Conditions: Acute Myeloid Leukemia
Keywords: Gilteritinib ASP2215 Safety and Efficacy Acute Myeloid Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 356
Healthy volunteers: no

Brief summary:
The purpose of this study was to compare relapse-free survival between participants with FLT3/ITD AML in first morphologic complete remission (CR1) who underwent hematopoietic stem cell transplant (HCT) and were randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two year period.

Detailed description:
Participants with FLT3/ITD AML in first morphologic complete remission (CR1) undergone allogeneic hematopoietic stem cell transplant (HCT) were randomized to receive gilteritinib or placebo 30 to 90 days after HCT for a two year period. Participants wiere stratified according to: 1) conditioning regimen intensity (myeloablative vs. reduced intensity/non-myeloablative), 2) time from first day of hematopoietic cell infusion to randomization (30-60 days vs. 61-90 days) and 3) presence vs absence of or unknown minimal residual disease (MRD) from the most recent pre-registration bone marrow (BM) aspirate.

Arms:
arm 1: Participants received gilteritinib 120 milligrams (mg) (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-defined discontinuation criterion was met. arm 2: Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-defined discontinuation criterion was met.

Interventions: intervention 1: gilteritinib intervention 2: Placebo
Intervention descriptions: intervention 1: oral intervention 2: oral

Protocol document:
Prot_000.pdf: 
 
 
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Trial of 
the FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following 
Allogeneic Transplant for Patients with FLT3/ITD AML 
BMT CTN PROTOCOL 1506 
ASTELLAS PROTOCOL 2215-CL-0304 
Version 4.0 dated August 19, 2022 
Protocol History: 
Version 1.0 23Sep2016 
Version 1.1 [JP] Nonsubstantial Amendment 1 dated 09Nov2016 
Version 1.1 [FR] Nonsubstantial Amendment 2 dated 03Nov2016 
Version 1.1 [UK] Nonsubstantial Amendment 3 dated 20Mar2017 
Version 1.1 [DE] Nonsubstantial Amendment 4 dated 03May2017 
Version 1.2 [FR] Nonsubstantial Amendment 5 dated 19Jul2017 
Version 2.0 Substantial Amendment 1 dated 20Nov2017 
Version 2.1 Nonsubstantial Amendment 6 dated 19Feb2018 
Version 2.2 [UK] Nonsubstantial Amendment 7 dated 28Feb2018 
Version 3.0 Substantial Amendment 2 dated 15Mar2019 
Study Chairpersons 
 
 
 
Protocol Team 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
Astellas Pharma Global Development, Inc. 
IND #117,548 
EudraCT #2016-001061-83 
1Massachusetts General Hospital 
 
11Memorial Sloan Kettering Cancer Center 
2Johns Hopkins University 
 
12University of Pennsylvania 
3Astellas Pharma Global Development, Inc. 
 
13Dana-Farber Cancer Institute 
4National Marrow Donor Program 
 
14Rush University Medical Center 
5Ohio State University 
 
15Fred Hutchinson Cancer Research Center 
6CIBMTR / Medical College of Wisconsin 
 
16Washington University, St. Louis 
7University of Kansas 
 
17Emory University 
8Mayo Clinic 
 
18 University of Minnesota  
9Penn State University 
 
19The Emmes Corporation  
10University of Florida  
 
20National Heart, Lung and Blood Institute 
PPD
PPD


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Approval Signature (Protocol Chair/Officer) 
 
 
Approval Signature (Protocol Chair/Officer) 
 
PPD
PPD


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US Core Study Participants:  
 
Baylor College of Medicine 
Dana Farber Cancer Institute Consortium 
Brigham & Women’s Hospital 
Massachusetts General Hospital 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
H. Lee Moffitt Cancer Center 
Johns Hopkins University 
Medical College of Wisconsin 
Memorial Sloan-Kettering Cancer Center 
Mount Sinai Consortium 
Mayo Clinic, Rochester MN 
Vanderbilt University 
Northside Hospital Atlanta Consortium 
BMT Program at Northside Hospital 
University of Miami 
Ohio State Consortium 
Ohio State University 
University of California, San 
Francisco 
University of North Carolina 
Virginia Commonwealth 
University 
Oregon Health & Sciences University 
Consortium 
 
Oregon Health & Sciences University 
 
University Hospitals of Cleveland 
Case Western Reserve University 
Cleveland Clinic Foundation 
Loyola University 
Stanford University 
University of Florida Consortium 
University of Florida 
Emory University Medical Center 
University of Michigan Consortium 
Barbara Ann Karmanos 
Cancer Center 
University of Minnesota 
University of Pennsylvania Cancer Center 
Washington University, Barnes Jewish 
Hospital 
 
Other participating sites 
will include BMT CTN 
Affiliate sites in the US and 
Canada as well as sites in 
Europe and Asia -Pacific.


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List of Abbreviations 
5HT1R 
5-hydroxytryptamine receptor 1 
5HT2BR 
5-hydroxytryptamine receptor 2B 
AE 
Adverse event 
aGRFS 
Acute Graft-versus-host disease-free relapse-free survival 
ALL 
Acute lymphocytic leukemia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
APGD 
Astellas Pharma Global Development 
AST 
Aspartate aminotransferase 
AUST 
Astellas US Technologies 
BCRP 
Breast cancer resistance protein 
BM 
Bone marrow 
BMT 
Bone marrow transplant 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
Ctrough 
Concentration at the end of the dosing interval 
CBC 
Complete blood count 
cGRFS 
Chronic Graft-versus-host disease-free relapse-free survival 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CK 
Creatine kinase 
CMV 
Cytomegalovirus 
CPAP 
Continuous positive airway pressure 
CR 
Complete remission 
CR1 
First morphologic complete remission 
CRF 
Case report form 
CRc 
Composite complete remission rate 
CRi 
Complete remission with incomplete hematologic recovery 
CRO 
Contract research organization 
CRp 
Complete remission with incomplete platelet recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCC 
Data Coordinating Center 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DLI 
Donor lymphocyte infusion 
DLT 
Dose limiting toxicity 
DSMB 
Data Safety Monitoring Board 
EBMT 
European Society for Blood and Marrow Transplantation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EFS 
Event-free survival 
EQ-5D-5L 
EuroQol Group-5 Dimension-5 Level  
EOT 
End of treatment 
FACT-BMT 
Functional Assessment of Cancer Therapy-Bone Marrow Transplant 
FACT-G 
Functional Assessment of Cancer Therapy-General  
FACT-Leu 
Functional Assessment of Cancer Therapy-Leukemia  


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FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FL 
FLT3 ligand 
FLT3 
FMS-like tyrosine kinase 3 
GCP  
Good Clinical Practice 
GEE 
Generalized estimating equations 
GFR 
Glomerular filtration rate 
GMP 
Good Manufacturing Practice 
GVHD 
Graft-versus-host disease 
GVL 
Graft-versus-leukemia 
HBV 
Hepatitis B virus 
HCT 
Hematopoietic cell transplant 
HIV 
Human immunodeficiency virus 
HQL 
Health-related quality of life 
HR  
Hazard ratio 
HSCT 
hematopoietic stem cell transplantation 
HTLV 
Human T-lymphotropic virus 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ID 
Identifier 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalization ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITD 
Internal tandem duplication 
ITT 
Intention-to-treat 
LA-CRF 
Liver Abnormality-CRF 
LFS 
Leukemia-free survival 
LFT 
Liver function test 
MAC 
Myeloablative conditioning 
MRD 
Minimal residual disease 
MTD  
Maximum tolerated dose 
NAAT 
Nucleic acid amplification test 
NCCN 
National Comprehensive Cancer Network 
NDA 
New Drug Application 
NGS 
Next-generation sequencing 
NHLBI 
National Heart, Lung and Blood Institute 
NMA 
Non-myeloablative conditioning  
NRM 
Non-relapse mortality 
NYHA 
New York Heart Association 
OS 
Overall survival 
P-gp 
P-glycoprotein 
PB 
Peripheral blood 
PCR 
Polymerase chain reaction 
PKAS 
Pharmacokinetic analysis set 
PRES 
Posterior reversible encephalopathy syndrome 
PT  
Preferred term 


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QTcF 
Fridericia-corrected QT interval 
R-IWG 
Revised International Working Group  
RFS 
Relapse-free survival 
RIC 
Reduced intensity conditioning 
R/R 
relapsed or refractory 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPRT 
Sequential probability ratio test 
SUSAR 
Suspected unexpected serious adverse reaction 
T4 
Thyroxine 
TBL 
Total bilirubin 
TKI 
Tyrosine kinase inhibitor 
Tregs 
Regulatory T-cells 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
URD  
Unrelated donor 
VAS 
Visual analog scale 
WBC 
White blood cell count 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Version 4.0 Substantial Amendment 3 
19Aug2022 
Version 3.0 Substantial Amendment 2 
15Mar2019 
Version 2.2 [UK] Nonsubstantial Amendment 7 
28Feb2018 
Version 2.1 Nonsubstantial Amendment 6 
19Feb2018 
Version 2.0 Substantial Amendment 1 
20Nov2017 
Version 1.2 [FR] Nonsubstantial Amendment 5 
19Jul2017 
Version 1.1 [DE] Nonsubstantial Amendment 4 
03May2017 
Version 1.1 [UK] Nonsubstantial Amendment 3 
20Mar2017 
Version 1.1 [FR] Nonsubstantial Amendment 2 
03Nov2016 
Version 1.1 [JP] Nonsubstantial Amendment 1 
09Nov2016 
Original Protocol 
23Sep2016 
Amendment 3 [Substantial] 19Aug2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
and EU Clinical Trial Regulation. 
Overall Rationale for the Amendment: 
The primary reason for the amendment is to accommodate the change of the primary analysis 
to 2.5 years after the last participant was randomized. 
Summary of Changes 
Substantial Changes 
Section 
Number 
Description of Change 
Brief Rationale 
Synopsis, 
2.4.3,5.1.5, 
5.2, 5.5.2, 
5.5.3.1 
• 
Change in timing of primary analysis 
• 
Addition of power calculation for 2.5 years 
after last participant was randomized 
To accommodate the change 
of the primary analysis to 2.5 
years after last participant was 
randomized. 
Synopsis, 
2.2.2.2, 
3.2.1, 5.2, 
5.3, 5.5.3.1 
The secondary objective of OS is changed to a key 
secondary objective, and the description of timing 
for the OS analyses is updated. 
To clarify timing of OS 
analyses based upon changes 
to primary analysis timing 
and to add additional OS 
testing if OS is not positive at 
the primary analysis. 
2.4.4 
80% of RFS events have occurred is removed from 
the Criteria for Removal from Study. 
To align with the change in 
timing of the primary 
analysis. 
5.5.2 
Updates made to the sensitivity analyses for the 
primary endpoint analysis of RFS. 
To revise censoring rules for 
participants who completed 
study treatment and no 
information on confirmed 
relapse or death is available. 


