biopsy ···················································52
5.3.1.1
Minimal Residual Disease (MRD)···············································52
5.3.2
Relapse····················································································53
5.3.3
Survival Time, Remission Status and Other Efficacy Endpoints··················53
5.3.3.1
Survival Status and Subsequent Anti-leukemic Treatments and Their 
Outcomes ···········································································53
5.3.3.2
Overall Survival (OS) ·····························································53
5.3.3.3
Relapse-free Survival (RFS) ·····················································54
5.3.3.4
Event-free Survival (EFS) ························································54
5.4
Safety Assessment ············································································54
5.4.1
Vital Signs················································································54
5.4.2
Adverse Events ··········································································55
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································55
5.4.3
Laboratory Assessments································································55
5.4.4
Physical Examination···································································55
5.4.5
Electrocardiogram (ECG) ······························································56
5.4.6
Chest X-ray or Computed Tomography Scan········································56
5.4.7
Multigated Acquisition Scan or Echocardiogram ···································56
5.5
Adverse Events and Other Safety Aspects ·················································57
5.5.1
Definition of Adverse Events (AEs) ··················································57
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································57
5.5.3
Criteria for Causal Relationship to the Study Drug ·································58
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························59
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································59
5.5.6
Follow-up of Adverse Events··························································61
5.5.7
Monitoring of Common Serious Adverse Events ···································61
5.5.8
Procedure in Case of Pregnancy·······················································61
5.5.9
Emergency Procedures and Management of Overdose ·····························62
5.5.10
Supply of New Information Affecting the Conduct of the Study··················62
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (Specific to Investigational sites in Japan) ·······63
5.6
Test Drug Concentration ·····································································63
5.6.1
Pharmacokinetics········································································63
5.7
Other Measurements, Assessments or Methods ···········································63


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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25 Apr 2019
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5.7.1
Patient Reported Outcome Measures ·················································63
5.7.1.1
EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L)··············63
5.7.1.2
Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) ········64
5.7.1.3
Functional Assessment of Cancer Therapy-Anemia (FACT-An)············64
5.7.1.4
Resource Utilization·······························································64
5.7.2
Exploratory Biomarker Analyses······················································65
5.7.2.1
FLT3 Mutation Status·····························································65
5.7.2.2
Minimal Residual Disease (MRD) Assessment································65
5.7.3
Whole Blood and Buccal Sample for Future Pharmacogenomic Analysis 
(Retrospective Pharmacogenomic Analysis) (Optional)····························65
5.8
Total Amount of Blood·······································································66
6
DISCONTINUATION············································································66
6.1
Discontinuation of Individual Subject(s)···················································66
6.2
Discontinuation of the Site···································································67
6.3
Discontinuation of the Study·································································67
7
STATISTICAL METHODOLOGY ···························································67
7.1
Sample Size····················································································68
7.2
Analysis Set····················································································68
7.2.1
Full Analysis Set (FAS) ································································68
7.2.2
Per Protocol Set (PPS) ··································································68
7.2.3
Safety Analysis Set (SAF)······························································68
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································69
7.3
Demographics and Other Baseline Characteristics········································69
7.3.1
Demographics············································································69
7.3.2
Medical History··········································································69
7.3.3
Disease History ··········································································69
7.3.4
Prior and Concomitant Medications···················································69
7.3.5
Subject Disposition······································································69
7.3.6
Treatment Compliance··································································69
7.3.7
Extent of Exposure ······································································70
7.4
Analysis of Efficacy ··········································································70
7.4.1
Analysis of Primary Endpoint ·························································70
7.4.2
Analysis of Secondary Endpoints ·····················································71
7.4.2.1
Key Secondary Endpoints ························································71


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
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7.4.2.2
Other Secondary Endpoints ······················································71
7.4.3
Analysis of Exploratory Endpoints····················································72
7.4.4
Subgroup Analysis ······································································72
7.5
Analysis of Safety·············································································72
7.5.1
Adverse Events ··········································································72
7.5.2
Laboratory Assessments································································73
7.5.3
Vital Signs················································································73
7.5.4
Physical Examination···································································73
7.5.5
ECGs······················································································73
7.5.6
ECOG performance scores ·····························································73
7.6
Analysis of Pharmacokinetics ·······························································73
7.7
Protocol Deviations and Other Analyses···················································74
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················74
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········74
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················74
8.1
Procedure for Clinical Study Quality Control ·············································74
8.1.1
Data Collection ··········································································74
8.1.2
Specification of Source Documents···················································75
8.1.3
Clinical Study Monitoring······························································76
8.1.4
Direct Access to Source Data/Documents············································76
8.1.5
Data Management ·······································································76
8.1.6
Protocol Deviations ·····································································76
8.1.7
End of Trial in All Participating Countries···········································77
8.2
Ethics and Protection of Subject Confidentiality··········································77
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································77
8.2.2
Ethical Conduct of the Study···························································78
8.2.3
Informed Consent of Subjects ·························································78
8.2.3.1
Subject Information and Consent················································78
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························78
8.2.4
Subject Confidentiality ·································································79
8.3
Administrative Matters ·······································································79
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····79
8.3.2
Documents and Records Related to the Clinical Study ·····························79


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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8.3.3
Protocol Amendment and/or Revision················································82
8.3.4
Insurance of Subjects and Others······················································82
8.3.5
Signatory Investigator for Clinical Study Report····································83
9
QUALITY ASSURANCE········································································83
10
STUDY ORGANIZATION······································································83
10.1
Independent Data-Monitoring Committee (IDMC)·······································83
10.2
Independent Review Committee (IRC)·····················································83
10.3
Other Study Organization ····································································83
11
REFERENCES ····················································································84
12
APPENDICES ·····················································································86
12.1
List of Excluded and Cautionary Concomitant Medications·····························86
12.2
Liver Safety Monitoring and Assessment ··················································90
12.3
Laboratory Tests ··············································································93
12.4
Common Serious Adverse Events···························································95
12.5
Retrospective Pharmacogenomics Substudy (Optional)··································97
12.6
Definition of Complete Remission··························································99
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2 ································ 100
14
SPONSOR’S SIGNATURES·································································· 126
List of In-text Tables
Table 1
Schedule of Assessments·····································································25
Table 2
Test Drug (Gilteritinib Tablets 40 mg) ·····················································45
Table 3
Study Drug Dose Levels ·····································································49
Table 4
Guidelines for Study Drug Dose Interruption or Reduction Event······················49
Table 5
ECOG Performance Status···································································52


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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25 Apr 2019
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I.
SIGNATURES
1.  SPONSOR’S SIGNATURE
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the 
end of this document.


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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2.  INVESTIGATOR’S SIGNATURE
A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of 
the FLT3 Inhibitor Gilteritinib (ASP2215) Administered as Maintenance 
Therapy Following Induction/Consolidation Therapy for Subjects with 
FLT3/ITD AML in First Complete Remission
ISN/Protocol 2215-CL-0302
Version 3.0 Incorporating Substantial Amendment 2
25 April 2019
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)
Address:


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL
24h-Contact for Serious 
Adverse Events (SAEs)
See Section 5.5.5
, MD
, Global Medical Oncology Science
Mobile: 
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
For investigational sites in Japan:
Japan/Asia Development I, Astellas Pharma Inc.
Phone: 03-3244-1097
Fax: 03-3243-5737
Medical Monitor/Medical 
Expert:
, MD
, Oncology Development
Astellas Pharma Global Development
Office:
Mobile:
Email:  
Clinical Research Contact 
(Global):
, Clinical Science
Astellas Pharma Global Development, Inc.
Office: 
Cell: 
E-mail: 
Clinical Research Contacts 
(Japan):
Corporate Name: Astellas Pharma Inc.
Location: 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan
Phone No.: 03-3244-1097    Fax: 03-3243-5737
Sponsor’s personnel: 
Contact numbers during nonbusiness hours and for emergency: 
Phone No.: 
Contact Information for the 
Clinical Research 
Organization
(CRO) Japan:
Corporate Name: Parexel International
Location: 6F Kayaba-cho First Building, 1-17-21, Shinkawa, Chuo-
ku, Tokyo 104-0033, Japan
Phone No.: 03-3537-5493  Fax: 03-6888-1486
CRO’s personnel: 
 
Contact numbers during nonbusiness hours and for emergency:
Phone No.: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Sponsor: APGD
ISN/Protocol 2215-CL-0302
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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of Abbreviations
5HT1R
5-hydroxytryptamine receptor 1
5HT2BR
5-hydroxytryptamine receptor 2B
ΔQTcF
Fridericia-corrected QT interval corrected relative to baseline
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
ANCOVA
Analysis of Covariance
APGD
Astellas Pharma Global Development, Inc.
APL
Acute promyelocytic leukemia
AST
Aspartate aminotransferase
AUCinf
Area under the concentration-time curve from the time of dosing extrapolated to 
time infinity
AUST
Astellas United States Technologies
AXL
AXL tyrosine kinase
BCRP
Breast cancer resistance protein
CK
Creatine kinase
Cmax
Maximum concentration
CNS
Central nervous system
CR
Complete remission
CR1
First complete remission
CRc
Composite complete remission
CRi
Complete remission with incomplete hematologic recovery
CRO
Contract Research Organization
CRp
Complete remission with incomplete platelet recovery
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ct/Cmax
Tissue concentration/maximum tissue concentration 
Ctrough
Observed trough concentration
CYP
Cytochrome P450
DLT
Dose-limiting toxicities
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group


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Abbreviations
Description of Abbreviations
eCRF
Electronic Case Report Form
EFS
Event-free survival
EML4-ALK
Echinoderm microtubule-associated protein-like 4-ALK variant 1
EQ-5D-5L
EuroQol Group-5 Dimension-5 Level Instrument
ER
Emergency room
FACT-An
Functional Assessment of Cancer Therapy-Anemia
FACT-Leu
Functional Assessment of Cancer Therapy-Leukemia
FAS
Full Analysis Set
FLT3
FMS-like tyrosine kinase 3
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GMP
Good Manufacturing Practice
hERG
human ether-à-go-go-related gene
HSCT
Hematopoietic stem cell transplant
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICU
Intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IND
Investigational new drug
INR
International normalization ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive response technology
ITD
Internal tandem duplication
IWG
International Working Group
LA-CRF
Liver Abnormality-Case Report Form
LFT
Liver function test
LLN
Lower limit of normal
LTK
Leukocyte receptor TK
MATE1
Multidrug and toxin extrusion protein 1
MDRD
Modification of Diet in Renal Disease
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MUGA
Multigated acquisition scan


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ISN/Protocol 2215-CL-0302
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Abbreviations
Description of Abbreviations
NCI
National Cancer Institute
NDA
New Drug Application
NGS
Next-generation sequencing
NOAEL
No observed adverse effect level
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
OATP
Organic anion transporting polypeptide
OCT
Organic cation transporter
OS
Overall survival
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set
PR
Partial remission
PRES
Posterior reversible encephalopathy syndrome
PRO
Patient reported outcome
PT
Preferred term
QTc
Corrected QT interval
QTcF
Fridericia-corrected QT interval
RFS
Relapse-free survival
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
STAT5
Signal transducer and activator of transcription 5
SUSAR
Suspected unexpected serious adverse reaction
TAM
Tyro-3, AXL and Mer
TEAE
Treatment-emergent adverse event
TK
Tyrosine kinase
TLFs
Tables, listings and figures
TRKA
Tropomyosin receptor kinase A
ULN
Upper limit of normal
VAS
Visual analogue scale


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ISN/Protocol 2215-CL-0302
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Definition of Key Study Terms
Terms
Definition of terms
Baseline 
Observed values/findings which are regarded observed starting point for 
comparison.  
Enroll
To register or enter into a clinical trial.  NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.  
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained adverse events and/or survival are done in this 
period.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the 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.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:  
25 Apr 2019 / Version 3.0
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
Protocol Number:
2215-CL-0302
Name of Study Drug:  
ASP2215/Gilteritinib
Phase of Development:  
2
Title of Study:  
A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the FLT3 Inhibitor 
Gilteritinib (ASP2215) Administered as Maintenance Therapy Following Induction/Consolidation 
Therapy for Subjects with FLT3/ITD AML in First Complete Remission
Planned Study Period:
From 4Q2016 to 3Q2021
Study Objectives:  
Primary Objective:
The primary objective is to compare relapse-free survival (RFS) between subjects with FMS-like 
tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first 
complete remission (CR1) without transplant and who are randomized to receive gilteritinib or 
placebo beginning after completion of induction/consolidation chemotherapy for a 2-year period.
Secondary Objectives:
Key secondary objective is to:
●
Compare overall survival (OS) in subjects treated with gilteritinib as maintenance therapy after 
induction/consolidation with those treated with placebo.
The secondary objectives are to:
Evaluate the safety and efficacy of gilteritinib versus placebo in terms of:
●
Event-free survival (EFS), adverse events (AEs), clinical laboratory, vital signs, 
electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance 
scores.
●
Examine the relationship of minimal residual disease (MRD), as determined using a next-
generation sequencing (NGS) platform specific to FLT3/ITD mutations, with RFS and OS.
Exploratory Objectives:
The exploratory objectives are to:
●
Assess relationship between gilteritinib exposure and Fridericia-corrected QT interval (QTcF) for 
subjects participating in the ECG/PK sampling subset.
●
Explore the pharmacokinetics of gilteritinib (and metabolite, if applicable) in study population 
using a population pharmacokinetics approach.
●
Determine FLT3 mutation status at relapse.
●
Evaluate the safety and efficacy of gilteritinib in terms of:
○Patient reported signs, symptoms and impacts of AML (Functional Assessment of Cancer 
Therapy-Leukemia [FACT-Leu], Functional Assessment of Cancer Therapy-Anemia 
[FACT-An])
○EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L)
●
Evaluate healthcare resource utilization including hospitalization, intensive care unit (ICU) visits, 
emergency room (ER) visits, transfusion and use of antibiotics.


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
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Version 3.0 Incorporating Substantial Amendment 2
Planned Total Number of Study Centers and Locations:
Approximately 200 centers
North America (Canada & US), Europe, Asia/Pacific, Central and South America and rest of world
Study Population:
Subjects with FLT3/ITD AML in CR1 (including complete remission with incomplete platelet 
recovery [CRp] and complete remission with incomplete hematologic recovery [CRi]) following 
induction/consolidation therapy
Number of Subjects to be Enrolled/Randomized:
The target sample size is approximately 85 randomized subjects.
Study Design Overview:
This is a phase 2, randomized, placebo-controlled, double-blind, 2-arm study to compare the effect of 
gilteritinib as maintenance therapy versus placebo after induction/consolidation in subjects with 
FLT3/ITD AML in CR1 (including CRp and CRi).
Subjects in CR1 (including CRp and CRi) will be approached for this study after 
induction/consolidation therapy is complete and a decision not to proceed with transplantation is 
made or a suitable donor could not be identified. 
Approximately 85 subjects will be randomized in a 2:1 ratio to receive gilteritinib or placebo.
Randomization will be stratified based on:
●
Age < 60 or ≥ 60 years.
●
Geographic region, North America or Europe or Asia/Pacific/Central America/South America/ 
rest of world.
●
Presence of MRD at screening; yes or no.
●
Use of FLT3 inhibiting agents during induction/consolidation; yes or no.
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects will be 
administered treatment up to 2 years, or until a discontinuation criterion is met. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after which the 
subjects will enter the long-term follow-up period for collection of subsequent AML treatment, 
remission status, and survival (cause of death and date of death).
Inclusion/Exclusion Criteria:
Inclusion Criteria at Screening:
A subject is eligible for the clinical study if all of the following apply:
1.
Institutional Review Board-/Independent Ethics Committee-approved written informed consent 
and privacy language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act Authorization for United States sites) must be obtained from the subject or 
legally authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2.
Subject is considered an adult according to local regulation at the time of signing informed 
consent form (ICF).
3.
Subject consents to allow access to his or her diagnostic bone marrow aspirate or peripheral 
blood sample and/or the DNA derived from that sample, if available, that may be used to validate 
a companion diagnostic test for gilteritinib.


Sponsor: APGD
ISN/Protocol 2215-CL-0302
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Version 3.0 Incorporating Substantial Amendment 2
4.
Subject has confirmed morphologically documented AML, excluding acute promyelocytic 
leukemia (APL), in CR1 (including CRp and CRi).  For the purposes of enrollment, CR will be 
defined as < 5% blasts in the bone marrow with no morphologic characteristics of acute leukemia 
(e.g., Auer rods) in the bone marrow with no evidence of extramedullary disease such as central 
nervous system involvement or granulocytic sarcoma.
5.
Subject will not proceed with transplantation as either a decision not to proceed with 
transplantation has been made either on the recommendation of the treating physician or by the 
patient or a suitable donor could not be identified.
6.
Subject is < 2 months from the start of the last cycle of consolidation and should have completed 
the recommended number of consolidations per local practice.
7.
Subject has had no use of investigational agents, with the exception of FLT3 inhibiting agents 
during induction and/or consolidation therapy, within the prior 4 weeks.
8.
Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or peripheral 
blood as determined by the local institution at diagnosis.
9.
Subject has an ECOG performance status 0 to 2.
10. Subject must meet the following criteria as indicated on the clinical laboratory tests:
●
Serum creatinine ≤ 1.5 institutional upper limit of normal (ULN), or if serum creatinine 
outside normal range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m2 as 
calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation.
●
Serum total bilirubin ≤ 2.5 mg/dL (43 µmol/L), except for subjects with Gilbert’s 
syndrome.
●
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN.
●
Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN).
●
Absolute neutrophil count (ANC) ≥ 500/µl and platelets ≥ 20000/µl (unsupported by 
transfusions).
11. Subject is suitable for oral administration of study drug.
12. Female subject must either:
●
Be of nonchildbearing potential:
○
Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
○
Documented surgically sterile or status posthysterectomy (at least 1 month prior to 
screening)
●
Or, if of childbearing potential, 
○
Agree not to try to become pregnant during the study and for 6 months after the final 
study drug administration
○
And have a negative urine or serum pregnancy test at screening
○
And, if heterosexually active, agree to consistently use highly effective contraception 
per locally accepted standards in addition to a barrier method starting at screening 
and throughout the study period and for 6 months after the final study drug 
administration.


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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25 Apr 2019
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*Highly effective forms of birth control include:
Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation,
Established intrauterine device (IUD) or intrauterine system (IUS),
Bilateral tubal occlusion,
Vasectomy (A vasectomy is a highly effective contraception method provided 
the absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.)
Male is sterile due to a bilateral orchiectomy.
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual activity during the entire period of risk associated 
with the study drug.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle 
of the subject.
*List is not all inclusive.  Prior to enrollment, the investigator is responsible for 
confirming subject will utilize highly effective forms of birth control per locally 
accepted standards during the protocol defined period.  
13. Female subject must agree not to breastfeed starting at screening and throughout the study 
period, and for 2 months and 1 week after the final study drug administration.
14. Female subject must not donate ova starting at screening and throughout the study period, and for 
6 months after the final study drug administration.
15. Male subject and their female partners who are of childbearing potential must be using highly 
effective contraception per locally accepted standards in addition to a barrier method starting at 
screening and continue throughout the study period and for 4 months and 1 week after the final 
study drug administration.
16. Male subject must not donate sperm starting at screening and throughout the study period and for 
4 months and 1 week after the final study drug administration.
17. Subject agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion Criteria (at either Screening or Randomization):
A subject will be excluded from participation in this clinical study if any of the following apply:
1.
Subject has had prior allogeneic transplant.
2.
Subject has QTcF interval > 450 msec (average of triplicate determinations based on central 
reading).
3.
Subject with Long QT Syndrome.
4.
Subject with hypokalemia and hypomagnesemia at screening (defined as values below LLN).
5.
Subject has clinically active central nervous system leukemia.
6.
Subject is known to have human immunodeficiency virus infection.


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ISN/Protocol 2215-CL-0302
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7.
Subject has active hepatitis B or C.
8.
Subject has an uncontrolled infection.  If a bacterial or viral infection is present, the subject must 
be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to 
randomization.  If a fungal infection is present, the subject must be receiving definitive systemic 
anti-fungal therapy and have no signs of progressing infection for 1 week prior to randomization.
9.
Subject has progressing infection defined as hemodynamic instability attributable to sepsis or 
new symptoms, worsening physical signs or radiographic findings attributable to infection.  
Persisting fever without other signs or symptoms will not be interpreted as progressing infection. 
10. Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart 
Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure NYHA class 
3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan 
performed within 1 month prior to study entry results in a left ventricular ejection fraction that is 
≥ 45%.
11. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome 
P450 (CYP) 3A.
12. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of 
P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the 
care of the subject.  
13. Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine 
receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor 
with the exception of drugs that are considered absolutely essential for the care of the subject.
14. Subject has a serious medical or psychiatric illness likely to interfere with participation in this 
clinical study.
15. Subject has prior malignancies, except resected basal cell carcinoma or treated cervical
carcinoma in situ.  Cancer treated with curative intent ≥5 years previously will be allowed.  
Cancer treated with curative intent < 5 years previously will not be allowed.
16. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product:  
ASP2215/gilteritinib tablets containing 40 mg of active ingredient.
Dose:  
120 mg once daily (continuous)
Mode of Administration:  
ASP2215/gilteritinib will be administered orally.  


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Comparative Drug:  
Matching placebo tablets.
Dose:  
Matching placebo for ASP2215/gilteritinib 120 mg daily (continuous).
Mode of Administration:  
Placebo will be administered orally.
Concomitant Medication Restrictions or Requirements:
Treatment with concomitant drugs that are strong inducers of CYP3A is prohibited.  Treatment with 
concomitant drugs that are strong inhibitors or inducers of P-gp and concomitant drugs that target 
serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor are to be avoided with the exception of 
drugs that are considered absolutely essential for the care of the subject.  Treatment with concomitant 
drugs that are strong inhibitors of CYP3A should be avoided with the exception of antibiotics, 
antifungals and antivirals that are used as standard of care to prevent or treat infections.  Grapefruit 
juice should not be ingested during study treatment.  If strong CYP3A inhibitors are used 
concomitantly, subjects should be monitored for AEs.
Duration of Treatment:
Gilteritinib or placebo will be given daily for up to 2 years.  After treatment discontinuation, subjects 
will have a 30-day follow-up visit for safety, after which the subjects will enter the long-term follow-
up period and be contacted every 3 months until final database lock for collection of subsequent AML 
treatment, remission status, and survival (cause of death and date of death) information.  Study drug 
will not be provided during the follow-up period.
Discontinuation Criteria from Treatment:
Gilteritinib or placebo therapy will continue for a maximum of 2 years from initiation of therapy until 
1 of the following criteria applies:
●
Subject declines further study participation (i.e., withdrawal of consent).
●
Subject is noncompliant with the protocol based on the investigator or Medical Monitor 
assessment.
●
Subject is found to have significantly deviated from any 1 of the inclusion or exclusion criteria 
after enrollment (subjects having clinical benefit may be kept in the study after discussion with 
the Medical Monitor).
●
Subject develops an intolerable or unacceptable toxicity.
●
Investigator/sub-investigator determines that the continuation of the study treatment will be 
detrimental to the subject.
●
Subject relapses.
●
Subject begins other anti-leukemic therapy.
●
Subject becomes eligible for and proceeds to transplant.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject.
●
Female subject becomes pregnant.
●
Death.






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●
Same analysis as primary analysis on the FAS, but RFS is censored at end of treatment.
●
Same analysis as primary analysis on the FAS, but RFS is defined by using investigator 
assessed relapse.
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint of OS will be analyzed on the FAS using a stratified log-rank 
test with the same strata as in the primary analysis of RFS.  With the sequential multiple test 
procedure to control for overall type I error at the 1-sided 0.075 significance level, formal significance 
testing of OS will be conducted only if the RFS comparison is statistically significant.  Otherwise, OS 
analysis will be considered exploratory.
For the key secondary endpoint of OS, sensitivity analyses will be performed as below:
●
Unstratified log-rank test on the FAS
●
Stratified Cox proportional hazards model with the same strata as in primary analysis on 
the FAS
●
Same analysis as primary analysis but on the PPS
●
Same analysis as primary analysis on the FAS, but OS is censored at the first 
hematopoietic stem cell transplant and first subsequent anti-leukemic treatment, whichever 
occurs first.
Pharmacokinetics:
Sparse (predose) pharmacokinetic samples will be collected in all subjects. 
Additional ECGs and/or time-matched plasma samples will be collected in a subset of approximately 
40 subjects at the following visits and time points:
●
Day 15 – 4 hours  (± 1 hour) postdose
●
Day 29 – 4 hours (± 1 hour) postdose
Pharmacodynamics:
Not applicable.
Safety:
The safety analysis set is defined as all randomized subjects who received at least 1 dose of study 
treatment. 
The safety evaluation will be based mainly on AEs, clinical laboratory, vital signs, ECGs and ECOG 
performance status.  Descriptive statistics will be used to summarize safety data.  All safety data will 
be summarized by the actual treatment received.
All summaries of AEs will include only treatment-emergent events unless otherwise stated.  AEs will 
be categorized by SOC and Preferred Term using MedDRA and will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
AML: acute myeloid leukemia; CR1: first complete remission; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; ITD: internal tandem duplication; MRD: minimal 
residual disease.


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Table 1
Schedule of Assessments
Assessments
Screening
D1
D8
D9
D15
D29
Months
2-6a
Subsequent Visitsa,b
(every 2 months, 
i.e., Month 8, 
Month 10, etc.)
Month 24/
EOTc
30-Day 
Follow-up
Long-term 
Follow-upd
Windows
Day -14 to -1
+/- 1d
+/-1d
+/- 1d
+/- 5d
+/- 10d
+/- 7d
+7d
+/-7d
Signed ICF
X
Medical and Disease History
X
Randomization
X
Physical Examinatione
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
12-lead ECGf (all subjects)
X
X
X
Xg
X
X
X
X
X
12-lead ECG – ECG/PK sampling subset – additional time pointsh
X
X
Chest X-ray (or CT of chest) 
X
Pregnancy Test for WOCBPi
X
X
X
X
X
MUGA or ECHOj
X
Clinical Laboratory Tests 
(chemistry, hematology, coagulation, urinalysis)k
Xk,l
X
X
X
X
Xk
Xk
Xk
Thyroid Function Testm
X
Xm
Xm
Xm
Patient reported outcome toolsn
X
X
X
X
Resource utilization
X
X
X
X
FLT3 Mutation Status (local results)o
Xo
Bone Marrow Biopsy and/ or Aspiration for disease assessment and 
MRDp
Xp
Xp
Xp
Xp
PK Sample Collection (all subjects)q
X
X
X
X
X
X
X
PK Sample Collection – ECG/PK sampling subset – additional time 
points
Xr
Xr
PGx (whole blood and buccal swab)s
X
AE/SAE Assessment
X
X
X
X
X
X
X
X
Xt
Xu
Prior and Concomitant Medicationsv
Xv
X
X
X
X
X
X
X
Survival and subsequent anti-leukemic treatments and their 
outcomes
Xt
X
Gilteritinib or Placebo Dosing at the Clinicw
X
X
X
X
X
X
Footnotes appear on next page


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AE: adverse event; CT: computed tomography; D: day; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; 
FLT3: FMS-like tyrosine kinase 3; ICF: informed consent form; MRD: minimal residual disease; MUGA: multigated acquisition scan; PGx: pharmacogenomics; PK: pharmacokinetic; 
QTcF: Fridericia-corrected QT interval; SAE: serious adverse event; WOCBP: women of childbearing potential. 
a
Visits should be scheduled based on day 1.
b
After month 6, subjects will be seen every 2 months for the duration of study treatment, up to 2 years (month 8, month 10, month 12, etc.).
c
If subject relapses and/or permanently discontinues treatment, an end of treatment visit should be conducted within 7 days of last dose. 
d
Telephone contact every 3 months after the 30-day follow-up visit. Additional contacts may be made to support key analyses.  Follow-up will continue until the final database lock, 
which is estimated to occur after the last subject enrolled reaches the 30-day follow-up visit.
e
Height measurement performed only at screening. Weight measurement should be performed at screening and each monthly visit.
f
Screening ECG is required.  ECG assessment will be evaluated in all subjects before dosing on day 1, day 8, day 15, day 29 and each subsequent visit. Predose assessments should 
be taken within 1 hour before drug administration. 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. The mean QTcF of the triplicate ECG tracings based on central reading will be used for all treatment 
decisions. 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 by 
central read).
g
If the mean QTcF from day 1 to day 8 has increased > 30 ms with no other known etiology, a confirmatory ECG should be performed on day 9. If the day 8 and 9 ECGs confirm the 
> 30 ms increase in QTcF, then the investigator should assess if a dose modification should occur as per the dose interruption or reduction guideline in the protocol.
h
For subjects participating in the ECG/PK sampling subset, additional ECGs will be performed 4 hours (+/-1 hour) postdose on day 15 and day 29. 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 
are to be performed prior to obtaining the time-matched PK sample (at day 15 and day 29), therefore must be started at least 10 to 15 minutes before the PK draw.
i
Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin).
j
MUGA scans or ECHO are to be performed at screening for subjects with history of congestive heart failure New York Heart Association Class 3 or 4 (unless MUGA scan or 
ECHO performed within 1 month prior to screening revealed left ventricular ejection fraction ≥ 45%).
k
Urinalysis is only required at screening. Additional laboratory tests may be performed according to institutional standard of care. 
l
All subjects must be randomized off of central results. Labs can be repeated during the screening period for eligibility.
m
Thyroid function tests will be repeated after every 2 months of therapy beginning at month 2 (month 2, month 4, month 6, etc.).
n
Includes EuroQol Group 5-dimension 5-level instrument, Functional Assessment of Cancer Therapy-Anemia and Functional Assessment of Cancer Therapy-Leukemia.  If possible, 
subject reported outcome measures should be performed prior to any other assessments on that visit day.
o
The documentation of a FLT3-ITD mutation in the past will be used to confirm eligibility criteria at screening. For randomized subjects, if bone marrow aspirate or peripheral blood 
sample and/or DNA derived from the sample at the time of diagnosis are available, additional testing of this sample may be performed.  
Footnotes continued on next page


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p
Bone marrow aspirate is required and bone marrow biopsy in addition is preferred.  In case of inadequate aspirate, bone marrow biopsy is required.  
Bone marrow samples will be collected at screening and months 3, 6, 12, 18 and 24 and assessed by the local lab. If a subject relapses, a bone marrow sample should also be 
performed at the time of relapse. Only bone marrow samples showing relapse will be sent to a central lab. If bone marrow aspirate is unobtainable at relapse (e.g., dry tap), a 
peripheral blood smear should be collected along with bone marrow biopsy and sent to the central lab.
MRD assessment will be performed at screening and months 3, 6, 12, and 24/EOT.  MRD performed at EOT should be performed only if the subject discontinued treatment for a 
reason other than relapse.  For MRD, the first 0.25-0.75 mL of bone marrow aspirate will be collected and sent by overnight carrier to a central laboratory.  A peripheral blood 
sample is not acceptable for MRD assessment.
If a subject relapses, FLT3 mutations will be assessed at the time of relapse by a central lab.  If bone marrow aspirate is unavailable at relapse, a peripheral blood sample is 
acceptable to be collected for assessment of FLT3 mutations.  
q
Trough PK samples will be collected in all subjects predose (within 1 hour of dose administration) on day 1, day 8, day 15, day 29, at months 2-6 and every subsequent visit 
(month 8, month 10, etc.) and at EOT.
r
For subjects participating in the ECG/PK sampling subset, additional PK sample will be collected 4 hours (+/-1 hour) postdose on day 15 and day 29.  
s
Whole blood and buccal swab collected predose on day 1 for subjects who consent to participate in the PGx study.  
t
Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs.
u
Only SAE data that is possibly or probably related to study drug will be collected.
v
Includes medications taken within 28 days prior to day 1.
w
Gilteritinib or placebo is taken daily at home except for clinic days when it will be taken at the clinic.


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


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2013; Rochlitz et al, 1999].  AXL inhibition suppresses the growth of human FLT3-positive 
AML in vivo [Park et al, 2013].  In addition, AXL inhibition is also effective against 
FLT3-negative AML expressing AXL in vivo [Ben-Batalla et al, 2013].
ASP2215/gilteritinib is a new chemical entity discovered by Astellas Pharma Inc. in 
collaboration with Kotobuki Pharmaceutical Co., Ltd.  Gilteritinib has an inhibitory effect on 
TKs, mainly FLT3, AXL 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 either FLT3-ITD, FLT3-D835Y or FLT3-ITD-D835Y.
Considering the high risk of relapse in patients in remission, post-remission therapy aimed at 
prolonging remission duration is warranted.  Allogeneic HSCT is recommended to prevent 
relapse.  However, HSCT is limited to fitter patients with an available donor.  For patients 
who are not undergoing HSCT, maintenance therapy aimed at eradicating residual disease 
and prolonging disease remission is a possible alternative.  Currently, there is no approved or 
universally accepted maintenance treatment, nor is there a conclusive clinical trial 
demonstrating the benefit of an agent in maintenance setting for AML with FLT3-ITD.  This 
clinical trial is designed to test the hypothesis that maintenance therapy with a potent FLT3 
inhibitor will lead to improved relapse-free survival (RFS) for patients with FLT3/ITD AML 
in remission after induction/consolidation treatment.  The trial is a randomized double-blind 
study comparing gilteritinib to placebo. 
1.2
Nonclinical and Clinical Data
Nonclinical and clinical data for gilteritinib available as of the writing of this protocol are 
summarized below.  Please refer to the current version of the ASP2215 Investigator’s 
Brochure.
1.2.1
Nonclinical Data
1.2.1.1 Summary of In Vitro Pharmacology Studies
Gilteritinib in vitro studies showed the inhibition of activities of a series of tyrosine kinases: 
FLT3, nucleophosmin 1-ALK, leukocyte receptor TK (LTK), ALK and AXL kinases at 1 and 
5 nmol/L, and tropomyosin receptor kinase A (TRKA), ROS, RET and MER kinases at 
5 nmol/L by over 50%.  Gilteritinib inhibited FLT3, LTK, AXL, echinoderm microtubule-
associated protein-like 4-ALK variant 1 (EML4-ALK) and KIT kinase activities with half-
maximal inhibitory concentration (IC50) values of 0.291, 0.350, 0.726, 1.2 and 229 nmol/L, 
respectively.
Gilteritinib inhibited the cell growth of Ba/F3 cells expressing FLT3-ITD, FLT3-D835Y and 
FLT3-ITD-D835Y (IC50 values ranged from 1.6 to 2.1 nmol/L) and the growth of MV4-11 cells, 
a human AML cell line expressing FLT3-ITD, with an IC50 value of 0.92 nmol/L.
In MV4-11 cells, treatment with gilteritinib inhibited FLT3 phosphorylation (phosphorylation 
levels of 100%, 86%, 19% and 7% with gilteritinib at 0, 0.1, 1, and 10 nmol/L, respectively).  


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In addition, gilteritinib inhibited phosphorylation of signal transducer and activator of 
transcription 5 (STAT5), AKT and extracellular signal-regulated kinase in MV4-11 cells.  
Gilteritinib at 3 and 10 nmol/L significantly increased the population of MV4-11 cells in G1 
phase, suggesting that gilteritinib arrests the cell cycle in this cell line.  ASP2215 at 10 and 
30 nmol/L significantly increased the annexin-V-positive population in MV4-11 cells, 
indicating that gilteritinib induces apoptosis in this cell line.
Gilteritinib also inhibited cell growth and ALK phosphorylation in NCI-H2228 cells, human 
non-small cell lung cancer (NSCLC) cells endogenously expressing EML4-ALK.
Gilteritinib inhibited AXL phosphorylation in AXL-overexpressed PC9 (PC9 AXL) cells.  
The combination treatment of gilteritinib and erlotinib showed more effective growth 
inhibition in PC9 AXL cells compared to erlotinib alone, suggesting that overexpression of 
AXL confers resistance to erlotinib in NSCLC cells.
The affinity of gilteritinib to 46 receptors, 5 ion channels, 3 transporters and the inhibitory 
effect of gilteritinib on 3 enzyme reactions were evaluated.  Gilteritinib inhibited radioligand 
binding to adenosine A1 (rat) receptor, serotonin 5-hydroxytryptamine receptor 1 (5HT1R) 
receptor (nonselective, rat), serotonin 5-hydroxytryptamine receptor 2B (5HT2BR) receptor 
(human) and sigma receptor (nonselective, guinea pig) with IC50 values of 4.57, 4.90, 0.190 
and 0.615 μmol/L, respectively.  Gilteritinib inhibited human 5HT2BR receptor function in a 
cell function assay with an IC50 value of 5.82 μmol/L without showing agonistic activity.
1.2.1.2 Summary of In Vivo Pharmacology Studies
Gilteritinib induced significant growth inhibition of MV4-11 tumors and tumor regression in 
vivo.  At 6 and 10 mg/kg per day, gilteritinib induced complete tumor regression for 4 out of 
6 and 6 out of 6 mice, respectively.  Body weight of the mice treated with gilteritinib was not 
affected at any tested doses.  After single oral administration of gilteritinib in the xenograft 
mice, the phosphorylation of FLT3 and STAT5 in MV4-11 tumors was inhibited at doses of 
1, 3, 6 and 10 mg/kg.
Gilteritinib in combination with cytarabine and daunorubicin or in combination with 
cytarabine and idarubicin showed superior antitumor efficacy in mice xenografted with 
MV4-11 cells compared to gilteritinib alone or to either chemotherapy combinations without 
gilteritinib.
In the erlotinib-resistant HCC827 tumors, once-daily oral administration of gilteritinib did 
not inhibit tumor growth; however, in combination with erlotinib, tumor regression was 
induced by 46% after the 13-day treatment.


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1.2.1.3 Summary of Nonclinical Pharmacokinetics
After a single oral administration, Cmax and AUCinf increased more than dose-proportionally 
from 1 to 10 mg/kg in rats and slightly more than dose proportionally from 0.3 to 3 mg/kg in 
dogs.  The absolute oral bioavailability was 26.8% at 1 mg/kg in rats and 88.2% at 0.3 mg/kg 
in dogs.
[14C] - gilteritinib-derived radioactivity in nonpigmented rats was distributed to be the highest 
in the liver and detectable at 72 hours in many tissues.  In pigmented rats, the concentration of 
radioactivity decreased over time and was below the lower limit of quantification by 4 weeks 
postdose in most tissues.  However, the elimination of radioactivity from the ciliary body and 
retina and choroid were notably slow, and tissue concentration/maximum tissue concentration 
(Ct/Cmax) ratios at 17 weeks postdose were 32.7% and 42.8%, respectively.  The plasma 
protein binding ratios of gilteritinib in mice, rats, rabbits, dogs and monkeys ranged between 
approximately 75% and 90%, and ranged from 90.2% to 90.5% in humans.  The major 
binding protein in human plasma was human serum albumin.
After oral administration of [14C] - gilteritinib at 1 mg/kg to nonpigmented rats, the urinary 
and fecal excretion of radioactivity within 168 hours was 1.4% and 89.9% of the dose, 
respectively.  The urinary and biliary excretion of radioactivity within 48 hours was 8.6% and 
29.3% of the dose, suggesting that the oral absorption was at least 37.9%.  A part of the 
biliary excretion is assumed to undergo enterohepatic circulation.
Refer to [Section 1.2.2.2] for assessments using human biomaterials.
1.2.1.4 Summary of Nonclinical Safety
In safety pharmacology studies, gilteritinib showed a concentration-dependent suppression 
effect on the human ether-à-go-go-related gene (hERG) current in hERG-transfected human 
embryonic kidney 293 cells at concentrations of 3 × 10-6, 1 × 10-5 and 3 × 10-5 mol/L with 
compensated suppression rates of 18.1%, 32.8% and 70.7%, respectively.  Suppression was 
not observed at 1 × 10-6 mol/L.  The IC50 was 1.6 × 10-5 mol/L.
Gilteritinib showed no effects on the central nervous system (CNS) in rats at 10 mg/kg.  At 
30 mg/kg and higher, decreased urination was noted.  In addition, at 100 mg/kg, decreased 
defecation was noted.  The changes in urination and defecation resolved during the recovery 
period.
Gilteritinib did not show any effect on the cardiovascular or respiratory system in dogs up to 
100 mg/kg, or on the CNS at 1 mg/kg.  At 3 mg/kg and higher, the following signs were 
noted: retching at 3 mg/kg, vomiting and positive fecal occult blood at 10 mg/kg and higher, 
a decrease in the blood Ca2+concentration at 30 mg/kg, and salivation and an increase 
followed by a decrease in the blood Ca2+ concentration at 100 mg/kg.  All of the findings 
recovered.
In the single oral dose toxicity study in rats, the approximate lethal dose level was 300 mg/kg 
for males and females. The major change was a gastrointestinal hemorrhagic disorder at 100 
and 300 mg/kg.  Reversibility of the changes noted in the surviving animals was seen.  


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No definitive single oral dose toxicity study in dogs was conducted.  In the 4-week toxicity 
study in dogs, a dose of 1000 mg/kg per day caused deaths and moribund sacrifices on day 2.  
The cause of death and moribundity was considered to be deterioration of general condition 
caused by gastrointestinal hemorrhage.
In the 1-week oral repeated dose toxicity study in rats, interstitial pneumonia in the lung and 
vacuolar change in the rod-cone layer of the retina were observed in a male at 30 mg/kg per 
day.  In the 13-week oral repeated dose toxicity study in rats, deaths occurred at 20 mg/kg per 
day in both sexes.  Target organ toxicity was identified in the gastrointestinal tract, immune 
system, hematopoietic system, eye, lung, kidney and liver. The no observed adverse effect 
level (NOAEL) was lower than 2.5 mg/kg per day for males and females.  The changes noted 
during the dosing period recovered or tended to recover during the 4-week recovery period.  
The severely toxic dose in 10% of the animals in rats was considered to be 20 mg/kg per day.  
In the 4-week oral repeated dose study in dogs, mortality occurred at 10 mg/kg per day or 
more.  Target organ toxicity was identified in the gastrointestinal tract, immune system, 
hematopoietic system, eye, kidney and liver.  The NOAEL was 1 mg/kg per day for males 
and females.  Reversibility of most of the test article-related changes was indicated by the 
end of the 4-week recovery period.  The highest non-severely toxic dose in dogs was 
considered to be 5 mg/kg per day.  In the 13-week oral repeated dose study in dogs, mortality 
occurred at 5 mg/kg per day.  Target organ toxicity was identified in the lung, lacrimal gland, 
urinary bladder, epithelial tissue, gastrointestinal tract, immune system, hematopoietic system, 
eye, kidney and liver.  The NOAEL was 1 mg/kg per day for males and females.  
Reversibility of most of the test article-related changes was indicated by the end of the 
4-week recovery period.
Gilteritinib did not induce gene mutation in the definitive in vitro reversion test in bacteria.  
Similarly, gilteritinib did not induce chromosomal aberrations in the definitive in vitro 
chromosomal aberration test in mammalian cells.  The definitive in vivo micronucleus test 
showed that gilteritinib has a potential to induce micronuclei in mice.  Based on the results of 
the battery of genotoxicity studies above, it was concluded that 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.  The NOAEL for dams and embryo-fetal development was 
10 mg/kg per day.
Gilteritinib showed no potential to induce phototoxicity to cultured mammalian cells.
1.2.2
Clinical Data
1.2.2.1 Clinical Pharmacokinetics and Pharmacodynamics
The pharmacokinetic parameters of unchanged drug after single and multiple doses of 
gilteritinib to AML subjects were investigated in the dose escalation cohort of Study 
2215-CL-0101.  Assessment of Ctrough over time for individual subjects (both dose escalation 
and dose expansion cohorts) showed that in most subjects, the trough concentration of 
gilteritinib appeared to reach steady state by day 15 of multiple administrations of gilteritinib


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from 20 to 120 mg once daily.  Plasma inhibitory assay from the samples collected predose and 
postdose on days 1, 8, 15 and 29 demonstrated sustained inhibition of phospho-FLT3 at doses 
80 mg and higher.
The effect of strong and moderate cytochrome P450 (CYP)3A4 inhibitors and strong CYP3A4 
inducers on gilteritinib exposure was assessed in relapsed or refractory AML subjects (Study 
2215-CL-0101) and healthy subjects (Study 2215-CL-0108).  In relapsed or refractory AML 
subjects, there was a less than 2-fold increase in gilteritinib exposure when gilteritinib was 
coadministered with moderate or strong CYP3A4 inhibitors.  In healthy subjects, gilteritinib 
exposure increased approximately 2-fold when gilteritinib was coadministered with 
itraconazole, a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor.  Coadministration of 
gilteritinib with rifampicin, a strong CYP3A4 inducer, resulted in an approximate 70% 
decrease in gilteritinib exposure.  Collectively, these data support monitoring subjects who 
require concomitant medications that are strong CYP3A4 inhibitors and restricting use of 
concomitant medications that are strong CYP3A4 inducers.
Preliminary results from a drug-drug interaction assessment in a subset of relapsed or 
refractory AML subjects (2215-CL-0101) indicate cephalexin (MATE 1 substrate) exposure 
was comparable after single dose administration of cephalexin alone and in combination with 
gilteritinib (administered once daily). These results suggest coadministration of MATE1 
substrates and gilteritinib is not expected to result in a clinically-relevant drug-drug interaction.
A preliminary analysis of the relationship between ASP2215 plasma concentration and 
Fridericia-corrected QT interval (QTcF) change from baseline (ΔQTcF) was performed on data 
from the 2215-CL-0101 study (data cutoff 31 Oct 2015).  This assessment included 
1359 observations from 199 patients.  A model-averaging approach was used to develop a 
robust model to describe and predict the ASP2215 concentration-ΔQTcF relationship.  A 
concentration-related increase in ΔQTcF was observed and the mean ΔQTcF at the mean 
steady-state Cmax at 120 mg was predicted to be less than the 10 msec-threshold considered 
clinically significant.  Additionally, 4.1% of relapse/refractory subjects had a maximum post-
baseline QTcF interval >500 msec.  These data indicate clinically-relevant corrected QT 
interval (QTc) prolongation is not anticipated.  
With increasing dose of gilteritinib, increasing plasma concentrations of creatine kinase (CK) 
were observed.  Comparison of day matched CK corrected relative to baseline with Ctrough
ASP2215 values showed a correlation with a positive slope.  Similarly, comparison of the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grade for CK elevations with gilteritinib Ctrough values showed increasing incidence of higher 
CTCAE grades with increasing drug exposure.  However, almost all of the elevations were 
grade 1 and grade 2.  Overall, increasing CK plasma concentrations from baseline appeared to 
correlate with increasing ASP2215 plasma concentrations; the mechanism for this effect is 
unknown.


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1.2.2.2 Studies Using Human Biomaterials
In Caco-2 cells, the permeability of gilteritinib was between that of known low and high 
permeability markers.  Gilteritinib was a substrate for P-gp but not a substrate for breast cancer 
resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1, OATP1B3 or 
organic cation transporter (OCT)1.  Gilteritinib demonstrated a potential to inhibit BCRP and 
multidrug and toxin extrusion (MATE)1 at clinically relevant concentrations of gilteritinib.  
However, preliminary results from the drug-drug interaction assessment of coadministration of 
gilteritinib and cephalexin, a MATE1 substrate, in relapsed or refractory AML subjects (Study 
2215-CL-0101) indicate lack of a clinically-significant interaction between gilteritinib and 
MATE1 substrates (see Section 1.2.2.1).  Based on EMA Guideline on the Investigation of 
Drug Interaction (Jun 2012), gilteritinib may also inhibit liver transporters OCT1 and 
OATP1B1 at clinically relevant drug exposures.  No major human-specific gilteritinib 
metabolites were formed by liver microsomes or hepatocytes.  The main enzyme involved in 
the metabolism of gilteritinib was estimated to be CYP3A4.  Gilteritinib has a potential to 
induce CYP enzyme activities (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and 
CYP3A4/5) and mRNA levels (CYP2B6, CYP2C8, CYP2C9 and CYP3A4).  However, these 
results should be interpreted with caution because these effects were not uniformly observed in 
all donor samples and the concentration-dependency of these effects could not be evaluated.  
For CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2D6 inhibition, IC50 values were 
> 100 μmol/L.  Very weak direct inhibition of CYP2C19 and CYP3A was observed.  Overall, 
gilteritinib showed minimal direct inhibition of CYP enzymes at clinically relevant 
concentrations.
1.2.2.3 Clinical Safety
Ongoing study 2215-CL-0101 is an open-label, dose escalation, first-in-human study in 
subjects with relapsed or refractory AML, with concomitant expansion cohort for multiple 
doses.  One cycle is defined as 28 days and the subject will receive oral gilteritinib daily.  The 
study treatment will continue until 1 of the discontinuation criterion is met.
The starting dose level of gilteritinib was 20 mg daily, and the decision to dose escalate to the 
next dose level was made based on the assessment of safety variables including occurrence of 
grade 2 adverse events (AE) or dose-limiting toxicities (DLTs).  The maximum tolerated dose 
(MTD) in the study was determined to be 300 mg.
This study has 2 cohorts of subjects:
●
Cohort 1: Dose escalation cohort (20, 40, 80, 120, 200, 300 and 450 mg doses)
●
Cohort 2: Dose expansion cohort (20, 40, 80, 120, 200 and 300 mg doses)
As of 31 Oct 2015, of the first 252 subjects that received gilteritinib, the majority of subjects 
(245 [97.2%]) experienced at least 1 treatment-emergent adverse event (TEAE).  Overall, the 
most frequently reported TEAE (occurring in at least 10% of subjects) include: febrile 
neutropenia (38.5%), diarrhea (33.7%), anemia (29.0%), fatigue (28.2%), aspartate 
aminotransferase (AST) increased (23.0%), edema peripheral (22.6%), dyspnea and pyrexia 
(21.8% each), cough and constipation (18.7% each), epistaxis (17.9%), nausea (17.5%), 


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dizziness (17.1%), alanine aminotransferase (ALT) increased and hypotension (16.7% each), 
vomiting (15.9%), hypokalemia (15.1%), hypocalcemia (14.7%), platelet count decreased 
(13.5%), blood creatinine increased (13.1%), acute myeloid leukemia and hyponatremia 
(12.7% each), pneumonia (12.3%), sepsis (11.9%), fall (11.5%), arthralgia and 
hypomagnesemia and thrombocytopenia (11.1% each), blood alkaline phosphatase increased 
and headache (10.7% each), and hypoxia (10.3%).
A total of 183 (72.6%) subjects experienced at least 1 TEAE considered by the investigator to 
be possibly or probably related to study drug.  Common drug-related TEAEs (occurring in at 
least 5% of subjects) include diarrhea (16.3%), fatigue (13.1%), increased AST (11.9%), 
anemia (9.1%), constipation (8.3%), increased ALT (8.3%), peripheral edema (8.3%), 
decreased platelet count (7.5%), nausea (7.5%), thrombocytopenia (6.7%), vomiting (6.7%), 
increased creatine phosphokinase (6.3%), dizziness (6.3%), dysgeusia (6.3%) and increased 
transaminases (6.0%).
Eighty-seven (34.5%) subjects experienced a TEAE that resulted in death: AML in 32 (12.7%) 
subjects; multi-organ failure in 7 (2.8%) subjects; respiratory failure in 6 (2.4%) subjects; 
sepsis and septic shock in 4 (1.6%) subjects each, pneumonia, cardiac arrest and intracranial 
hemorrhage in 3 (1.2%) subjects each; disease progression and renal failure in 2 (0.8%) 
subjects each; anemia, neutropenia, peripheral edema, bronchopulmonary aspergillosis, 
enterococcal infection, lung infection, pyoderma, staphylococcal bacteremia, staphylococcal 
sepsis, malignant neoplasm progression, cerebral ischemia, loss of consciousness, acute 
respiratory failure, hypoxia, pulmonary embolism, colitis, ventricular fibrillation, ventricular 
tachycardia, neutropenic colitis, bacteremia, cellulitis, diabetic ketoacidosis, sudden death  and 
hemoptysis each in 1 (0.4%) subject.  One event of intracranial hemorrhage, 1 event of septic 
shock, 1 event of respiratory failure and sepsis, 1 event of pulmonary embolism, 1 event of 
neutropenia, 1 event of pyoderma, 1 event of ventricular fibrillation and the event of 
hemoptysis were considered possibly related to gilteritinib by the investigator.  One event of 
respiratory failure was considered probably related to gilteritinib by the investigator.  
The majority of subjects (198 [78.6%]) experienced a serious TEAE. Serious TEAEs that 
occurred in 2 or more subjects include febrile neutropenia (30.6%), AML (12.7%), sepsis 
(11.9%), pneumonia (9.5%), acute renal failure (8.3%), pyrexia (6.7% each), bacteremia 
(5.2%), hypotension and respiratory failure (4.8% each), fungal pneumonia (4.0%), diarrhea 
(3.2%), multi-organ failure, urinary tract infection and hypoxia (2.8% each), subdural 
hematoma, septic shock, lung infection, cellulitis, gastrointestinal hemorrhage, leukocytosis 
and syncope (2.4% each), atrial fibrillation (2.0%), anemia, clostridium difficile colitis, cardiac 
arrest, vomiting, increased AST, hyponatremia and acute febrile neutrophilic dermatosis (1.6% 
each), upper respiratory tract infection, clostridium difficile infection, skin infection, 
bronchopulmonary aspergillosis, hyperbilirubinemia, disease progression, small intestinal 
obstruction, nausea, blood creatine phosphokinase increased, dehydration, squamous cell 
carcinoma of skin, intracranial hemorrhage, dyspnea, respiratory distress, angioedema, 
hematoma, renal failure and convulsion (1.2% each), ejection fraction decreased, liver function 
test (LFT) abnormal, pericardial effusion, tachycardia, transaminases increased, increased 


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ALT, urosepsis, fall, streptococcal bacteremia, lobar pneumonia, enterococcal bacteremia, 
clostridial infection, fatigue, mucosal inflammation, pancytopenia, acute graft-versus-host 
disease in skin, epistaxis, sinusitis, soft tissue infection, staphylococcal bacteremia, back pain, 
urinary retention, acute respiratory failure, muscular weakness, pleural effusion, pulmonary 
embolism, renal tubular necrosis, mental status changes and posterior reversible 
encephalopathy syndrome (PRES [0.8% each]).
Sixty-nine (27.4%) subjects experienced a serious TEAE that was considered related to the 
study drug by the investigator. Drug-related serious TEAEs that occurred in 2 or more subjects 
include febrile neutropenia (2.4%), renal failure acute, gastrointestinal hemorrhage and 
increased AST (1.6% each), blood bilirubin increased, blood creatine phosphokinase increased, 
hypotension (1.2% each), nausea, LFT abnormal, pyrexia, sepsis, increased ALT, muscular 
weakness, transaminases increased, small intestinal obstruction, hypoxia, PRES and vomiting 
(0.8% each).
A preliminary analysis of the relationship between gilteritinib plasma concentration and 
ΔQTcF was performed on data from the 2215-CL-0101 study (data cutoff 31 Oct 2015). This 
assessment included 1359 observations from 199 patients. A model-averaging approach was 
used to develop a robust model to describe and predict the gilteritinib concentration-ΔQTcF 
relationship. A concentration-related increase in ΔQTcF was observed. The model-predicted 
increase in mean QTcF is 5.8 msec (1-sided upper 95% CI: 8.0 msec) at the mean steady state 
Cmax (282 ng/mL) associated with once daily dosing of 120 mg gilteritinib. These data indicate 
QTc prolongation is expected to be less than the 10-msec threshold considered clinically 
significant.
An exposure-related increase in circulating CK concentration relative to baseline was also 
observed in relapse/refractory AML subjects enrolled in Study 2215-CL-0101.  Almost all CK 
elevations were grade 1 and grade 2, however CTCAE Grade 3 and 4 AEs related to elevated 
CK occurred in higher gilteritinib dose groups. Similarly, a significant correlation between 
gilteritinib concentration and aspartate aminotransferase change from baseline (ΔAST) was 
also observed. However, the incidence of ≥Grade 3 events related to elevated AST was < 3% 
(data cutoff 31 Oct 2015).
After the data cutoff, 1 subject in the 200 mg dose group developed altered mental status and 
1 episode of seizure with magnetic resonance imaging (MRI) results consistent with PRES. 
Gilteritinib was discontinued and the subject’s symptoms resolved. 
There were 2 subjects who experienced retinoic acid syndrome (differentiation syndrome) that 
was considered by the investigator to be related to gilteritinib. FLT3 inhibitors may 
differentiate leukemic blasts to mature neutrophils. Subjects who develop differentiation 
syndrome may present with increases in neutrophil counts, unexplained fever, acute respiratory 
distress with interstitial pulmonary infiltrates, and/or vascular capillary leak syndrome.
As of 31 Oct 2015, 23 subjects experienced a DLT. All DLTs occurred in the dose expansion 
cohort, with the exception of 2 subjects in the 450 mg dose escalation cohort that experienced 
grade 3 increased AST and grade 3 diarrhea. No further subjects will be enrolled in the 


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450 mg dose group. None of the doses below 450 mg met the criteria for pausing 
enrollment. The MTD in Study 2215-CL-0101 is considered 300 mg.
1.2.2.4 Clinical Efficacy
In Study 2215-CL-0101, as of 31 Oct 2015, 252 patients have received gilteritinib.  Response 
was assessed based on central assessment supplemented by local assessment (i.e., derived 
response) and investigator reported response.  Patients are included in the dose group of the 
initial dose received prior to any dose increase or decrease, unless otherwise noted.
Nearly all patients who achieved a derived response of partial remission (PR) or composite 
complete remission (CRc) at the end of treatment were FLT3-mutation positive.  Based on the 
derived response in the 174 FLT3-mutation positive patients at the end of treatment, 66 (37.9%) 
patients achieved CRc, and the best overall response rate was 49.4% (i.e., 66/174 patients).  
Eleven (6.3%) patients achieved CR, 9 (5.2%) patients achieved complete remission with 
incomplete platelet recovery (CRp), 46 (26.4%) patients achieved complete remission with 
incomplete hematologic recovery (CRi) and 20 (11.5%) patients achieved PR.
Overall, the majority of CRc and PR events were observed in FLT3-mutation positive patients 
in dose groups of 80 mg and greater.  The derived CRc rate at the end of treatment in the 
FLT3-mutation positive population at doses of 80 mg and above was 42.5% overall and 41.7%, 
51.9%, 37.7%, 33.3% and 0 in the 80, 120, 200, 300 and 450 mg dose groups, respectively.
Median survival for 80, 120, 200, 300 and 450 mg dose groups was 198, 218, 224, 157 and 
51 days, respectively. 
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Gilteritinib Data
The nonclinical and clinical studies, which are referred to in this section, are as of the writing 
of this protocol.  Please refer to the current version of the ASP 2215 Investigator’s Brochure.
1.3.2
Gilteritinib Nonclinical Data
Major findings in the safety pharmacology studies were vomiting, positive fecal occult blood 
and increased/decreased blood Ca2+ in dogs, and decreased urination and defecation in rats.  
In the oral 13-week repeated dose toxicity study in rats, and the 4- and 13-week repeated dose 
toxicity studies in dogs, mortality occurred at 20, 10 and 5 mg/kg per day, respectively.  With 
respect to other major target organ toxicities, effects on the lacrimal gland, urinary bladder, 
epithelial tissue, gastrointestinal tract, immune system, hematopoietic system, eye, liver, 
kidney and/or lung were observed in rats and dogs at 2.5 mg/kg per day or more.  All major 
findings were reversible and monitorable.
Gilteritinib has a potential to induce genotoxicity in vivo.  Gilteritinib showed teratogenic 
potential and embryo-fetal deaths in the embryo-fetal development study in rats.


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1.3.3
Gilteritinib Clinical Data
Preliminary data from clinical study 2215-CL-0101 demonstrated efficacy in FLT3-mutation 
positive patients with relapsed/refractory AML, with a tolerable safety profile. 
Expected adverse drug reactions for gilteritinib include (by preferred term) peripheral edema, 
increased blood creatine phosphokinase, increased ALT, increased AST and myopathy 
(Astellas data on file).
Refer to [Section 1.2.2.3] for a comprehensive summary of safety findings.
1.4
Risk-Benefit Assessment
AML with activating FLT3 mutations such as FLT3-ITD and FLT3 point mutation around 
D835 decrease the prognosis for AML patients.  Even patients who achieve remission with 
induction chemotherapy have very high risk of relapse.  Once relapsed, AML is incurable in 
most of the patients.  Gilteritinib inhibits the growth of cells with FLT3-ITD and FLT3 point 
mutation (D835).  Gilteritinib has shown anti-leukemic activity in an ongoing trial in 
FLT3-mutation positive AML patients.  When used after successful remission induction, 
gilteritinib can potentially delay or prevent relapse and thus improve the long term outcome.
The potential undesirable effects of gilteritinib in humans based on toxicities observed in the 
nonclinical studies and in the recent clinical study in subjects with AML are summarized in 
[Section 1.2.1.4 and Section 1.2.2.3].  As with any investigational agent, subjects may 
experience side effects that are more severe than those observed in the nonclinical and 
clinical studies or may experience side effects not observed in nonclinical and clinical 
studies.  Findings of potential concern for clinical trials with gilteritinib include effects on the 
gastrointestinal tract, immune system, hematopoietic system, eye, liver and kidney.
Subjects will have adequate and appropriate monitoring during this study to monitor for AEs 
and minimize risk.  The Independent Data Monitoring Committee (IDMC) will perform 
periodic review of the data as documented in the IDMC Charter.
The potential risks identified from the nonclinical and clinical studies are judged to be 
acceptable in light of the potential benefits.  The MTD in clinical study 2215-CL-0101 was 
determined to be 300 mg, and the recommended phase 2 dose was determined to be 120 mg 
(please refer to the current ASP2215 Investigator’s Brochure for more detailed information).  
Strict adherence to the eligibility criteria is essential to ensure that appropriate subjects are 
selected for participation.  Equally important is strict adherence to the schedule of safety 
assessments to ensure that subjects are appropriately monitored.


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2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
The primary objective is to compare RFS between subjects with FLT3/ITD AML in first 
complete remission (CR1) without transplant and who are randomized to receive gilteritinib 
or placebo beginning after completion of induction/consolidation chemotherapy for a 2-year 
period.
2.1.2
Secondary Objectives
2.1.2.1 Key Secondary Objective
Compare overall survival (OS) in subjects treated with gilteritinib as maintenance therapy 
after induction/consolidation with those treated with placebo.
2.1.2.2 Additional Secondary Objectives
The secondary objectives are to evaluate the safety and efficacy of gilteritinib versus placebo 
in terms of:
●
Event-free survival (EFS), AEs, clinical laboratory, vital signs, electrocardiograms 
(ECGs) and Eastern Cooperative Oncology Group (ECOG) performance scores.
●
Examine the relationship of minimal residual disease (MRD), as determined using a 
next-generation sequencing (NGS) platform specific to FLT3/ITD mutations, with RFS 
and OS.
2.1.3
Exploratory Objectives
The exploratory objectives are to:
●
Assess relationship between gilteritinib exposure and QTcF for subjects participating in 
the ECG/PK sampling subset.
●
Explore the pharmacokinetics of gilteritinib (and metabolite, if applicable) in study 
population using a population pharmacokinetics approach.
●
Determine FLT3 mutation status at relapse.
●
Evaluate the safety and efficacy of gilteritinib in terms of:
○
Patient reported signs, symptoms and impacts of AML (Functional Assessment of 
Cancer Therapy-Leukemia [FACT-Leu], Functional Assessment of Cancer 
Therapy-Anemia [FACT-An])
○
EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L)
●
Evaluate healthcare resource utilization including hospitalization, intensive care unit 
(ICU) visits, emergency room (ER) visits, transfusion and use of antibiotics


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2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a phase 2, randomized, placebo-controlled, double-blind, 2-arm study to compare the 
effect of gilteritinib as maintenance therapy versus placebo after induction/consolidation in 
subjects with FLT3/ITD AML in CR1 (including CRp and CRi).  The trial will be conducted 
at approximately 200 centers in North America, Europe, South America, Central America, 
and Asia/Pacific and rest of world.
Subjects in CR1 (including CRp and CRi) will be approached for this study after 
induction/consolidation therapy is complete and a decision not to proceed with 
transplantation is made or a suitable donor could not be identified. 
Approximately 85 subjects will be randomized in a 2:1 ratio to receive gilteritinib or placebo.
Randomization will be stratified based on:
●
Age < 60 or ≥ 60 years.
●
Geographic region, North America or Europe or Asia/Pacific/Central America/South 
America/rest of world.
●
Presence of MRD at screening, yes or no.
●
Use of FLT3 inhibiting agents during induction/consolidation, yes or no.
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects 
will be administered treatment up to 2 years, or until a discontinuation criterion is met. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, and survival (cause of death and date of death).
2.2.2
Dose Rationale
Gilteritinib has been evaluated in relapsed and refractory AML patients in the US (clinical 
study 2215-CL-0101) and Japan (clinical study 2215-CL-0102) at doses from 20 mg to 
450 mg.  In the US study, the MTD was determined to be 300 mg and in the Japan study, 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 trials.  Please refer to the current 
ASP2215 Investigator’s Brochure for more detailed information.
2.3
Endpoints 
2.3.1
Primary Endpoints
The primary efficacy endpoint is RFS, defined as the time from randomization until relapse 
or death from any cause, whichever comes first.
Leukemia relapse will be defined as bone marrow blasts 5% or higher (not attributable to 
regenerating bone marrow), any circulating blasts, any extramedullary blast foci as per 
Revised International Working Group (IWG) criteria.


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2.3.2
Secondary Endpoints 
The key secondary efficacy endpoint is:
●
OS, defined as the time from randomization until death from any cause.
Additional secondary efficacy endpoints are:
●
EFS
●
MRD 
Safety Endpoints
●
AEs
●
Serum chemistry, hematology, coagulation and urinalysis
●
Vital signs
●
ECGs
●
Physical examination findings
●
ECOG performance status
2.3.3
Exploratory Endpoints
●
ECGs at specified visits and time points with time-matched gilteritinib plasma 
concentrations
●
Gilteritinib metabolite concentrations (if applicable)
●
FLT3 mutation status at relapse
●
Signs, symptoms and impacts of AML as measured with patient-reported outcome 
instruments
●
Healthcare resource utilization including hospitalization, ICU visits, ER visits, 
transfusion and use of antibiotics.
●
Gilteritinib plasma concentrations
3
STUDY POPULATION
3.1
Selection of Study Population 
Subjects diagnosed with FLT3/ITD AML in CR1, including CRp and CRi defined in 
[Appendix 12.6], for whom a decision not to proceed with transplantation has been made, or 
a suitable donor could not be identified. 
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act Authorization for United States sites) must 
be obtained from the subject or legally authorized representative prior to any study-
related procedures (including withdrawal of prohibited medication, if applicable).