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Nonsubstantial Changes 
Section 
Number 
Description of Change 
Brief Rationale 
Cover page 
Update protocol team. 
To provide updated 
information. 
Outline of 
Treatment 
Plan, 2.4.3, 
4.4.5, 5.1.5 
Clarification of duration of follow-up timing for the 
study and for an individual participant. 
To improve clarity. 
1 
Update Introduction language around FLT3 
treatments. 
To align with up-to-date 
literature and gilteritinib 
information. 
1.2.4 
Clinical experience information is updated. 
To align with up-to-date 
literature and gilteritinib 
information. 
2.2.2.3, 
3.3.7 
Addition of FACT-Leu, HQL and GVHD-related 
exploratory objective. 
To compare leukemia-
specific and HQL between 
participants treated with 
Gilteritinib vs. placebo, and 
to compare potential 
interactions between 
treatment with gilteritinib and 
GVHD. 
2.3.1 
Expansion of Inclusion Criterion #12 with 
mandatory UK language for Male contraception 
requirements. 
To align with the UK-specific 
inclusion criteria. 
2.7 
“Discontinuation” is added to text describing Table 
3 and Table 3 title is updated from Dose 
“Reduction” to “Modification” 
To improve consistency with 
details in Table 3. 
2.9.7 
Clarification of unblinding requirements 
To improve consistency and 
clarity. 
3.1, 4.4.5 
(Table 4, 
footnote p), 
5.1.3 
Relapse definition changed from “leukemia” to 
“morphological” 
To improve consistency and 
clarity. 
4.4.5 (Table 
4) 
Removal of concomitant medications assessment at 
30-day follow-up, study drug dispensation at 
24month/EOT 
To improve consistency and 
clarity 
4.6.2 
The classification of “always serious events” is 
updated to “important medical events” 
To align with new 
terminology used in the 
electronic data capture 
system. 
5.1.6 
Removal of PPS 
Analysis set no longer needed 
5.1.6.3 
The reference to the Classification Meeting is 
removed. 
To correct an error as there is 
no longer a Classification 
Meeting. 
5.5.3.7 
“Severity” is updated to “CTCAE grade” 
To improve consistency and 
clarity. 


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Section 
Number 
Description of Change 
Brief Rationale 
5.5.3.8 
Study drug “compliance” is updated to study drug 
“dose intensity.” 
To improve consistency and 
clarity. 
5.5.4.1, 
5.5.4.2, 
5.5.4.3, 
5.5.4.4, 
5.5.4.5 
Addition of details around analysis of HQL, GRFS 
and resource utilization endpoints. 
To provide additional details. 
5.5.4.4 
The subgroup analysis is updated to remove FLT3 
ITD allelic ratio from the diagnostic sample and 
Kaplan-Meier estimates of RFS, and added CR 
status prior to randomization, time from transplant 
to randomization and cytogenic risk factors. 
There are too few of 
participants with data for a 
meaningful analysis. 
Throughout 
Minor administrative-type changes, e.g., typos, 
format, numbering, consistency throughout the 
protocol.   
To provide clarifications to 
the protocol and to ensure 
complete understanding of 
study procedures. 
 
 
 


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PROTOCOL SYNOPSIS 
BMT CTN PROTOCOL 1506 / ASTELLAS PROTOCOL 2215-CL-0304 
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Trial of the 
FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following 
Allogeneic Transplant for Patients with FLT3/ITD AML 
 
Study Chairpersons: 
Yi-Bin Chen, Mark Levis 
 
Study Design:  
This is a double-blind, placebo-controlled, randomized, multi-center 
Phase III trial which participants with FMS-like tyrosine kinase 3 
(FLT3) / internal tandem duplication (ITD) (FLT3/ITD) acute 
myeloid leukemia (AML) in first morphologic complete remission 
(CR1) undergo allogeneic hematopoietic cell transplant (HCT) and 
are randomized to receive gilteritinib or placebo beginning after the 
time of engraftment for a two-year period.  Participants will be 
stratified according to 3 factors: 1) conditioning regimen intensity 
(myeloablative vs reduced intensity/non-myeloablative), 2) time 
from first day of hematopoietic cell infusion to randomization 
(30-60 days vs 61-90 days) and 3) presence vs absence of or 
unknown minimal residual disease (MRD) from a pre-registration 
bone marrow (BM) aspirate.   
 
Primary Objective: 
The primary objective is to compare relapse-free survival (RFS) 
between participants with FLT3/ITD AML in CR1 who undergo 
HCT and are randomized to receive gilteritinib or placebo 
beginning after the time of engraftment for a two-year period.   
 
Secondary Objectives: 
The key secondary objective is: 
1. To compare overall survival (OS) in participants treated with 
gilteritinib as maintenance therapy after HCT compared to 
those treated with placebo. 
Additional secondary objectives include: 
2. To determine the safety and tolerability of gilteritinib after 
HCT.    
3. To compare non-relapse mortality (NRM) and event-free 
survival (EFS) (where events include relapse, death, stopping 
therapy and administration of donor lymphocyte infusion (DLI) 
or new therapy for suspicion of disease) in participants treated 
with gilteritinib as maintenance therapy after HCT compared to 
those treated with placebo. 
4. To compare 6-month cumulative incidence of grades II-IV and 
III-IV acute graft-versus-host disease (GVHD) and 12-month 
and 24-month cumulative incidence of mild, moderate, and 


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severe chronic GVHD in participants treated with gilteritinib as 
maintenance therapy after HCT compared to those treated with 
placebo. 
5. To examine the effect of pre- and post-transplant MRD on RFS 
and OS. 
6. To compare incidence and severity of infection in participants 
treated with gilteritinib as maintenance therapy after HCT 
compared to those treated with placebo.  
 
Eligibility Criteria: 
Participants who are legal adults by local regulation with a 
diagnosis of AML harboring a FLT3/ITD mutation. Participants 
must be in CR1 prior to transplant, as defined by < 5% blasts in the 
BM with no morphologic characteristics of acute leukemia (e.g., 
Auer rods) in the BM with no evidence of extra-medullary 
leukemia. Participants must begin preparative chemotherapy for 
allogeneic transplant as consolidation therapy within 30 days after 
the confirmatory registration BM aspirate. In order to receive the 
study drug, participants must achieve engraftment, defined as 
absolute neutrophil count (ANC) ≥ 500 cells/µL and non-transfused 
platelet count ≥ 20000/µL.  Participants must be registered for the 
study prior to the start of conditioning for the transplant. 
Participants will be allowed to receive any conditioning regimen, 
any GVHD prophylaxis regimen, and HCT from any graft- or 
donor-source. Registered participants who are not randomized will 
be replaced. 
 
Treatment Description: A BM aspirate and/or biopsy will be obtained after engraftment is 
achieved, but prior to initiation of the study drug, to confirm an 
ongoing leukemia-free state. Between days +30 and +90 after the 
start day of transplant (day 0), participants will be randomized and 
initiate study drug, gilteritinib 120 mg orally per day or placebo 
(target initiation time is between days 30 to 45 post HCT).  Study 
drug treatment will continue for 24 months (730 days) from the 
start of therapy.   
 
Accrual Objective: 
This clinical trial will randomize 173 participants per arm 
(346 total participants).   
 
Study Duration: 
The estimated accrual period is 24 months.  Participants will be 
treated and assessed for up to 24 months (730 days) following the 
initiation of study drug.  The primary analysis will occur 2.5 years 
after the last participant was randomized or when approximately 
122 events have been observed for the primary endpoint, 
whichever occurs first.  If RFS is not statistically significant or 
both RFS and OS are statistically significant at the primary 
analysis, the study, including follow-up, will be stopped.  If RFS is 
statistically significant but OS is not statistically significant at the 


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primary analysis, participants will be followed for relapse and 
survival for a total of 5 years after the last participant is 
randomized.  
For an individual participant, study duration will last for 2.5 to 
5.5 years if the RFS is not statistically significant or if both the 
RFS and OS are statistically significant at the primary analysis; 
otherwise, study duration for an individual participant will last up 
to 5 to 8 years. 
 
Lab Correlates: 
DNA will be prepared from pre- and post-transplant BM aspirate 
samples for analysis of MRD using a next-generation sequencing 
(NGS) assay.  Where available, DNA from the participant’s 
diagnostic BM aspirate, or blood if aspirate is not available, will be 
analyzed for FLT3/ITD mutant-to-wild type allelic ratio.  The same 
diagnostic specimen will be analyzed for AML-associated 
mutations using an NGS platform. 


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OUTLINE OF TREATMENT PLAN 
 
 
Abbreviations: AML: acute myeloid leukemia; ANC: absolute neutrophil count; BM: bone marrow; CR1: first 
morphologic complete remission; FLT3: FMS-like tyrosine kinase 3; GVHD: graft-versus-host disease; HCT: 
hematopoietic cell transplant; ITD:  internal tandem duplication; MRD: minimal residual disease. 
 