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2.
Subject is considered an adult according to local regulation at the time of signing 
informed consent form (ICF).
3.
Subject consents to allow access to his or her diagnostic bone marrow aspirate or 
peripheral blood sample and/or the DNA derived from that sample, if available, that may 
be used to validate a companion diagnostic test for gilteritinib.
4.
Subject has confirmed morphologically documented AML, excluding acute 
promyelocytic leukemia (APL), in CR1 (including CRp and CRi).  For the purposes of 
enrollment, CR will be defined as < 5% blasts in the bone marrow with no morphologic 
characteristics of acute leukemia (e.g., Auer rods) in the bone marrow with no evidence 
of extramedullary disease such as central nervous system involvement or granulocytic 
sarcoma.
5.
Subject will not proceed with transplantation as either a decision not to proceed with 
transplantation has been made either on the recommendation of the treating physician or 
by the patient or a suitable donor could not be identified.
6.
Subject is < 2 months from the start of the last cycle of consolidation and should have 
completed the recommended number of consolidations per local practice.
7.
Subject has had no use of investigational agents, with the exception of FLT3 inhibiting 
agents during induction and/or consolidation therapy, within the prior 4 weeks.
8.
Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or 
peripheral blood as determined by the local institution at diagnosis.
9.
Subject has an ECOG performance status 0 to 2.
10. Subject must meet the following criteria as indicated on the clinical laboratory tests:
●
Serum creatinine ≤ 1.5 institutional upper limit of normal (ULN), or if serum 
creatinine outside normal range, then glomerular filtration rate (GFR) 
> 40 mL/min/1.73m2 as calculated with the 4-parameter Modification of Diet in 
Renal Disease (MDRD) equation.
●
Serum total bilirubin ≤ 2.5 mg/dL (43 µmol/L), except for subjects with Gilbert’s 
syndrome.
●
Serum AST and ALT < 3 x ULN.
●
Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN).
●
Absolute neutrophil count (ANC) ≥ 500/µl and platelets ≥ 20000/µl (unsupported by 
transfusions).
11. Subject is suitable for oral administration of study drug.
12. Female subject must either:
●
Be of nonchildbearing potential:
○
Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or


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○
Documented surgically sterile or status posthysterectomy (at least 1 month 
prior to screening)
●
Or, if of childbearing potential, 
○
Agree not to try to become pregnant during the study and for 6 months after 
the final study drug administration
○
And have a negative urine or serum pregnancy test at screening
○
And, if heterosexually active, agree to consistently use highly effective 
contraception per locally accepted standards in addition to a barrier method 
starting at screening and throughout the study period and for 6 months after 
the final study drug administration.
*Highly effective forms of birth control include:

Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,

Established intrauterine device (IUD) or intrauterine system (IUS),

Bilateral tubal occlusion,

Vasectomy (A vasectomy is a highly effective contraception method provided the 
absence of sperm has been confirmed.  If not, an additional highly effective method 
of contraception should be used.)

Male is sterile due to a bilateral orchiectomy.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual activity during the entire period of risk associated with 
the study drug.  The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical study and the preferred and usual lifestyle of the 
subject.
*List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming subject 
will utilize highly effective forms of birth control per locally accepted standards during the protocol 
defined period
13. Female subject must agree not to breastfeed starting at screening and throughout the 
study period, and for 2 months and 1 week after the final study drug administration.
14. Female subject must not donate ova starting at screening and throughout the study 
period, and for 6 months after the final study drug administration.
15. Male subject and their female partners who are of childbearing potential must be using
highly effective contraception per locally accepted standards in addition to a barrier 
method starting at screening and continue throughout the study period and for 4 months 
and 1 week after the final study drug administration.
16. Male subject must not donate sperm starting at screening and throughout the study period 
and for 4 months and 1 week after the final study drug administration.
17. Subject agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.


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3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has had prior allogeneic transplant.
2.
Subject has QTcF interval > 450 msec (average of triplicate determinations based on 
central reading).
3.
Subject with Long QT Syndrome.
4.
Subject with hypokalemia and hypomagnesemia at screening (defined as values below LLN).
5.
Subject has clinically active CNS leukemia.
6.
Subject is known to have human immunodeficiency virus infection.
7.
Subject has active hepatitis B or C.
8.
Subject has an uncontrolled infection.  If a bacterial or viral infection is present, the 
subject must be receiving definitive therapy and have no signs of progressing infection 
for 72 hours prior to randomization.  If a fungal infection is present, the subject must be 
receiving definitive systemic anti-fungal therapy and have no signs of progressing 
infection for 1 week prior to randomization.
9.
Subject has progressing infection defined as hemodynamic instability attributable to 
sepsis or new symptoms, worsening physical signs or radiographic findings attributable 
to infection.  Persisting fever without other signs or symptoms will not be interpreted as 
progressing infection.   
10. Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
electrocardiographic evidence of acute ischemia, congestive heart failure New York 
Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart 
failure NYHA class 3 or 4 in the past, unless a screening echocardiogram (ECHO) or 
multigated acquisition scan (MUGA) performed within 1 month prior to study entry 
results in a left ventricular ejection fraction that is ≥ 45%.
11. Subject requires treatment with concomitant drugs that are strong inducers of CYP3A.
12. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers 
of P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely 
essential for the care of the subject.  
13. Subject requires treatment with concomitant drugs that target serotonin 5HT1R or 
5HT2BR or sigma nonspecific receptor with the exception of drugs that are considered 
absolutely essential for the care of the subject.
14. Subject has a serious medical or psychiatric illness likely to interfere with participation 
in this clinical study.


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15. Subject has prior malignancies, except resected basal cell carcinoma or treated cervical
carcinoma in situ.  Cancer treated with curative intent ≥5 years previously will be
allowed.  Cancer treated with curative intent < 5 years previously will not be allowed.
16. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation.
Waivers to the exclusion criteria will NOT be allowed. 
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
Gilteritinib is an oral drug that is available in a 40 mg tablet.  The tablets are contained within 
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 dose and 
the corresponding number of tablets that need to be taken each day.  The gilteritinib 40 mg 
tablet product information is listed in [Table 2].
Table 2
Test Drug (Gilteritinib Tablets 40 mg)
Test Drug
Gilteritinib Tablets 40 mg
Code name
ASP2215
Active ingredient
Chemical name: C29H44N8O3•1/2 C4H4O4
Composition and 
dosage form
One tablet contains 40 mg of ASP2215 in free form.
Gilteritinib Tablets are round light-yellow film-coated tablets.
Lot No.
Described in separately prepared “Study Drug Handling Procedures”
Storage
Gilteritinib should be stored according to labeled storage conditions and should not be 
stored above the temperature specified on the gilteritinib label.  Store in original container.
4.1.2
Comparative Drug(s) 
The placebo for gilteritinib (inactive ingredients) will be supplied as a 40 mg placebo to 
match tablet.  The tablets contain mannitol, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, hypromellose (2910), talc, polyethylene glycol 8000, titanium 
oxide and yellow ferric oxide, which are all well characterized excipients.  The placebo 
tablets are identical in size and appearance to gilteritinib tablets.
4.2
Packaging and Labeling
Gilteritinib used in this study will be prepared, packaged and labeled under the responsibility 
of qualified staff at Astellas Pharma Global Development, Inc. (APGD)-Astellas United 
States Technologies (AUST) or Sponsor’s designee in accordance with APGD-AUST or 
Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, International Council on Harmonisation (ICH) of Technical Requirements 


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for Registration of Pharmaceuticals for Human Use Good Clinical Practice (GCP) guidelines 
and applicable local laws/regulations.
Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations with identifier 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.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator/or designee and
●
that such deliveries are recorded,
●
that study drug is handled and stored according to labeled storage conditions,
●
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
that any unused study drug is returned to the Sponsor or standard procedures for the 
alternative disposition of unused study drug are followed.
Drug inventory and accountability records for the study drugs will be kept by the 
investigator, head of study site (specific to sites in Japan), 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 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 medication.  Any discrepancies must be accounted for and 
documented.  Appropriate forms of deliveries and returns must be signed by the site staff 
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Specific to Japan
In Japan, the head of the study site or the study drug storage manager should take 
accountability of the study drugs as follows:
●
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written by the Sponsor.
●
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study site, the use by each subject and the return to the 
Sponsor or alternative disposal of unused study drugs.  These records should include 
dates, quantities, batch/serial numbers, expiration dates (if applicable) and the unique 
code numbers assigned to the study drugs and subjects.
●
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol and 
reconcile all the study drugs supplied from the Sponsor.  
4.4
Blinding
This is a double-blind study.  Subjects will be randomized to receive gilteritinib or placebo in 
a double-blind fashion such that the investigator, Sponsor’s study management team, clinical
staff, nor the subject will know which agent is being administered.  The randomization 
number will be assigned based on information obtained from the Interactive Response 
Technology (IRT).
4.4.1
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
The randomization list and study medication blind will be maintained by the IRT system.
The IDMC will be provided access to the dosing assignment for periodic review of the 
unblinded data as documented in the IDMC Charter.
4.4.2
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting.  Individual Emergency Codes 
will be provided to the limited staff who are responsible to break the codes for all SUSAR 
cases for reporting purposes.
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject.  The time, 
date, subject number and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file.  They must only be requested by the investigator 
or other persons designated as sub-investigators.  No subjects or other study personnel will be 
made aware of the treatment given to any subject unless a medical emergency necessitates 
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Unblinding of the study drug should only be considered for participant safety and/or evidence 
of documented relapse contingent upon knowing the blinded study drug assignment. Astellas 
Data Science Group will remain blinded.
●
Unblinding for patient safety by the investigator or designated sub-investigator must be 
reported immediately to the Sponsor (Astellas Medical Monitor) and must include an 
explanation of why the study medication was unblinded. If possible, the Sponsor should 
be contacted prior to unblinding of the study drug.
●
Unblinding for documented relapse by the investigator or designated sub-investigator
must be reported to the Sponsor (Astellas Medical Monitor), including an explanation and 
evidence of relapse prior to unblinding of the study drug.  Relapse can be based on the 
investigator’s assessment or the IRC adjudication.
4.5
Assignment and Allocation
Enrollment, randomization and study drug assignment will be performed via IRT.  Prior to 
the initiation of the study treatment, the site staff will contact the IRT in order to determine 
the randomly assigned treatment.  Specific procedures for randomization through the IRT are 
contained in the study procedures manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Gilteritinib or placebo are oral tablets that subjects will take once daily without food for 
continuous daily dosing.  Subjects will be instructed to take the daily gilteritinib or placebo 
dose with water as close to the same time each morning as possible.  Dose reductions are 
permitted (see [Section 5.1.2]).  Gilteritinib or placebo can be taken at least 2 hours after or 
1 hour before food.  Gilteritinib or placebo will be self-administered at home when subjects are 
not scheduled for clinic visits.  If a subject forgets to take a dose in the morning and within 
6 hours of the planned dosing time, they should be instructed to take their dose.  If the subject 
forgets to take their daily dose and more than 6 hours has passed the planned dosing time, they 
should be instructed to wait for the next morning to dose.  If vomiting occurs after dosing, the 
subject should not receive another dose, but just wait until the next morning to dose.
Assigned treatment should continue until unacceptable toxicity occurs, or the subject meets a 
treatment discontinuation criterion as provided in [Section 6.1].
5.1.2
Interruption or Reduction in Dose of the Study Drug(s)
Guidelines for gilteritinib or placebo dose interruption and reduction are provided in 
[Table 4].
Additionally, if the investigator deems it necessary to ensure subject safety, dosing may be 
interrupted or reduced for reasons other than those provided in [Table 4].  In the unusual 


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circumstance that dosing is interrupted or reduced for reasons not specified in the tables, the 
investigator should promptly inform the study medical monitor or his/her designee.
The dose levels potentially used include the following [Table 3].
Table 3
Study Drug Dose Levels
Dose Level (DL)
Gilteritinib/Placebo Dose
DL -2
40 mg
DL -1
80 mg
DL 1 (starting dose)
120 mg
The study drug dose may be initially reduced by 1 dose level per day.  The study drug dose 
can be further reduced by a second dose level.  Note that dose reductions should occur in a 
step-wise manner.  Only 2 dose level reductions are permitted.  
The study drug will be interrupted if a grade 3 or greater AE occurs and the investigator 
judges that AE to be possibly or probably related to the study drug.  When the grade of AE 
decreases to ≤ 1, the study drug may be resumed at the next lower dose level, unless the 
investigator deems the AE was, in retrospect, not related to the study drug, at which point the 
original dose may be resumed.  If an AE occurs that prevents administration of the study drug 
(e.g., surgery that precludes an oral drug, intubation for respiratory failure), and that AE is 
judged to be not caused by the study drug, the study drug may be resumed at the original 
dose when deemed appropriate by the investigator.
Table 4
Guidelines for Study Drug Dose Interruption or Reduction Event
Guidelines for Dose Reduction or Interruption Event
Event
Action 
First occurrence: Grade 3 or greater AE 
possibly or probably related to the study 
drug 
The study drug will be interrupted until resolution of 
the AE to grade ≤ 1.  The participant may then resume 
treatment at 80 mg per day (resumption at original dose 
level permitted as detailed in Section 5.1.2).
Second occurrence: Recurrence of the 
same AE or appearance of a new AE grade 
3 or greater probably or possibly due to the 
study drug 
The study drug will be interrupted until resolution of 
the AE to grade ≤ 1.  The participant may resume 
treatment at 40 mg per day.
Third occurrence: Recurrence of a prior 
AE or appearance of a new AE grade 3 or 
greater probably or possibly due to the 
study drug 
The study drug will be discontinued.
Table continued on next page


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Guidelines for Dose Reduction or Interruption Event
Event
Action 
At any point, in retrospect, if the 
investigator determines a prior grade 3 or 
greater AE which was initially attributed as 
possibly, or probably related to study drug 
is now deemed unrelated
The study drug will be re-escalated to dose that the 
participant was on at the time of the AE.
QTcF > 500 ms
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 reading). Cardiology consult 
will be obtained as medically indicated. If the repeat 
ECG confirms a mean of the triplicate QTcF > 500 ms, 
dosing of study treatment will be interrupted for up to 
14 days.  While study drug may be interrupted 
temporarily based on machine read, the central reading 
should be used for final treatment decisions.  If QTcF 
resolves to ≤ 480 ms by central reading within 14 days 
from study drug interruption, the participant may 
resume dosing at the reduced dose of 80 mg (or if 
currently at 80 mg, reduction to 40 mg).  
QTcF day 8 increase > 30 ms
If the mean triplicate QTcF on day 8 has increased 
> 30 ms compared to the mean triplicate QTcF on day 1 
with no other known etiology, then a confirmatory ECG 
will be performed day 9. If the day 9 mean triplicate 
QTcF also shows an increase of > 30 ms compared to 
that of day 1, then dose reduction to 80 mg should be 
considered.  
AE: adverse event; ECG: electrocardiogram; QTcF: Fridericia-corrected QT interval.
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy)
All medications and concomitant treatments administered from 28 days prior to day 1 through 
the end of treatment visit must be recorded in the electronic case report form (eCRF).  Treatment 
with concomitant drugs that are strong inducers of CYP3A are prohibited.  Treatment with 
concomitant drugs that are strong inhibitors or inducers of P-gp and concomitant drugs that 
target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor are to be avoided with the 
exception of drugs that are considered absolutely essential for the care of the subject.  Treatment 
with concomitant drugs that are strong inhibitors of CYP3A should be avoided with the 
exception of antibiotics, antifungals and antivirals that are used as standard of care to prevent or 
treat infections.  Grapefruit juice should not be ingested during study treatment.  If strong 
CYP3A inhibitors are used concomitantly, subjects should be closely monitored for AEs.
Precaution should be used in use of gilteritinib with concomitant drugs that are known to 
prolong QT intervals or QTc.


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Precaution should be used in use of gilteritinib with concomitant drugs that are substrates of 
BCRP, since the transporter has been shown to be inhibited by gilteritinib in in vitro studies. 
Common strong CYP3A inhibitors, strong CYP3A inducers, drugs targeting the serotonin 
receptor, P-gp inhibitors or inducers and drugs known to prolong QT or QTc intervals are 
listed in [Appendix 12.1].  The investigator should consult individual labels for all drugs that 
the subject is taking to evaluate if they fall into any of the above named categories.  For 
concomitant drugs that have the potential to prolong QT or QTc intervals, a cardiology consult 
should be obtained as medically indicated.  Any other treatments of AML (including but not 
limited to chemotherapy, radiotherapy, surgery, HSCT, immunotherapy or cellular therapy) are 
prohibited during therapy with gilteritinib.  Participation in another interventional study while 
on treatment is prohibited.
Refer to [Appendix 12.1, List of Excluded and Cautionary Concomitant Medications] for 
additional details on excluded medications. 
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period.  Compliance will be verified by the accounting of study drug at each visit after Baseline 
(day 1).  When study drug is administered at the research facility, it will be administered under 
the supervision of study personnel.
Compliance of the study drug will be monitored by the accounting of unused medication 
returned by the subject at visits.  Compliance will be documented.
The dose of study drug administered to each subject will be recorded on the appropriate form 
at every visit.  Reasons for reduction or interruption will also be recorded when applicable.  
This information at every visit will be used to assess compliance with the treatment except in 
cases where directed by protocol or principal investigator (e.g., account for dose interruptions, 
adjustments, etc.). 
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information will be collected for all subjects and will include age, sex, race and 
ethnicity.
5.2.2
Medical History
Medical history includes all significant medical conditions other than AML that have resolved 
prior to informed consent.  Conditions that are ongoing at the time of consent will be collected 
as baseline conditions on the Medical History eCRF.  Details that will be collected include the 
onset date, recovery date and CTCAE grade [National Cancer Institute, 2010] version 4.03, if 
applicable for ongoing conditions.


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5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
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, lumbar puncture results if performed (red blood 
cells, white blood cells with differential, cytospin results) and related genetic syndromes.  
Dates for diagnostic procedures will be collected.
5.2.3.2 FMS-like Tyrosine Kinase 3 Mutation Status
All subjects must have documented FLT3/ITD AML at the time of AML diagnosis. 
Additionally, FLT3/ITD mutation status will be analyzed using the diagnostic specimen 
(when available) by a Sponsor-designated central laboratory.  
FLT3 mutation status will be analyzed at relapse by a Sponsor-designated central laboratory. 
5.2.3.3 Performance Status
The ECOG Scale [Oken et al, 1982] will be used to assess performance status [Table 5] and 
will be obtained and recorded according to the Schedules of Assessments [Table 1].
Table 5
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
ECOG: Eastern Cooperative Oncology Group.
5.3
Efficacy Assessment
5.3.1
Bone Marrow Aspirate and Biopsy
Bone marrow samples will be analyzed locally according to the Schedule of Assessments 
[Table 1].  Bone marrow aspirate is required and bone marrow biopsy in addition is preferred. 
In case of inadequate aspirate, bone marrow biopsy is required.  If a subject relapses, the 
relapse bone marrow sample must also be analyzed by a Sponsor-designated central laboratory.
5.3.1.1 Minimal Residual Disease (MRD)
MRD will be analyzed by a Sponsor-designated central laboratory according to the Schedule of 
Assessments [Table 1].  The first 0.25-0.75 mL of bone marrow aspirate will be collected and 


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sent by overnight carrier to the central laboratory for assessment of MRD.  A peripheral blood 
sample is not acceptable for MRD assessment.
5.3.2
Relapse
Relapse after CR (including CRp and CRi), is defined as bone marrow blasts 5% or higher 
(not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary 
blast foci as per Revised IWG criteria.  Relapse events will be adjudicated by an independent 
review committee and will be used in the efficacy assessments, unless specifically stated 
otherwise. 
5.3.3
Survival Time, Remission Status and Other Efficacy Endpoints
5.3.3.1 Survival Status and Subsequent Anti-leukemic Treatments and Their 
Outcomes
Information on survival status, remission status, subsequent anti-leukemic treatments and 
outcomes will be collected for all subjects during long-term follow-up.
The first survival status will occur at the 30-day follow-up.  After the 30-day follow-up, the 
subject or caregiver will continue to be contacted via telephone by site personnel for 
follow-up every 3 months.  Data may be supplemented by site records when available at the 
time of the contact (e.g., treatment records, outcomes).  Follow-up will continue until the 
final database lock, which is estimated to occur when the last subject enrolled reaches the 
30-day follow-up visit.
Additional contacts may be made to support key analyses (e.g., final analysis or analyses by 
the IDMC).
Reasonable effort should be made to contact any subjects lost to follow-up during the course 
of the study in order to complete study-related assessments and retrieve any outstanding data 
and study drug.  Following unsuccessful telephone contact, an effort to contact the subject by 
mail using a method that provides proof of receipt should be attempted.  Contact via an 
alternate, preapproved contact is permissible if the subject is not reachable.  Such efforts 
should be documented in the source documents.
If a subject death occurs during the serious adverse event (SAE) reporting period or if the 
death occurs after the SAE reporting period but is determined by the investigator to be related 
to study drug, then the associated AE with outcome of death will also be reported on the 
eCRF and SAE Worksheet.  If a subject death does not meet the criteria of an SAE, then 
death and anti-leukemic treatment and outcome up through the date of death should be 
collected and entered in the eCRF.
5.3.3.2 Overall Survival (OS)
OS is defined as the time from the date of randomization until the date of death from any 
cause.  For surviving subjects, non-events will be censored at the date of last known date alive.
Date of last known date alive is defined as the latest of the following dates: treatment 
discontinuation date, last dosing administration date, last disease assessment date, last adverse 


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event (start date or stop date) or the last follow-up date on which the subject was known to be 
alive.
5.3.3.3 Relapse-free Survival (RFS)
RFS is defined as the time from the date of randomization until the date of documented 
relapse or death from any cause, whichever occurs first.
If a subject experiences relapse or death, the subject is defined as having RFS event related to 
either “relapse” or “death,” and the event date is the date of relapse or death.
For a subject who is not known to have relapse or death, RFS is censored at the date of last 
relapse-free assessment date.
5.3.3.4 Event-free Survival (EFS)
EFS is defined as the time from the date of randomization until the date of documented 
relapse, or discontinuation of the treatment, or initiation of other anti-leukemic treatment or 
death from any cause, 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 discontinues the treatment or initiates anti-leukemic treatment, the subject is 
defined as having EFS event and the event date is the date of study drug discontinuation or 
date of start of anti-leukemic treatment, respectively.
For a subject who is not known to have relapse or death or treatment discontinuation or 
initiation of the other anti-leukemic treatment, EFS is censored at the date of last relapse-free 
assessment date.
Subject becomes eligible for and proceeds to transplant will be considered non-event and 
censored at the time of HSCT.
5.4
Safety Assessment
5.4.1
Vital Signs
Vital signs, including systolic and diastolic blood pressures (mmHg), radial pulse rate 
(beats/minute) and temperature will be obtained and recorded at the times specified in the 
Schedules 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.


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5.4.2
Adverse Events
AE (including SAE) collection will begin from time of informed consent and continue 
through 30 days after the last dose of study drug.  During the long-term follow-up period, 
only SAE data that is possibly or probably related to study drug will be collected.  SAE data 
will be collected, at a minimum, 7 days after the date of last dose, if the subject undergoes 
HSCT.  AEs will be documented at each clinic visit, but can be collected at any time.  Any 
AE that meets the definition of an SAE will also be reported on a separate form to the 
Sponsor.  See [Section 5.5 Adverse Events and Other Safety Aspects] for information 
regarding AE collection and data handling.
5.4.2.1 Adverse Events of Possible Hepatic Origin
See [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in LFTs (e.g., AST, ALT, bilirubin, etc.) or 
is suspected to be due to hepatic dysfunction. 
Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored.  
5.4.3
Laboratory Assessments
[Appendix 12.3] contains the laboratory tests that will be performed centrally during the 
conduct of the study.  Refer to the Schedules of Assessments [Table 1] for study visit 
collection dates.  Additional laboratory tests should be performed according to institutional 
standard of care.  Local testing of bone marrow aspirate and/or biopsy at screening and 
months 3, 6, 12, 18 and 24 and at the time of relapse will be reported in the eCRF.  Clinical 
significance of out-of-range laboratory findings is to be determined and documented by the 
investigator or delegated sub-investigator who is a qualified physician.
5.4.4
Physical Examination 
Standard, full physical examinations will be performed to assess general appearance, skin, 
eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 
neurologic status, mental status and lymphatic systems.  Genitourinary and rectal system 
examinations are to be performed only if clinically indicated.  Physical examinations will be 
conducted at the visits outlined in the Schedules of Assessments [Table 1].  Each physical 
examination will include the observation and review of body system and include weight at 
screening and each monthly visit.  Height is only required at screening.  If clinically 
significant worsening of findings from predose (day 1) is noted at any study visit, the changes 
will be documented as AEs on the AE page of the eCRF. Clinical significance is defined as 
any variation in physical findings, which has medical relevance that could result in an 
alteration in medical care.  The investigator will continue to monitor the subject until the 
parameter returns to grade ≤ 1 or to the baseline (pretreatment) condition or until the 
investigator determines that follow-up is no longer medically necessary.


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5.4.5
Electrocardiogram (ECG) 
A 12-lead ECG will be performed during the screening period, predose on day 1, day 8, 
day 15 and at each subsequent visit.  Predose assessments should be taken within 1 hour 
before drug administration.  The 12-lead ECGs will be recorded in triplicate (3 separate 
ECGs, 10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and 
transmitted electronically for central reading (see [Section 7.5.5]).  The mean of the triplicate 
ECG from central read should be used for all final treatment decisions and AE reporting.
For day 8 ECG, if the mean QTcF from day 1 to day 8 has increased > 30 ms with no other 
known etiology, a confirmatory ECG should be performed on day 9.  If the day 8 and 9 ECGs 
confirm the > 30 ms increase in QTcF, then the investigator should assess if study drug dose 
modification should occur as per the dose interruption or reduction guideline in 
[Section 5.1.2].
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 study drug per the interruption or reduction 
guidelines in [Section 5.1.2].
At a subset of sites, approximately 40 subjects will have additional ECGs as part of the 
pharmacokinetic sampling substudy.  On day 15 and day 29, ECGs will be performed at 
predose (within 1 hour before study drug) and 4 hours postdose (+/- 1 hour) in triplicate and 
transmitted electronically for central reading.  Triplicate 12 lead ECGs should be obtained 
after the subject has rested quietly and is awake in a fully supine position (or semirecumbent 
if supine is not tolerated) for 10 minutes before the first ECG from a triplicate and at least 
5 minutes apart per time point.
ECGs are to be performed prior to obtaining the time-matched pharmacokinetic sample; 
therefore, the ECGs must be started at least 10 to 15 minutes before the pharmacokinetic 
blood draw.  At scheduled ECG time points that coincide with other nonpharmacokinetic 
study procedures, ECG collection should be given priority.  At scheduled time points where 
ECGs coincide with pharmacokinetic sampling, ECGs should be performed prior to 
pharmacokinetic sample collection ensuring that pharmacokinetic samples are collected at the 
scheduled time point. 
5.4.6
Chest X-ray or Computed Tomography Scan
Chest X-ray or computed tomography (CT) scan is to be performed at screening.  A chest 
X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start 
of screening.
5.4.7
Multigated Acquisition Scan or Echocardiogram
A MUGA or ECHO is to be performed at screening for subjects with a history of NYHA 
Class 3 or 4 congestive heart failure (unless MUGA or ECHO performed within 1 month 
prior to screening revealed left ventricular ejection fraction ≥ 45%).


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


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usually be considered serious.  Examples of such events are intensive treatment in an ER or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Safety special situations on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)
All of the special situations noted above should be recorded on the eCRF.  Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and on the SAE worksheet/report. 
The Sponsor has a list of events that they classify as “always serious” events.  If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
Causal relationship
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and/or in  which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals.  Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge).


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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 4.03). The items that are not stipulated in the NCI-CTCAE Version 4.03 
will be assessed according to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations 
noted; intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
SAE collection will begin from time of informed consent through 30 days after last dose of 
study drug.  During the long-term follow-up period, only SAE data that the investigator 
assesses as possibly or probably related to study drug will be collected. SAE data will be 
collected, at a minimum, 7 days after the date of last dose of study drug, if the subject 
undergoes HSCT.  In the case of an SAE, the investigator must contact the Sponsor by 
telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax immediately (within 
24 hours of awareness).  If the faxing of an SAE Worksheet is not possible or is not possible 
within 24 hours, the local drug safety contact should be informed by phone.
The following paragraph is specific to investigational sites in Japan
For Japan, in the case of an SAE, the investigator or sub-investigator must report to the head 
of the study site and must contact the delegated contract research organization (CRO) by 
telephone or fax immediately (within 24 hours of awareness).  The investigator should 
complete and submit JUTOKUNA YUUGAIJISHOU HOUKOKUSHO containing all 
information that is required by the Regulatory Authorities to the delegated CRO by fax 
immediately (within 24 hours of awareness) and to the head of the hospital. If the faxing 
of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not possible or is not possible within 
24 hours, the delegated CRO should be informed by phone.  
For contact details for each country/region, see Section II Contact Details of Key Sponsor's 
Personnel.  Please fax the SAE Worksheet to:
Astellas Pharma Global Development, Inc. (APGD)
Pharmacovigilance 
North American Fax number: 888-396-3750


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(North American Alternate Fax number: 847-317-1241)
International Fax number: +44-800-471-5263
Email: safety-us@astellas.com
Specific to investigational sites in Japan
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE Worksheet to:
PAREXEL International
Global Monitoring Operations
Fax number: 03-6888-1486
Japan/Asia Development I, Astellas Pharma Inc.
Phone: 03-3244-1097
Fax number: 03-3243-5737
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should be recorded on the medical records and on the eCRF.
The following minimum information is required:
●
ISN/Study number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e. Investigational 
New Drug [IND] Safety Reports) to the regulatory agencies (i.e. FDA) as necessary, and will 
inform the investigators of such regulatory reports.  Investigators must submit safety reports 
as required by their IRB/IEC within timelines set by regional regulations (i.e., EU, electronic 
Common Technical Document, FDA).  Documentation of the submission to and receipt by 
the IRB/IEC of expedited safety reports should be retained by the site.
The Sponsor/delegated CRO will notify all investigators responsible for ongoing clinical 
studies with the study drug of all SAEs which require submission per local requirements to 
IRB/IEC/head of the study site.
The heads of the study sites/investigators should provide written documentation of IRB/IEC 
notification for each report to the Sponsor.
The investigators may contact the Sponsor's Medical Monitor/Expert for any other problem 
related to the safety, welfare, or rights of the subject.


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For SUSAR from a blinded trial, unblinded CIOMS-I report will be submitted to the 
authorities and IRB/IEC where required.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the AE progresses to an SAE, or if a subject experiences a new SAE, 
the investigator must immediately report the information to the Sponsor. 
Please refer to [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed 
instructions on Drug Induced Liver Injury.
5.5.7
Monitoring of Common Serious Adverse Events
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure.  SAEs classified as “common” are provided in [Appendix 12.4 Common 
Serious Adverse Events] for your reference.  The list does NOT change your reporting 
obligations or prevent the need to report an AE meeting the definition of an SAE as detailed 
above.  The purpose of this list is to alert you that some events reported as SAEs may not 
require expedited reporting to the regulatory authorities based on the classification of 
“common serious adverse events” as specified in [Appendix 12.4 Common Serious Adverse 
Events]. The Sponsor will monitor these events throughout the course of the study for any 
change in frequency.  Any changes to this list will be communicated to the participating 
investigational sites.  Investigators must report individual occurrences of these events as 
stated in [Section 5.5.5] Reporting of Serious Adverse Events]. 
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 6 months for female subjects and 4 months and 1 week for partners of male 
subjects from the discontinuation of dosing, the investigator should report the information to 
the Sponsor as if it is an SAE.  The expected date of delivery or expected date of the end of 
the pregnancy, last menstruation, estimated conception date, pregnancy result and neonatal 
data etc., should be included in this information.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs.  Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion


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●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator.  The investigator will report the pregnancy to 
the Sponsor as an SAE.
5.5.9
Emergency Procedures and Management of Overdose
In the event of suspected study drug overdose, the subject should receive supportive care and 
monitoring.  The Medical Monitor/Expert should be contacted as applicable.
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities.  Investigators should inform the IRB/IEC of such information when 
needed.
The following 2 paragraphs are specific to investigational sites in Japan:
1.
When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Enforcement Regulations of the Act on 
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics, in 
compliance with Article 80-2 Paragraph 6 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, the Sponsor should inform all the 
investigators involved in the clinical study, the head of the study site and the regulatory 
authorities of such information.  The head of the study site who receives such 
information will decide whether the clinical study should be continued after hearing the 
opinions of the IRB.  The investigator will supply the new information to the subjects, in 
compliance with [Section 8.2.3.2 Supply of New and Important Information Influencing 
the Subject's Consent and Revision of Written Information.].
2.
In addition to the above item (1), when the head of the study site receives the revisions of 
the Investigator's Brochure, protocol, or written information, information on the matters 
covering the quality of the study drug, efficacy and safety, information necessary for 
conducting the clinical study properly, or documents to be examined by the IRB should 
be sent to the IRB.