 


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TABLE OF CONTENTS 
CHAPTER 1 ......................................................................................................................... 1-1 
1. 
BACKGROUND AND RATIONALE .................................................................... 1-1 
1.1. 
Introduction .............................................................................................................. 1-1 
1.2. 
Gilteritinib (ASP2215) ............................................................................................. 1-3 
1.2.1. ASP2215 Mechanism of Action ............................................................................... 1-3 
1.2.2. ASP2215 Pharmacokinetics .................................................................................... 1-4 
1.2.3. ASP2215 Formulation.............................................................................................. 1-4 
1.2.4. ASP2215 Clinical Experience .................................................................................. 1-4 
1.2.5. ASP2215 Dose Rationale ......................................................................................... 1-5 
1.3. 
Rationale ................................................................................................................... 1-5 
CHAPTER 2 ......................................................................................................................... 1-1 
2. 
STUDY DESIGN ...................................................................................................... 2-1 
2.1. 
Study Overview ........................................................................................................ 2-1 
2.2. 
Hypothesis and Specific Objectives ......................................................................... 2-1 
2.2.1. Hypothesis ................................................................................................................. 2-1 
2.2.2. Study Objectives ....................................................................................................... 2-1 
2.3. 
Participant Eligibility ............................................................................................... 2-2 
2.3.1. Registration Eligibility Criteria .............................................................................. 2-2 
2.3.2. Randomization Eligibility Criteria ......................................................................... 2-5 
2.3.3. Inclusion of Women, Minorities and Other Underrepresented Populations ..... 2-7 
2.4. 
Treatment Plan ......................................................................................................... 2-7 
2.4.1. Agent Administration - Gilteritinib versus Placebo ............................................. 2-8 
2.4.2. Duration of Therapy ................................................................................................ 2-8 
2.4.3. Duration of Follow-Up ............................................................................................. 2-9 
2.4.4. Criteria for Removal from Study ........................................................................... 2-9 
2.5. 
Graft-versus-host Disease (GVHD) during Therapy ........................................... 2-10 
2.5.1. Management of Acute GVHD ............................................................................... 2-10 
2.5.2. Management of Chronic GVHD ........................................................................... 2-10 
2.6. 
General Concomitant Medication and Supportive Care Guidelines ................. 2-10 
2.6.1. Antimicrobials ........................................................................................................ 2-10 
2.6.2. Tapering of GVHD Prophylaxis ........................................................................... 2-10 
2.6.3. Donor Lymphocyte Infusions ................................................................................ 2-11 
2.6.4. Prohibited Therapy ................................................................................................ 2-11 
2.6.5. Other Concomitant Treatment (Medication and Non-medication Therapy)... 2-11 
2.7. 
Dose Modifications ................................................................................................. 2-12 
2.8. 
Participant Risks .................................................................................................... 2-13 
2.8.1. Therapy Toxicities.................................................................................................. 2-13 
2.9. 
Study Drug Supply ................................................................................................. 2-13 
2.9.1. Gilteritinib .............................................................................................................. 2-13 
2.9.2. Placebo .................................................................................................................... 2-13 
2.9.3. Packaging and Labeling ........................................................................................ 2-13 
2.9.4. Study Drug Handling ............................................................................................. 2-14 
2.9.5. Blinding ................................................................................................................... 2-15 


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2.9.6. Retention of the Assignment Schedule ................................................................. 2-15 
2.9.7. Breaking the Treatment Code by the Sponsor .................................................... 2-15 
CHAPTER 3 ......................................................................................................................... 2-1 
3. 
STUDY ENDPOINTS .............................................................................................. 3-1 
3.1. 
Primary Endpoint .................................................................................................... 3-1 
3.2. 
Secondary Endpoints ............................................................................................... 3-2 
3.2.1. Overall Survival (OS) .............................................................................................. 3-2 
3.2.2. Safety and Tolerability of Gilteritinib after HCT ................................................. 3-2 
3.2.3. Non-relapse Mortality.............................................................................................. 3-2 
3.2.4. Event-free Survival (EFS) ....................................................................................... 3-2 
3.2.5. Cumulative Incidence of Acute GVHD .................................................................. 3-2 
3.2.6. Cumulative Incidence of Chronic GVHD .............................................................. 3-2 
3.2.7. Detection of Minimal Residual Disease (MRD) ..................................................... 3-2 
3.2.8. Incidence and Severity of Infection ........................................................................ 3-3 
3.3. 
Exploratory Endpoints............................................................................................. 3-3 
3.3.1. Health-related Quality of Life ................................................................................. 3-3 
3.3.2. Resource Utilization ................................................................................................. 3-4 
3.3.3. Rate of Non-randomization ..................................................................................... 3-4 
3.3.4. Gilteritinib Pharmacokinetics ................................................................................. 3-4 
3.3.5. FLT3 Mutation Status at Relapse........................................................................... 3-4 
3.3.6. FLT3/ITD Allelic Frequencies ................................................................................ 3-4 
3.3.7. GVHD-free relapse-free survival (GRFS) ............................................................. 3-4 
3.3.8. Correlative Studies ................................................................................................... 3-5 
CHAPTER 4 ......................................................................................................................... 3-6 
4. 
PARTICIPANT REGISTRATION, ENROLLMENT AND EVALUATION .... 4-6 
4.1. 
Approaching Participants, Eligibility Screening and Obtaining Consent ........... 4-6 
4.2. 
Determination of Eligibility for Randomization .................................................... 4-6 
4.3. 
Randomization Procedure ....................................................................................... 4-6 
4.4. 
Participant Evaluations ........................................................................................... 4-7 
4.4.1. Pre-transplant Evaluations and Requirements ..................................................... 4-7 
4.4.2. Pre-transplant Bone Marrow Aspirate and Biopsy .............................................. 4-8 
4.4.3. Evaluations after Transplant and Prior to Randomization ................................. 4-8 
4.4.4. Evaluations during Treatment ................................................................................ 4-9 
4.4.5. Evaluations after Treatment ................................................................................. 4-11 
4.4.6. Evaluations for Non-Randomized Participants .................................................. 4-16 
4.4.7. Evaluations for Participants who are Randomized but do not Start Study Drug 4-
16 
4.5. 
Data Reporting ....................................................................................................... 4-16 
4.5.1. Criteria for Forms Submission ............................................................................. 4-16 
4.5.2. Reporting Participant Death ................................................................................. 4-16 
4.6. 
AE Reporting .......................................................................................................... 4-16 
4.6.1. Definition of AEs .................................................................................................... 4-16 
4.6.2. Definition of SAEs .................................................................................................. 4-17 
4.6.3. Criteria for Causal Relationship to the Study Drug ........................................... 4-19 


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4.6.4. Criteria for Defining the Severity of an AE ......................................................... 4-19 
4.6.5. Criteria for Defining Expectedness ...................................................................... 4-20 
4.6.6. AE Reporting Guidelines....................................................................................... 4-20 
4.6.7. Monitoring of Common SAEs ............................................................................... 4-20 
4.6.8. Procedure in Case of Pregnancy ........................................................................... 4-21 
4.6.9. Emergency Procedures and Management of Overdose ...................................... 4-21 
CHAPTER 5 ......................................................................................................................... 4-1 
5. 
STATISTICAL CONSIDERATIONS .................................................................... 5-1 
5.1. 
Study Design and Objectives ................................................................................... 5-1 
5.1.1. Accrual ...................................................................................................................... 5-1 
5.1.2. Randomization ......................................................................................................... 5-1 
5.1.3. Primary Endpoint .................................................................................................... 5-1 
5.1.4. Primary Hypothesis ................................................................................................. 5-1 
5.1.5. Duration of Follow-up ............................................................................................. 5-1 
5.1.6. Definition of Analysis Populations.......................................................................... 5-2 
5.2. 
Sample Size and Power Considerations .................................................................. 5-2 
5.3. 
Interim Analysis and Stopping Guidelines ............................................................. 5-3 
5.3.1. Guidelines for Safety Monitoring ........................................................................... 5-3 
5.4. 
Demographic and Baseline Characteristics............................................................ 5-4 
5.5. 
Analysis Plan ............................................................................................................. 5-5 
5.5.1. Participant Disposition ............................................................................................ 5-5 
5.5.2. Analysis of the Primary Endpoint .......................................................................... 5-5 
5.5.3. Analysis of Secondary Endpoints ........................................................................... 5-6 
5.5.4. Analysis of Exploratory Endpoints ........................................................................ 5-9 
5.5.5. Handling of Missing Data, Outliers, Visit Windows and Other Information .. 5-10 
 
List of In-text Tables 
Table 1 
Event Categorizations for Specific Scenarios ....................................................... 2-9 
Table 2 
Strong CYP3A Inducers ...................................................................................... 2-11 
Table 3 
Guidelines for Dose Modification Event ............................................................ 2-12 
Table 4 
Schedule of Assessments .................................................................................... 4-12 
Table 5 
Criteria for Causal Relationship .......................................................................... 4-19 
Table 6 
Definition for Severity of an AE ......................................................................... 4-20 
Table 7 
Operating Characteristics of Sequential Testing Procedure from a Simulation Study 
with 10000 Replications......................................................................................................... 5-4 
 
APPENDIX A: 
Human Subjects 
APPENDIX B: 
Investigator’s Signature 
APPENDIX C: 
Operational and Administrative Considerations 
APPENDIX D: 
New York Heart Association Classification of Cardiac Disease 
APPENDIX E: 
Derivation of a Sequential Test Statistic for Censored Exponential 
Data 
APPENDIX F: 
Karnofsky Performance Status Scale 


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APPENDIX G: 
HCT-specific Comorbidity Index Score 
APPENDIX H: 
List of Excluded and Precautionary Medications 
APPENDIX I:  
Diagnosis and Severity Scoring for Acute and Chronic GVHD 
APPENDIX J:  
Liver Safety Monitoring and Assessment 
APPENDIX K: 
Common Serious Adverse Events 
APPENDIX L: 
Characterization of Conditioning Regimens 
APPENDIX M: 
Correlative Laboratory Studies 
APPENDIX N: 
References 
 


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CHAPTER 1 
 
1. BACKGROUND AND RATIONALE 
1.1. Introduction 
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that confers a 
generally poor prognosis.  Although it can occur in children, its peak incidence is during the 
seventh decade of life.  There are roughly 21000 new cases per year in the US,1 and it has a 
similar incidence in other developed countries, including Europe.  AML patients are now 
routinely stratified at diagnosis into different risk categories based on screening for recurrent 
genetic abnormalities which define unique subtypes of the disease.  Overall survival (OS) for 
AML patients has been increasing each decade, particularly for patients under age 60, 
presumably because of improvements in supportive care, tailoring therapy according to risk 
category, and advances in hematopoietic cell transplant (HCT) techniques.2  However, 
relapse post-allogeneic HCT remains a significant challenge, and novel treatment strategies 
are needed in the post-transplant setting, especially for those with poor prognosis AML. 
Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) receptor are one of the most 
common genetic lesions in AML, and are associated with an overall poor prognosis.3  The 
most common mutation, found in 23% of de novo AML, is a FLT3/internal tandem 
duplication (ITD), usually localized to the juxtamembrane domain.  Point mutations in the 
kinase domain, typically at residue aspartate 835, are found in 7% of cases and only rarely 
are both mutations seen concurrently at initial diagnosis.  Both mutations constitutively 
activate FLT3 and, in the case of ITD mutations, lead to aberrant downstream signaling.  
FLT3 mutations are believed to act as second, or cooperating hits in leukemogenesis,4,5 most 
often occurring with NPM1 mutations and in the context of a diploid karyotype.  De novo 
AML at diagnosis is polyclonal, the relative allelic burden of each mutation reflects the 
mixture of different sub-clones.5  Patients with FLT3/ITD AML who present with a high 
FLT3 mutant allelic burden fare much more poorly than their counterparts with low or 
intermediate allelic ratios.6,7  FLT3/ITD AML patients typically present with leukocytosis and 
a hypercellular bone marrow (BM), and they respond to conventional induction 
chemotherapy with remission rates similar to those seen in other subtypes.  However, they 
are much more likely to relapse and relapse quickly; the presence of a FLT3/ITD mutation at 
relapse is one of the worst prognostic features known.8,9 
Given the aggressive nature of the disease and the exceptionally poor prognosis at relapse, 
allogeneic transplant in first remission is now widely recommended for patients with FLT3 
mutations.10  Allogeneic transplant is the most effective post-remission therapy for reducing 
the risk of relapse in AML, and the preponderance of literature (as well as National 
Comprehensive Cancer Network [NCCN] guidelines) supports this approach for FLT3/ITD 
AML.  However, the literature also suggests that while allogeneic transplant reduces the risk 
of relapse in comparison to consolidation chemotherapy, it is less effective for FLT3/ITD 
AML than for other AML subtypes, that is, patients with a FLT3/ITD mutation are more 
likely to relapse following allogeneic transplant than AML patients lacking a FLT3/ITD 