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5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (Specific to Investigational sites in Japan)
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects.  When the investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the investigator should take the following actions. 
1.
Describe the contents of the deviation or amendment and the reasons for it in a written 
notice, and immediately send the document stating the deviation or amendment and the 
reasons to the Sponsor and the head of the study site.  Keep a copy of the notice.
2.
Consult with the Sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol.  Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor.
5.6
Test Drug Concentration
5.6.1
Pharmacokinetics
Sparse pharmacokinetic samples will be collected to evaluate gilteritinib plasma 
concentrations as outlined in the Schedule of Assessments [Table 1]. 
At a subset of sites, approximately 40 subjects on day 15 and day 29 will have dense 
pharmacokinetic sampling as outlined in the Schedule of Assessments [Table 1].  Samples 
will be collected predose (within 1 hour before study drug administration) and 4 hours 
(± 1 hour) postdose.
Plasma samples may also be used for metabolite profiling of gilteritinib.  The reports for the 
metabolite profiling and identification will not be incorporated into the clinical study report.
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.  Please refer to the Laboratory Manual for more detailed information on 
this topic.
5.7
Other Measurements, Assessments or Methods
5.7.1
Patient Reported Outcome Measures
EQ-5D-5L, FACT-Leu, and FACT-An will be assessed during the study period to report the
subject’s experience of symptoms/treatment and quality of life.
5.7.1.1 EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L)
The EQ-5D-5L is a self-reported questionnaire.  The EQ-5D-5L is being used as a measure of 
respondents' health-related quality of life.  The EQ-5D-5L consists of the EuroQol Group-5 
Dimension descriptive system and the EuroQol Group Visual Analogue Scale (VAS).  The 
EuroQol Group-5 Dimension descriptive system comprises of 5 dimensions of health: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression.  Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems.  The VAS records the respondent's self-rated health status on a graduated (0-100) 


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scale, where the endpoints are labeled ‘best imaginable health state’ and ‘worst imaginable 
health state’ with higher scores for higher health-related quality of life.  The EQ-5D-5L will 
be administered at site visits directly to the subjects via an electronic patient reported 
outcome (PRO) device during treatment through the end-of-treatment visit.  It will be 
administered as outlined in the Schedule of Assessments [Table 1].  If possible, patient 
reported outcome measures should be performed prior to any other assessments on that visit 
day. 
5.7.1.2 Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)
The FACT-Leu [Cella et al, 2012] is designed to measure leukemia-specific signs, symptoms 
and the impact of leukemia on subjects.  The 44-item scale has global and domain scores 
including physical well-being, social/family well-being, emotional well-being, functional 
well-being and additional leukemia-specific concerns.  The FACT-Leu has a 7-day recall 
period.  The FACT-Leu will be administered at site visits directly to the subjects via an 
electronic PRO device.  It will be administered as outlined in the Schedule of Assessments 
[Table 1].  If possible, patient reported outcome measures should be performed prior to any 
other assessments on that visit day.
5.7.1.3 Functional Assessment of Cancer Therapy-Anemia (FACT-An)
The FACT-An is designed to measure patient experiences associated with anemia.  It 
includes 13 items that are designed to measure fatigue associated with anemia and 7 items 
that assess other symptoms and impacts associated with anemia, such as shortness of breath 
and dizziness.  It also includes the same generic physical well-being, social/family 
well-being, emotional well-being, functional well-being domains as the FACT-Leu.  These 
redundant scales will not be administered as part of the FACT-An; only the 
20 anemia-specific items will be administered.
5.7.1.4 Resource Utilization
Healthcare resource utilization in this study population will include hospitalization, ICU 
visits, ER visits, transfusion and use of antibiotics.  Details on hospitalizations and other 
relevant resource utilization will be collected at each study visit as indicated in the Schedule 
of Assessments [Table 1].
For each hospitalization, reason, admission and discharge dates, ward type (normal vs ICU) 
and type and reason for hospitalization will be recorded in the eCRF.
The following other resource utilization will be recorded in the eCRF: number of blood 
transfusions, number of units of each transfusion, number of antibiotic intravenous infusions 
and type of antibiotic.


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5.7.2
Exploratory Biomarker Analyses
5.7.2.1 FLT3 Mutation Status
FLT3/ITD mutation status and allelic ratio will be analyzed using the diagnostic specimen 
(when available) by a Sponsor-designated central laboratory.  All subjects must have 
documented FLT3/ITD AML at the time of AML diagnosis.
FLT3 mutation status will be analyzed at relapse by a Sponsor-designated central laboratory.
The manufacturer of the FLT companion diagnostic assay will analyze the diagnostic 
samples (when available) with the FLT3 companion diagnostic assay.  The results may be 
used to seek regulatory approval if a companion diagnostic for FLT3/ITD is indicated for the 
patient population in this study.  All biomarker samples collected will be stored for a period 
up to 15 years following study database hard lock.  Please refer to the Laboratory Manual for 
more detailed information on this topic.
5.7.2.2 Minimal Residual Disease (MRD) Assessment
MRD will be measured from bone marrow samples as outlined in the Schedule of 
Assessments [Table 1].  FLT3/ITD mutation ratio will be measured in relation to total FLT3.  
Changes in FLT3/ITD mutation ratio will be compared with baseline/screening samples.
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. Please refer to the Laboratory Manual for more detailed information on 
this topic.
Additional protein or genetic biomarkers related to AML and gilteritinib activity may be 
analyzed. 
5.7.3
Whole Blood and Buccal Sample for Future Pharmacogenomic Analysis 
(Retrospective Pharmacogenomic 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 
randomization, a 3-6 mL sample of whole blood and buccal swab sample will be collected for 
subjects who provide separate consent.  Samples will be shipped to a Sponsor-designated 
banking CRO.
Labels should uniquely identify each sample and contain at least:
●
Protocol number (2215-CL-0302),
●
Subject number, and
●
Purpose and biological matrix (i.e., “biobanking”, “whole blood”, “buccal sample”).
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate Laboratory Manual.
See [Appendix 12.5, Retrospective PGx Substudy] for further details on the banking 
procedures.


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5.8
Total Amount of Blood
The total amount of blood collected for study assessments for each subject will vary 
depending on how long they stay on treatment.
At any time during the study, if any laboratory abnormalities are found for a subject, if results 
are needed before central laboratory results are available or for disease assessment, then 
additional blood may be drawn for monitoring.
Additional blood beyond standard monitoring that will be drawn for this study will include 
draws for eligibility assessment, serum chemistry, hematology, coagulation and pregnancy 
test at specific study defined time points, pharmacokinetics and bioanalytical sampling.
The maximum amount of blood collected for study specific assessments during screening is 
approximately 17 mL.
The maximum amount of blood collected for study specific assessments during month 1 is 
approximately 60 mL.
The maximum amount of blood collected for study specific assessments during months 2 and 
4 is approximately 16 mL.
The maximum amount of blood collected for study specific assessments during months 3 and 
5 is approximately 14 mL.
The maximum amount of blood collected for study specific assessments during month 6 and 
beyond is approximately 16 mL.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled or randomized in the study and for whom study 
treatment is permanently discontinued prematurely for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice.  The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
Gilteritinib or placebo therapy will continue for a maximum of 2 years from initiation of 
therapy until 1 of the following criteria applies:
●
Subject declines further study participation (i.e., withdrawal of consent).
●
Subject is noncompliant with the protocol based on the investigator or Medical Monitor 
assessment.


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●
Subject is found to have significantly deviated from any 1 of the inclusion or exclusion 
criteria after enrollment (subjects having clinical benefit may be kept in the study after 
discussion with the Medical Monitor).
●
Subject develops an intolerable or unacceptable toxicity.
●
Investigator/sub-investigator determines that the continuation of the study treatment will 
be detrimental to the subject.
●
Subject relapses.
●
Subject begins other anti-leukemic therapy.
●
Subject becomes eligible for and proceeds to transplant.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject.
●
Female subject becomes pregnant.
●
Death.
Discontinuation Criteria from Post-Treatment Follow-Up for Individual Subjects: 
●
Subject declines further study participation (i.e., withdraws consent).
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject.
●
More than 3 years has passed from the subject’s 30-day follow-up visit.
●
Death.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor (for investigational sites in Japan: and the head of the Study 
site).
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advance notice is not required if the study is stopped due to safety concerns.  If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD-US. 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.
Prior to database lock, a Final Review of Data and Tables, Listings and Figures (TLFs) 
Meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification.  If required, consequences for the statistical analysis 


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will be discussed and documented.  A meeting to determine analysis set classifications may 
also be held prior to database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
The study is a multicenter, double-blind, placebo-controlled, randomized phase 2 trial 
comparing gilteritinib as maintenance therapy versus placebo in FLT3/ITD AML subjects in
CR1. The target number of randomized subjects is approximately 85; 57 in gilteritinib arm 
and 28 in placebo arm.
The median RFS time in the placebo arm is assumed to be 15 months, based on RATIFY 
control arm data on subjects with FLT3 mutation achieving CR1 after induction and 
consolidation.  A total of 54 relapse or death events will provide 83.2% power to detect a 
hazard ratio of 0.5 (corresponding to 24% difference in 2-year RFS rates) with 1-sided 
significance level of 0.075.  The sample size estimation of 85 subjects assumes 
approximately 2 years of accrual.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
7.2.1
Full Analysis Set (FAS)
The full analysis set will consist of all subjects who are randomized.  This will be the primary 
analysis set for efficacy analyses.  Subjects will be analyzed based on the randomized 
treatment.
7.2.2
Per Protocol Set (PPS)
The per protocol set will consist of the subset of the FAS who do not meet criteria for PPS 
exclusion.  These criteria are to capture relevant non-adherence to the protocol and will be 
defined in the SAP.  The sensitivity analyses for the primary and key secondary endpoints 
will be performed on the PPS.  Select demographic and baseline characteristics may also be 
summarized for the PPS.
7.2.3
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used.  The 
SAF consists of all randomized subjects who took at least 1 dose of study treatment, and will 
be used for safety analyses.  The subjects will be analyzed based on the actual treatment 
received. 


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7.2.4
Pharmacokinetic Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of the population administered at least 
1 dose of gilteritinib, have at least 1 measurable concentration datum and for whom both the 
date and time of dosing and PK 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 determined at the Classification 
Meeting and documented in the Classification Specifications.
7.3
Demographics and Other Baseline Characteristics 
7.3.1
Demographics
Demographics and other baseline characteristics will be summarized by treatment group 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.
7.3.2
Medical History
A detailed medical history for each subject will be obtained during screening period and will 
be summarized by treatment group for the SAF.
7.3.3
Disease History
Each subject’s complete cancer history will be listed.  The number and percentage of subjects 
will be used to summarize the AML subtype and FLT3 mutation status.
7.3.4
Prior and Concomitant Medications
The frequency of concomitant medications (prescription, over-the-counter and nutritional 
supplements) will be summarized by treatment group and preferred term for SAF.  
Medications will be coded using the WHO drug dictionary.  Medications will be counted by 
the number of subjects who took each medication.  A subject taking the same medication 
multiple times will only be counted once for that medication.  Medications will be presented 
in decreasing order of frequency based on the total number of subjects who took each 
medication.
7.3.5
Subject Disposition
The number and percentage of all subjects during the study will be reported per treatment 
group for various disposition parameters including analysis sets, reason for treatment 
discontinuation, reason for study discontinuation, lost to follow-up, and protocol deviation.
7.3.6
Treatment Compliance
Treatment compliance is defined as the total number of doses of study drug actually taken by 
the subject divided by the number of doses of study drug expected to be taken during the 
study multiplied by 100.  Descriptive statistics for study drug compliance will be presented 
for the entire study period for the SAF by treatment group.


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7.3.7
Extent of Exposure
Exposure to treatment, measured by the duration of treatment in number of days will be 
summarized by treatment group 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). The total dose 
administered, number and proportion of subjects with dose reduction, and dose interruption 
will be tabulated.
7.4
Analysis of Efficacy 
7.4.1
Analysis of Primary Endpoint 
The primary analysis of RFS will be performed at 1-sided 0.075 significance level to test the 
null hypothesis that RFS in the gilteritinib arm is worse than or equal to RFS in the placebo 
arm versus the alternative hypothesis that RFS in the gilteritinib arm is better than RFS in the 
placebo arm.  The primary analysis will be conducted when the planned 54 relapse or death 
events have been observed.  The primary efficacy endpoint of RFS will be analyzed on the 
FAS using the stratified log-rank test with strata on age at randomization, screening MRD 
status, geographic region and use of FLT3 inhibiting agents during induction/consolidation as 
described below. 
Age:
●
< 60 years
●
≥ 60 years
Geographic Region:
●
North America
●
Europe
●
Asia/Pacific/South and Central America/rest of world
Presence of screening MRD:
●
Yes
●
No
Use of FLT3 inhibiting agents during induction/consolidation:
●
Yes
●
No
Kaplan-Meier curves will be used to describe the RFS in each arm.  Median RFS time and 
RFS rates at 1, 2, and 3 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves.
In order to evaluate the robustness of the primary analysis of RFS, sensitivity analyses will be 
performed as below:
●
Unstratified log-rank test on the FAS


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●
Stratified Cox proportional hazards model with the same strata as in primary analysis on 
the FAS
●
Same analysis as primary analysis but on the PPS
●
Same analysis as primary analysis on the FAS, but RFS is censored at the last evaluable 
disease assessment without relapse when relapse or death is documented after more than 
1 missed disease assessment.
●
Same analysis as primary analysis on the FAS, but RFS is censored at end of treatment.
●
Same analysis as primary analysis on the FAS, but RFS is defined by using investigator 
assessed relapse.
7.4.2
Analysis of Secondary Endpoints 
7.4.2.1 Key Secondary Endpoints 
The key secondary analysis of OS will be performed at 1-sided 0.075 significance level to 
test the null hypothesis that OS in the gilteritinib arm is worse than or equal to OS in the 
placebo arm versus the alternative hypothesis that OS in the gilteritinib arm is better than OS 
in the placebo arm.  The endpoint OS will be analyzed on the FAS using the stratified 
log-rank test with strata on age at randomization, screening MRD status, geographic region 
and use of FLT3 inhibiting agents during induction/consolidation. 
With the sequential multiple test procedure to control for overall type I error at the 1-sided 
0.075 significance level, formal significance testing of OS will be conducted only if the RFS 
comparison is statistically significant.  Otherwise, OS analysis will be considered 
exploratory.
Kaplan-Meier curves will be used to describe the OS in each arm.  Median OS time and OS 
rates at 1, 2, 3, and 4 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves.
For the key secondary endpoint of OS, sensitivity analyses will be performed as below:
●
Unstratified log-rank test on the FAS
●
Stratified Cox proportional hazards model with the same strata as in primary analysis on 
the FAS
●
Same analysis as primary analysis but on the PPS
●
Same analysis as primary analysis on the FAS, but OS is censored at the first HSCT and 
first subsequent anti-leukemic treatment, whichever occurs first.
7.4.2.2 Other Secondary Endpoints 
●
Stratified log-rank test for EFS on the FAS
●
Analyze the relationship between MRD and RFS, and that between MRD and OS on the 
FAS.


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7.4.3
Analysis of Exploratory Endpoints 
Analysis of covariance (ANCOVA) model will be used to analyze change from baseline to 
post-baseline visits for the global and domain scores, individual items and item clusters of the 
FACT-Leu.  The same analytic will be used for FACT-An. 
ANCOVA model will be used for the change from baseline EQ-5D-5L VAS to post-baseline 
visits and shift table for the 5 dimensions (mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression) from baseline to end-of-treatment visit. 
The Cochran-Mantel-Haenszel method will be used for resource utilization status 
(hospitalization, blood transfusion, antibiotic intravenous infusions, ICU visit, and ER visit).  
ANOVA model will be used for resource utilization counts (hospital stays, duration of 
medications, blood transfusions, antibiotic intravenous infusions, ICU visit, and ER visit).
FLT3/ITD mutation status of the diagnostic bone marrow or blood sample will be summarized 
for local results and central results. 
FLT3 mutation status at relapse will be summarized.
7.4.4
Subgroup Analysis
Subgroup analysis will be performed on primary and key secondary efficacy endpoint for age 
group (< 60 and ≥ 60 years), geographic region (North America, Europe, Asia/Pacific/South 
and Central America/rest of world), presence of screening MRD (Yes, No), use of FLT3 
inhibiting agents during induction/consolidation (Yes, No), sex, baseline ECOG performance 
status, and race. 
7.5
Analysis of Safety
The safety evaluation will be based mainly on AEs, clinical laboratory results, vital sign 
measurements, ECGs, physical examination findings and ECOG performance status.  
Descriptive statistics will be used to summarize safety data.  All safety data will be 
summarized by the actual treatment received and the analyses will be performed on the SAF.
7.5.1
Adverse Events 
All AEs recorded on treatment including within 30 days from the last dose of study treatment 
will be classified as treatment-emergent AEs.  AEs will be categorized by SOC and PT using 
the MedDRA dictionary and will be graded according to the NCI-CTCAE version 4.03.
The number and percent of subjects experiencing 1 or more AE(s) will be summarized by 
treatment group, SOC and PT.  The number and percentage of subjects with at least 1 grade 3 
or higher AE will be summarized by treatment group, SOC and preferred term (PT).
Distribution of the maximum severity (grade) and treatment-related AEs will be summarized 
by treatment group, SOC and PT. Distribution of SAEs, discontinuations due to AE and 
deaths on study will be presented for each treatment group. 


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Additional summary tables will be generated for the following population subsets: subjects 
with SAEs including deaths, subjects who discontinue due to AEs and investigator-attributed 
relationship to study drug for AEs and SAEs.
All summaries of AEs will include only treatment-emergent events unless otherwise stated.  
Listings of AEs, SAEs, deaths and withdrawals due to AEs will be presented.
7.5.2
Laboratory Assessments
Clinical laboratory evaluations (including serum chemistry, hematology, coagulation and 
urinalysis) and their changes from baseline will be summarized by the actual treatment 
received using descriptive statistics.  Clinically significant abnormalities in laboratory values 
will be presented for each treatment.  Shift tables will present shift from baseline to worst 
grade for selected variables using the NCI-CTCAE grade.  Frequency of subjects with 
laboratory values outside normal range will be generated in addition to tabulation of worst 
toxicity grade.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by the actual treatment received and time point.
7.5.4
Physical Examination 
Physical examination findings will be listed by the actual treatment received. All clinically 
significant abnormal findings will be recorded as medical history or AEs and graded using 
NCI-CTCAE guidelines.
7.5.5
ECGs 
The 12-lead ECG results will be summarized by treatment group and time point. Overall 
ECG interpretation will be summarized for each time point. A shift analysis table showing 
shifts from baseline in overall ECG (normal, abnormal) will be provided. ECG parameters 
and their change from baseline will be summarized by treatment group using descriptive 
statistics.
The correlation between gilteritinib exposure and QTcF for subjects participating in the 
ECG/PK sampling subset will be analyzed.
7.5.6
ECOG performance scores
ECOG performance scores will be summarized by the actual treatment received and visit.
7.6
Analysis of Pharmacokinetics
Based on pharmacokinetic data obtained within this study, a separate population 
pharmacokinetic analysis will be performed.  Data from this study may be pooled with other 
studies for analysis.  The prospective details of this analysis will be specified in a separate 
population pharmacokinetic analysis plan.


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The plasma concentrations will be summarized for gilteritinib using descriptive statistics, 
including number of subjects, mean, standard deviation, minimum, median, maximum, 
geometric mean, and coefficient of variation of the mean and geometric mean.  Time-course 
of drug concentrations will be plotted as appropriate.
Population pharmacokinetic/pharmacodynamic analysis will be performed to assess the 
relationship between gilteritinib exposure and QTcF. Data from this study may be pooled 
with other studies for analysis. Details of this analysis will be specified in a separate 
population pharmacokinetic/pharmacodynamic analysis report.
7.7
Protocol Deviations and Other Analyses
Protocol deviations as defined in [Section 8.1.6 Protocol Deviations] will be summarized for 
all randomized subjects by treatment group and total as well as by site.  A data listing will be 
provided by site and subject.   
The 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. 
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable. 
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses by visit will be outlined in the SAP.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The 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.


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The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Certain laboratory tests are performed at a central laboratory per the Schedule of Assessments 
[Table 1].  Laboratory data performed at a central laboratory will be transferred electronically 
to the Sponsor or designee at predefined intervals during the study.  The laboratory will 
provide the Sponsor or designee with a complete and clean copy of the data. 
ECG results are performed at a central ECG reading laboratory.  Central ECG read data will 
be transferred electronically to the Sponsor or designee at predefined intervals during the 
study.  The central ECG laboratory will provide the Sponsor or designee with a complete and 
clean copy of the data.
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
Electronic PRO:
Subject diaries and questionnaires will be completed by the subject on an electronic device.  
The information completed by the subject on the electronic device will be automatically 
uploaded into a central website.  The investigator or site designee should review the diaries 
and questionnaire data on the website for correct completion while the subject is at the site.  
The questionnaire data will be transferred electronically to Sponsor or designee at predefined 
intervals during the study.  The vendor will provide Sponsor or designee with a complete and 
clean copy of the data.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated ICFs 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
AEs and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable) 


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8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents.  The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring.  They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents 
(refer to [Section 8.1.2 Specification of Source Documents]) when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities.  The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management.  All study specific processes and definitions 
will be documented by Data Management.  eCRF completion will be described in the eCRF 
instructions.  Coding of medical terms and medications will be performed using MedDRA 
and WHO Drug Dictionary, respectively.
8.1.6
Protocol Deviations 
A 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 trial subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who:
●
Entered into the study even though they did not satisfy entry criteria.  
●
Developed withdrawal criteria during the study and not withdrawn.  
●
Received wrong treatment or incorrect dose.  
●
Received excluded concomitant treatment.  


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When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified.  The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.  
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File.  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the last subject’s last contact.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
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 IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required.  During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects.  
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year.  The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies, or for Astellas Pharma Europe 


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BV/Astellas Pharma Europe Ltd.-sponsored studies within 1 year after last subject out or 
termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed (specific to investigational sites in Japan: 
place a personal seal) and dated by the subject or his/her guardian or legal representative, the 
person who administered the informed consent and any other signatories according to local 
requirements.  A copy of the signed (specific to investigational sites in Japan: or sealed)
ICF will be given to the subject and the original will be placed in the subject’s medical 
record.  An entry must also be made in the subject’s dated source documents to confirm that 
informed consent was obtained prior to any study-related procedures and that the subject 
received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction).  The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
2.
The investigator must update their ICF and submit it for approval to the IRB/IEC.  The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study.  The investigator 
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally.  The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF (specific to 
investigational sites in Japan: place a personal seal). A copy of the signed (specific to 
investigational sites in Japan: or sealed) ICF will be given to the subject and the 
original will be placed in the subject’s medical record.  An entry must be made in the 
subject’s records documenting the re-consent process.


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8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited.  Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy.  Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor.  However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., Health Insurance Portability and 
Accountability Act). 
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor.  Details should be disclosed only to the persons involved in the 
approval or conduct of the study.  The investigator may use this information for the purpose 
of the study only.  It is understood by the investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the drug 
and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies.  In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The Sponsor will provide the investigator and/or institution with the following:
●
Study protocol (and amendments, where applicable)
●
Investigator’s Brochure (and amendments, where applicable)
●
CRFs (specific to investigational sites in Japan: and JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO)
●
Study drug with all necessary documentation
●
Study contract


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In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the Sponsor: 
●
Financial disclosure in compliance with US federal regulation 21CFR Part 54
●
Signed and dated FDA form 1572
●
Signed Investigator's Statement in this protocol and eCRF
●
Current Curricula Vitae of all investigators
●
List of sub investigators and collaborators 
●
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY)
●
Specific to investigational sites in Japan: Instruction and decision of the head of the 
study site
●
Study contract
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee)
At the end of the study, the sponsor is responsible for the collection of:
●
Unused study documentation,
●
Unused study drug
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs, and Investigator's File) and relevant correspondence.  These documents are to 
be kept on file for the appropriate term determined by local regulation (for US sites, 2 years 
after approval of the New Drug Application (NDA) or discontinuation of the IND).  The 
Sponsor will notify the site/investigator if the NDA/Marketing Authorization Application/J-
NDA is approved or if the IND/Investigational Medicinal Product Dossier/CHIKEN 
TODOKE is discontinued.  The investigator agrees to obtain the Sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records.  The Sponsor will archive and 
retain all documents pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.  All data will be entered on the CRFs supplied 
for each subject.
The following 2 paragraphs are specific to investigational sites in Japan:
The records to be retained at the study sites are the ones listed as essential documents in 
GCP.  These records shall be retained by the head of the study site or the record keeper 
designated by the head until notice issued by the Sponsor on completion of the retention 
period is received.  These documents are also subject to direct access and should be provided 
upon request from the Sponsor or regulatory authorities.
The head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until the 
date defined in number 1 or number 2 below, whichever comes later.


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1.
Approval date of marketing of the test drug (if development of the drug is stopped, until 
3 years after the decision to discontinue development is notified)
2.
Until 3 years after discontinuation or termination of the study.
The following are the major documents to be retained at the study site.
1.
Source documents (clinical data, documents, and records for preparing the eCRF) 
hospital records, medical records, test records, memoranda, administration records, data 
recorded by automatic measuring instruments, reproductions or transcripts verified as 
precise copies, microfiche, negative films, microfilms/magnetic media, X-ray films, 
subject files and study-related records kept at either a pharmacy, a laboratory, or medical 
technical office, as well as subject registration forms, laboratory test slips including 
central measurement, worksheets specified by the Sponsor, records of clinical 
coordinators, and records related to the clinical study selected from those verified in 
other departments or hospitals. 
2.
Contracts, written ICFs, written information, and other documents or their copies 
prepared by the study personnel.  A letter of request for clinical study (including a 
request for continuation/amendment), letter of request for review, notice of clinical study 
contract, clinical study contract, notification of discontinuation or completion of clinical 
study, written information for informed consent (including revisions), signed and dated 
written informed consent (including revisions), Curriculum Vitae of investigators, list of 
sub-investigators, list of signatures and print of seals (copy), and CRFs (copy), etc.  
3.
The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical 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 clinical study 
whose period exceeds 1 year or the adequacy of continuously conducting the clinical 
study from which information on adverse drug reactions is obtained, and other 
documents obtained. An agreed-upon protocol (including revisions), Investigator's 
Brochure (including revisions), operational procedures for the investigator, materials and 
information supplied by the Sponsor (e.g., AE report), matters reported by the 
investigator (revisions of the protocol, AE reports, etc.), operational procedures for the 
IRB, the list of names of the IRB members, materials for IRB review (including 
continuous deliberation), IRB review records (including continuous deliberation), and 
the review result report of the IRB (including continuous deliberation), etc. 
4.
Records of control for study drugs and other duties related to the clinical study.  
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and the prescriptions for 
concomitant medications
The documents of the Efficacy and Safety Evaluation Committee (minutes and SOPs and 
others) and the judgment committee outside the study sites (minutes and SOPs and others) 
shall be retained by the Sponsor.


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8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments.  
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required.  The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).  In 
Japan, it is followed by the approval of the head of the study site.
Amendments to this protocol must be signed by the Sponsor and the investigator.  Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety and/or efficacy.  Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor.  An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements.  The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File. 
Specific to Japan
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage.  However, if it was caused intentionally 
or was due to gross negligence by the study site, the Sponsor will consult with the study site 
about handling the injury, based on the agreed study contract.  Compensation for the study-
related injury is provided by the following procedures:
1.
If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and other necessary measures.  The Sponsor should be 
notified of the injury. 
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 
compensation settlement. 
3.
The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract. 
4.
The Sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above.


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8.3.5
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.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities.  The audit may include on-site review of regulatory 
documents, case report forms, and source documents.  Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee (IDMC) 
The IDMC will be responsible for the review of subject safety and enrollment rates during 
periodic review as defined in the IDMC charter.  
Members of the IDMC will be independent from the Sponsor and also will not participate as 
investigators in the trial.  Additional details regarding responsibilities and membership 
requirements will be included in the IDMC charter.
10.2
Independent Review Committee (IRC)
The Independent Review Committee (IRC) will be responsible for adjudicating relapse 
events for the purpose of RFS endpoint as defined in IRC charter.  Members of the IRC will 
be independent from the Sponsor and also will not participate as investigators in the trial.  
Additional details regarding responsibilities and membership requirements will be included 
in the in the IRC charter.
10.3
Other Study Organization
Specific to investigational sites in Japan: 
The Japan site contact list is kept as a separate attachment to the protocol.


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11
REFERENCES
American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 2014.
ASP2215 Investigator’s Brochure, 2015.
Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, et al. Axl, a 
prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of 
leukemia cells with bone marrow stroma. Blood. 2013;122:2443-52.
Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, et al. Impact of FLT3 internal tandem 
duplication on the outcome of related and unrelated hematopoietic transplantation for adult 
acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 
2012;30:735-41.
Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality 
of life in leukemia: The Functional Assessment of Cancer Therapy–Leukemia(FACT-Leu) 
Questionnaire. Value Health. 2012;15:1051-8. 
Chevallier P, Labopin M, Turlure P, Prebet T, Pigneux A, Hunault M, et al. A new Leukemia 
Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia 
patients: a GOELAMS study. Leukemia. 2011;25:939-44.
Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal 
tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large 
cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776-84.
Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, et al. Receptor tyrosine kinase AXL is 
induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute 
myeloid leukemia. Cancer Lett. 2008;268:314-24.
Hwang, IK, Shih, WJ, DeCani, JS. Group sequential designs using a family of type I error probability 
spending functions. Stat Med. 1990;9:1439-45.
Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert Opin Ther Targets. 2015;19:37-54.
Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of 
salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first 
relapse. Blood. 2011;117:3294-301.
Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, 
signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 
2008;100:35-83.
Moreno I, Martín G, Bolufer P, Barragán E, Rueda E, Román J, et al. Incidence and prognostic value 
of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. 
Haematologica. 2003;88:19-24.
O'Donnell MR, Abboud CN, Altman J, Appelbaum FR, Arber DA, Attar E, et al. Acute myeloid 
leukemia. J Natl Compr Canc Netw. 2012;10:984-1021.


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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55.
Park IK, Mishra A, Chandler J, Whitman SP, Marcucci G, Caligiuri MA. Inhibition of the receptor 
tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute 
myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 
2013;121:2064-73.
Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of 
integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079-89.
Rochlitz C, Lohri A, Bacchi M, Schmidt M, Nagel S, Fopp M, et al. Axl expression is associated with 
adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia 
(AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research 
(SAKK). Leukemia. 1999;13:1352-8.
Schlenk RF, Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol. 2009;16:98-104.
Tallman MS. New strategies for the treatment of acute myeloid leukemia including antibodies and 
other novel agents. Hematology Am Soc Hematol Educ Program. 2005:143-50.
Tiesmeier J, Müller-Tidow C, Westermann A, Czwalinna A, Hoffmann M, Krauter J, et al. Evolution 
of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and 
response to salvage therapy. Leuk Res. 2004;28:1069-74.
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of 
D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 
2001;97:2434-9.
Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem 
duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. 
Leukemia. 2005;19:1345-9.


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12
APPENDICES
12.1
List of Excluded and Cautionary Concomitant Medications
The following list describes medications and foods that are common strong inhibitors of 
CYP3A. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A.  
Strong CYP3A Inhibitors
Drug Type
Generic Drug Name
Human Immunodeficiency Virus Protease 
Inhibitors
Indinavir
Nelfinavir
Lopinavir/ritonavir
Ritonavir
Saquinavir
Food/Juice
Grapefruit juice
Others
Boceprevir
Telaprevir
Clarithromycin
Telithromycin
Conivaptan
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Nefazodone
CYP: cytochrome P450.
Source: Table 3 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited.  The 
following list describes medications and foods that are common strong inducers of CYP3A.  
This list should not be considered all inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to induce CYP3A.
Strong CYP3A Inducers
Drug Type
Generic Drug Name
Antiepileptic, Anticonvulsant
Carbamazepine
Phenytoin
Antibiotic
Rifampicin
Food/Juice Supplement
St. John’s Wort
CYP: cytochrome P450.
Source: Table 4 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf


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The following 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.
Drugs Targeting Serotonin Receptors 
Drug Type
Generic Drug Name
Affinity or function to 5HT2BR
Eletriptan Hydrobromide
Affinity or function to 5HT1R
Almotriptan Malate
Aripiprazole
Avitriptan
Buspirone Hydrochloride
Dihydroergotamine Mesylate
Droperidol
Eletriptan Hydrobromide
Ergoloid Mesylates
Ergonovine Maleate
Ergotamine Tartrate
Frovatriptan Succinate
Haloperidol
Decanoate
Lesopitron
Methylergonovine Maleate
Methylergotamine
Methysergide Maleate
Naratriptan Hydrochloride
Pizotifen
Quetiapine Fumarate
Rizatriptan Benzoate
Sumatriptan Succinate
Tegaserod Maleate
Thioridazine Hydrochloride
Ziprasidone Hydrochloride
Ziprasidone Mesylate
Zolmitriptan
Zotepine
5HT1R: 5-hydroxytryptamine receptor 1; 5HT2BR: 5-hydroxytryptamine receptor 2B.
The following list describes medications and foods that are common inhibitors or inducers of 
P-gp. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit or induce P-gp.