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mutation.10  This may be a reflection of the fact that patients with FLT3/ITD AML tend to 
have a higher disease burden even in remission (with higher rates of minimal residual disease 
[MRD]).  Furthermore, there are recent data suggesting that for patients with a high FLT3 
mutant allelic burden, even allogeneic transplant confers little benefit.7 Therefore, the 
currently accepted paradigm of induction chemotherapy followed by consolidation with 
allogeneic transplant remains inadequate for many patients. 
FLT3 tyrosine kinase inhibitors (TKIs) have been studied extensively over the past several 
years.11  First generation, multi-targeted TKIs such as lestaurtinib and midostaurin had only 
modest activity, but more recent drugs have shown significant clinical activity as single 
agents.  Effective, sustained FLT3 inhibition induces clearance of peripheral blasts and 
terminal myeloid differentiation of marrow blasts in patients with relapsed or refractory 
FLT3/ITD AML.  Agents such as sorafenib, quizartinib, crenolanib, and gilteritinib can 
induce a complete remission (CR) or, more commonly, a CR with incomplete count recovery, 
in up to half of relapsed patients, and several pivotal randomized trials of these drugs are 
currently underway.  Importantly, there is a growing body of literature suggesting that FLT3 
TKIs can confer clinical benefit in the post-transplant setting.12,13  Two randomized trials of 
sorafenib as maintenance therapy post-transplant in participants with FLT3-ITDmut AML 
showed reductions in the risk of relapse with sorafenib as compared with placebo14 and non-
maintenance.15  In a randomized trial of midostaurin as maintenance therapy post-transplant 
in participants with FLT3/ITD AML, midostaurin added to standard of care improved RFS at 
18 months by 13% compared with standard of care alone.16  As a result of the emerging 
evidence described in the literature, clinical practice recommendations from the European 
Society for Blood and Marrow Transplantation17,18 now recommend post-transplant 
maintenance therapy with an FLT3 inhibitor for patients with FLT3/ITD AML who have 
undergone allogeneic hematopoietic stem cell transplantation (HSCT).  NCCN guidelines, as 
well as guidelines for AML care in Sweden, have also included the option of FLT3 inhibitor 
maintenance therapy for patients with FLT3/ITD AML in remission post-transplant, with 
sorafenib as the recommendation. 
The observed benefits could result from two potential mechanisms.  The first is inhibition of 
an essential kinase in residual AML cells present in the post-transplant BM.  While FLT3 
inhibition may simply lead to suppressed growth of these residual tumor cells, the FLT3 TKI 
may synergize with any graft-versus-leukemia (GVL) effect that exists during the 
maintenance therapy.  This is the same mechanism believed to account for the benefit of 
BCR-ABL inhibitors used in the post-transplant setting for Ph+ acute lymphocytic leukemia 
(Ph+ ALL) or high risk chronic myeloid leukemia.19,20 
The second possible mechanism is immunologic.  Graft-versus-host disease (GVHD) is one 
of the major morbidities of allogeneic transplant, but its collateral effect, namely GVL, forms 
the basis for much of the therapeutic benefit of allogeneic transplant.21  GVHD/GVL is 
thought to be mediated by donor T-cells, counterbalanced by regulatory T-cells (Tregs), 
notably the subset characterized by flow cytometry as CD4+/CD25+/FoxP3+.22  Treg 
homeostasis is directly controlled by myeloid dendritic cells,23 which in turn are dependent 
on FLT3 ligand (FL, the cognate ligand for the FLT3 receptor) for proliferation.24  Increases 


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in FL, therefore, have the effect of expanding the Treg population,25 which is postulated to 
suppress GVHD.  Conversely, FLT3 inhibition would be expected to augment GVHD/GVL.  
While this theoretically could result in significant toxicity to the patient, thus far none of the 
clinical studies have reported worsening GVHD as a limitation of the maintenance therapy 
with FLT3 TKIs.  This includes the randomized placebo-controlled trial of sorafenib as post-
transplant maintenance therapy, in which Grade ≥ 3 adverse events of acute and/or chronic 
GVHD and skin toxicity were reported at a greater incidence in sorafenib-treated participants 
compared with placebo;14 the authors concluded that sorafenib maintenance treatment was 
not significantly more toxic than placebo and that dose reductions to manage adverse effects 
did not appear to abolish efficacy. 
In summary, allogeneic transplant is currently the most effective consolidation therapy for 
patients with FLT3/ITD AML, but relapse after transplant remains a significant problem.  
FLT3 inhibitors have demonstrated clinical activity in this disease, and their use in the post-
transplant setting appears to be safe and tolerable.  The underlying hypothesis of this clinical 
trial is that maintenance therapy with a potent FLT3 inhibitor after allogeneic transplant will 
lead to improved relapse-free survival (RFS) for participants with FLT3/ITD AML.  This 
multi-center international clinical trial is designed to prove or disprove this hypothesis by 
randomizing FLT3/ITD AML participants who have completed an allogeneic transplant to 
maintenance therapy with a FLT3 TKI versus placebo, in double-blind fashion.  Of the FLT3 
TKIs in current clinical development, there are five that would be reasonable choices to study 
in this context: midostaurin,26 sorafenib,26 crenolanib,27 quizartinib,28 and gilteritinib.29  Due 
to less favorable side effect profiles, sorafenib (hand-foot syndrome and gastrointestinal 
toxicity) and both midostaurin and crenolanib (nausea requiring pre-medication) would be 
problematic in a placebo-controlled trial.  Although it is extremely well-tolerated by patients, 
quizartinib is associated with QT prolongation and myelosuppression, both of which could 
complicate the care of post-transplant patients.  Gilteritinib (ASP2215) causes minimal side 
effects, and neither widespread QT prolongation nor myelosuppression were noted in a trial 
enrolling more than 250 participants.  Furthermore, it has been administered as maintenance 
therapy to 16 participants post-transplant, and no significant safety signals were noted.  Of all 
5 compounds, quizartinib and gilteritinib have proven to be the most effective at inhibiting 
FLT3 in vivo, and gilteritinib appears to be the most tolerable.  Gilteritinib, therefore, 
represents the best candidate for this trial. 
1.2. Gilteritinib (ASP2215) 
1.2.1. ASP2215 Mechanism of Action 
Gilteritinib (ASP2215) is a novel small molecule pyrazinecarboxamide derivative with 
inhibitory activity against FLT3.  It has inhibitory activity against the two most common 
FLT3-activating mutations (ITD and kinase domain).  It is active against most resistance-
conferring point mutant forms of FLT3 that arise during therapy with type 2 inhibitors such 
as sorafenib or quizartinib, specifically the kinase domain mutations at residue D835 and the 
gatekeeper mutation at residue F691.30  It is more than 10-fold less potent against KIT.  
Among 79 tyrosine kinases tested, ASP2215 hemifumarate inhibited activities of FLT3, 


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NPM1-ALK, LTK, ALK and AXL kinases at 1 and 5 nmol/L, and TRKA, ROS, RET and 
MER kinases at 5 nmol/L by over 50%.  The half maximal inhibitory concentration (IC50) 
values for FLT3, EML4-ALK, and KIT kinases were 0.291, 1.2, and 229 nmol/L, 
respectively.  ASP2215 hemifumarate inhibited the cell growth of Ba/F3 cells expressing 
FLT3-ITD, FLT3-D835Y, and FLT3-ITD-D835Y with IC50 values of 1.8, 1.6, and 2.1 
nmol/L, respectively.  ASP2215 hemifumarate inhibited the growth of MV4-11 cells with an 
IC50 value of 0.92 nmol/L.  In MV4-11 cells, treatment of ASP2215 hemifumarate at 0, 0.1, 
1, and 10 nmol/L resulted in FLT3 phosphorylation of 100%, 86%, 19%, and 7%, 
respectively.  ASP2215 hemifumarate induced significant growth inhibition of MV4-11 
tumors and tumor regression in vivo.  Further, ASP2215 hemifumarate at 6 and 10 mg/kg per 
day induced complete tumor regression for 4 and 6 out of 6 mice, respectively.  Body weight 
of the mice treated with ASP2215 hemifumarate was not affected at any tested doses. 
1.2.2. ASP2215 Pharmacokinetics 
The main enzyme involved in the metabolism of ASP2215 is estimated to be cytochrome 
P450 (CYP)3A4.  ASP2215 has an induction potential of 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. ASP2215 has direct 
inhibitory effects on CYP2C19 and CYP3A4, but not direct inhibitory effects on CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, or CYP2D6. After oral administration of [14C] ASP2215 
hemifumarate at 1 mg/kg to rats, 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. 
ASP2215 is a substrate for P-glycoprotein (P-gp), but not for breast cancer resistance protein 
(BCRP). ASP2215 has the potential of P-gp and BCRP inhibition.  In AML participants 
treated in the 2215-CL-0101 Phase 1/2 study, the mean half-life of ASP2215 was greater than 
48 hours. 
1.2.3. ASP2215 Formulation 
Please refer to the current version of the ASP2215 Investigator’s Brochure for details on 
gilteritinib tablet formulation. 
1.2.4. ASP2215 Clinical Experience 
Gilteritinib is approved in more than 40 countries for the treatment of adult patients who have 
relapsed or refractory (R/R) AML with a FLT3 mutation. 
In a global phase 3 clinical study (2215-CL-0301), gilteritinib demonstrated improved OS, 
supported by favorable results in event-free survival (EFS), complete remission (CR), 
complete remission/complete remission with partial hematological recovery and transfusion 
dependencies, in participants with FLT3 R/R AML.  Study 2215-CL-0101, a global phase 1/2 
study, provided further support for efficacy, which included prolonged survival and deep 
molecular responses in this participant population.  Gilteritinib monotherapy was well 