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P-gp Inhibitors or Inducers
Transporter
Gene
Inhibitor
Inducer
P-gp 
ABCB1
Amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, dronedarone, 
erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir and ritonavir, 
quercetin, quinidine, ranolazine, 
verapamil
Avasimibe, 
carbamazepine,
phenytoin, rifampin, 
St John’s wort, 
tipranavir/ritonavir 
P-gp: P-glycoprotein.
Source: Table 12 in http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm#major
Drugs That May Prolong QT or QTc
The following list describes drugs that are known to prolong QT or QTc.  This list should not 
be considered all inclusive.  Consult individual drug labels for specific information on 
whether a compound is known to prolong QT or QTc.
Drug Type
Generic Drug Name
Class IA antiarrhythmics
Quinidine
Procainamide
Disopyramide
Class IC antiarrhythmics
Flecainide 
Propafenone 
Moricizine
Class III antiarrhythmics 
Amiodarone
Sotalol
Bretylium
Ibutilide
Dofetilide
Antipsychotics
Thioridazine
Mesoridazine
Chlorpromazine
Prochlorperazine
Trifluoperazine
Fluphenazine
Perphenazine
Pimozide
Risperidone
Ziprasadone
Lithium
Haloperidol
Table continued on next page


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Drug Type
Generic Drug Name
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
Antimalarials
Amodiaquine
Atovaquone
Chloroquine
Doxycycline
Halofantrine
Mefloquine 
Proguanil
Primaquine
Pyrimethamine
Quinine
Sulphadoxine
Antiprotozoals
Pentamidine
Antiemetics
Droperidol
Dolasetron
Granisetron
Ondansetron
Antiestrogens
Tamoxifen
Immunosuppressants
Tacrolimus


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 × ULN, or bilirubin > 2 × ULN, should undergo detailed 
testing for liver enzymes (including at least ALT, AST, alkaline phosphatase, and total 
bilirubin).  Testing should be repeated within 48-72 hours of notification of the test results.  
For studies for which a central laboratory is used, alerts will be generated by the central lab 
regarding moderate and severe liver abnormality to inform the investigator, study monitor 
and study team.  Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3× ULN 
or
> 2× ULN
Severea
> 3× ULN
and
> 2× ULN
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal
a. See definition of Hy’s Law later in this appendix.
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8× ULN
●
ALT or AST > 5× ULN for more than 2 weeks  
●
ALT or AST > 3× ULN and international normalized ratio (INR) > 1.5 (If INR testing is 
applicable/evaluated).
●
ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests.  The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) that has been developed globally and can be activated for any 
study or an appropriate document.  Subjects with confirmed abnormal liver function testing 
should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  


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Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE.  The 
Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset-diseases should be recorded as AEs on the AE page of the eCRF.  
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted.  Non-alcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic, and/or diabetic patients and may be 
associated with fluctuating aminotransferase levels.  The investigator should ensure that 
the medical history form captures any illness that pre-dates study enrollment that may be 
relevant in assessing hepatic function. 
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets.  Medications, including dose, should be entered on the concomitant 
medication page of the eCRF.  Information on alcohol, other substance use, and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
○
acute viral hepatitis (A,B, C, D, E or other infectious agents) 
○
ultrasound or other imaging to assess biliary tract disease
○
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study.  The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment.  Discontinuation of treatment should be considered 
if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks 
●
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.


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a Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 
(or transplant).  The 2 “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“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 3x ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome 
[Temple, 2006].
References
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  
Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3.


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12.3
Laboratory Tests
Panel/Assessment
Matrix/Collection 
Tube
Parameters to be Analyzed
Hematology
Approximately 5 mL 
into EDTA tube
White Blood Cell Count
White Blood Cell Differential
Red Blood Cell Count
Hemoglobin
Hematocrit
Mean Corpuscular Volume
Platelet Count
Mean Corpuscular Hemoglobin Concentration
Mean Corpuscular Hemoglobin 
Blast Count
Chemistry
Approximately 8 mL 
into serum tube
Sodium
Potassium
Chloride 
Bicarbonate
Blood Urea Nitrogen
Creatinine
Uric Acid
Glucose
Calcium
Phosphate
Magnesium
Albumin
Total Protein
Alkaline Phosphatase
Lactate Dehydrogenase
Creatine Kinase
Aldolase
Triglycerides
Total Cholesterol
Globulin
Liver Function Tests including:
Total Bilirubin
Alanine Aminotransferase
Aspartate Aminotransferase
Thyroid function tests including:
TSH
Free T4
Pregnancy Test
1 mL serum or urine
Human Chorionic Gonadotropin
Coagulation Profile 
Approximately 
2-4.5 mL into sodium 
citrate tube
INR (with PT if reported)
aPTT
Fibrinogen (Screening Only)
D-Dimer (Screening Only)
Table continued on next page


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Panel/Assessment
Matrix/Collection 
Tube
Parameters to be Analyzed
Urinalysis
Urine collection cup
Color
Appearance
Specific Gravity
pH
Bilirubin
Blood 
Glucose
Ketones
Leukocyte esterase
Nitrite
Protein
Urobilinogen
Bone Marrow
Aspirate 0.25 – 0.75 mL
Blood 1 mL – 3 mL
2 to 3 bedside smears 
slides and/or biopsy d
Blast count and cell countsa
Flow cytometry for blastsa
FLT3 mutation statusb, c
MRDb
Pharmacokinetic
2 mL blood into 
dipotassium EDTA 
tube, processed to 1 mL 
plasma in transfer tube
Gilteritinib concentration
Pharmacogenomics 
(for subjects who 
provide separate PGx 
consent)
3 mL into EDTA tube
Buccal swab
PGx analyses to be determined
aPTT: activated partial thromboplastin time; FLT3: FMS-like tyrosine kinase 3; Free T4: free thyroxine; 
INR: international normalized ratio; MRD: minimal residual disease; PGx: pharmacogenomics; 
PT: prothrombin time; TSH: thyroid-stimulating hormone. 
a. Performed locally, however relapse sample will also be sent to a central lab for subjects who relapse.
b. Assessed by central laboratory.
c. Performed on historical/diagnostic bone marrow sample and relapse samples only.
d. Required to be sent to central laboratory when local bone marrow assessment shows relapse.


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12.4
Common Serious Adverse Events
The following is a list of serious adverse events that the Sponsor considers to be associated 
with the disease state being studied.  The list does NOT change your reporting obligations or 
prevent the need to report an adverse event meeting the definition of an SAE as detailed in 
[Section 5.5.2 Definition of Serious Adverse Event].  The purpose of this list is to alert you 
that some events reported as SAEs may not require expedited reporting to the regulatory 
authorities based on the classification of “common serious adverse events”.  You are required 
to follow the requirements detailed in [Section 5.5.5 Reporting of Serious Adverse Events].  
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to regulatory agencies.  If aggregate analysis of these events indicate they 
occur more frequently with study drug, an expedited IND safety report may be submitted to 
regulatory agencies.  
Serious Adverse Events Caused by Active AML
Grades usually
observed with 
Active AML
HEMATOLOGIC AE
Anemia
0-4
Bone marrow hypocellular
0-4
CD4 lymphocytes decreased
0-4
Disseminated Intravascular Coagulation
0-3
Leukocytosis
0-4
Lymphocyte count decreased
0-4
Lymphocyte count increased
0-4
Neutropenia
0-4
Neutrophil count decreased
0-4
Platelet count decreased
0-4
Purpura
0-3
Thrombocytopenia
0-4
White blood cell decreased
0-4
INFECTION-RELATED AE
Bacterial infection (regardless of organ-system involved or specific bacterial 
cause)
0-3
Chills
0-3
Cough
0-3
Febrile neutropenia
0-4
Fever
0-5
Flu-like symptoms
0-3
Fungal infections (regardless of organ-system involved or fungal cause)
0-3
Mucositis
0-4
Periodontal disease
0-3
Pneumonia
0-5
Sepsis/septicemia/bacteremia (all causes)
0-5
Sinusitis
0-4
Sore throat
0-3
Table continued on next page


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Serious Adverse Events Caused by Active AML
Grades usually
observed with 
Active AML
PSYCHIATRIC AND NERVOUS SYSTEM RELATED AE
Anxiety
0-2
Cognitive disturbance
0-3
Confusion
0-5
Depressed level of consciousness
0-5
Depression
0-3
Libido decreased
0-2
Meningismus
0-5
Seizure
0-5
Somnolence
0-5
Syncope
3
Other AE
Activated partial thromboplastin time prolonged
0-2
Alanine aminotransferase increased
0-2
Alkaline phosphatase increased
0-2
Anorexia
0-2
Aspartate aminotransferase increased
0-2
Blood bilirubin increased
0-2
Bone and/or joint pain
0-2
Bruising
0-2
Bleeding/hemorrhage
0-5
Diarrhea
0-3
Dyspnea
0-5
Fatigue
0-3
Flushing
0-2
Gamma-glutamyltransferase increased
0-1
GVHD - Acute and Chronic
0-2
Hypertrophied gums
0-1
Hyperuricemia
0-1
Hypokalemia
0-2
Hypotension
0-2
Hypoxia
0-3
INR increased
0-1
Lactate dehydrogenase increased
0-2
Malaise
0-2
Multiorgan failure
0-5
Nausea
0-2
Oral dysesthesia
0-2
Petechiae
0-2
Pruritus
0-3
Skin and subcutaneous tissue disorders
0-3
Transient ischemic attacks
0-2
Tumor Lysis Syndrome
3-5
Vasculitis
0-5
Vomiting
0-3
Weight loss
0-2
AE: adverse event; AML: acute myeloid leukemia; GVHD: graft versus host disease; INR: international normalized ratio. 


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


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


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12.6
Definition of Complete Remission
Complete remission (CR)
For subjects to be classified as being in CR, they must have bone marrow regenerating 
normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an 
absolute neutrophil count > 1 × 109/L and platelet count ≥ 100 × 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 platelet transfusion).  There should be no 
evidence of extramedullary leukemia.
Complete remission with incomplete hematologic recovery (CRi)
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for 
incomplete hematological recovery with residual neutropenia < 1 × 109/L with or without 
complete platelet recovery.  RBC and platelet transfusion independence is not required.
Complete remission with incomplete platelet recovery (CRp)
For subjects to be classified as being in CRp, they must achieve CR except for incomplete 
platelet recovery (< 100 × 109/L).


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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2
The purpose of this amendment is:
Substantial Changes
1. Title and Text Phase Updated
DESCRIPTION OF CHANGE: 
The study is changed from a phase 3 to phase 2.
RATIONALE:
The study is changed from Phase 3 to 2 based on the reduction in the sample size.
2. Update the Number of Subjects Enrolled 
DESCRIPTION OF CHANGE:
Prior text indicating target numbers for enrollment based on an adaptive design is modified to 
remove the adaptive design element and provide approximate enrollment numbers moving 
forward.
RATIONALE:
The sample size is re-calculated per revised assumption of hazard ratio (from 0.6 to 0.5), 
significance level (from 0.025 to 0.075, 1-sided), expected power (from 90% to 83.2%) and 
change in planned accrual and follow-up period.  The target number of randomized subjects 
is then reduced from 354 to 85 with 54 relapse-free survival (RFS) events (reduced from 182) 
expected at the time of primary analysis.
3. Removal of Interim Analysis
DESCRIPTION OF CHANGE:
The interim analysis that was originally planned is removed.
RATIONALE:
The reduction in enrollment size negates the need for an interim analysis.
4. Update of Text for Inclusion Criterion 3 
DESCRIPTION OF CHANGE:
Inclusion criterion 3 makes note of a diagnostic test that was previously under development 
but is now available. The revision reflects this change in the diagnostic test status.
RATIONALE:
To update the criterion to reflect the current status of the diagnostic test.


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5. Modification of Duration of Treatment 
DESCRIPTION OF CHANGE:
The duration of treatment no longer includes the requirement for a 3-year follow-up (to start 
after the 30-day follow-up) or for 80% of the subjects to have a relapse-free survival (RFS) 
event, whichever comes first.
RATIONALE:
The three year follow-up cap has been removed due to the revised timing of the final 
analysis.  Subjects will be followed every three months until the final database lock which is 
estimated to occur when the last subject enrolled reaches the 30-day follow-up visit.
6. Update of Statistical Methods 
DESCRIPTION OF CHANGE:
The primary analysis hypothesis test on the primary endpoint of RFS is changed from the 
Wald test based on stratified Cox-proportional hazards model to a stratified log-rank test, and 
the stratified Cox-proportional hazards model is then used as sensitivity analysis.
A weighted statistics model (CHW method) will no longer be applied to the primary endpoint 
analysis.
RATIONALE:
The primary analysis hypothesis test is changed to log-rank test, which doesn’t rely on the 
proportional hazards assumption.
The CHW method is no longer applied with interim analysis removed.
7. Change to Unblinding Practice 
DESCRIPTION OF CHANGE:
Language is added to clarify the conditions under which unblinding could occur, including in 
the event of documented relapse.
RATIONALE:
Now that gilteritinib is FDA-approved for relapsed acute myeloid leukemia (AML), it is not 
ethical to keep the patient unblinded if they relapse, therefore this is removed.
Non-Substantial Changes
1. Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes, e.g., typos, format, numbering, consistency 
throughout the protocol.  


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RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.
2. Update Contact Information of Key Sponsor’s Personnel
DESCRIPTION OF CHANGE:
Names and contact information for key personnel are updated (Section II).
RATIONALE:
As the study has progressed, key personnel have changed; the modifications reflect the 
current individuals working on this study.
II  Amendment Summary of Changes:
Title
WAS:
A Phase 3 Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of the FLT3 
Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following
Induction/Consolidation Therapy for Subjects with FLT3/ITD AML in First Complete 
Remission
Protocol for Phase 3 Study of ASP2215
IS AMENDED TO:
A Phase 3 2 Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of the FLT3 
Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following
Induction/Consolidation Therapy for Subjects with FLT3/ITD AML in First Complete 
Remission
Protocol for Phase 3 2 Study of ASP2215
List of Abbreviations and Definition of Key Terms
List of Abbreviations
DELETED
IA
Interim Analysis
IV Synopsis, Planned Study Period
WAS:
From 4Q2016 to 4Q2023
IS AMENDED TO:
From 4Q2016 to 4Q2023 3Q2021


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IV Synopsis, Number of Subjects to be Enrolled/Randomized
WAS:
Initial target sample size is 354 randomized subjects.  According to the adaptive design, the 
independent data monitoring committee (IDMC) may recommend to enroll up to a maximum 
of 444 randomized subjects.
IS AMENDED TO:
Initial The target sample size is approximately 354 85 randomized subjects.  According to 
the adaptive design, the independent data monitoring committee (IDMC) may recommend to 
enroll up to a maximum of 444 randomized subjects.
IV Synopsis, Study Design Overview
WAS:
This is a phase 3, randomized, placebo-controlled, double-blind, 2-arm study to compare the 
effect of gilteritinib as maintenance therapy versus placebo after induction/consolidation in 
subjects with FLT3/ITD AML in CR1 (including CRp and CRi).
Subjects in CR1 (including CRp and CRi) will be approached for this study after 
induction/consolidation therapy is complete and a decision not to proceed with 
transplantation is made or a suitable donor could not be identified. 
Approximately 354 subjects will be randomized in a 2:1 ratio to receive gilteritinib or 
placebo.
Randomization will be stratified based on:
●
Age < 60 or ≥ 60 years.
●
Geographic region, North America or Europe or Asia/Pacific/Central America/South 
America/ rest of world.
●
Presence of MRD at screening; yes or no.
●
Use of FLT3 inhibiting agents during induction/consolidation; yes or no.
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects 
will be administered treatment up to 2 years, or until a discontinuation criterion is met. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, and survival (cause of death and date of death).
A formal interim analysis (IA) for sample size re-estimation will be performed by an IDMC 
when approximately 50% of the total planned RFS event size of 182 (i.e., 91 relapse or death 
events) have occurred.  After IA, the sample size may increase from 354 randomized subjects 
up to 444 randomized subjects (25% increase).
IS AMENDED TO:
This is a phase 3 2, randomized, placebo-controlled, double-blind, 2-arm study to compare 
the effect of gilteritinib as maintenance therapy versus placebo after induction/consolidation 
in subjects with FLT3/ITD AML in CR1 (including CRp and CRi).
Subjects in CR1 (including CRp and CRi) will be approached for this study after 
induction/consolidation therapy is complete and a decision not to proceed with 


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transplantation is made or a suitable donor could not be identified. 
Approximately 354 85 subjects will be randomized in a 2:1 ratio to receive gilteritinib or 
placebo.
Randomization will be stratified based on:
●
Age < 60 or ≥ 60 years.
●
Geographic region, North America or Europe or Asia/Pacific/Central America/South 
America/ rest of world.
●
Presence of MRD at screening; yes or no.
●
Use of FLT3 inhibiting agents during induction/consolidation; yes or no.
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects 
will be administered treatment up to 2 years, or until a discontinuation criterion is met. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, and survival (cause of death and date of death).
A formal interim analysis (IA) for sample size re estimation will be performed by an IDMC 
when approximately 50% of the total planned RFS event size of 182 (i.e., 91 relapse or death 
events) have occurred.  After IA, the sample size may increase from 354 randomized subjects 
up to 444 randomized subjects (25% increase).
IV Synopsis, Inclusion Criteria and 3 Study Population
3.2 Inclusion Criterion #3
WAS:
3.  Subject consents to allow access to his or her diagnostic bone marrow aspirate or 
peripheral blood sample and/or the DNA derived from that sample, if available, that may be 
used to validate a companion diagnostic test that is being developed in parallel with 
gilteritinib.
IS AMENDED TO:
3.  Subject consents to allow access to his or her diagnostic bone marrow aspirate or 
peripheral blood sample and/or the DNA derived from that sample, if available, that may be 
used to validate a companion diagnostic test that is being developed in parallel with for
gilteritinib.


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IV Synopsis, Duration of Treatment
WAS:
Gilteritinib or placebo will be given daily for up to 2 years.  Subjects will be followed for up 
to 3 years after the 30-day follow-up visit, or until 80% of the subjects have an RFS event, 
whichever comes first.  Study drug will not be provided during the follow-up period.
IS AMENDED TO:
Gilteritinib or placebo will be given daily for up to 2 years.  Subjects will be followed for up 
to 3 years after the 30 day follow up visit, or until 80% of the subjects have an RFS event, 
whichever comes first.  After treatment discontinuation, subjects will have a 30-day 
follow-up visit for safety, after which the subjects will enter the long-term follow-up 
period and be contacted every 3 months until final database lock for collection of 
subsequent AML treatment, remission status, and survival (cause of death and date of 
death) information.  Study drug will not be provided during the follow-up period.
IV Synopsis, Endpoints for Evaluation
WAS:
Primary Endpoint
The primary efficacy endpoint is RFS, defined as the time from randomization until relapse 
or death from any cause, whichever comes first.
Leukemia relapse will be defined as bone marrow blasts 5% or higher (not attributable to 
regenerating bone marrow), any circulating blasts, any extramedullary blast foci as per 
Revised International Working Group (IWG) criteria.
IS AMENDED TO:
Primary Endpoint
The primary efficacy endpoint is RFS per Independent Review Committee (IRC) 
adjudication, defined as the time from randomization until relapse or death from any cause, 
whichever comes first.
Leukemia relapse will be defined as bone marrow blasts 5% or higher (not attributable to 
regenerating bone marrow), any circulating blasts, any extramedullary blast foci as per 
Revised International Working Group (IWG) criteria.
IV Synopsis, Statistical Methods
Sample Size Justification
WAS:
The study is a multicenter, double-blind, placebo-controlled, randomized phase 3 trial with 1 
planned IA, comparing gilteritinib as maintenance therapy versus placebo, in FLT3/ITD 
AML subjects in CR1.  The initial target number of randomized subjects is 354; 236 in 
gilteritinib arm and 118 in placebo arm.
The median RFS time in the placebo arm is assumed to be 15 months, based on RATIFY 
control arm data on subjects with FLT3 mutation achieving CR1 after induction and 


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consolidation.  A total of 182 relapse or death events will provide 90% power to detect a 
hazard ratio of 0.6 (corresponding to 18% difference in 2-year RFS rates) with 1-sided 
significance level of 0.025.  The sample size estimation of 354 subjects assumes 
approximately 2 years of accrual and 5% drop out per year.
Randomization will be stratified by age, geographic region, the presence of minimal residual 
disease and use of FLT3 inhibiting agents during induction/consolidation.
Age:
●
< 60 years
●
≥ 60 years
Geographic Region:
●
North America
●
Europe
●
Asia/Pacific/South and Central America/rest of world
Presence of MRD in the screening bone marrow sample:
●
Yes
●
No
Use of FLT3 inhibiting agents during induction/consolidation: 
●
Yes
●
No
A formal IA will be performed when approximately 91 relapse or death events (50% of the 
planned RFS event size of 182) have occurred in the study.
IS AMENDED TO:
The study is a multicenter, double-blind, placebo-controlled, randomized phase 3 2 trial with 
1 planned IA, comparing gilteritinib as maintenance therapy versus placebo, in FLT3/ITD 
AML subjects in CR1.  The initial target number of randomized subjects is 354 85; 
approximately 236 57 in gilteritinib arm and 118 28 in placebo arm.
The median RFS time in the placebo arm is assumed to be 15 months, based on RATIFY 
control arm data on subjects with FLT3 mutation achieving CR1 after induction and 
consolidation.  A total of 182 54 relapse or death events will provide 90 83.2% power to 
detect a hazard ratio of 0.6 0.5 (corresponding to 18 24% difference in 2-year RFS rates) with 
1-sided significance level of 0.025 0.075.  The sample size estimation of 354 85 subjects 
assumes approximately 2 years of accrual and 5% drop out per year.
Randomization will be stratified by age, geographic region, the presence of minimal residual 
disease and use of FLT3 inhibiting agents during induction/consolidation.
Age:
●
< 60 years
●
≥ 60 years
Geographic Region:
●
North America
●
Europe
●
Asia/Pacific/South and Central America/rest of world
Presence of MRD in the screening bone marrow sample:
●
Yes


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●
No
Use of FLT3 inhibiting agents during induction/consolidation: 
●
Yes
●
No
A formal IA will be performed when approximately 91 relapse or death events (50% of the 
planned RFS event size of 182) have occurred in the study.
IV Synopsis, Statistical Methods
Efficacy
WAS:
Primary Efficacy Analysis
The primary outcome of the trial is RFS from the time of randomization, treated as a time to 
event variable.  The primary analysis will be conducted when the planned relapse or death 
events have been observed.  RFS will be compared between arms on full analysis set (FAS) 
population with all randomized subjects using the stratified Cox proportional hazards model 
with strata on age at randomization, screening MRD status, geographic region and use of 
FLT3 inhibiting agents during induction/consolidation.  Kaplan-Meier estimates of RFS will 
also be described for each arm, along with 95% confidence intervals at 1, 2, and 3 years.  The 
FAS is defined as all subjects who were randomized and the analysis will be based on the 
randomized treatment arms.
The primary analysis of the primary endpoint will be performed at 1-sided 0.025 significance 
level to test the null hypothesis that RFS in the gilteritinib arm is worse than or equal to RFS 
in the placebo arm versus the alternative hypothesis that RFS in the gilteritinib arm is better 
than RFS in the placebo arm.  The weighted statistic proposed by Cui, Hung and Wang 
(1999) will be used for the primary analysis of the primary endpoint at the end of the study. 
In order to evaluate the robustness of the primary analysis of RFS, 2 sensitivity analyses will 
be performed.  One sensitivity analysis is the same as the primary analysis except that it 
censors RFS at the end of treatment.  The other sensitivity is the same as the primary analysis 
except that it censors at the last evaluable disease assessment without relapse when relapse or 
death is documented after more than 1 missed disease assessment.
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint of OS will be analyzed on the FAS using the stratified 
Cox proportional hazards model with the same strata as in the primary analysis of RFS.  With 
the sequential multiple test procedure to control for overall type I error at the 1-sided 0.025 
significance level, formal significance testing of OS will be conducted only if the RFS 
comparison is statistically significant.  Otherwise, OS analysis will be considered 
exploratory.
Pharmacokinetics:
Sparse (predose) pharmacokinetic samples will be collected in all subjects. 
Additional ECGs and/or time-matched plasma samples will be collected in a subset of 
approximately 90 subjects (targeting approximately 60 subjects in the gilteritinib arm and 30 
subjects in the placebo arm) at the following visits and time points:


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●
Day 15 – 4 hours  (± 1 hour) postdose
●
Day 29 – 4 hours (± 1 hour) postdose
Pharmacodynamics:
Not applicable.
Safety:
The safety analysis set is defined as all randomized subjects who received at least 1 dose of 
study treatment. 
The safety evaluation will be based mainly on AEs, clinical laboratory, vital signs, ECGs and 
ECOG performance status.  Descriptive statistics will be used to summarize safety data.  All 
safety data will be summarized by the actual treatment received.
All summaries of AEs will include only treatment-emergent events unless otherwise stated.  
AEs will be categorized by SOC and Preferred Term using MedDRA and will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
IS AMENDED TO:
Primary Efficacy Analysis
The primary outcome of the trial is RFS per IRC adjudication from the time of 
randomization, treated as a time to event variable.  The primary analysis will be conducted 
when the planned relapse or death events have been observed.  RFS will be compared 
between arms on full analysis set (FAS) population with all randomized subjects using the 
stratified Cox proportional hazards model log-rank test with strata on age at randomization, 
screening MRD status, geographic region and use of FLT3 inhibiting agents during 
induction/consolidation.  Kaplan-Meier estimates of RFS will also be described for each arm, 
along with 95% confidence intervals at 1, 2, and 3 years.  The FAS is defined as all subjects 
who were randomized and the analysis will be based on the randomized treatment arms.
The primary analysis of the primary endpoint will be performed at 1-sided 0.025 significance 
level to test the null hypothesis that RFS in the gilteritinib arm is worse than or equal to RFS 
in the placebo arm versus the alternative hypothesis that RFS in the gilteritinib arm is better 
than RFS in the placebo arm.  The weighted statistic proposed by Cui, Hung and Wang 
(1999) will be used for the primary analysis of the primary endpoint at the end of the study. 
In order to evaluate the robustness of the primary analysis of RFS, 2 the sensitivity analyses 
will be performed as follows:
●
Unstratified log-rank test on the FAS
●
Stratified Cox proportional hazards model with the same strata as in primary 
analysis on the FAS
●
Same analysis as primary analysis but on the per protocol set (PPS)
●
Same analysis as primary analysis on the FAS, but RFS is censored at the last 
evaluable disease assessment without relapse when relapse or death is documented 
after more than 1 missed disease assessment.
●
Same analysis as primary analysis on the FAS, but RFS is censored at end of 
treatment.
●
Same analysis as primary analysis on the FAS, but RFS is defined by using 


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investigator assessed relapse.
One sensitivity analysis is the same as the primary analysis except that it censors RFS at the 
end of treatment.  The other sensitivity is the same as the primary analysis except that it 
censors at the last evaluable disease assessment without relapse when relapse or death is 
documented after more than 1 missed disease assessment.
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint of OS will be analyzed on the FAS using the a stratified 
Cox proportional hazards model log-rank test with the same strata as in the primary analysis 
of RFS.  With the sequential multiple test procedure to control for overall type I error at the 
1-sided 0.025 0.075 significance level, formal significance testing of OS will be conducted 
only if the RFS comparison is statistically significant.  Otherwise, OS analysis will be 
considered exploratory.
For the key secondary endpoint of OS, sensitivity analyses will be performed as below:
●
Unstratified log-rank test on the FAS
●
Stratified Cox proportional hazards model with the same strata as in primary 
analysis on the FAS
●
Same analysis as primary analysis but on the PPS
●
Same analysis as primary analysis on the FAS, but OS is censored at the first 
hematopoietic stem cell transplant and first subsequent anti-leukemic treatment, 
whichever occurs first.
Pharmacokinetics:
Sparse (predose) pharmacokinetic samples will be collected in all subjects. 
Additional ECGs and/or time-matched plasma samples will be collected in a subset of 
approximately 90 40 subjects (targeting approximately 60 subjects in the gilteritinib arm and 
30 subjects in the placebo arm) at the following visits and time points:
●
Day 15 – 4 hours  (± 1 hour) postdose
●
Day 29 – 4 hours (± 1 hour) postdose
Pharmacodynamics:
Not applicable.
Safety:
The safety analysis set is defined as all randomized subjects who received at least 1 dose of 
study treatment. 
The safety evaluation will be based mainly on AEs, clinical laboratory, vital signs, ECGs and 
ECOG performance status.  Descriptive statistics will be used to summarize safety data.  All 
safety data will be summarized by the actual treatment received.
All summaries of AEs will include only treatment-emergent events unless otherwise stated.  
AEs will be categorized by SOC and Preferred Term using MedDRA and will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.


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IV Synopsis, Statistical Methods
DELETED
Interim Analyses:
A formal IA will be performed when approximately 91 relapse or death events (50% of the 
planned RFS event size of 182) have occurred in the study.  Since the study is not planned to 
be terminated based on the efficacy results at the IA, the conservative Gamma ( 40) alpha
spending function (Hwang et al, 1990) will be used to allocate 1 sided alpha=5*10 11 to 
spend at the IA. 
Details for the IA, monitoring subject safety, enrollment rates and event rates will be 
contained in the IDMC charter.  Recommendations regarding study conduct will be made by 
the IDMC based on their independent assessment.  The IDMC may recommend increasing 
sample size to a maximum of 444 accordingly based on interim analysis.  The adaptive 
strategy details will be described in the IDMC charter with restricted access.
The primary endpoint at the final analysis will be tested at the 1 sided significance level at 
0.025 based on Gamma ( 40) alpha spending function, which allocates 1 sided alpha=5*10
11 to the IA.


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V.  Flow Chart and Schedule of Assessments
Flow Chart
WAS:
IS AMENDED TO:
V.  Flow Chart and Schedule of Assessments
Table 1  Schedule of Assessments, Footnote d
WAS:
d. Telephone contact every 3 months. Additional contacts may be made to support key 
analyses.  Subjects will be followed for up to 3 years after the 30-day follow-up visit.
IS AMENDED TO:
d.  Telephone contact every 3 months after the 30-day follow-up visit. Additional contacts 
may be made to support key analyses.  Follow-up will continue until the final database 
lock, which is estimated to occur after the last subject enrolled reaches the 30-day 
follow-up visit.  Subjects will be followed for up to 3 years after the 30 day follow up 
visit.