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tolerated and generated high composite complete remission (CRc) and best overall response 
(i.e., CRc + partial remission [PR]) rates and promising survival results in participants with 
FLT3 R/R AML.  
Please refer to the current version of the ASP2215 Investigator’s Brochure for more detailed 
information. 
1.2.5. ASP2215 Dose Rationale  
Gilteritinib has been evaluated in relapsed and refractory AML participants 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.  
1.3. Rationale 
This multi-center phase III clinical trial will evaluate the impact of maintenance therapy with 
the FLT3 inhibitor gilteritinib on the RFS of participants with FLT3/ITD AML who have 
successfully undergone allogeneic transplant.  A dose of 120 mg has been chosen on the basis 
of a monotherapy trial, which demonstrated complete FLT3 inhibition in FLT3/ITD AML 
participants.29 A maintenance period of 2 years (24 months) has been chosen based on Center 
for International Blood and Marrow Transplant Research (CIBMTR) data that indicate the 
vast majority of relapses occur by this time after allogeneic HCT. Because it is placebo-
controlled and double-blinded, the results that emerge from this study will establish whether 
or not FLT3 inhibition in this setting can prevent relapse, and whether or not it has an impact 
on GVHD in these participants.  Additionally, the trial may establish the utility of monitoring 
MRD using a next-generation sequencing (NGS) platform.  A validated MRD assay would 
represent an important advance for the field, as it would allow for the design of more 
efficient trials testing novel agents in the treatment of FLT3/ITD AML. 
 


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CHAPTER 2 
2. STUDY DESIGN 
2.1. Study Overview 
The study is a two-arm, double-blind, placebo-controlled, randomized, multi-center trial in 
which participants with FLT3/ITD AML in first morphologic CR (CR1) undergoing 
allogeneic HCT will be randomized to receive gilteritinib or placebo 30 to 90 days after HCT 
for a two-year period. Participants will be stratified according to: 1) conditioning regimen 
intensity (myeloablative vs reduced intensity/non-myeloablative), 2) time from first day of 
hematopoietic cell infusion to randomization (30-60 days vs 61-90 days) and 3) presence vs 
absence of or unknown MRD from the most recent pre-registration BM aspirate.   
2.2. Hypothesis and Specific Objectives 
2.2.1. 
Hypothesis 
The underlying hypothesis of this clinical trial is that maintenance therapy with a FLT3 
inhibitor after allogeneic transplant will lead to improved RFS for participants with FLT3/ITD 
AML in CR1.  The hypothesis will be tested by randomizing participants with FLT3/ITD AML 
who have undergone allogeneic transplant and are in CR1 to one of two arms, in double-blind 
fashion: 1) maintenance therapy with 120 mg per day of the FLT3 inhibitor, gilteritinib; or 2) 
placebo. 
2.2.2. 
Study Objectives 
2.2.2.1. The primary objective is to compare RFS between participants with FLT3/ITD AML 
in CR1 who undergo HCT and are randomized to receive gilteritinib or placebo 
beginning after the time of engraftment for a two-year period.  
2.2.2.2. Secondary objectives include: 
The key secondary objective is to compare OS in participants treated with gilteritinib as 
maintenance therapy after HCT compared to those treated with placebo. 
Additional secondary objectives include: 
● To determine the safety and tolerability of gilteritinib after HCT.    
● To compare non-relapse mortality (NRM) and event-free survival (EFS) (where events 
include relapse, death, stopping therapy and administration of donor lymphocyte infusion 
(DLI) or new therapy for suspicion of disease) in participants treated with gilteritinib as 
maintenance therapy after HCT compared to those treated with placebo. 
● To compare 6-month cumulative incidence of grades II-IV and III-IV acute GVHD 
(aGVHD) and 12-month and 24-month cumulative incidence of mild, moderate, and 
severe chronic GVHD in participants treated with gilteritinib as maintenance therapy 
after HCT compared to those treated with placebo. 
● To examine the effect of pre- and post-transplant MRD on RFS and OS. 
● To compare incidence and severity of infection in participants treated with gilteritinib as 
maintenance therapy after HCT compared to those treated with placebo. 


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2.2.2.3. Exploratory objectives include: 
● To examine health-related quality of life (HQL) 
● To compare leukemia-specific health-related quality of life (as measured by Functional 
Assessment of Cancer Therapy-Leukemia [FACT-Leu]) in participants treated with 
gilteritinib as maintenance therapy after HCT compared to those treated with placebo 
● To assess the effect of gilteritinib as maintenance therapy after HCT compared to placebo 
on disease- and treatment-related symptoms as well the proximal and distal impacts of 
changes in symptoms (e.g., functioning, and health-related quality of life [HQL]) as 
measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplant 
(FACT-BMT), FACT-Leu and EuroQol Group-5 Dimension-5 Level (EQ-5D-5L) 
● To examine healthcare resource utilization 
● To estimate the proportion of participants who are willing and able to be randomized to 
maintenance and describe the frequencies of events that preclude randomization 
● To assess gilteritinib pharmacokinetics using population pharmacokinetic modeling 
● To evaluate FLT3 mutation status and other potential genomic and/or other biomarkers 
that may correlate to treatment outcome 
● To compare GVHD-free relapse-free survival (GRFS), aGVHD-free relapse-free survival 
(aGRFS) and chronic GVHD-free relapse-free survival (cGRFS) in participants treated 
with gilteritinib as maintenance therapy after HCT compared to those treated with 
placebo 
 
2.3. Participant Eligibility 
This trial will have a three-step enrollment process: 
● Enrollment into the screening segment will occur after informed consent is signed 
● Registration will occur prior to HCT after all registration eligibility criteria are met 
● Randomization will occur after HCT once the participant is ready to begin the study drug 
and after all randomization eligibility criteria are met 
 
2.3.1. 
Registration Eligibility Criteria 
Registration will be done prior to HCT.  
2.3.1.1. 
Registration Inclusion Criteria 
A participant is eligible for registration to the clinical study if all of the following apply: 
1. Participant is considered a suitable candidate for HCT and has an acceptable source of 
allogeneic donor cells, as defined per institutional practice (allogeneic HCT for any donor 
source [matched sibling, unrelated donor (URD), mismatched URD, related 
haploidentical, or umbilical cord blood] and any graft source [umbilical cord, BM, 
peripheral blood (PB)], and any conditioning [myeloablative conditioning (MAC), 


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reduced intensity conditioning (RIC), or non-myeloablative conditioning (NMA)] will be 
permitted). 
2. Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written 
informed consent and privacy language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act Authorization (HIPAA) for US sites) obtained from 
the participant or legally authorized representative prior to any study-related procedures 
(including withdrawal of prohibited medication, if applicable). 
3. Participant is considered a legal adult by local regulation at the time of signing informed 
consent form (ICF). 
4. Participant consents to allow access to his or her diagnostic BM aspirate or PB sample 
and/or the DNA derived from that sample, if available, that may be used to validate a 
companion diagnostic that is being developed in parallel with gilteritinib. 
5. Participant has confirmed, morphologically documented AML in CR1. For the purposes 
of registration, CR1 will be defined as < 5% blasts in the BM with no morphologic 
characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of 
extramedullary disease such as central nervous system involvement or granulocytic 
sarcoma. 
a. Participant has not received more than 2 cycles of induction chemotherapy to 
achieve CR1. The induction cycles can be the same regimen or different regimens. 
The regimen(s) may contain conventional agents, investigational agents, or a 
combination of both. 
b. Participants with CR with incomplete count recovery (CRp or CRi) are allowed. 
Incomplete platelet recovery (CRp) is defined as CR with platelet count 
< 100 x 109/L. Incomplete blood count recovery (CRi) is defined as CR with 
residual neutropenia < 1 x 109/L with or without complete platelet recovery. Red 
blood cell count (RBC) and platelet transfusion independence is not required.   
c. The maximum time allowed from establishment of CR1 to registration is 
12 months. 
6. Participant has presence of the FLT3/ITD activating mutation in the BM or PB as 
determined by the local institution at diagnosis. 
7. Participant must meet the following criteria as indicated on the clinical laboratory tests: 
a. Serum creatinine within normal range, or if serum creatinine outside normal 
range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m2 as calculated 
with the Cockcroft-Gault equation with adjustment if total body weight is ≥ 125% 
of ideal body weight. 
b. Total bilirubin (TBL) ≤ 2.5 mg/dL, except for participants with Gilbert’s 
syndrome. 
c. Serum AST and/or alanine aminotransferase (ALT) < 3 x institutional upper limit 
of normal (ULN). 
8. Participant has left ventricular ejection fraction (LVEF) at rest ≥ 40%. 
9. Participant has diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for 
hemoglobin) ≥ 50% predicted and/or forced expiratory volume in 1 second (FEV1) 
≥ 50% predicted. 


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10. Female participants must either: 
● Be of non-childbearing potential: 
o postmenopausal (defined as at least 1 year without menses) prior to 
screening, or 
o documented as surgically sterilized (at least 1 month prior to the screening 
visit) 
● Or, if of childbearing potential,  
o Agree not to try to become pregnant during the study and for 6 months after 
the final study drug administration 
o And have a negative serum pregnancy test at screening  
o And, if heterosexually active, agree to consistently use highly effective 
contraception per locally accepted standards in addition to a barrier 
method starting at screening and throughout the study period and for 
6 months after the final study drug administration. 
11. Female participants must agree not to breastfeed or donate ova throughout the study drug 
treatment period and for 6 months after the final study drug administration. 
12. Male participants (even if surgically sterilized), and their partners who are women of 
childbearing potential must be using highly effective contraception in addition to a 
barrier method throughout the study drug treatment period and for 127 days after the final 
study drug administration.  
In the UK, highly effective forms of birth control include: 
● Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation  
● Established intrauterine device or intrauterine system  
● 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 
13. Male participants must not donate sperm throughout the study drug treatment period and 
for 127 days after the final study drug administration. 
14. Participant is able to take an oral medication. 
15. Participant agrees not to participate in another interventional study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed. 
2.3.1.2. 
Registration Exclusion Criteria  
A participant will be excluded from participation in this clinical study if any of the following 
apply: 
1. Participant has had a prior allogeneic transplant. 
2. Participant has Karnofsky performance status score < 70% (APPENDIX F). 
3. Participant requires treatment with concomitant drugs that are strong inducers of CYP3A 
(APPENDIX H) within 14 days of start of study drug. 


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4. Participant 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 participant (APPENDIX H). 
5. Participant has a Fridericia-corrected QT interval (QTcF) > 450 msec (average of 
triplicate determinations) per central read. 
6. Participant has long QT Syndrome at screening. 
7. Participant has a known infection with human immunodeficiency virus (HIV). 
8. Participant has active hepatitis B infection as determined by nucleic acid amplification 
test (NAAT) or surface antigen assay.  Participants who have acquired immunity from 
past exposure (HBcAb positive/HBsAb positive/HBsAg negative) are eligible. 
9. Participant has active hepatitis C infection as determined by NAAT. NAAT must be 
performed if the participant has positive serology for hepatitis C.  Participants who have 
had past exposure and have no detectable virus either through spontaneous clearance or 
treatment are eligible.   
10. Participant has an uncontrolled infection. If a bacterial or viral infection is present, the 
participant must be receiving definitive therapy and have no signs of progressing 
infection for 72 hours prior to registration. If a fungal infection is present, the participant 
must be receiving definitive systemic anti-fungal therapy and have no signs of 
progressing infection for 1 week prior to registration. 
● Progressing infection is 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. 
11. Participant has had a myocardial infarction within 6 months prior to registration or New 
York Heart Association (NYHA) Class III or IV heart failure (APPENDIX D), 
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic 
evidence of acute ischemia. 
12. Participant has a serious medical or psychiatric illness likely to interfere with 
participation in this clinical study. 
13. Participant is breast feeding or pregnant. 
14. Participant has prior malignancies, except lobular breast carcinoma in situ, fully resected 
basal cell or squamous cell carcinoma of skin 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.  
Waivers to the exclusion criteria will NOT be allowed.   
2.3.2. Randomization Eligibility Criteria 
After engraftment, participants will undergo a BM aspirate and/or biopsy to ensure continued 
CR status.  Engraftment is defined as absolute neutrophil count (ANC) ≥ 500 cells/µL and 
platelets ≥ 20000/µL on 3 consecutive measurements (each occurring at least 1 day apart). 


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The participant must not have had a platelet transfusion within 7 days prior to the first 
measurement.  
BM aspirate and/or biopsy must be performed ≤ 30 days prior to randomization and can be 
repeated if necessary to meet the 30-day requirement. Aspirate is required and BM biopsy in 
addition is preferred. If aspirate is unobtainable (e.g., dry tap), BM biopsy is required.  Once 
aspirate and/or biopsy confirm continued morphological CR status, participants can then 
proceed to randomization.   
2.3.2.1. 
Randomization Inclusion Criteria 
To be randomized, participants must meet the following criteria: 
A. Participant is ≥ 30 days and ≤ 90 days from hematopoietic cell infusion. 
B. Participant has achieved engraftment. Engraftment is defined as ANC ≥ 500 cells/µL and 
platelets ≥ 20000/µL on 3 consecutive measurements (each occurring at least 1 day 
apart). The participant must not have had a platelet transfusion within 7 days prior to the 
first measurement. 
C. Participant has confirmed ongoing morphologically documented AML in CR1. For the 
purposes of randomization, CR1 will be defined as < 5% blasts with no morphologic 
characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of 
extramedullary disease such as central nervous system involvement or granulocytic 
sarcoma. 
D. Participant meets the following criteria as indicated on the clinical laboratory tests: 
● Serum creatinine within normal range, or if serum creatinine outside normal range, 
then GFR > 40 mL/min/1.73m2 as calculated with the Cockcroft-Gault equation 
with adjustment if total body weight is ≥ 125% of ideal body weight. 
● TBL ≤ 2.5 mg/dL, except for participants with Gilbert’s syndrome. 
● Serum AST and/or ALT < 3 x institutional ULN. 
● Serum potassium and magnesium greater than or equal to the institutional lower 
limit of normal. 
E. If the participant has developed overall grades II-IV aGVHD, the following criteria must 
be met to be randomized: 
● No requirement of > 0.5 mg/kg of prednisone (or equivalent) daily dose within 
1 week of randomization 
● No escalation of systemic immunosuppression in terms of increase of 
corticosteroids or addition of new agent/modality within 2 weeks of randomization 
(Note that increasing calcineurin inhibitors or sirolimus to achieve therapeutic 
trough levels is allowed. Topical skin and topical gastrointestinal steroids are 
allowed.) 
F. Participant is able to take oral medication 
Waivers to the inclusion criteria will NOT be allowed. 
2.3.2.2. 
Randomization Exclusion Criteria 
A participant will be excluded from randomization in this clinical study if any of the 
following apply: 


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A. Participant requires treatment with concomitant drugs that are strong inducers of CYP3A 
(APPENDIX H) within 14 days of starting study drug. 
B. Participant requires treatment with concomitant drugs that target serotonin 5HT1R or 
5HT2BR or sigma nonspecific receptor with the exception of drugs that are considered by 
the investigator to be absolutely essential for the care of the participant and for which no 
acceptable alternative exists (APPENDIX H). 
C. Participant has a QTcF interval > 450 msec (average of triplicate determinations) by 
central read. 
D. Participant has a need for supplemental oxygen with the exception of using previously 
existing non-invasive continuous positive airway pressure (CPAP) at night. 
E. Participant has used investigational agents within 4 weeks of randomization. 
F. Participant has used experimental therapy for aGVHD within 4 weeks of randomization. 
If unsure of the definition of “experimental”, discussion with the one of the protocol 
chairs is recommended. 
G. Participant has an uncontrolled infection. If a bacterial or viral infection is present, the 
participant 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 
participant must be receiving definitive systemic anti-fungal therapy and have no signs of 
progressing infection for 1 week prior to randomization. 
● Progressing infection is 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. 
Waivers to the exclusion criteria will NOT be allowed.   
2.3.3. Inclusion of Women, Minorities and Other Underrepresented Populations 
The inclusion and exclusion criteria listed above should have no effect on the enrollment of 
these traditionally underrepresented groups in clinical studies.  Accrual of women and 
minorities will be monitored to determine whether rates of enrollment are reflective of the 
distribution of potentially eligible women and minorities in the population served. 
2.4. Treatment Plan 
Randomization should occur anytime between days 30 to 90 after day zero (the day of 
allograft infusion) of HCT.  BM aspirate and/or biopsy after engraftment after HCT must be 
done to confirm ongoing remission and must be performed ≤ 30 days prior to randomization.  
Please note that the recommended window to randomize participants is between 30 to 
45 days after HCT, but the protocol allows randomization up to day +90 after HCT.  Study 
drug should be started within 24 hours of randomization. Day 1 of the treatment period is 
defined as the date of randomization.  Study drug will be administered on an outpatient basis 
but may be continued in the inpatient setting if participants require inpatient evaluation. 
Expected toxicities and potential risks as well as dose modifications for gilteritinib are 
described in Sections 2.7 and 2.8 (Dose Modifications and Participant Risks).  No 
investigational or commercial agents or therapies other than study drug may be administered 
with the intent to treat the participant’s malignancy. 


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2.4.1. 
Agent Administration - Gilteritinib versus Placebo 
Gilteritinib or placebo is an oral tablet and participants will take 3, 40 mg tablets once daily in 
the morning for continuous daily dosing.  Participants will be instructed to take the daily dose 
with water as close to the same time each morning as possible.  Gilteritinib or placebo can be 
taken at least 2 hours after or 1 hour before consuming food. Study drug will be 
self-administered at home when participants are not scheduled for clinic visits. If participant 
is scheduled for a clinic visit, they will take their medication after the pharmacokinetic blood 
draw.  If a participant forgets to take a dose in the morning (or their pharmacokinetic blood 
draw is on that day) and it is within 6 hours of the planned dosing time, he/she will be 
instructed to take his/her dose. If the participant forgets to take the daily dose (or their 
pharmacokinetic blood draw is on that day) and more than 6 hours has passed the planned 
dosing time, he/she will be instructed to wait for the next morning to dose.  If vomiting 
occurs after dosing, the participant should not receive another dose, but should wait until the 
next morning to dose.  Missed or vomited doses will not be replaced. (Refer to Section 2.7 
for information on dose modifications).  
2.4.2. Duration of Therapy 
Gilteritinib or placebo therapy will continue for a maximum of 24 months (730 days) from 
randomization or until one of the following criteria applies: 
● Disease relapse 
● Unacceptable adverse event (AE)(s), 
● Participant decides to withdraw from treatment 
● Participant does not follow instructions 
● General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
● Participant begins other anti-leukemic therapy.  
If the participant discontinues treatment early, then the reason for treatment discontinuation 
and the date the participant was removed must be documented in the study-specific case 
report form (CRF). Alternative care options will be discussed with the participant.  
Participants removed from treatment for unacceptable AEs will be followed until resolution 
or stabilization of the AE.  
Participants that discontinue treatment early will continue to be followed for relapse, if not 
yet documented, and survival.  
Table 1 below further clarifies the impact of scenarios on event definitions for time-to-event 
analyses and action on specific events and treatment:  


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Table 1 
Event Categorizations for Specific Scenarios 
Scenario 
Event for Relapse-
Free Survival 
(primary endpoint) 
Event for 
Event-Free 
Survival 
Study 
Drug 
Death 
Yes 
Yes 
Stop 
Drug discontinuation 
No 
Yes 
Stop 
Bone marrow blasts ≥ 5% 
Yes 
Yes 
Stop 
Circulating blasts 
Yes 
Yes 
Stop 
Extramedullary blast foci 
Yes 
Yes 
Stop 
Detectable disease (via cytogenetics, flow cytometry or 
PCR) not meeting R-IWG criteria38 for relapse - 
No clinical action taken 
No 
No 
Continue 
Immunosuppression rapidly tapered or stopped because 
of detectable disease (via cytogenetics, flow cytometry 
or PCR), not meeting R-IWG criteria for relapse 
No 
No 
Continue 
Hypomethylating agents, chemotherapy, oral anticancer 
agents, DLI or cellular therapies given because of 
detectable disease (via cytogenetics, flow cytometry or 
PCR), not meeting R-IWG criteria for relapse 
No 
Yes 
Stop 
 DLI given for infectious complications* 
No 
No 
Continue 
DLI given for modulation of T cell chimerism in the 
peri-transplant or the post-transplant period per 
institutional protocol is allowed. 
No 
No 
Continue 
DLI: donor lymphocytic infusion; PCR: polymerase chain reaction; RFS: relapse-free survival; R-IWG: Revised 
International Working Group 
*DLI given for modulation of T cell chimerism in the peri-transplant or the post-transplant period per 
institutional protocol is allowed. 
 