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1.3  Summary of Key Safety Information for Study Drugs
1.3.1
Gilteritinib Data
WAS:
The nonclinical and clinical studies, which are referred to in this section, are described in 
more detail in the ASP2215 Investigator’s Brochure [2015].
IS AMENDED TO:
The nonclinical and clinical studies which are referred to in this section are described in more 
detail in the ASP2215 Investigator’s Brochure [2015] as of the writing of this protocol.  
Please refer to the current version of the ASP 2215 Investigator’s Brochure.
2.2 Study Design and Dose Rationale
2.2.1
Study Design
WAS:
This is a phase 3, randomized, placebo-controlled, double-blind, 2-arm study to compare the 
effect of gilteritinib as maintenance therapy versus placebo after induction/ consolidation in 
subjects with FLT3/ITD AML in CR1 (including CRp and CRi).  The trial will be conducted 
at approximately 200 centers in North America, Europe, South America, Central America, 
and Asia/Pacific and rest of world.
Subjects in CR1 (including CRp and CRi) will be approached for this study after 
induction/consolidation therapy is complete and a decision not to proceed with 
transplantation is made or a suitable donor could not be identified. 
Approximately 354 subjects (up to a maximum of 444 subjects) will be randomized in a 
2:1 ratio to receive gilteritinib or placebo.
Randomization will be stratified based on:
●
Age < 60 or ≥ 60 years.
●
Geographic region, North America or Europe or Asia/Pacific/Central America/South 
America/rest of world.
●
Presence of MRD at screening, yes or no.
●
Use of FLT3 inhibiting agents during induction/consolidation, yes or no.
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects 
will be administered treatment up to 2 years, or until a discontinuation criterion is met. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, and survival (cause of death and date of death).
A formal interim analysis (IA) for sample size re-estimation will be performed by an IDMC 
when approximately 50% of the total planned RFS event size of 182 (i.e., 91 relapse or death 
events) have occurred.  After IA, the sample size may increase from 354 randomized subjects 
up to 444 randomized subjects (25% increase).
IS AMENDED TO:
This is a phase 3 2, randomized, placebo-controlled, double-blind, 2-arm study to compare 


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the effect of gilteritinib as maintenance therapy versus placebo after induction/consolidation 
in subjects with FLT3/ITD AML in CR1 (including CRp and CRi).  The trial will be 
conducted at approximately 200 centers in North America, Europe, South America, Central 
America, and Asia/Pacific and rest of world.
Subjects in CR1 (including CRp and CRi) will be approached for this study after 
induction/consolidation therapy is complete and a decision not to proceed with 
transplantation is made or a suitable donor could not be identified. 
Approximately 354 85 subjects (up to a maximum of 444 subjects) will be randomized in a 
2:1 ratio to receive gilteritinib or placebo.
Randomization will be stratified based on:
●
Age < 60 or ≥ 60 years.
●
Geographic region, North America or Europe or Asia/Pacific/Central America/South 
America/rest of world.
●
Presence of MRD at screening, yes or no.
●
Use of FLT3 inhibiting agents during induction/consolidation, yes or no.
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects 
will be administered treatment up to 2 years, or until a discontinuation criterion is met. 
After treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after 
which the subjects will enter the long-term follow-up period for collection of subsequent 
AML treatment, remission status, and survival (cause of death and date of death).
A formal interim analysis (IA) for sample size re estimation will be performed by an IDMC 
when approximately 50% of the total planned RFS event size of 182 (i.e., 91 relapse or death 
events) have occurred.  After IA, the sample size may increase from 354 randomized subjects 
up to 444 randomized subjects (25% increase).
4.4  Blinding
4.4.2  Breaking the Treatment Code by the Sponsor
WAS:
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting.  Individual Emergency Codes 
will be provided to the limited staff who are responsible to break the codes for all SUSAR 
cases for reporting purposes.
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject.  The time, 
date, subject number and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file.  They must only be requested by the investigator 
or other persons designated as sub-investigators.  No subjects or other study personnel will be 
made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure.
Unblinding of the study medication should only be considered for subject safety or when 


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critical therapeutic decisions are contingent upon knowing the blinded study drug 
assignment.  Any unblinding by the investigational staff must be reported immediately to the 
Sponsor and must include an explanation of why the study medication was unblinded.  If 
possible, the Sponsor should be contacted prior to unblinding of the study medication.
IS AMENDED TO:
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting.  Individual Emergency Codes 
will be provided to the limited staff who are responsible to break the codes for all SUSAR 
cases for reporting purposes.
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject.  The time, 
date, subject number and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file.  They must only be requested by the investigator 
or other persons designated as sub-investigators.  No subjects or other study personnel will be 
made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure.
Unblinding of the study medication should only be considered for subject safety or when 
critical therapeutic decisions are contingent upon knowing the blinded study drug 
assignment.  Any unblinding by the investigational staff must be reported immediately to the 
Sponsor and must include an explanation of why the study medication was unblinded.  If 
possible, the Sponsor should be contacted prior to unblinding of the study medication.
Unblinding of the study drug should only be considered for participant safety and/or 
evidence of documented relapse contingent upon knowing the blinded study drug 
assignment.  Astellas Data Science Group will remain blinded.

Unblinding for patient safety by the investigator or designated sub-investigator must 
be reported immediately to the Sponsor (Astellas Medical Monitor) and must 
include an explanation of why the study medication was unblinded.  If possible, the 
Sponsor should be contacted prior to unblinding of the study drug.

Unblinding for documented relapse by the investigator or designated sub-
investigator must be reported to the Sponsor (Astellas Medical Monitor), including 
an explanation and evidence of relapse prior to unblinding of the study drug.  
Relapse can be based on the investigator’s assessment or the IRC adjudication.
5.3  Efficacy Assessment
5.3.3.1 Survival Status and Subsequent Anti-leukemic Treatments and Their Outcomes
WAS:
Information on survival status, remission status, subsequent anti-leukemic treatments and 
outcomes will be collected for all subjects during long-term follow-up.


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The first survival status will occur at the 30-day follow-up.  After the 30-day follow-up, the 
subject or caregiver will continue to be contacted via telephone by site personnel for follow-
up every 3 months.  Data may be supplemented by site records when available at the time of 
the contact (e.g., treatment records, outcomes).  Follow-up will continue for up to 3 years 
after the 30-day follow-up visit, or until 80% of the subjects have an RFS event, whichever 
comes first.
Additional contacts may be made to support key analyses (e.g., interim/final analysis or 
analyses by the IDMC).
IS AMENDED TO:
Information on survival status, remission status, subsequent anti-leukemic treatments and 
outcomes will be collected for all subjects during long-term follow-up.
The first survival status will occur at the 30-day follow-up.  After the 30-day follow-up, the 
subject or caregiver will continue to be contacted via telephone by site personnel for follow-
up every 3 months.  Data may be supplemented by site records when available at the time of 
the contact (e.g., treatment records, outcomes).  Follow-up will continue for up to 3 years 
after the 30 day follow up visit, or until 80% of the subjects have an RFS event, whichever 
comes first until the final database lock, which is estimated to occur when the last 
subject enrolled reaches the 30-day follow-up visit.
Additional contacts may be made to support key analyses (e.g., interim/final analysis or 
analyses by the IDMC)
5.4  Safety Assessment
5.4.5  Electrocardiogram (ECG)
WAS:
At a subset of sites, approximately 90 subjects (targeting approximately 60 subjects in the 
gilteritinib arm and 30 subjects in the placebo arm) will have additional ECGs as part of the 
pharmacokinetic sampling substudy.  On day 15 and day 29, ECGs will be performed at 
predose (within 1 hour before study drug) and 4 hours postdose (+/- 1 hour) in triplicate and 
transmitted electronically for central reading.  Triplicate 12 lead ECGs should be obtained 
after the subject has rested quietly and is awake in a fully supine position (or semirecumbent 
if supine is not tolerated) for 10 minutes before the first ECG from a triplicate and at least 
5 minutes apart per time point.
IS AMENDED TO:
At a subset of sites, approximately 90 40 subjects (targeting approximately 60 subjects in the 
gilteritinib arm and 30 subjects in the placebo arm) will have additional ECGs as part of the 
pharmacokinetic sampling substudy.  On day 15 and day 29, ECGs will be performed at 
predose (within 1 hour before study drug) and 4 hours postdose (+/- 1 hour) in triplicate and 
transmitted electronically for central reading.  Triplicate 12 lead ECGs should be obtained 
after the subject has rested quietly and is awake in a fully supine position (or semirecumbent 
if supine is not tolerated) for 10 minutes before the first ECG from a triplicate and at least 
5 minutes apart per time point.


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5.6  Test Drug Concentration
5.6.1  Pharmacokinetics
WAS:
Sparse pharmacokinetic samples will be collected to evaluate gilteritinib plasma 
concentrations as outlined in the Schedule of Assessments [Table 1]. 
At a subset of sites, approximately 90 subjects (targeting approximately 60 subjects in the 
gilteritinib arm and 30 subjects in the placebo arm) on day 15 and day 29 will have dense 
pharmacokinetic sampling as outlined in the Schedule of Assessments [Table 1].  Samples 
will be collected predose (within 1 hour before study drug administration) and 4 hours 
(± 1 hour) postdose.
IS AMENDED TO:
Sparse pharmacokinetic samples will be collected to evaluate gilteritinib plasma 
concentrations as outlined in the Schedule of Assessments [Table 1]. 
At a subset of sites, approximately 90 40 subjects (targeting approximately 60 subjects in the 
gilteritinib arm and 30 subjects in the placebo arm) on day 15 and day 29 will have dense 
pharmacokinetic sampling as outlined in the Schedule of Assessments [Table 1].  Samples 
will be collected predose (within 1 hour before study drug administration) and 4 hours 
(± 1 hour) postdose.
5.7  Other Measurements, Assessments or Methods
5.7.2.1  FLT3 Mutation Status
WAS:
FLT3/ITD mutation status and allelic ratio will be analyzed using the diagnostic specimen 
(when available) by a Sponsor-designated central laboratory.  All subjects must have 
documented FLT3/ITD AML at the time of AML diagnosis.
FLT3 mutation status will be analyzed at relapse by a Sponsor-designated central laboratory.
The FLT3 Mutation Assay Companion Diagnostic is an investigational use only assay that is 
being developed in parallel with gilteritinib.  The manufacturer of the assay will analyze the 
diagnostic samples (when available) with the FLT3 companion diagnostic assay.  The results 
may be used to seek regulatory approval if a companion diagnostic for FLT3/ITD is indicated 
for the patient population in this study.  All biomarker samples collected will be stored for a 
period up to 15 years following study database hard lock.  Please refer to the Laboratory 
Manual for more detailed information on this topic.
IS AMENDED TO:
FLT3/ITD mutation status and allelic ratio will be analyzed using the diagnostic specimen 
(when available) by a Sponsor-designated central laboratory.  All subjects must have 
documented FLT3/ITD AML at the time of AML diagnosis.
FLT3 mutation status will be analyzed at relapse by a Sponsor-designated central laboratory.


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The FLT3 Mutation Assay Companion Diagnostic is an investigational use only assay that is 
being developed in parallel with gilteritinib.  The manufacturer of the FLT companion 
diagnostic assay will analyze the diagnostic samples (when available) with the FLT3 
companion diagnostic assay.  The results may be used to seek regulatory approval if a 
companion diagnostic for FLT3/ITD is indicated for the patient population in this study.  All 
biomarker samples collected will be stored for a period up to 15 years following study 
database hard lock.  Please refer to the Laboratory Manual for more detailed information on 
this topic.
7  STATISTICAL METHODOLOGY
7.1  Sample Size
WAS:
The study is a multicenter, double-blind, placebo-controlled, randomized phase 3 trial with 1 
planned IA, comparing gilteritinib as maintenance therapy versus placebo, in FLT3/ITD 
AML subjects in CR1. The initial target number of randomized subjects is 354; 236 in 
gilteritinib arm and 118 in placebo arm.
The median RFS time in the placebo arm is assumed to be 15 months, based on RATIFY 
control arm data on subjects with FLT3 mutation achieving CR1 after induction and 
consolidation.  A total of 182 relapse or death events will provide 90% power to detect a 
hazard ratio of 0.6 (corresponding to 18% difference in 2-year RFS rates) with 1-sided 
significance level of 0.025.  The sample size estimation of 354 subjects assumes 
approximately 2 years of accrual and 5% drop out per year.
After IA, the sample size may increase from 354 randomized subjects up to 444 randomized 
subjects (25% increase).
IS AMENDED TO:
The study is a multicenter, double-blind, placebo-controlled, randomized phase 3 2 trial with 
1 planned IA, comparing gilteritinib as maintenance therapy versus placebo in FLT3/ITD 
AML subjects in CR1. The initial target number of randomized subjects is approximately 354
85; 236 57 in gilteritinib arm and 118 28 in placebo arm.
The median RFS time in the placebo arm is assumed to be 15 months, based on RATIFY 
control arm data on subjects with FLT3 mutation achieving CR1 after induction and 
consolidation.  A total of 182 54 relapse or death events will provide 90 83.2% power to 
detect a hazard ratio of 0.6 0.5 (corresponding to 18 24% difference in 2-year RFS rates) with 
1-sided significance level of 0.025 0.075.  The sample size estimation of 354 85 subjects
assumes approximately 2 years of accrual and 5% drop out per year.
After IA, the sample size may increase from 354 randomized subjects up to 444 randomized 
subjects (25% increase).


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ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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Version 3.0 Incorporating Substantial Amendment 2
7.2  Analysis Set
7.2.4  Pharmacokinetic Analysis Set (PKAS)
WAS:
The pharmacokinetic analysis set (PKAS) consists of the population administered at least 
1 dose of study drug (gilteritinib), have at least 1 measurable concentration datum 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 determined at the 
Classification Meeting and documented in the Classification Specifications.
IS AMENDED TO:
The pharmacokinetic analysis set (PKAS) consists of the population administered at least 
1 dose of study drug (gilteritinib), have at least 1 measurable concentration datum and for 
whom both the date and time of dosing on the day of and PK 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 determined at the Classification Meeting and documented in the Classification 
Specifications.
7.4  Analysis of Efficacy 
7.4.1  Analysis of Primary Endpoint
WAS:
The primary analysis of RFS will be performed at 1-sided 0.025 significance level to test the 
null hypothesis that RFS in the gilteritinib arm is worse than or equal to RFS in the placebo 
arm versus the alternative hypothesis that RFS in the gilteritinib arm is better than RFS in the 
placebo arm.  The weighted statistic proposed by Cui, Hung and Wang (1999) will be used 
for the primary analysis of the primary endpoint at the end of the study. The primary analysis 
will be conducted when the planned 182 relapse or death events have been observed.  The 
primary efficacy endpoint of RFS will be analyzed on the FAS using the stratified Cox 
proportional hazards model with strata on age at randomization, screening MRD status, 
geographic region and use of FLT3 inhibiting agents during induction/consolidation as 
described below. 
Age:
●
< 60 years
●
≥ 60 years
Geographic Region:
●
North America
●
Europe
●
Asia/Pacific/South and Central America/rest of world
Presence of screening MRD:
●
Yes


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ISN/Protocol 2215-CL-0302
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Version 3.0 Incorporating Substantial Amendment 2
●
No
Use of FLT3 inhibiting agents during induction/consolidation:
●
Yes
●
No
Kaplan-Meier curves will be used to describe the RFS in each arm.  Median RFS time and 
RFS rates at 1, 2, and 3 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves.
In order to evaluate the robustness of the primary analysis of RFS, sensitivity analyses will be 
performed as below:
●
Unstratified Cox proportional hazards model on the FAS
●
Stratified Cox proportional hazards model on the PPS
●
Stratified Cox proportional hazards model on the FAS where RFS is censored at the last 
evaluable disease assessment without relapse when relapse or death is documented after 
more than 1 missed disease assessment.
●
Stratified Cox proportional hazards model on the FAS where RFS is censored at end of 
treatment.
●
Stratified Cox proportional hazards model on the FAS where RFS is defined by using 
investigator assessed relapse.
IS AMENDED TO:
The primary analysis of RFS will be performed at 1-sided 0.025 0.075 significance level to 
test the null hypothesis that RFS in the gilteritinib arm is worse than or equal to RFS in the 
placebo arm versus the alternative hypothesis that RFS in the gilteritinib arm is better than 
RFS in the placebo arm.  The weighted statistic proposed by Cui, Hung and Wang (1999) 
will be used for the primary analysis of the primary endpoint at the end of the study.  The 
primary analysis will be conducted when the planned 182 54 relapse or death events have 
been observed.  The primary efficacy endpoint of RFS will be analyzed on the FAS using the 
stratified Cox proportional hazards model log-rank test with strata on age at randomization, 
screening MRD status, geographic region and use of FLT3 inhibiting agents during 
induction/consolidation as described below. 
Age:
●
< 60 years
●
≥ 60 years
Geographic Region:
●
North America
●
Europe
●
Asia/Pacific/South and Central America/rest of world
Presence of screening MRD:
●
Yes
●
No


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
Astellas
Page 120 of 126
Version 3.0 Incorporating Substantial Amendment 2
Use of FLT3 inhibiting agents during induction/consolidation:
●
Yes
●
No
Kaplan-Meier curves will be used to describe the RFS in each arm.  Median RFS time and 
RFS rates at 1, 2, and 3 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves.
In order to evaluate the robustness of the primary analysis of RFS, sensitivity analyses will be 
performed as below:
●
Unstratified Cox proportional hazards model log-rank test on the FAS
●
Stratified Cox proportional hazards model on the PPS
●
Stratified Cox proportional hazards model on the FAS where RFS is censored at the last 
evaluable disease assessment without relapse when relapse or death is documented after 
more than 1 missed disease assessment.
●
Stratified Cox proportional hazards model on the FAS where RFS is censored at end of 
treatment.
●
Stratified Cox proportional hazards model on the FAS where RFS is defined by using 
investigator assessed relapse.
●
Stratified Cox proportional hazards model with the same strata as in primary 
analysis on the FAS
●
Same analysis as primary analysis but on the PPS
●
Same analysis as primary analysis on the FAS, but RFS is censored at the last 
evaluable disease assessment without relapse when relapse or death is documented 
after more than 1 missed disease assessment.
●
Same analysis as primary analysis on the FAS, but RFS is censored at end of 
treatment.
●
Same analysis as primary analysis on the FAS, but RFS is defined by using 
investigator assessed relapse.
7.4  Analysis of Efficacy 
7.4.2.1  Key Secondary Endpoints and 7.4.2.2 Other Secondary Endpoints
WAS:
The key secondary analysis of OS will be performed at 1-sided 0.025 significance level to 
test the null hypothesis that OS in the gilteritinib arm is worse than or equal to OS in the 
placebo arm versus the alternative hypothesis that OS in the gilteritinib arm is better than OS 
in the placebo arm.  The endpoint OS will be analyzed on the FAS using the stratified Cox 
proportional hazards model with strata on age at randomization, screening MRD status, 
geographic region and use of FLT3 inhibiting agents during induction/consolidation. 
With the sequential multiple test procedure to control for overall type I error at the 1-sided 
0.025 significance level, formal significance testing of OS will be conducted only if the RFS 
comparison is statistically significant.  Otherwise, OS analysis will be considered 
exploratory.


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ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
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Version 3.0 Incorporating Substantial Amendment 2
Kaplan-Meier curves will be used to describe the OS in each arm.  Median OS time and OS 
rates at 1, 2, 3, and 4 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves.
For the key secondary endpoint of OS, sensitivity analyses will be performed as below:
●
Unstratified Cox proportional hazards model on the FAS
●
Stratified Cox proportional hazards model on the PPS
●
Stratified Cox proportional hazards model on the FAS where OS is censored at the first 
HSCT and first subsequent anti-leukemic treatment, whichever occurs first.
7.4.2.2 Other Secondary Endpoints 
●
Stratified Cox proportional hazards model for EFS on the FAS
●
Analyze the relationship between MRD and RFS, and that between MRD and OS on the 
FAS.
IS AMENDED TO:
The key secondary analysis of OS will be performed at 1-sided 0.025 0.075 significance level 
to test the null hypothesis that OS in the gilteritinib arm is worse than or equal to OS in the 
placebo arm versus the alternative hypothesis that OS in the gilteritinib arm is better than OS 
in the placebo arm.  The endpoint OS will be analyzed on the FAS using the stratified Cox 
proportional hazards model log-rank test with strata on age at randomization, screening 
MRD status, geographic region and use of FLT3 inhibiting agents during 
induction/consolidation. 
With the sequential multiple test procedure to control for overall type I error at the 1-sided 
0.025 0.075 significance level, formal significance testing of OS will be conducted only if the 
RFS comparison is statistically significant.  Otherwise, OS analysis will be considered 
exploratory.
Kaplan-Meier curves will be used to describe the OS in each arm.  Median OS time and OS 
rates at 1, 2, 3, and 4 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves.
For the key secondary endpoint of OS, sensitivity analyses will be performed as below:
●
Unstratified Cox proportional hazards model on the FAS
●
Stratified Cox proportional hazards model on the PPS
●
Stratified Cox proportional hazards model on the FAS where OS is censored at the first 
HSCT and first subsequent anti leukemic treatment, whichever occurs first.
●
Unstratified log-rank test on the FAS
●
Stratified Cox proportional hazards model with the same strata as in primary 
analysis on the FAS
●
Same analysis as primary analysis but on the PPS
●
Same analysis as primary analysis on the FAS, but OS is censored at the first HSCT 
and first subsequent anti-leukemic treatment, whichever occurs first.
7.4.2.2 Other Secondary Endpoints 
●
Stratified Cox proportional hazards model log-rank test for EFS on the FAS
●
Analyze the relationship between MRD and RFS, and that between MRD and OS on the 


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ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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Version 3.0 Incorporating Substantial Amendment 2
FAS.
7  Statistical Methodology
7.8  Interim Analysis (and Early Discontinuation of the Clinical Study)
WAS:
A formal IA will be performed when approximately 91 relapse or death events (50% of the 
planned RFS event size of 182) have occurred in the study.  Since the study is not planned to 
be terminated based on the efficacy results at the IA, the conservative Gamma (-40) alpha-
spending function (Hwang et al, 1990) will be used to allocate 1-sided alpha=5*10-11 to 
spend at the IA. 
Details for the IA, monitoring subject safety, enrollment rates and event rates will be 
contained in the IDMC Charter.  Recommendations regarding study conduct will be made by 
the IDMC based on their independent assessment.  The IDMC may recommend increasing 
sample size to a maximum of 444 for the whole study accordingly based on interim analysis.  
The adaptive strategy details will be described in the IDMC charter with restricted access.
The primary endpoint at the final analysis will be tested at the 1-sided significance level at 
0.025 based on Gamma (-40) alpha-spending function, which allocates 1-sided alpha=5*10-11
to the IA. 
IS AMENDED TO:
A formal IA will be performed when approximately 91 relapse or death events (50% of the 
planned RFS event size of 182) have occurred in the study.  Since the study is not planned to 
be terminated based on the efficacy results at the IA, the conservative Gamma ( 40) alpha
spending function (Hwang et al, 1990) will be used to allocate 1 sided alpha=5*10-11 to 
spend at the IA. 
Details for the IA, monitoring subject safety, enrollment rates and event rates will be 
contained in the IDMC Charter.  Recommendations regarding study conduct will be made by 
the IDMC based on their independent assessment.  The IDMC may recommend increasing 
sample size to a maximum of 444 for the whole study accordingly based on interim analysis.  
The adaptive strategy details will be described in the IDMC charter with restricted access.
The primary endpoint at the final analysis will be tested at the 1 sided significance level at 
0.025 based on Gamma ( 40) alpha spending function, which allocates 1 sided alpha=5*10-11
to the IA. 
Not applicable.
10  Study Organization
10.1  Independent Data-Monitoring Committee (IDMC)
WAS:
The IDMC will be responsible for the review of subject safety, enrollment rates and event 
(relapse or death) rates during periodic review and interim analysis as defined in the IDMC 
charter.  The IDMC may recommend increasing event size and sample size accordingly based 
on interim analysis. The adaptive strategy details will be described in the IDMC charter with 


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
Astellas
Page 123 of 126
Version 3.0 Incorporating Substantial Amendment 2
restricted access.
Members of the IDMC will be independent from the Sponsor and also will not participate as 
investigators in the trial.  Additional details regarding responsibilities and membership 
requirements will be included in the IDMC charter.
IS AMENDED TO:
The IDMC will be responsible for the review of subject safety, and enrollment rates and 
event (relapse or death) rates during periodic review and interim analysis as defined in the 
IDMC charter.  The IDMC may recommend increasing event size and sample size 
accordingly based on interim analysis. The adaptive strategy details will be described in the 
IDMC charter with restricted access.
Members of the IDMC will be independent from the Sponsor and also will not participate as 
investigators in the trial.  Additional details regarding responsibilities and membership 
requirements will be included in the IDMC charter.
11  References
DELETED
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55:853 7.
12.4
Common Serious Adverse Events
Serious Adverse Events Caused by Active AML
WAS:
INFECTION-RELATED AE
Bacterial infection (regardless of organ-system involved or specific bacterial 
cause)
0-3
Chills
0-3
Cough
0-3
Febrile neutropenia (without infection)
0-4
Fever
0-5
Flu-like symptoms
0-3


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Version 3.0 Incorporating Substantial Amendment 2
Other AE
Activated partial thromboplastin time prolonged
0-2
Alanine aminotransferase increased
0-2
Alkaline phosphatase increased
0-2
Anorexia
0-2
Aspartate aminotransferase increased
0-2
Blood bilirubin increased
0-2
Bone and/or joint pain
0-2
Bruising
0-2
Bleeding/hemorrhage
0-5
Diarrhea
0-2
Dyspnea
0-5
Fatigue
0-3
Flushing
0-2
Gamma-glutamyltransferase increased
0-1
GVHD - Acute and Chronic
0-2
Hypertrophied gums
0-1
Hyperuricemia
0-1
Hypokalemia
0-2
Hypotension
0-2
Hypoxia
0-3
INR increased
0-1
Lactate dehydrogenase increased
0-2
Malaise
0-2
Multiorgan failure
0-5
Nausea
0-2
Oral dysesthesia
0-2
Petechiae
0-2
Pruritus
0-3
Skin and subcutaneous tissue disorders
0-3
Transient ischemic attacks
0-2
Tumor Lysis Syndrome
3-5
Vasculitis
0-5
Vomiting
0-2
Weight loss
0-2


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
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Version 3.0 Incorporating Substantial Amendment 2
IS AMENDED TO:
INFECTION-RELATED AE
Bacterial infection (regardless of organ-system involved or specific bacterial 
cause)
0-3
Chills
0-3
Cough
0-3
Febrile neutropenia (without infection)
0-4
Fever
0-5
Flu-like symptoms
0-3
Other AE
Activated partial thromboplastin time prolonged
0-2
Alanine aminotransferase increased
0-2
Alkaline phosphatase increased
0-2
Anorexia
0-2
Aspartate aminotransferase increased
0-2
Blood bilirubin increased
0-2
Bone and/or joint pain
0-2
Bruising
0-2
Bleeding/hemorrhage
0-5
Diarrhea
0-2 3
Dyspnea
0-5
Fatigue
0-3
Flushing
0-2
Gamma-glutamyltransferase increased
0-1
GVHD - Acute and Chronic
0-2
Hypertrophied gums
0-1
Hyperuricemia
0-1
Hypokalemia
0-2
Hypotension
0-2
Hypoxia
0-3
INR increased
0-1
Lactate dehydrogenase increased
0-2
Malaise
0-2
Multiorgan failure
0-5
Nausea
0-2
Oral dysesthesia
0-2
Petechiae
0-2
Pruritus
0-3
Skin and subcutaneous tissue disorders
0-3
Transient ischemic attacks
0-2
Tumor Lysis Syndrome
3-5
Vasculitis
0-5
Vomiting
0-2 3
Weight loss
0-2


Sponsor: APGD
ISN/Protocol 2215-CL-0302
EudraCT number 2016-001643-39
- CONFIDENTIAL -
25 Apr 2019
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Version 3.0 Incorporating Substantial Amendment 2
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
Sponsor: Astellas Pharma Global Development, Inc. 
SAP Final Version 3.0 
ISN/Protocol: 2215-CL-0302 
12-Aug-2021
Astellas 
Page 1 of 48 
STATISTICAL ANALYSIS PLAN 
Final Version 3.0, dated 12-Aug-2021 
A Phase 2 Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial of the FLT3 
Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following 
Induction/Consolidation Therapy for Subjects with FLT3/ITD AML in First Complete 
Remission 
ISN/Protocol: 2215-CL-0302 
IND number: 117,548 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor. 
NCT02927262


Sponsor: Astellas Pharma Global Development, Inc. 
SAP Final Version 3.0 
ISN/Protocol: 2215-CL-0302 
12-Aug-2021 
Astellas 
Page 2 of 48 
Table of Contents 
1 
INTRODUCTION ································
································
··················
 8 
2 
FLOW CHART AND VISIT SCHEDULE ································
····················
 9 
3 
STUDY OBJECTIVES AND DESIGN ································
························
 13 
3.1 
Study Objectives ································
································
··············
 13 
3.1.1 
Primary Objective ································
································
·······  13 
3.1.2 
Secondary Objectives ································
································
···  13 
3.1.3 
Exploratory Objectives: ································
································
· 13 
3.2 
Study Design ································
································
···················
 14 
3.3 
Randomization ································
································
·················
 14 
4 
SAMPLE SIZE································
································
·····················
 14 
5 
ANALYSIS SETS ································
································
·················
 15 
5.1 
Full Analysis Set (FAS) ································
································
······  15 
5.2 
Safety Analysis Set (SAF) ································
································
···  15 
5.3 
Pharmacokinetics Analysis Set (PKAS) ································
····················
 15 
6 
ANALYSIS VARIABLES ································
································
·······  15 
6.1 
Efficacy Endpoints ································
································
············
 15 
6.1.1 
Primary Efficacy Endpoint ································
·····························
 16 
6.1.2 
Secondary Efficacy Endpoints ································
·························
 18 
6.1.3 
Exploratory Endpoints ································
································
··  19 
6.2 
Safety Variables ································
································
···············
 20 
6.3 
Pharmacokinetics Variables································
································
··  20 
6.4 
Other Variables ································
································
················
 21 
7 
STATISTICAL METHODOLOGY ································
···························
 22 
7.1 
General Considerations ································
································
·······  22 
7.2 
Study Population ································
································
··············
 22 
7.2.1 
Disposition of Subjects ································
································
· 22 
7.2.2 
Protocol Deviations ································
································
·····  23 
7.2.3 
Demographic and Other Baseline Characteristics ································
···  23 
7.2.4 
Previous and Concomitant Medications ································
··············
 24 
7.2.5 
Previous and Concomitant Transfusions ································
·············
 24 
7.2.6 
Prior AML Chemotherapy ································
·····························
 24 


Sponsor: Astellas Pharma Global Development, Inc. 
SAP Final Version 3.0 
ISN/Protocol: 2215-CL-0302 
12-Aug-2021 
Astellas 
Page 3 of 48 
7.2.7 
Previous and Concomitant Non-Medication Therapy ·······························
 24 
7.2.8 
Subsequent AML Therapy ································
·····························
 24 
7.3 
Study Drugs ································
································
····················
 25 
7.3.1 
Exposure ································
································
··················
 25 
7.3.2 
Treatment Compliance ································
································
··  25 
7.4 
Analysis of Efficacy ································
································
··········
 25 
7.4.1 
Analysis of Primary Endpoint ································
·························
 25 
7.4.2 
Analysis of Secondary Endpoints ································
·····················
 26 
7.4.3 
Analysis of Exploratory Endpoints ································
····················
 27 
7.5 
Analysis of Safety ································
································
·············
 28 
7.5.1 
Adverse Events ································
································
··········
 28 
7.5.2 
Clinical Laboratory Evaluation ································
························
 31 
7.5.3 
Vital Signs ································
································
················
 32 
7.5.4 
Electrocardiograms (ECGs) ································
····························
 32 
7.5.5 
Pregnancies ································
································
···············
 34 
7.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores ·············
 34 
7.6 
Analysis of PK ································
································
·················
 34 
7.6.1 
Analysis of Sparse Pharmacokinetic Samples ································
·······  34 
7.6.2 
Analysis of Pharmacokinetic for ECG/PK sampling subset ························
 34 
7.7 
Analysis of Pharmacodynamics ································
·····························
 34 
7.8 
Subgroups of Interest ································
································
·········  34 
7.9 
Other Analyses ································
································
················
 35 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 35 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········  35 
7.11.1 
Missing Data ································
································
·············
 35 
7.11.2 
Outliers ································
································
···················
 37 
7.11.3 
Visit Windows ································
································
···········
 37 
7.11.4 
Pooling Strata ································
································
············
 37 
7.11.5 
Blinding································
································
···················
 37 
8 
DOCUMENT REVISION HISTORY ································
·························
 38 
9 
REFERENCES ································
································
····················
 42 
10 
APPENDICES ································
································
·····················
 43 
10.1 
Appendix 1: Key Contributors and Approvers ································
············
 43 
10.2 
Appendix 2: Search Strategy for Adverse Events of Interest ····························
 47 


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I. 
LIST of ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special safety interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine transaminase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APGD 
Astellas Pharma Global Development 
ASCM 
Analysis Set Classification Meeting  
ASP2215 
Astellas Compound code for 2215 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete remission 
CR1 
First complete remission 
CRc 
Composite complete remission 
CRi 
Complete remission with incomplete hematologic recovery 
CRp 
Complete remission with incomplete platelet recovery 
CS 
Classification Specifications 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
EFS 
Event-free survival 


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Abbreviations 
Description of abbreviations 
EQ-5D-5L 
EuroQol Group-5 dimension-5 level  
ER 
Emergency room 
FAB 
French-American-British  
FACT-An 
Functional Assessment of Cancer Therapy-Anemia 
FACT-Leu 
Functional Assessment of Cancer Therapy-Leukemia 
FAS 
Full analysis set 
FLT3 
FMS-like tyrosine kinase 
FSI 
First subject in 
H 
High 
HEOR 
Health Economics and Outcomes Research 
HSCT 
Hematopoietic stem cell transplant 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IDAC 
Independent data analysis center 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational new drug 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
ISN 
International Study Number 
ITD 
Internal tandem duplication 
IU/L 
International units/liter 
IWG 
International Working Group 
L 
Low 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
Min 
Minute 
mL 
Milliliter 
mmHg 
millimeters of mercury 
MRD 
Minimal residual disease 
msec 
milliseconds 
MUGA 
Multigated acquisition scan 
N 
Number 
NCI 
National Cancer Institute 


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Abbreviations 
Description of abbreviations 
NE 
Not Evaluable 
NGS 
Next-generation sequencing 
NR 
Non-Response 
OS 
Overall Survival 
PD 
Protocol Deviation 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
PRO 
Patient reported outcome 
PT 
Preferred Term 
QD 
quaque die, a Latin phrase meaning “every day” 
QTc 
QT interval corrected for heart rate 
QTcF 
Fridericia-corrected QT interval 
RBC 
Red blood cell 
RFS 
Relapse-free survival 
RR 
Interval between 2 consecutive r waves on an ECG 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
Systolic blood pressure 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
TKD 
Tyrosine kinase domain 
ULN 
Upper limit of normal 
US 
United State 
VAS 
Visual analogue scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 
 


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


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.  
The final SAP will be approved prior to the primary database lock. Any changes from the 
analyses planned in the SAP will be justified in the Clinical Study Report (CSR). 
 