2.4.3. Duration of Follow-Up  
Participants will return to the clinic for study visits while on study drug for up to  24 months 
(730 days) following the initiation of study drug. The primary analysis will occur 2.5 years 
after the last participant was randomized or when approximately 122 events have been 
observed for the primary endpoint, whichever occurs first.  If RFS is not statistically 
significant or both RFS and OS are statistically significant at the primary analysis, the study, 
including follow-up, will be stopped.  If RFS is statistically significant but OS is not 
statistically significant at the primary analysis, participants will be followed for relapse and 
survival for a total of 5 years after the last participant is randomized.  
For an individual participant, study duration will last for 2.5 to 5.5 years if the RFS is not 
statistically significant or if both the RFS and OS are statistically significant at the primary 
analysis; otherwise, study duration for an individual participant will last up to 5 to 8 years.  
2.4.4. Criteria for Removal from Study  
Participants will be withdrawn from study drug when any of the criteria listed in Section 2.4.2 
applies. Participants who complete 24 months (730 days) of study drug and those who 


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discontinue study drug early will continue to be followed for survival and other outcomes 
until one of the following criteria is met: 
● Participant decides to withdraw consent for further follow-up on survival and other 
outcomes. 
● Participant is lost to follow-up despite reasonable efforts by the investigator to locate the 
participant. 
● 5 years have passed from the last participant randomized. 
● Death. 
The reason for study removal and the date the participant was removed must be documented 
in the study-specific CRF.  
2.5. Graft-versus-host Disease (GVHD) during Therapy 
If a participant develops new onset GVHD, or experiences an increase in the severity of 
pre-existing GVHD requiring an escalation of immunosuppressive medication, every effort 
should be made to continue the study drug without any dose reduction.  If the participant is 
unable to take oral medications as a result of GVHD, the study drug can be withheld until the 
participant is able to resume oral medications. 
2.5.1. Management of Acute GVHD 
Acute GVHD should be managed per institutional guidelines.  Therapies considered standard 
are allowed and use of investigational therapy while on study drug is prohibited.  Discussion 
with one of the protocol chairs is recommended if uncertainty exists.  
2.5.2. Management of Chronic GVHD 
Chronic GVHD should be managed per institutional guidelines. Therapies considered 
standard are allowed and use of investigational therapy while on treatment is prohibited.  
Discussion with one of the protocol chairs is recommended if uncertainty exists. 
2.6. General Concomitant Medication and Supportive Care Guidelines 
All medications and concomitant treatments administered from 7 days prior to treatment 
day 1 through the end of treatment visit must be recorded in the electronic case report form 
(eCRF).  
2.6.1. Antimicrobials 
Antibacterial, antiviral and antifungal prophylaxis during and after allogeneic HCT are 
recommended and can be administered based on local institutional guidelines. 
2.6.2. Tapering of GVHD Prophylaxis 
Institutional practice should be followed for tapering immunosuppressive therapy in the 
absence of GVHD.  There are no formal recommendations given that participants receiving 
HCT from any type of donor, after any conditioning and receiving any GVHD prophylaxis 
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2.6.3. Donor Lymphocyte Infusions 
Pre-emptive/prophylactic administration of donor lymphocytes for disease progression is not 
permitted in this protocol. DLI for infectious complications is allowed. DLI given for 
modulation of T cell chimerism in the peri-transplant or the post-transplant period per 
institutional protocol is allowed. 
2.6.4. Prohibited Therapy 
Concomitant use of other anti-cancer therapies, other anti-AML maintenance, or 
investigational agents is not permitted while participants are receiving study drug during the 
treatment phase of the study. Participation in another interventional study while on treatment 
is prohibited. Treatment with concomitant drugs that are strong inducers of CYP3A within 
14 days of start of study drug are prohibited.  These are listed in Table 2 below: 
Table 2 
Strong CYP3A Inducers 
Drug/Food/Supplement Type 
Food, Supplement or Generic Drug Name 
Antiepileptic, Anticonvulsant 
Carbamazepine, Phenytoin 
Antibiotic 
Rifampicin 
Supplement 
St. John’s wort 
CYP: cytochrome P450 
2.6.5. Other Concomitant Treatment (Medication and Non-medication Therapy) 
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 
should be avoided with the exception of drugs that are considered absolutely essential for the 
care of the participant. 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, 
participants should be closely monitored for AEs. 
Precaution should be used in use of gilteritinib with concomitant drugs that are known to 
prolong QT or QTc intervals. 
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 H. The investigator should consult individual labels for all drugs that 
the participant is taking to evaluate if they fall into any of the above named categories.  
Participants undergoing allogeneic transplantation are expected to be receiving treatment 
with a number of approved drugs that are known to be CYP3A substrates and/or inhibitors.  
Because gilteritinib is also a CYP3A4 substrate, drug-drug interactions between the study 
drug and conventional agents (e.g., azoles) are anticipated.  Participating centers will adhere 


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to institutional practice regarding the monitoring of serum levels of immunosuppressive 
agents such as tacrolimus or azoles.  Regardless of which concomitant medications are 
administered, there will be no dose modification of gilteritinib in the absence of drug-related 
toxicity.  
2.7. Dose Modifications 
All AEs occurring after randomization will be reported and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
The study drug will be interrupted if a grade 3 or greater AE occurs and the local principal 
investigator judges that AE to be possibly, probably or definitely related to the study drug.  
When the grade of AE decreases to baseline or grade ≤ 1, the study drug may be resumed at 
the next lower dose level, unless the local investigator deems the AE was, in retrospect, 
unlikely to be or 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 local investigator. Guidelines for dose interruption, reduction and 
discontinuation are provided in Table 3. 
Table 3 
Guidelines for Dose Modification 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 
baseline or grade ≤ 1.  The participant may then resume with one 
dose level reduction (to 80 mg or if currently at 80 mg to 40 mg 
per day).  If participant is at 40 mg per day at the time of the event, 
then study drug will be discontinued.  Resumption at original dose 
level permitted as detailed in Section 2.7. 
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 
baseline or grade ≤1.  The participant may resume treatment at 
40 mg per day.  If participant is at 40 mg per day at the time of the 
event, then study drug will be discontinued. 
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. 
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 the dose that the participant 
was on at the time of the AE. 
Table continued on next page 


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Event 
Action  
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, 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 of the pre-randomization 
ECG 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 the pre-randomization 
ECG, then dose reduction by 1 dose level should be considered.   
AE: adverse event; ECG: electrocardiogram; QTcF: Fridericia-corrected QT interval  
 
2.8. Participant Risks 
2.8.1. Therapy Toxicities 
Please refer to the current ASP2215 Investigators Brochure for details on therapy toxicities.  
2.9. Study Drug Supply 
2.9.1. Gilteritinib 
Gilteritinib is an oral drug that is available in a 40 mg tablet. In addition to the active 
ingredient, gilteritinib 40 mg tablets contain well-characterized excipients. Gilteritinib tablets 
are round light-yellow film-coated tablets. Refer to the current ASP2215 Investigator’s 
Brochure for further details.   
2.9.2. Placebo 
Placebo tablets are identical in size and appearance to gilteritinib tablets and contain well-
characterized excipients. Refer to the current ASP2215 Investigator’s Brochure for further 
details.   
2.9.3. Packaging and Labeling 
All study drug used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Global Development (APGD)-Astellas US 
Technology (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) 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 which identifies the contents as 
investigational drug.  Temperature logs must be maintained by the site with the storage 
temperatures recorded daily (at minimum). Study centers will be provided bottles containing 


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blinded study drug (gilteritinib or placebo).  Refer to the current Pharmacy Manual for 
further details on storage.   
2.9.4. 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: 
● all deliveries are recorded, 
● the study drug is handled and stored according to labeled storage conditions, 
● only study drug with appropriate expiry/retest is dispensed to study participants in 
accordance with the protocol, and 
● all unused study drug is returned to the Sponsor or designee, or standard procedures for 
alternative disposition of unused study drug are followed. 
Study drug inventory and accountability records for the study drugs will be kept by the 
investigator, or designee. Study drug accountability throughout the study must be 
documented and reconciled.  
The following guidelines are therefore pertinent: 
● The investigator agrees not to supply study drugs to any persons except the eligible 
participants in this study in accordance with the protocol. 
● The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs. 
● A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which participant. 
● 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 study drug. Any discrepancies must be accounted for and documented. 
Appropriate forms of deliveries and returns must be signed by the site staff delegated this 
responsibility. 
● The site must return study drug to the Sponsor or designee (after reconciliation by the site 
monitor) at the end of the study or upon expiration. In rare cases, study drug may be 
destroyed at the study site only if agreed upon by the Sponsor. A copy of the standard 
institutional procedure for destroying investigational drugs will be provided to the sponsor 
or designee upon request.  
The following paragraph is specific to investigational sites in 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. 


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● 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 participant 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 participants. 
● The study drug storage manager should prepare and retain records that document 
adequately that the participants were provided the doses specified by the protocol and 
reconcile all the study drugs supplied from the Sponsor. 
2.9.5. Blinding 
This is a double-blind study. Participants 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 participant will know which agent is being administered. The 
randomization number will be assigned based on information obtained from the Interactive 
Response Technology (IRT) system and Advantage eClinicalSM. 
2.9.6. Retention of the Assignment Schedule 
The randomization list and study medication blind will be maintained by the IRT system. 
The Data Safety Monitoring Board (DSMB) will be provided access to the dosing assignment 
for periodic review of the unblinded data as documented in the DSMB Charter and the study-
specific DSMB Charter Addendum. 
2.9.7. Breaking the Treatment Code by the Sponsor 
The Sponsor may break the treatment code for participants 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 for breaking the codes for all SUSAR cases 
for reporting purposes. 
The treatment code for each randomized participant will be provided by the IRT in the event 
of medical emergency or documented morphological relapse requiring knowledge of the 
treatment assigned to the participant. The time, date, participant 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 participants or other study personnel will be made aware of the 
treatment given to any participant unless a medical emergency necessitates such disclosure. 
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.  
● 
Unblinding for participant 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. 


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● 
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.  The Astellas Medical 
Monitor must provide approval for individual participant unblinding for relapse prior to 
the principal investigator unblinding the participant. 
The study will be unblinded after database lock for the primary analysis. 