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2 
FLOW CHART AND VISIT SCHEDULE 
 
Flow Chart 
 
 
AML: acute myeloid leukemia; CR1: first complete remission; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; ITD: internal tandem duplication; MRD: minimal residual 
disease. 
Note that French patients would be followed up every 3 months for 3 years after 30-day follow-up visit. 
 




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AE: adverse event; CT: computed tomography; D: day; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; 
FLT3: FMS-like tyrosine kinase 3; ICF: informed consent form; MRD: minimal residual disease; MUGA: multigated acquisition scan; PGx: pharmacogenomics; PK: pharmacokinetic; 
QTcF: Fridericia-corrected QT interval; SAE: serious adverse event; WOCBP: women of childbearing potential.  
a  Visits should be scheduled based on day 1. 
b  After month 6, subjects will be seen every 2 months for the duration of study treatment, up to 2 years (month 8, month 10, month 12, etc.). 
c  If subject relapses and/or permanently discontinues treatment, an end of treatment visit should be conducted within 7 days of last dose.  
d  Telephone contact every 3 months after the 30-day follow-up visit. Additional contacts may be made to support key analyses.  Follow-up will continue until the final database lock, 
which is estimated to occur after the last subject enrolled reaches the 30-day follow-up visit. 
e  Height measurement performed only at screening. Weight measurement should be performed at screening and each monthly visit. 
f  Screening ECG is required.  ECG assessment will be evaluated in all subjects before dosing on day 1, day 8, day 15, day 29 and each subsequent visit. Predose assessments should 
be taken within 1 hour before drug administration. 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. The mean QTcF of the triplicate ECG tracings based on central reading will be used for all 
treatment decisions. 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 by central read). 
g  If the mean QTcF from day 1 to day 8 has increased > 30 ms with no other known etiology, a confirmatory ECG should be performed on day 9. If the day 8 and 9 ECGs confirm the 
> 30 ms increase in QTcF, then the investigator should assess if a dose modification should occur as per the dose interruption or reduction guideline in the protocol. 
h  For subjects participating in the ECG/PK sampling subset, additional ECGs will be performed 4 hours (+/-1 hour) postdose on day 15 and day 29. 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 
are to be performed prior to obtaining the time-matched PK sample (at day 15 and day 29), therefore must be started at least 10 to 15 minutes before the PK draw. 
i  Woman of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin). 
j  MUGA scans or ECHO are to be performed at screening for subjects with history of congestive heart failure New York Heart Association Class 3 or 4 (unless MUGA scan or 
ECHO performed within 1 month prior to screening revealed left ventricular ejection fraction ≥ 45%). 
k  Urinalysis is only required at screening. Additional laboratory tests may be performed according to institutional standard of care.  
l  All subjects must be randomized off of central results. Labs can be repeated during the screening period for eligibility. 
m  Thyroid function tests will be repeated after every 2 months of therapy beginning at month 2 (month 2, month 4, month 6, etc.). 
n  Includes EuroQol Group 5-dimension 5-level instrument, Functional Assessment of Cancer Therapy-Anemia and Functional Assessment of Cancer Therapy-Leukemia.  If possible, 
subject reported outcome measures should be performed prior to any other assessments on that visit day. 
o  The documentation of a FLT3-ITD mutation in the past will be used to confirm eligibility criteria at screening. For randomized subjects, if bone marrow aspirate or peripheral blood 
sample and/or DNA derived from the sample at the time of diagnosis are available, additional testing of this sample may be performed.   
Footnotes continued on next page 
 
 


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p  Bone marrow aspirate is required and bone marrow biopsy in addition is preferred.  In case of inadequate aspirate, bone marrow biopsy is required.   
Bone marrow samples will be collected at screening and months 3, 6, 12, 18 and 24 and assessed by the local lab. If a subject relapses, a bone marrow sample should also be 
performed at the time of relapse. Only bone marrow samples showing relapse will be sent to a central lab. If bone marrow aspirate is unobtainable at relapse (e.g., dry tap), a 
peripheral blood smear should be collected along with bone marrow biopsy and sent to the central lab. 
MRD assessment will be performed at screening and months 3, 6, 12, and 24/EOT.  MRD performed at EOT should be performed only if the subject discontinued treatment for a 
reason other than relapse.  For MRD, the first 0.25-0.75 mL of bone marrow aspirate will be collected and sent by overnight carrier to a central laboratory.  A peripheral blood 
sample is not acceptable for MRD assessment. 
If a subject relapses, FLT3 mutations will be assessed at the time of relapse by a central lab.  If bone marrow aspirate is unavailable at relapse, a peripheral blood sample is 
acceptable to be collected for assessment of FLT3 mutations.   
q  Trough PK samples will be collected in all subjects predose (within 1 hour of dose administration) on day 1, day 8, day 15, day 29, at months 2-6 and every subsequent visit 
(month 8, month 10, etc.) and at EOT. 
r  For subjects participating in the ECG/PK sampling subset, additional PK sample will be collected 4 hours (+/-1 hour) postdose on day 15 and day 29.   
s  Whole blood and buccal swab collected predose on day 1 for subjects who consent to participate in the PGx study.   
t  Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
u  Only SAE data that is possibly or probably related to study drug will be collected. 
v  Includes medications taken within 28 days prior to day 1. 
w  Gilteritinib or placebo is taken daily at home except for clinic days when it will be taken at the clinic. 
 
 
 
 
 


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3 
STUDY OBJECTIVES AND DESIGN 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective is to compare relapse-free survival (RFS) between subjects with 
FLT3/ITD AML in first complete remission (CR1) without transplant and who are 
randomized to receive gilteritinib or placebo beginning after completion of 
induction/consolidation chemotherapy for a two-year period. 
3.1.2 
Secondary Objectives 
The key secondary objective is to compare overall survival (OS) in subjects treated with 
gilteritinib as maintenance therapy after induction/consolidation with those treated with 
placebo. 
Additional secondary objectives are to evaluate the safety and efficacy of gilteritinib versus 
placebo in terms of: 
● 
Event-free survival (EFS)  
● 
Relationship of minimal residual disease (MRD), as determined using a next-generation 
sequencing (NGS) platform specific to FLT3/ITD mutations, with RFS and OS 
● 
AEs  
● 
Clinical laboratory  
● 
Vital signs  
● 
Electrocardiograms (ECGs)  
● 
Eastern Cooperative Oncology Group (ECOG) performance scores 
3.1.3 
Exploratory Objectives: 
The exploratory objectives are to: 
● 
Assess relationship between gilteritinib exposure and QTcF for subjects participating in 
the ECG/PK sampling subset 
● 
Explore the pharmacokinetics of gilteritinib (and metabolite, if applicable) in study 
population using a population pharmacokinetics approach 
● 
Determine FLT3 mutation status at relapse 
● 
Evaluate the safety and efficacy of gilteritinib under in terms of: 
○ Patient reported signs, symptoms and impacts of AML (Functional 
Assessment of Cancer Therapy-Leukemia [FACT-Leu],  
○ Functional Assessment of Cancer Therapy-Anemia [FACT-An]) 
○ EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L) 
● 
Evaluate the healthcare resource utilization including hospitalization, intensive care unit 
(ICU) visits, emergency room (ER) visits, transfusion and use of antibiotics. 


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3.2 
Study Design 
This is a phase 2, randomized, placebo-controlled, double-blind, 2-arm study to compare the 
effect of gilteritinib as maintenance therapy versus placebo after induction/consolidation in 
subjects with FLT3/ITD AML in CR1 (including CRp and CRi).  The trial will be conducted 
at approximately 200 centers in North America, Europe, South America, Central America, 
Asia/Pacific and rest of world. 
Subjects in CR1 will be approached for this study after induction/consolidation therapy is 
complete and a decision not to proceed with transplantation is made or a suitable donor could 
not be identified.  
Subjects will enter the screening period up to 14 days prior to the start of treatment.  Subjects 
will be administered treatment up to 2 years, or until a discontinuation criterion is met.  
After treatment completion/discontinuation, subjects will have a 30-day follow-up visit for 
safety, after which the subjects will enter the long-term follow-up period for collection of 
subsequent AML treatment including hematopoietic stem cell transplant (HSCT), remission 
status, and survival (cause of death and date of death). 
3.3 
Randomization 
Enrollment, randomization and study drug assignment will be performed via Interactive 
Response Technology (IRT).  Prior to the initiation of the study treatment, the site staff will 
contact the IRT in order to determine the randomly assigned treatment.  Specific procedures 
for randomization through the IRT are contained in the study procedures manual. 
Approximately 85 subjects will be randomized in a 2:1 ratio to receive gilteritinib or placebo.  
Randomization will be stratified based on: 
● 
Age (< 60 or ≥ 60 years) 
● 
Geographic region (North America or Europe or Asia/Pacific/Central America/South 
America/Rest of World) 
● 
Presence of MRD at screening (yes or no) 
● 
Use of FLT3 inhibiting agents during induction/consolidation (yes or no). 
4 
SAMPLE SIZE 
The target number of randomized subjects is 85; 57 in gilteritinib arm and 28 in placebo arm. 
The median RFS time in the placebo arm is assumed to be 15 months, based on RATIFY 
control arm data on subjects with FLT3 mutation achieving CR1 after induction and 
consolidation.  A total of 54 relapse or death events will provide 83.2% power to detect a 
hazard ratio of 0.5 (corresponding to 24% difference in 2-year RFS rates) with 1-sided 
significance level of 0.075.  The sample size estimation of 85 subjects assumes 
approximately 2 years of accrual. 


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5 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
Full Analysis Set (FAS) will be used for efficacy analysis.  Safety Analysis Set (SAF) will be 
used for the analyses of safety and biomarker variables. Pharmacokinetic Analysis Set 
(PKAS) will be used for pharmacokinetic analyses.  The data from all randomized subjects 
will be included in the data tables, listings, and figures.  Detailed criteria for the FAS and 
SAF will be laid out in Classification Specifications (CS) and the allocation of subjects to 
FAS and SAF will be determined prior to the database hard lock. 
5.1 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all subjects who are randomized and will be used 
for efficacy analyses.  Subjects will be analyzed based on the randomized treatment. 
The FAS will be used for summaries of efficacy data, patient reported outcomes, resource 
utilization, as well as selected demographic and baseline characteristics. 
5.2 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) consists of all randomized subjects who took at least one dose 
of study drug (gilteritinib or placebo).  Subjects will be analyzed based on the actual 
treatment received.  
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety variables.  
5.3 
Pharmacokinetics Analysis Set (PKAS) 
The pharmacokinetic analysis set (PKAS) consists of the randomized subjects in SAF who 
were administered at least 1 dose of study drug, and for whom at least one measurable 
plasma concentration datum is available and for whom both the date and time of dosing on 
the day of PK sampling and the date and time of PK 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. 
The PKAS will be used for all tables, listings and graphical summaries of the PK data.  
At a subset of sites, subjects participating in the ECG/PK sampling subset (PKAS ECG/PK 
subset) will have additional PK sample collected 4 hours (± 1 hour) postdose on day 15 and 
day 29.  
6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
Relapse after CR (including CRp and CRi), is defined as bone marrow blasts 5% or higher 
(not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary 
blast foci as per Revised International Working Group (IWG) criteria. Relapse events will be 


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adjudicated by an independent review committee (IRC) as defined in IRC charter and will be 
used in the definitions of efficacy endpoints, unless specifically stated otherwise. 
6.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is Relapse-free survival (RFS) per IRC adjudication, defined 
as the time from the date of randomization until the date of documented relapse, or death 
from any cause, whichever occurs first (relapse date or death date – randomization date + 1).   
If a subject experiences relapse or death, the subject is defined as having RFS event related to 
either “relapse” or “death,” and the event date is the date of relapse or death. 
For a subject who is not known to have relapse or death, RFS is censored at the date of last 
evaluable relapse-free disease assessment (last relapse-free disease assessment date – 
randomization date +1). For subjects who are censored, last relapse-free disease assessment 
date refers to the subject’s last disease assessment date. A subject who has no post-treatment 
disease assessment or has no study treatment will be censored at randomization date. 
At each visit during treatment, disease assessment date refers to the date of bone marrow 
aspiration or biopsy assessment.  In the event that central bone marrow assessment is not 
performed or bone marrow is not adequate, local bone marrow assessment date will be used.  
If no aspirate or biopsy is available and subject is evaluated based on blast count from 
peripheral blood at a visit that bone marrow is expected to be collected, the date when the 
peripheral blood sample is drawn will be used. 
A disease assessment will be considered as not evaluable (NE), if only extramedullary 
leukemia is absent but neither bone marrow nor peripheral blood sample is available. 
If a subject goes off study treatment without relapse but relapse is reported in eCRF during 
follow-up period, the IRC adjudication will still be performed. In such a case, if there is no an 
adjudicated relapse, the subject is defined as having RFS event related to “relapse” and the 
event date is the date of relapse reported in eCRF. Otherwise, the following date after end of 
treatment will be considered as disease assessment date and used for censoring of RFS for the 
subject who goes off study treatment without relapse: 
● 
For subjects with subsequent AML therapy or HSCT: The start date of subsequent AML 
therapy or the date of initiation of HSCT (as reported in subsequent AML therapy 
eCRF), whichever is earlier. 
● 
For subjects without subsequent AML therapy and HSCT: The last date known alive 
collected in survival status follow-up.  
During the final analyses, only relapses or deaths occurring on or prior to the cutoff date are 
counted as RFS events.  Subjects with relapses or deaths after the cutoff date will be censored 
at the last evaluable relapse-free disease assessment date on or before cutoff date. 
RFS will also be defined in alternative ways to fulfill the sensitivity analyses: 
● 
RFS will be defined similarly as above except that a subject is censored at the end of 
treatment. 


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● 
RFS will be defined similarly as above except that a subject is censored at the last 
evaluable disease assessment without relapse when relapse or death is documented after 
more than 1 missed disease assessment. 
● 
RFS will be defined similarly as above by using investigator assessed relapse. 
 
Primary 
Sensitivity 1  
(Censored at EOT) 
Sensitivity 2 
(Missing >1 assessment) 
Scenarios  
Indicator [Event 
Type]; 
RFS date 
Indicator [Event Type]; 
RFS date  
Indicator [Event Type]; 
RFS date 
Relapsed confirmed by 
adjudication*  
Event [type=relapse]; 
Date of relapse 
Event [type=relapse]; 
Date of relapse; 
 
If relapse after EOT,  
Non-Event [type=censor]; 
Date of EOT 
Event [type=relapse]; 
Date of relapse; 
 
If relapse after ≥2 missed 
assessments,  
Non-Event [type=censor]; 
Date of last assessment 
before missing assessment  
Relapsed after EOT  
Event [type=relapse]; 
Date of relapse 
Non-Event [type=censor]; 
Date of EOT 
Non-Event [type=censor]; 
Date of last assessment 
Death without relapse 
Event [type=death]; 
Date of death;  
 
Event [type=death]; 
Date of death; 
 
If death after EOT or no 
treatment,  
Non-Event [type=censor]; 
Date of EOT or 
randomization, respectively 
Event [type=death]; 
Date of death; 
 
If death after EOT or no 
treatment or death after 2 
missed assessments,  
Non-Event [type=censor]; 
Date of last assessment or 
randomization or date of 
last assessment before 
missing assessment, 
respectively 
Not treated, no relapse, no death 
Non-Event 
[type=censor]; 
Date of randomization 
Non-Event [type=censor]; 
Date of randomization 
Non-Event [type=censor]; 
Date of randomization 
Treated, no post-baseline disease 
assessment, no relapse, no death 
Non-Event 
[type=censor]; 
Date of randomization 
Non-Event [type=censor]; 
Date of randomization 
Non-Event [type=censor]; 
Date of randomization 
Treated, ≥1 post-baseline disease 
assessment, no relapse, no death, 
and ended study treatment:     
     Initiation of subsequent  
    AML therapy including  
    HSCT 
Non-Event 
[type=censor]; 
Date at first initiation of 
subsequent AML 
therapy 
Non-Event [type=censor]; 
Date of EOT 
 
Non-Event [type=censor]; 
Date of last disease 
assessment 
 
Treated, ≥1 post-baseline disease 
assessment, no relapse, no death, 
and ended study treatment:     
     No initiation of  
     subsequent AML therapy  
     including HSCT 
Non-Event 
[type=censor]; 
Date of last known 
alive date 
Non-Event [type=censor]; 
Date of EOT  
 
Non-Event [type=censor]; 
Date of last disease 
assessment 
Treated, ≥1 post-baseline disease 
assessment, no relapse and 
ongoing with treatment 
Non-Event 
[type=censor]; 
Date of last disease 
assessment  
Non-Event [type=censor]; 
Date of last disease 
assessment  
Non-Event [type=censor]; 
Date of last disease 
assessment  
* RFS defined by using investigator assessed relapse will be the same as  “Primary” except for replacing 
“Relapsed confirmed by adjudication” with “Relapsed assessed by Investigator”. 
EOT: end of treatment 
 


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6.1.2 
Secondary Efficacy Endpoints 
6.1.2.1 Key Secondary Efficacy Endpoints 
● 
Overall survival (OS)  
OS is defined as the time from the date of randomization until the date of death from any 
cause (death date – randomization date + 1).   
For a subject who is not known to have died, OS is censored at the date of last known alive 
(date of last known alive – randomization date + 1).  The date of last known alive is the latest 
date that the subject is confirmed to be alive across the entire database. 
During the final analyses, only deaths occurring on or prior to the cutoff date are counted as 
OS events.  Subjects with death or last known alive date after the cutoff date will be censored 
at the cutoff date.  
As a sensitivity analysis, OS will be defined similarly as above, however, subjects initiate 
other anti-leukemic treatment or undergo HSCT will be censored at the first HSCT and first 
subsequent anti-leukemic treatment, whichever occurs first.  
6.1.2.2 Other Secondary Efficacy Endpoints 
● 
Event-free Survival (EFS) 
EFS is defined as the time from the date of randomization until the date of documented 
relapse (adjudicated), or premature discontinuation of the treatment before 2 years, or 
initiation of other anti-leukemic treatment, or death from any cause, whichever occurs first 
[earliest of (relapse date, treatment discontinuation date, start date of other anti-leukemic 
treatment, death date) – randomization date + 1]. 
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 discontinues the treatment or initiates other anti-leukemic treatment, the subject is 
defined as having EFS event related to either “treatment discontinuation” or “initiation of 
other anti-leukemic treatment”, and the event date is the date of study drug discontinuation or 
start date of other anti-leukemic treatment, respectively. HSCT won’t be considered as an 
EFS event. 
If multiple events occur on the same date, take the order of “relapse”, “death”, “treatment 
discontinuation”, and “initiation of other anti-leukemic treatment”. For example, if a subject 
has the same date for EOT and death, then the event should be “death”.  
For a subject who is not known to have relapse or death or treatment discontinuation or 
initiation of other anti-leukemic treatment, EFS is censored at the last evaluable relapse-free 
disease assessment date. If a subject undergoes an HSCT without these events, EFS will be 
censored at the last evaluable relapse-free assessment or the first HSCT, whichever occurs 
later. 
During the final analyses, only death, relapse, treatment discontinuation or initiation of other 
anti-leukemic treatment occurring on or prior to the cutoff date are counted as EFS events. 


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Subjects without these events before cutoff date will be censored at the last relapse-free 
disease assessment date or the first HSCT on or before the cutoff date, whichever occurs first. 
● 
Minimal Residual Disease (MRD) 
MRD will be analyzed from bone marrow samples by a Sponsor-designated central 
laboratory.  
FLT3/ITD mutation ratio will be measured in relation to total FLT3. For a patient with 
multiple ITD mutations, the overall FLT3/ITD mutation ratio will be calculated from the sum 
of all ITD mutations. Changes in FLT3/ITD mutation ratio from baseline will be compared. 
At each visit, the presence of MRD will be “Yes” if log10-transformed overall FLT3/ITD 
mutation ratio is greater than -4; otherwise, the presence of MRD will be “No”. 
6.1.3 
Exploratory Endpoints 
● 
FLT3/ITD mutation status at the time of AML diagnosis 
FLT3/ITD mutation status of the diagnostic bone marrow or blood sample will be defined for 
local and central results, respectively.  
● 
FLT3 mutation status at relapse 
FLT3 mutation status at relapse will be assessed.  
● 
EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L) 
The EQ-5D-5L is being used as a measure of respondents’ health-related quality of life.  The 
EQ-5D-5L consists of the EuroQol Group-5 Dimension descriptive system and the EuroQol 
Group Visual Analogue Scale (VAS). 
The EuroQol Group-5 Dimension descriptive system comprises of 5 dimensions of health: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression.  Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems. 
The VAS records the respondent's self-rated health status on a graduated (0 - 100) scale, 
where the endpoints are labeled ‘best imaginable health state’ and ‘worst imaginable health 
state’ with higher scores for higher health related quality of life. 
● 
Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)  
● 
The FACT-Leu [Cella et al, 2012] is a 44-item questionnaire designed to measure health-
related quality of life (HRQoL) and leukemia-specific symptoms.  The questionnaire 
includes a global score and 5 subscales including physical well-being (PWB), 
social/family well-being (SWB), emotional well-being (EWB), functional well-being 
(FWB), and a leukemia subscale (LeuS). In addition to the 5 subscales, the FACT-Leu 
can be used to calculate the Functional Assessment of Cancer Therapy-General 
(FACT-G) score, the FACT-Leu Trial Outcome Index (FACT-Leu TOI), and the 
FACT-Leu total score which is comprised of all 44 items included in the questionnaire.  
The FACT-Leu contains some of the most common patient reported signs, symptoms, 
and impacts of AML. The FACT-Leu has a 7-day recall period. A higher score indicates 
a better quality of life. Functional Assessment of Cancer Therapy-Anemia (FACT-An)  


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● 
The FACT-An [Cella D., 1997] is to assess specific quality of life concerns related to 
anemia and fatigue in patients with cancer. It consists of 13 items measuring fatigue 
associated with anemia and 7 items measuring other symptoms and impacts associated 
with anemia, such as shortness of breath and dizziness.  It also includes the same generic 
physical well-being, social/family well-being, emotional well-being, functional 
well-being domains as the FACT-Leu.  These redundant scales will not be administered 
as part of the FACT-An; only the 20 anemia-specific items will be administered. 
● 
Healthcare resource utilization including hospitalization, ICU visits, ER visits, 
transfusion and use of antibiotics 
6.2 
Safety Variables 
Safety will be assessed by evaluation of the following variables: 
● 
Treatment-emergent adverse events (TEAEs; frequency, CTCAE grade, seriousness, and 
relationship to study drug) 
o 
TEAE is defined as an AE observed after starting administration of the study 
treatment (gilteritinib or placebo) until 30 days from the last study treatment.  If the 
AE occurs on Day 1 and the onset check box is marked “Onset after first dose of 
study drug” or the onset check box is left blank, then the AE will be considered 
treatment emergent.  If the AE occurs on Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, then the AE will not be considered 
treatment emergent.  If a subject experiences an event both during the pre-
investigational period and during the investigational period, the event will be 
considered a TEAE only if it has worsened in severity (i.e. it is reported with a new 
start date).  Any AEs with onset dates completely missing will be considered 
TEAEs in summaries.  AEs with partially missing onset dates will be assumed 
TEAEs unless the available portion of the date indicates that the onset was strictly 
before start of study treatment or 30 days after the last study treatment. Missing or 
partial AE onset date will be imputed per Section 7.11.1.  
● 
A drug-related TEAE is defined as any TEAE with at least possible relationship 
(possibly or probably related) to study treatment as assessed by the investigator or with 
missing assessment of the causal relationship. 
● 
Serious adverse events (SAEs) include AEs that are flagged as serious by the 
investigator on eCRF, or upgraded by the Sponsor based on review of the Sponsor’s list 
of Always Serious term.  
● 
Adverse events of special safety interest (AESI) are defined in the Safety Review Plan 
for gilteritinib (as specified in Section 10.2, Appendix 2).  
● 
Clinical laboratory variables (hematology, biochemistry, coagulation, and urinalysis) 
● 
Vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) 
● 
12-lead electrocardiogram (ECG) 
● 
ECOG performance scores 
6.3 
Pharmacokinetics Variables 
Plasma concentration data of gilteritinib will be used in pharmacokinetic analysis. 


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Sparse pharmacokinetic samples will be collected in all subjects as outlined in the Schedule 
of Assessments [Table 1]. 
At a subset of sites, approximately 40 subjects (targeting approximately 27 subjects in the 
gilteritinib arm and 13 subjects in the placebo arm) participating in the ECG/PK sampling 
subset will have additional PK sample collected 4 hours (± 1 hour) postdose on day 15 and 
day 29.   
6.4 
Other Variables 
● 
Body Mass Index (BMI)  
BMI = weight (kg) / [height (m)]2 
● 
Duration of exposure (days) 
Duration of exposure = date of last dose – date of first dose + 1  
● 
Number of dosing days (days)  
Number of dosing days =  Date of last dose – Date of first dose + 1 – number of days 
without drug administration in between 
● 
Cumulative dose (mg) 
Cumulative dose = total dose of study drug taken during the study 
● 
Average daily dose (mg/day) 
Average daily dose = cumulative dose (mg)/number of dosing days (days)  
● 
Dose intensity (mg/day) 
Dose intensity = cumulative dose (mg)/duration of exposure (days) 
● 
Planned dose intensity (mg/day) 
Planned daily dose = 120 mg/day 
● 
Relative dose intensity (%) 
Relative dose intensity = dose intensity (mg/day)/planned daily dose (mg/day)*100% 
● 
Time from initial diagnosis of AML to time of randomization 
It will be calculated in days using the following formula: 
(Randomization date – date of initial diagnosis of AML) + 1 
Partial date of initial diagnosis of AML will be imputed per Section 7.11.1. 
● 
Previous and concomitant treatment (medication and non-medication therapy) 
Previous treatment is defined as treatment administered before the date of first dosing 
(exclusive).  
Concomitant treatment is defined as treatment administered between the date of first 
dose (inclusive) and the date of last dose (inclusive) of study drug.   
● 
Previous and concomitant transfusion 


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Previous transfusion is defined as transfusion received before the date of first dose of 
study drug, i.e., transfusion completed before the date of first dose. 
Concomitant transfusion is defined as transfusion received between the date of first dose 
(inclusive) and the date of last dose (inclusive) of study drug.   
7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum.  When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the relevant section.  In 
addition, for plasma concentrations, the coefficient of variation and the geometric mean will 
also be calculated.  Frequencies and percentages will be displayed for categorical data.  
Percentages by categories will be based on the number of subjects with no missing data, i.e., 
will add up to 100%.  
Summaries based on FAS (e.g., disposition, baseline and efficacy data) will be presented by 
randomized treatment group, unless specifically stated otherwise.  Safety analysis and other 
summaries based on SAF will be presented by actual treatment received.  Pharmacokinetic 
summaries based on PKAS will be presented by actual treatment received.  For subjects with 
dose decrease, actual treatment refers to the first dose received before dose change. 
All statistical comparisons will be made using 1-sided tests at α=0.075 significance level 
unless specifically stated otherwise. 
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
or higher on Unix.  Specifications for table, figure, and data listing formats can be found in 
the TLF specifications for this study. 
Baseline is defined as the last available measurement before or at the first dose date of study 
drug, or before or at the randomization (for subjects who receive no study drug).  Unless 
otherwise specified, all summaries will be presented by treatment group.  
For the definition of subgroups of interest please refer to Section 7.8. 
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be presented: 
● 
Number and percentage of subjects with informed consent, discontinued before 
randomization, randomized (overall only); 
For all randomized subjects, the following subject data will be presented by treatment group: 
● 
Number and percentage of subjects in each analysis set; 
● 
Number and percentage of subjects who completed or discontinued treatment by primary 
reason for treatment discontinuation;  


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● 
Number and percentage of subjects who completed or discontinued the 30-day follow-up 
evaluation by status; 
● 
Number and percentage of subjects who completed or discontinued the long term 
follow-up evaluation by status 
7.2.2 
Protocol Deviations 
Protocol deviations (PDs) as defined in the study protocol (Section 8.1.6 Protocol Deviations) 
will be assessed for all randomized subjects.  The number and percentage of subjects meeting 
any criteria will be summarized for each criterion and overall, by treatment group and total as 
well as by study site.  Subjects deviating from a criterion more than once will be counted 
once for the corresponding criterion.  Any subjects who have more than one protocol 
deviation will be counted once in the overall summary.  A data listing will be provided by 
site and subject. 
The protocol deviation criteria will be uniquely identified in the summary table and listing.  
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
7.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by descriptive statistics.  
Number and percentage of subjects allocated to treatment in each country and site will be 
presented by treatment group.  
Descriptive statistics for age, weight, body mass index (BMI), and height at study entry will 
be presented.  Frequency tabulations for sex, ethnicity, race, geographic region, age group, 
presence of MRD at screening, Use of FLT3 inhibiting agents during 
induction/consolidation, cytogenetic risk status and baseline ECOG (defined in Section 7.8) 
will be presented by treatment group. 
Frequency tabulations for AML disease history including AML subtype as classified by 
World Health Organization (WHO) classification and French-American-British (FAB) 
classification, risk status, antecedent hematological disorder, central nervous system 
leukemia, FLT3-ITD mutation status and FLT3 point mutation status will be presented by 
treatment group. 
Medical history other than AML and conditions existing at Baseline will be coded in 
MedDRA and summarized by System Organ Class (SOC) and Preferred Term (PT) as well as 
by PT alone, by treatment group for the SAF and FAS.  Baseline conditions are defined as 
those ongoing at the time of informed consent or arise following the time of informed 


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consent and before the first dose of study drug.  For ongoing medical conditions, Common 
Terminology Criteria for Adverse Events (CTCAE) grade will be provided in listing. 
FLT3/ITD mutation status of the diagnostic bone marrow or blood sample will be 
summarized for local results and central results. 
Results from lumbar puncture, baseline extramedullary leukemia and MUGA scan, if 
performed, will be provided in listing. 
7.2.4 
Previous and Concomitant Medications 
Previous medications are coded with World Health Organization – Drug Dictionary 
(WHO-DD), and will be summarized by therapeutic subgroup (Anatomical Therapeutic 
Chemical [ATC] 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO 
name (PT) by treatment group.   
As with previous medication, concomitant medication will be summarized for each treatment 
group by therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and 
preferred WHO name.   
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period.  A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups. 
Concomitant medication will also be summarized by PT by treatment group and presented in 
decreasing order of frequency based on the total number of subjects who took each 
medication.  
7.2.5 
Previous and Concomitant Transfusions 
Frequency tabulations of subjects who received transfusions and blood product will be 
presented for previous transfusion and concomitant transfusion by treatment group. 
Descriptive statistics will be presented for number of transfusion unit received per subject for 
each type of blood product. 
7.2.6 
Prior AML Chemotherapy 
Frequency tabulations of subjects with prior AML chemotherapy, response to first line 
therapy, regimen, type of treatment, prior use of FLT3 inhibitor, and best response to prior 
AML therapy will be presented by treatment group. Descriptive statistics will be presented for 
duration of response to prior AML therapy before randomization. 
7.2.7 
Previous and Concomitant Non-Medication Therapy 
Frequency tabulations of subjects with previous non-medication therapy and reason for use 
will be presented by treatment group.  Number of previous non-medication therapy received 
per subject will be summarized using descriptive statistics. 
7.2.8 
Subsequent AML Therapy 
Frequency tabulations of subjects with subsequent AML therapy, regimens, relapse prior to 
subsequent AML therapy, reason of starting subsequent AML therapy, and response to 


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subsequent AML treatment will be presented by treatment group. Descriptive statistics will 
be presented for duration of subsequent AML therapy. 
7.3 
Study Drugs 
7.3.1 
Exposure 
The following information on drug exposure will be presented by treatment group for the 
SAF: 
● 
Descriptive statistics for cumulative dose, average daily dose, dose intensity, relative 
dose intensity, and 
● 
Number and percentage of subjects with dose decrease or interruption. 
Duration of exposure and number of dosing days will be summarized by treatment group in 
two ways: 
● 
Descriptive statistics will be presented. 
● 
Exposure time will be categorized according to the following categories: 
o less than 3 months 
o at least 3 months, less than 6 months 
o at least 6 months, less than 12 months 
o at least 12 months, less than 18 months 
o 18 months or more 
o Unknown. 
Counts and percentages of subjects in each of these categories will be summarized by 
treatment group for the SAF. 
Listing of subjects with dose decrease or interruption will also be provided for SAF. 
7.3.2 
Treatment Compliance 
Overall compliance (including relative dose intensity) with the dosing schedule will be 
examined for subjects in the SAF. 
7.4 
Analysis of Efficacy  
7.4.1 
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis of the Primary Endpoint 
The primary efficacy analysis will be performed on the FAS to compare the RFS between 
gilteritinib and placebo. The null and alternative hypotheses for this comparison are: 
● 
H01: RFS in the gilteritinib arm is worse than or equal to RFS in the placebo arm 
● 
H11: RFS in the gilteritinib arm is better than RFS in the placebo arm.   
The analysis will be conducted using the stratified log-rank test with randomization strata as 
described in Section 3.3.  
The hazard ratio of the treatment effect along with 95% confidence interval will be presented. 
The assumption of proportionality of the hazard rates will be assessed. 


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The SAS codes to perform the log-rank test with strata will be similar to that shown below: 
PROC LIFETEST;             
TIME time * status (1); 
STRATA stratification_variables/ GROUP = treatment; 
RUN; 
Kaplan-Meier survival plots will be used to describe the RFS in each treatment group.  Median 
RFS and RFS rates at 1, 2 and 3 years with 95% confidence interval will be estimated from the 
Kaplan-Meier plots using the SAS code similar to that shown below: 
PROC LIFETEST; 
 
TIME time * status (1); 
 
STRATA treatment; 
RUN; 
Median follow-up of RFS estimated from reverse Kaplan-Meier curve will be provided. 
7.4.1.2 Sensitivity analyses of the Primary Endpoint 
The sensitivity analyses for the primary efficacy endpoint of RFS will be performed as 
described below: 
● 
Unstratified log-rank test on the FAS 
● 
Stratified Cox proportional hazards model with the same strata as in primary analysis on 
the FAS 
● 
Same analysis as primary analysis on the FAS, but RFS is censored at the last evaluable 
disease assessment without relapse when relapse or death is documented after more than 
1 missed disease assessment. 
● 
Same analysis as primary analysis on the FAS, but RFS is censored at end of treatment. 
● 
Same analysis as primary analysis on the FAS, but RFS is defined by using investigator 
assessed relapse. 
7.4.2 
Analysis of Secondary Endpoints 
7.4.2.1 Key Secondary Efficacy Analysis 
The key secondary efficacy endpoint of OS will be analyzed on the FAS in the same manner 
as RFS using the stratified log-rank test with the same strata as described in Section 7.4.1.1. 
The null and alternative hypotheses for this comparison are:  
● 
H02: OS in the gilteritinib arm is worse than or equal to OS in the placebo arm 
● 
H12: OS in the gilteritinib arm is better than OS in the placebo arm.  
With the sequential multiple test procedure to control for overall type I error, formal 
significance testing of OS will be conducted only if the RFS comparison is statistically 
significant.  Otherwise, OS analysis will be considered exploratory. 


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Kaplan-Meier curves will be used to describe the OS in each arm.  Median OS time and OS 
rates at 1, 2, 3 and 4 years along with 95% confidence interval will be estimated from the 
Kaplan-Meier curves. 
For the key secondary endpoint of OS, sensitivity analyses will be performed as below: 
● 
Unstratified log-rank test on the FAS 
● 
Stratified Cox proportional hazards model with the same strata as in primary analysis on 
the FAS 
● 
Same analysis as primary analysis on the FAS, but OS is censored at the first HSCT and 
first subsequent anti-leukemic treatment, whichever occurs first. 
7.4.2.2 Other Secondary Efficacy Analysis 
● 
Analysis of EFS 
EFS will be analyzed in the same manner as RFS in the FAS using the stratified log-rank test 
with the same strata as described in Section 7.4.1.1.  The hazard ratio of the treatment effect 
along with 95% confidence interval will be calculated.  Kaplan-Meier curve will be created 
for each treatment group.  Median time and 95% confidence interval, EFS rates at 1, 2 and 
3 years if appropriate and 95% confidence interval will be estimated from the Kaplan-Meier 
curve. 
● 
Analysis of MRD 
MRD will be analyzed in two ways measured as log10-transformed overall FLT3/ITD 
mutation ratio and presence/absence of MRD as defined in Section 6.1.2.2. 
Analysis of covariance (ANCOVA) model will be used to analyze the change from baseline 
of MRD measured as log10-transformed overall FLT3/ITD mutation ratio for post-baseline 
visits including treatment, age group, geographic region and use of FLT3 inhibiting therapy 
during induction/consolidation as fixed factors, and log10-transformed overall FLT3/ITD 
mutation ratio at baseline as covariate.  
The Cochran-Mantel-Haenszel (CMH) method will be used to measure the difference 
between treatment groups for the proportion of subjects with the absence of MRD while 
controlling for age group, geographic region and use of FLT3 inhibiting therapy during 
induction/consolidation. 
7.4.3 
Analysis of Exploratory Endpoints 
FLT3/ITD mutation status at the time of AML diagnosis will be summarized by the number 
and percentage of subjects by treatment group on FAS for local and central results, 
respectively.  
FLT3 mutation status at relapse will be summarized by the number and percentage of 
subjects by treatment group on FAS.  
Incidence of resource utilization including hospitalization, blood transfusion, antibiotic 
intravenous infusions, ICU visit and ER visit will be summarized by treatment group on FAS.  


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The difference between treatment groups will be tested using CMH test while controlling of 
stratification factors.  
Resource utilization counts including duration of hospital stays, duration of medications, 
blood transfusions, antibiotic intravenous infusions, ICU visit and ER visit will be 
summarized by treatment group using descriptive statistics (mean, standard deviation, 
minimum, maximum and median) on FAS. The difference between treatment groups will be 
tested with ANOVA while controlling of stratification factors. 
EQ-5D-5L VAS will be summarized by treatment group using descriptive statistics (mean, 
standard deviation, minimum, maximum and median) on FAS.  Additionally, change from 
baseline will be calculated as the post-baseline score minus the baseline score and 
summarized in the same way.  ANCOVA model will be used to evaluate change from 
baseline to post-baseline for the EQ-5D-5L VAS including treatment and stratification 
factors as fixed factors, and baseline score as covariate.  Shift table showing shift in each 
dimension score from baseline to each post-baseline visit will be provided for the 
5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). 
FACT-Leu global score and domain scores will be summarized by treatment group using 
descriptive statistics (mean, standard deviation, minimum, maximum and median) on FAS.  
Additionally, change from baseline will be calculated as the post-baseline value minus the 
baseline value and summarized in the same way.  ANCOVA model will be used to evaluate 
change from baseline to post-baseline for the global and domain scores, individual items and 
item clusters of the FACT-Leu treatment and stratification factors as fixed factor, and 
baseline score as covariate. 
FACT-An score will be summarized by treatment group using descriptive statistics (mean, 
standard deviation, minimum, maximum and median) on FAS.  Additionally, change from 
baseline will be calculated as the post-baseline value minus the baseline value and 
summarized in the same way.  ANCOVA model will be used to evaluate change from 
baseline to post-baseline scores including treatment and stratification factors as fixed factor, 
and baseline score as covariate.   
Additional exploratory analyses of patient reported outcomes (FACT-An, FACT-Leu) and 
heath outcome (EQ-5D-5L) may be performed and the details may be included in a separate 
Patient Reported Outcome Statistical Analysis Plan. 
7.5 
Analysis of Safety 
All analyses of safety will be presented by treatment group for SAF, unless specified 
otherwise.  
7.5.1 
Adverse Events 
Any adverse event (AE) recorded on treatment including within 30 days from the last study 
treatment will be classified as treatment-emergent AE (TEAE) and will be summarized.  
Serious TEAEs include SAEs upgraded by the Sponsor based on review of the Sponsor’s list 
of Always Serious terms if any upgrade was done. 


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The coding dictionary for this study will be MedDRA.  It will be used to summarize AEs by 
SOC and PT.  AEs will be graded using National Cancer Institute’s Common Terminology 
Criteria for AEs (NCI-CTCAE) version 4.03.  
An overview table to report the number and percentage of subjects and an overview table to 
report number of events and events adjusted by patient year from drug exposure will include 
the following details: 
● 
TEAEs, 
● 
Drug-related TEAEs, 
● 
TEAEs before investigator assessed relapse, 
● 
Drug-related TEAEs before investigator assessed relapse, 
● 
Serious TEAEs, 
● 
Drug-related serious TEAEs 
● 
TEAEs leading to death, 
● 
Drug-related TEAEs leading to death,  
● 
TEAEs leading to withdrawal of treatment, 
● 
Drug-related TEAEs leading to withdrawal of treatment,  
● 
TEAEs leading to dose reduction, 
● 
Drug-related TEAEs leading to dose reduction,  
● 
TEAEs leading to dose interruption, 
● 
Drug-related TEAEs leading to dose interruption,  
● 
Grade 3 or higher TEAEs,  
● 
Drug-related Grade 3 or higher TEAEs, 
● 
Any death.  
The number and percentage of subjects with TEAEs as classified by SOC and PT will also be 
summarized for each treatment group for the following: 
● 
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5% in any 
treatment group, 
● 
Common TEAEs that equal to or exceed a threshold of 10% in any treatment group 
● 
Drug-related common TEAEs that equal to or exceed a threshold of 10% in any 
treatment group 
The number and percentage of subjects with TEAEs and the number of events and events 
adjusted by patient year from drug exposure, as classified by SOC and PT will be 
summarized for each treatment group.  Summaries will be provided for: 
● 
TEAEs 
● 
Drug-related TEAEs,  
● 
TEAEs before investigator assessed relapse, 
● 
Drug-related TEAEs before investigator assessed relapse, 
● 
Serious TEAEs,  
● 
Drug-related serious TEAEs,  
● 
TEAEs leading to death, 


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● 
Drug-related TEAEs leading to death, 
● 
TEAEs leading to withdrawal of treatment,  
● 
Drug-related TEAEs leading to withdrawal of treatment,  
● 
TEAEs leading to dose reduction, 
● 
Drug-related TEAEs leading to dose reduction,  
● 
TEAEs leading to dose interruption, 
● 
Drug-related TEAEs leading to dose interruption,  
● 
Grade 3 or higher TEAEs, 
● 
Drug-related Grade 3 or higher TEAEs, 
● 
Death 
The number and percentage of subjects with TEAEs, as classified by PT only, will also be 
summarized for each treatment group for the following: 
● 
TEAEs 
● 
Drug-related TEAEs,  
The number and percentage of subjects with TEAE of special safety interest (AESI), as 
classified by AESI category and PT will be summarized for each treatment group for the 
following: 
● 
TEAEs with special safety interest, 
● 
Serious TEAEs with special safety interest, 
● 
TEAEs with special safety interest leading to withdrawal of treatment,  
● 
Drug related-TEAEs with special safety interest leading to withdrawal of treatment,  
● 
TEAEs with special safety interest leading to dose reduction, 
● 
Drug-related TEAEs with special safety interest leading to dose reduction,  
● 
TEAEs with special safety interest leading to dose interruption, 
● 
Drug-related TEAEs with special safety interest leading to dose interruption,  
● 
Grade 3 or higher TEAEs with special safety interest,  
● 
Drug-related Grade 3 or higher TEAEs with special safety interest 
AE summary tables will include subject counts as opposed to AE counts.  If a subject 
experiences more than one episode of a particular AE, the subject will be counted only once 
for that AE.  If a subject has more than one AE that codes to the same PT, the subject will be 
counted only once for that PT.  Similarly, if a subject has more than one AE within a SOC, 
the subject will be counted only once in that SOC. 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will also 
be summarized by NCI-CTCAE severity grade and by relationship to study drug.  In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity grade or relationship, then the subject will be counted only once with the worst 
severity grade and highest degree of relationship, however, if any of the severity grade or 
relationship values are missing then the subject will be counted only once with missing 
severity grade or relationship.  Drug related TEAEs will be presented in a similar way by 


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severity grade only. Serious TEAE will be presented in a similar way by relationship to study 
drug. 
All AEs, deaths, SAEs and withdrawals due to adverse events will be displayed in listings.  
7.5.2 
Clinical Laboratory Evaluation 
The baseline value is the last measurement taken prior to the first study drug administration. 
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, coagulation and 
urinalysis will be summarized using mean, standard deviation, minimum, maximum and 
median for each treatment group at each visit.  Additionally, change from baseline will be 
calculated as the post-baseline value minus the baseline value and summarized in the same 
way.  Each laboratory result will be classified as low (L), normal (N), or high (H) at each 
visit according to the central laboratory reference ranges.  
The number and percentage of subjects below and above reference range will be summarized 
for each treatment group at each visit. 
For hematology and biochemistry two types of shift tables will be presented:  
● 
Shift tables of changes based on reference range defined category (low, normal, high) 
from baseline to each visit as well as worst finding during the treatment period, and 
● 
Summary shifts of changes based on reference range defined category from baseline to 
each visit as well as worst finding during the treatment period (shift from high or normal 
to low, shift from low or normal to high, categorized increase [shift from low to normal, 
from low to high or from normal to high], categorized no change [value stays in the same 
reference range], categorized decrease [shift from high to normal, from high to low or 
from normal to low]). 
Laboratory results will also be graded using NCI-CTCAE v4.03, where possible.  Parameters 
that have criteria available for both low and high values, i.e., hypo- and hyper-, will be 
summarized for both criteria.  The same subject can be counted for both values if the subject 
has different laboratory values meeting each criterion.  NCI-CTCAE grade of laboratory 
evaluations will be summarized by number and percentage of subjects at each visit.  Shift 
tables of NCI-CTCAE grade change from baseline to worst post-baseline grade will also be 
presented. The number and percentage of subjects with grade 3 or 4 laboratory test result will 
be summarized by treatment group and laboratory parameter (the name of the adverse event 
associated with the abnormal laboratory test result will be presented).  
Laboratory results based on central assessment will be used for summaries as described 
above. Bone marrow results will be listed only.  
7.5.2.1 Liver Enzymes and Total Bilirubin  
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined.  The subject’s highest value post-baseline will be 
used.  


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Parameter 
Criteria 
ALT 
> 3xULN 
> 5xULN 
> 10xULN 
> 20xULN 
AST 
> 3xULN 
> 5xULN 
> 10xULN 
> 20xULN 
ALT or AST 
> 3xULN 
Total Bilirubin 
> 2xULN 
ALP 
> 1.5xULN 
ALT and/or AST AND Total Bilirubin(*) 
(ALT and/or AST > 3xULN) and 
(Total bilirubin > 2xULN) 
(*) Combination of values measured within same sample 
The number and percentage of subjects with potentially clinically significant values in liver 
enzymes and total bilirubin will be presented by treatment group. 
7.5.3 
Vital Signs 
The baseline value is the last measurement taken prior to the first study drug administration.   
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate, and 
body temperature) will be summarized using mean, standard deviation, minimum, maximum 
and median by treatment group and visit.  Additionally, change from baseline will be 
calculated as the post-baseline value minus the baseline value and summarized by treatment 
group and visit. 
Tables for potentially clinically significant vital signs will be generated using baseline value 
and highest post-baseline value for each subject for each treatment group. 
The following potentially clinically significant criteria are defined for each parameter: 
Vital Sign Variable 
Criteria 
SBP 
≥180 mmHg AND ≥20 mmHg change from baseline 
DBP 
≥105 mmHg AND ≥15 mmHg change from baseline 
Pulse Rate 
≥120 bpm AND ≥15 bpm change from baseline 
 
7.5.4 
Electrocardiograms (ECGs) 
12-lead ECGs will be recorded pre-dose (within 1 hour before study drug) at the scheduled 
visits for all subjects.   


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Additional ECGs will be collected on day 15 and day 29 at 4 hours post-dose (+/- 1 hour) for 
subjects participating in the ECG/PK sampling subset. 
Each ECG will be recorded in triplicate and transmitted electronically to central reading. 
The mean of the triplicate ECGs from central read should be used for all final treatment 
decisions, AE reporting and in the summary for analysis at each visit. 
ECG variables including changes from baseline will be summarized using mean, standard 
deviation, minimum, maximum and median for each treatment group at each visit.  
Number and percentage of subjects with normal and abnormal results as assessed by central 
read for the overall interpretation will be tabulated by treatment group at each visit.  A shift 
analysis table showing shift in overall ECG interpretation from baseline to each visit will be 
provided.  The worst of the three overall ECG interpretations will be used as the time-specific 
overall ECG interpretation for a subject. 
The QT interval corrected for heart rate by Fridericia’s formula, QTcF, is defined as: QTc (F) 
= QT/(RR)0.33, where RR interval is inversely proportional to heart rate (approximately RR = 
60/heart rate). 
The QTcF interval will be summarized using frequency tables for each treatment group at 
each visit for values of clinical importance using the range criteria below. 
 
QTcF Interval Criteria Value (msec) 
 
Cumulative Category 
Interval Category 
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450 
> 480 
> 500 
≤ 450 
> 450 to ≤ 480 
> 480 to ≤ 500 
> 500 
The QTcF interval will also be summarized by the frequencies of subjects with a change 
from baseline of clinical importance using the criteria identified below.  These summaries 
will be provided for each treatment group at each visit.  
 
Change from Baseline 
Variable 
Cumulative Category 
Interval Category 
QTcF Interval (msec) 
< 0  
≥ 0 
> 30 
> 60  
< 0  
≥ 0 to ≤ 30 
> 30 to ≤ 60 
> 60  
Number and percent of subjects with 12 lead ECG abnormalities as well as number and 
percent of subjects whose 12 lead ECG reading changed from normal at baseline to abnormal 
will be tabulated by treatment group at each treatment visit and time point.  
All ECG analyses will also be performed for subjects participating in the ECG/PK sampling 
subset in addition to SAF. 


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7.5.5 
Pregnancies 
A detailed listing of all pregnancies will be provided. 
7.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores 
Number and percent of subjects for each category of the ECOG performance scores at each 
assessment time will be provided by treatment group.  Negative change scores indicate an 
improvement and positive scores indicate a decline in performance. 
ECOG performance scores will also be summarized using shift table from baseline to post-
baseline score for each treatment group. 
7.6 
Analysis of PK 
PK analysis will be conducted on the PKAS.  
7.6.1 
Analysis of Sparse Pharmacokinetic Samples 
The plasma concentrations of sparse pharmacokinetic samples will be summarized for 
gilteritinib by visit and nominal time points using descriptive statistics, including number of 
subjects, mean, standard deviation, minimum, median, maximum, geometric mean, and 
coefficient of variation of the mean and geometric mean. 
Population pharmacokinetic analysis will be performed. Data from this study may be pooled 
with other studies for analysis. Details of this analysis will be specified in a separate 
population pharmacokinetic analysis plan. 
7.6.2 
Analysis of Pharmacokinetic for ECG/PK sampling subset  
For subjects participating in the ECG/PK sampling subset with additional pharmacokinetic 
samples collected, plasma concentrations will be summarized for gilteritinib by visit and 
nominal time points using descriptive statistics as described in Section 7.6.1. Time-course of 
drug concentrations will be plotted as appropriate. 
Population pharmacokinetic/pharmacodynamic analysis will be performed to assess the 
relationship between gilteritinib exposure and QTcF. Data from this study may be pooled 
with other studies for analysis. Details of this analysis will be specified in a separate 
population pharmacokinetic/pharmacodynamic analysis report. 
7.7 
Analysis of Pharmacodynamics 
Not applicable. 
7.8 
Subgroups of Interest  
Primary efficacy endpoint (RFS) and key secondary endpoint (OS) will be summarized by 
treatment group for the subgroups defined on the basis of the categorized variables listed 
below: 


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Grouping Variables 
Subgroups 
Age 
< 60 years 
≥ 60 years 
Sex 
Female 
Male 
Race 
White 
Black or African American 
Asian 
Other 
Baseline ECOG 
0-1 
≥ 2 
Geographic region 
North America 
Europe 
Asia/Pacific/South and Central America/Rest of World 
Presence of screening MRD 
Yes 
No 
Use of FLT3 inhibiting therapy 
during induction/consolidation 
Yes 
No 
Cytogenetic Risk Status 
Favorable 
Intermediate 
Unfavorable 
Other 
7.9 
Other Analyses 
Not applicable. 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not applicable. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.11.1 Missing Data  
Every effort will be made to resolve incomplete dates for death and disease relapse.  If a 
partial date cannot be resolved, the most conservative imputation methods will be used to 
complete the missing information.  
For primary endpoint RFS and key secondary endpoint OS, missing or incomplete death date 
will be imputed as the earliest feasible date on or after the date of last known alive as the 
examples shown in the table below.  The date of last known alive will be obtained as 
described in Section 6.1.1. 


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Incomplete Date of Death 
(YYYY MMM DD) 
Date of Last –Known Alive 
(YYYY MMM DD) 
Imputed Date of Death 
(YYYY MMM DD) 
2005 APR ?? 
2005 MAR 31 
2005 APR 01 
2005 ??? 13 
2005 MAR 31 
2005 APR 13 
2005 ??? ?? 
2005 MAR 31 
2005 MAR 31 
???? APR ?? 
2005 MAR 31 
2005 APR 01 
???? APR 13 
2005 MAR 31 
2005 APR 13 
???? ??? ?? 
2005 MAR 31 
2005 MAR 31 
 
Partial relapse dates will be imputed to the first day of the month of the missing parameter 
but not earlier than the last disease assessment date.  A month and year must be present or the 
date will remain missing. 
Missing or partial start and stop dates of adverse events and concomitant medication will be 
imputed using the following algorithm: 
● 
Imputation rules for partial or missing stop dates: 
o 
If the month and year are present, then impute as the last day of that month.  
o 
If only the year is present, impute as December 31 of that year. 
o 
If the stop date is entirely missing, assume the event or medication is ongoing. 
● 
Imputation rules for partial or missing start dates: 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
missing 
< 1st  
dose 
≥ 1st 
dose 
< 1st dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyym
m 
= 1st dose  
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose  
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose  
yyyy 
3 
1* 
3 
1 
n/a 
1 
1 
≠ 1st dose  
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute as the date of first dose; 2 = Impute as the first of the month; 3 = Impute as January 1 of the year; 
4 = Impute as January 1 of the stop year 
*For Subsequent AML therapy, the partial date with year only will be imputed as EOT date.  
The imputed dates will be used to determine whether an AE is treatment emergent. Listings 
of AEs and concomitant medications will present the actual partial dates; imputed dates will 
not be shown. 


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In the case of partial date of initial diagnosis of AML, the date will be imputed to the first day 
of the month. A month and year must be present or the date will remain missing. 
In the case of partial starting date of subsequent AML therapy, the date will be imputed to the 
first day of the month but not earlier than the last dosing date of the study drug. A month and 
year must be present or the date will remain missing. Concentrations below the lower limit of 
quantification (LLOQ) in PK should be assigned to be zero in the analysis of 
pharmacokinetic. 
7.11.2 Outliers 
All values will be included in the analyses. 
7.11.3 Visit Windows 
Visit windows are allowed for certain visits per the schedule of assessments.  Subject data 
will not be excluded from analyses due to the subject’s failure to comply with the visit 
schedule.  CRF visit will be used for analysis. In the case of multiple observations at a 
specific visit, the observation which is closest to the target date will be used.  If the 
observations have the same distance to the target visit, the latest one will be used. If more 
than one observation is made on the same day, an average value if continuous or the worst 
value if categorical will be included in the analysis.  
7.11.4 Pooling Strata 
In the RFS and OS analysis, if there is no event in at least one stratum combinations, or the 
Cox proportional hazard model does not converge due to small event size, the stratum 
combinations will be pooled in the order of geographic region, age group, use of FLT3 
inhibiting agents during induction/consolidation, and screening MRD status until the issue is 
resolved or the normal (un-stratified) Cox proportional hazard model is applied.  
All sensitivity analyses for the RFS and OS endpoints will apply the pooled strata. In the case 
that the criterions don’t meet, the un-stratified analysis will be used.  
7.11.5 Blinding 
Although the unblinding of the study drug could be considered for participant safety and/or 
evidence of documented relapse contingent upon knowing the blinded study drug assignment 
(more details can be found in protocol Section 4.4.2), to maintain trial integrity and increase 
the credibility of study results, the study statistician, supporting statisticians and statistical 
programmers will have no access to the randomized treatment information before the 
database lock.   
 


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8 
DOCUMENT REVISION HISTORY  
 


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Version Date 
Changes 
Comment/rationale for change 
1.0 
10-Oct-
2016 
NA 
Document finalized 
2.0 
29-Apr-
2019 
Updated Flow Chart, Schedule of 
Assessment and footnote 
Updated to keep consistent with 
protocol version 3.0 (amendment 
2) dated 25-Apr-2019. 
 
 
Updated Section 3 Study objectives 
and design with the following 
changes: 
• 
Reduced sample sizes from 
354 to 85 and number of RFS 
events needed from 182 to 54 
• 
Decreased Hazards ratio from 
0.6 to 0.5  
• 
Increased 1-sided alpha from 
0.025 to 0.075 
• 
Updated Power as 83.2% 
• 
Removed the interim analysis 
for sample size re-estimation 
Updated due to Protocol version 
3.0 (amendment 2) dated 25-
Apr-2019. 
 
 
Updated Section 5.4 Pharmacokinetics 
Analysis Set (PKAS) to clarify both 
dosing date/time and sampling 
date/time must be available. 
To clarify the detailed PKAS 
criteria. 
 
 
Updated Section 6.1.1 to clarify 
the definition of RFS: 
• 
Clarified the handling 
strategy while a subject 
goes off treatment without 
relapse that the relapse 
reported during long-term 
follow-up will be used for 
primary analysis of RFS 
• 
Clarified the RFS censoring 
rules to include the 
assessment date after end of 
treatment to censor RFS  
Previous definition of RFS was 
not clear while a subject goes off 
treatment without relapse. 
 
 
Updated Section 6.1.2.1: 
• 
Clarified the definition of last 
date known alive and move it 
under OS endpoint 
Previous definition of last date 
known alive didn’t cover all 
possible dates to support subject 
alive status 
 
 
Updated Section 6.2 and added 
Section 10.2 to clarify Adverse events 
of special safety interest (AESI) 
searching strategy 
Include AESI for more 
comprehensive analysis on AEs. 


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Version Date 
Changes 
Comment/rationale for change 
 
 
Updated Section 6.3 for numbers of 
PK subset 
Updated due to protocol version 
3.0 (amendment 2) dated 25-
Apr-2019. 
 
 
Updated Section 7.2 Study Population 
to add the following sections: 
• 
Added the section of prior 
AML chemotherapy 
• 
Added the section of 
subsequent AML therapy 
Add these sections to keep 
consistent with CRF data 
collected to summarize the prior 
and subsequent AML therapies.  
 
 
Updated Section 7.2.3 and 7.8 to add 
subgroup of cytogenetic risk status for 
demographics and subgroup analysis. 
Add the new subgroup per 
knowledge learned in ASP2215 
project 
 
 
Updated Section 7.4.1, for all time-to-
event analysis (RFS, OS and EFS): 
• 
Updated the primary analysis 
method as stratified log-rank 
test instead of stratified Cox 
proportional hazards model  
• 
Used the original primary 
analysis based on stratified 
Cox proportional hazards 
model as sensitivity 
Updated due to protocol version 
3.0 (amendment 2) dated 25-
Apr-2019. 
 
 
Updated Section 7.5.1 to include 
additional summaries of AEs and AE 
summaries by patient-year. 
Updated per knowledge learned 
in ASP2215 project 
 
 
Updated Section 7.5.2 to add the grade 
3 and 4 summary for selected lab test 
parameters 
Updated per knowledge learned 
in ASP2215 project 
 
 
Updated Section 7.5.4 to add ECG 
abnormalities  
Updated per knowledge learned 
in ASP2215 project 
 
 
Updated Section 7.10 Interim Analysis 
as Not Applicable 
Updated due to protocol version 
3.0 (amendment 2) dated 25-
Apr-2019. 


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Version Date 
Changes 
Comment/rationale for change 
 
 
Updated Section 7.11: 
• 
Added how to handle 
partial date in initial 
diagnosis of AML and 
subsequent AML 
therapy; 
• 
Modified the pooling strata 
section to clarify how strata 
pooling will be performed as 
appropriate. 
• 
Added the blinding section 
For clarification purpose 
 
 
Updated Section 7.11: 
• 
Removed the visit window 
table 
It is redundant 
3.0 
12-Aug-
2021 
Removed PPS and corresponding 
sections and add necessary sensitivity 
analysis to section 7.4 as appropriate 
The company did not endorse this 
analysis. 
 
 
Added the following summaries for 
overview and by SOC/PT: 
• 
TEAEs before investigator 
assessed relapse 
• 
Drug-related TEAEs before 
investigator assessed relapse, 
Was requested by IDMC.  
 
 
Added a table to show the 
definition of RFS and RFS 
variables for sensitivity 
analyses 
Easy for programming team to 
follow 
 
 
Added order of Event for 
EFS if multiple events on 
the same day 
Multiple events might have 
occurred on the same day 
 
 
Removed treatment 
compliance  
The calculation was based on 
unreliable drug accountability 
data 
 
 
Removed subgroup analysis 
per pooled strata 
Due to small sample size, the 
pooled strata may end up with at 
most one factor which has ready 
have subgroup analysis 
 
 


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9 
REFERENCES 
Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality 
of life in leukemia: the Functional Assessment of Cancer Therapy--Leukemia (FACT-Leu) 
questionnaire. Value Health. 2012;15:1051-8. 
Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the 
assessment of outcomes in cancer anemia and fatigue. Semin Hematol. 1997 Jul;34(3 Suppl 
2):13-9. 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 


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10 
APPENDICES 
10.1 
Appendix 1: Key Contributors and Approvers 
List of Key Contributors and Approvers 
Key Contributors 
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role. 


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Primary author (s) 
 
, MS 
 
Oncology Biostatistics 
Data Science 
Astellas Pharma Global Development, 
Inc. 
Contributors and Reviewers 
 
, PhD 
 
Oncology Biostatistics 
Data Science 
Astellas Pharma Global Development, 
Inc. 
 
 
Statistics 
Labcorp 
 
 
 MD  
 
Medical Science   
Astellas Pharma Global Development, 
Inc. 
, MD 
 
 
Medical Science   
Astellas Pharma Global Development, 
Inc. 
 
 
Clinical Sciences 
Astellas Pharma Global Development, 
Inc. 
 PhD 
 
Clinical Pharmacology & Exploratory 
Development  
Astellas Pharma Global Development, 
Inc. 
, PhD 
 
Clinical Pharmacology & Exploratory 
Development  
Astellas Pharma Global Development, 
Inc. 
, PhD 
 
Clinical Pharmacology & Exploratory 
Development  
Astellas Pharma Global Development, 
Inc. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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, MPH 
 
Global Health Economics & Outcomes 
Research (HEOR) – Oncology 
Global Medical Affairs Astellas Pharma 
Global Development, Inc. 
, PhD 
 
Medical Writing 
Astellas Pharma Global Development, 
Inc 
PPD
PPD
PPD
PPD


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Author and Approver Signatories  
(E-signatures are attached at end of document)  
/MS, 
, Oncology Biostatistics/Global Data Science 
was the study statistician for this study and the primary author of this Statistical Analysis 
Plan 
 
 
 
PhD, 
, Oncology Biostatistics/Global Data Science was the global 
statistical lead (STATL) for this project and biostatistics peer reviewer of this Statistical 
Analysis Plan 
 
 
 
This Statistical Analysis Plan was approved by: 
 
 
, MD 
, Global Medical Science 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


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10.2 
Appendix 2: Search Strategy for Adverse Events of Interest 
Risk 
Search Strategy: MedDRA Version 23.0 
Anaphylactic reaction 
Anaphylactic reaction (SMQ Broad) 
Cardiac failure 
Cardiac failure (SMQ Narrow) 
Creatine phosphokinase 
increased 
Rhabdomyolysis/ myopathy (SMQ Narrow) 
Blood creatine phosphokinase abnormal (PT=10005468 and 
Grade >=3) 
Blood creatine phosphokinase increased (PT=10005470 and 
Grade>=3) 
Blood creatine phosphokinase MM increased 
(PT=10005477 and Grade>=3) 
PT: Myalgia 
PT: Myositis 
PT: Muscular weakness 
Diarrhea 
Noninfectious diarrhoea (SMQ Broad) 
Differentiation Syndrome* 
PT: Acute interstitial pneumonitis, Acute kidney injury, 
Acute lung injury, Acute pulmonary oedema, Acute 
respiratory distress syndrome, Acute respiratory failure, 
Anuria, Atypical pneumonia, Blood creatinine increased, 
Blood pressure systolic decreased, Body temperature 
increased, Capillary leak syndrome, Cardiopulmonary 
failure, Cardiorenal syndrome, Cardiorespiratory distress, 
Cough, Differentiation syndrome, Dyspnoea, Febrile 
neutropenia, Fluid overload, Fluid retention, Generalised 
oedema, Hepatorenal failure, Hydraemia, Hypervolaemia, 
Hypotension, Lower respiratory tract infection, Lower 
respiratory tract inflammation, Lung infection, Lung 
infiltration, Multiple organ dysfunction syndrome, 
Noncardiogenic pulmonary oedema, Oedema, Oedema 
peripheral, Pericardial effusion, Pleural effusion, 
Pneumonia, Pneumonitis, Prerenal failure, Pulmonary 
congestion, Pulmonary oedema, Pulmonary toxicity, 
Pyrexia, Renal failure, Renal impairment, Renal injury, 
Respiratory arrest, Respiratory distress, Respiratory failure, 
Weight increased PTs 
Gastrointestinal obstruction 
Gastrointestinal obstruction (SMQ Narrow) 
Gastrointestinal perforation 
Gastrointestinal perforation (SMQ Narrow) 
Liver transaminase 
increased 
Liver related investigations, signs, and symptoms (SMQ 
Narrow) 


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