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CHAPTER 3 
 
3. STUDY ENDPOINTS 
3.1. Primary Endpoint 
The primary endpoint of this study is RFS. RFS will be measured from time of randomization 
to either morphological relapse or death, whichever comes first.  Morphological relapse will 
be defined as BM blasts 5% or higher (not attributable to regenerating BM), any 
circulating blasts (not attributable to regenerating BM or growth factors), or any 
extra-medullary blast foci as per Revised International Working Group (R-IWG) 
criteria. Documentation to support relapse diagnosis must be submitted to the Blinded 
Endpoint Adjudication Committee. Relapse documentation will be dependent on the type of 
relapse and may include but is not limited to: bone marrow biopsy reports, flow cytometry 
reports, tissue biopsy reports, and cerebrospinal fluid analysis reports. 
RFS (or leukemia-free survival; LFS) is the best predictor of both OS for AML patients who 
are in remission and/or have undergone allogeneic transplant.  A tight correlation between 
LFS and OS has been demonstrated to exist in AML patients treated with maintenance 
therapy,31 and a strong association between relapse after transplant and poor survival is 
well-established in the literature.32,33,34  RFS is particularly relevant for the participants in this 
study, as the presence of a FLT3/ITD mutation at relapse is one of the worst prognostic 
features in AML.   Greater than 80% of patients who relapse after allogeneic transplant do so 
within 2 years of transplant.34 Specifically, relapses among transplanted FLT3/ITD+ patients 
generally occur early in post-transplant course; from European Society for Blood and 
Marrow Transplantation (EBMT) and CIBMTR data, their incidence after 2 years of follow-
up in this group is rare.35  
The absence of relapse is also important for maintaining quality of life.  At relapse after 
transplant, the majority of patients undergo intensive therapy, which entails considerable 
morbidity, is largely ineffective to generate durable leukemic control, and is not uncommonly 
fatal due to toxicity.34 Investigational use of FLT3 inhibitors, as well as off-label use of 
sorafenib, is increasingly used in the place of traditional cytotoxic agents to treat post-
transplant FLT3/ITD+ AML relapse.  While available data show this approach to treat overt 
relapse has clinical activity and generally limited toxicity, the durability of both disease- and 
symptom-control is modest, which remains a concern.  Whether FLT3 inhibitor therapy of 
clinical relapse extends OS beyond that achieved with standard chemotherapy is to date 
unproven.  As well, rigorous quality of life comparisons among participants randomized to 
FLT3 inhibitors and traditional chemotherapy approaches have not yet been performed.   
Overall, it is expected that survival of participants who relapse after treatment on this 
protocol will be poor, regardless of whether they receive cytotoxic agents, FLT3 inhibitors, 
and/or cellular therapies such as DLIs. The vast majority of AML patients who relapse after 
transplant either die of their disease or die during attempts to re-achieve subsequent 
remissions. RFS therefore remains the single most important endpoint in a trial of 


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post-transplant AML patients in remission, as it correlates with both prolongation of survival 
and with quality of life after transplant. 
3.2. Secondary Endpoints 
3.2.1. Overall Survival (OS) 
The key secondary efficacy endpoint is OS. Time to OS is defined as the time to death from 
any cause after randomization. For surviving participants, non-events will be censored at the 
last known alive date.  
3.2.2. Safety and Tolerability of Gilteritinib after HCT 
All grade ≥ 3 toxicities according to CTCAE version 4.03 will be tabulated for each 
treatment arm.  The proportion of participants developing grade ≥ 3 AEs across treatment 
arms will be compared.  In addition, the incidence of all grade 1 to 4 toxicities according to 
CTCAE version 4.03 will be tabulated for each treatment arm and compared. Clinical 
laboratory evaluations and change from baseline will be described and compared. 
Electrocardiogram (ECG) results and change from baseline will be described and compared. 
Karnofsky Performance Status scores will be described and compared. The duration of drug 
use and dose of drug use will also be compared. 
3.2.3. Non-relapse Mortality  
An event for this endpoint is death without evidence of disease progression or recurrence.  
3.2.4. Event-free Survival (EFS) 
The cumulative incidence at 12 months and 24 months after randomization of EFS will be 
described and compared.  Events for EFS are as defined in Section 2.4.2. 
3.2.5. Cumulative Incidence of Acute GVHD 
The cumulative incidence at 6 months after randomization of grades II-IV and grades III-IV 
aGVHD will be described and compared.  Acute GVHD will be graded according to diagnosis 
and severity scoring used by the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN) (APPENDIX I).   
3.2.6. Cumulative Incidence of Chronic GVHD 
The cumulative incidence at 12 months and 24 months after randomization of chronic GVHD 
will be described and compared. Chronic GVHD will be graded according to diagnosis and 
severity scoring from the NIH 2014 Consensus Criteria (APPENDIX I).    
3.2.7. Detection of Minimal Residual Disease (MRD) 
The cumulative incidence of detection of FLT3/ITD MRD in participants who are FLT3/ITD 
MRD undetectable prior to randomization will be described.  Similarly, the pattern of 
eradication of FLT3/ITD MRD in participants who have detectable FLT3/ITD MRD prior to 
randomization will be described. 


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3.2.8. Incidence and Severity of Infection 
The cumulative incidence of CTCAE grades 3 to 5 infection in participants will be described 
and compared. 
3.3. Exploratory Endpoints 
3.3.1. Health-related Quality of Life 
The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) 
version 4.0 instrument is comprised of a general core questionnaire, the Functional 
Assessment of Cancer Therapy-General (FACT-G), which evaluates the HQL of participants 
receiving treatment for cancer, and a transplant-specific module, bone marrow transplant 
(BMT) Concerns, that addresses disease and treatment-related questions specific to 
BMT.  The FACT-G consists of four subscales developed and normed in cancer 
participants:  Physical Well-being, Social/Family Well-being, Emotional Well-being, and 
Functional Well-being.  Each subscale is positively scored, with higher scores indicating 
better functioning.  The FACT-BMT Total, which is the grand total of all items in the 
FACT-G and BMT modules, will be used as the outcome measure in summarizing the 
FACT-BMT data. 
The FACT-Leu is a modular approach to assess patient HQL and leukemia-specific 
symptoms using a ‘core’ set of questions (FACT-G), as well as a cancer site-specific 
leukemia subscale.36,37 The FACT-G will be administered as part of the FACT-BMT and it 
will not be repeated in the FACT-Leu. Only the leukemia-specific subscale consisting of 
17 items that assess patient concerns relating to leukemia (FACT-Leu) will be administered. 
Higher scores are reflective of better HQL. The FACT-Leu total score (score range: 0-176; 
combining FACT-Leu with the FACT-G scores from the FACT-BMT) will be used in 
analysis. 
The EQ-5D-5L is a self-reported questionnaire. The EQ-5D-5L is being used as a measure of 
respondent’s HQL. 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 HQL. 
HQL will be described from pre-transplant to last follow-up at 24 months after 
randomization. Additionally, HQL will be compared between the maintenance arms utilizing 
the FACT-BMT self-report, transplant-specific questionnaire, FACT-Leu, and the EQ-5D-
5L. The questionnaires will be scored according to standard procedures.  The self-report 
questionnaires will be completed prior to transplant, prior to randomization, on day 29, and at 
months 3, 6, 12, 18, and 24 after randomization. Comparisons of quality of life will be done 
between maintenance arms at each of the time points after randomization.  


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3.3.2. Resource Utilization 
Resource utilization will be assessed from randomization through end of treatment and will 
include hospitalization or emergency department visits (duration, underlying reasons, and 
setting specified: general ward, ICU, etc.), antibiotic use, and medication for AEs. 
3.3.3. Rate of Non-randomization 
The proportion of participants and reason for not achieving randomization 90 days post 
allogeneic HCT will be described. 
3.3.4. Gilteritinib Pharmacokinetics 
Gilteritinib concentrations will be measured at specified time points and used to perform 
population pharmacokinetic analysis. 
3.3.5.  FLT3 Mutation Status at Relapse 
FLT3 mutation(s) will be assessed from BM aspirates or blood samples obtained at time of 
relapse. 
3.3.6. FLT3/ITD Allelic Frequencies 
FLT3/ITD allelic frequencies will be analyzed using the diagnostic specimens when 
available. 
3.3.7. GVHD-free relapse-free survival (GRFS) 
GVHD-free relapse-free survival, aGRFS and cGRFS will be assessed in participants treated 
with gilteritinib as maintenance therapy after HCT compared to those treated with placebo.  
GRFS 
Time to GRFS is defined as the time from the date of randomization until the date of 
treatment-emergent aGVHD III-IV, or treatment-emergent chronic GVHD that requires new 
or additional immunosuppressive treatment, or morphological relapse (adjudicated by the 
Blinded Endpoint Review Committee) or death from any cause, whichever occurs first. 
Participants who are still alive and no GRFS event at the time of analysis will be censored at 
the last disease assessment without relapse or at the analysis cutoff date, whichever is earlier. 
aGRFS 
Time to aGRFS is defined as the time from the date of randomization until the date of 
treatment-emergent aGVHD III-IV, or morphological relapse (adjudicated by the Blinded 
Endpoint Review Committee) or death from any cause, whichever occurs first. Participants 
who are still alive and no aGRFS event at the time of analysis will be censored at the last 
disease assessment without relapse or at the analysis cutoff date, whichever is earlier.  
Treatment-emergent aGVHD III-IV event is defined as: 
• Development of new grade III-IV aGVHD after randomization  
• Worsening in the grade of aGVHD at the time of randomization by one point (e.g., 
grade II aGVHD at the time of randomization, progressing to grade III or more after 
randomization) 


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cGRFS 
Time to cGRFS is defined as the time from the date of randomization until the date of 
treatment-emergent chronic GVHD that requires new or additional immunosuppressive 
treatment, or morphological relapse (adjudicated by the Blinded Endpoint Review 
Committee) or death from any cause, whichever occurs first. Participants who are still alive 
and no cGRFS event at the time of analysis will be censored at the last disease assessment 
without relapse or at the analysis cutoff date, whichever is earlier.  
Treatment-emergent chronic GVHD event is defined as: 
• Development of new mild, moderate or severe chronic GVHD that requires new or 
additional immunosuppressive treatment after randomization  
• Worsening in the grade of chronic GVHD that requires new or additional 
immunosuppressive treatment at the time of randomization by one point (e.g. mild 
chronic GVHD at the time of randomization, progressing to moderate or severe chronic 
GVHD after randomization) 
3.3.8. Correlative Studies 
The presence or absence of additional AML-associated genomic and/or other biomarkers that 
may correlate to treatment outcome may be analyzed using the BM samples from diagnosis, 
during treatment, and the blood or BM samples from the time of relapse. Correlative analyses 
with other trial endpoints may be performed. In addition, future studies may be performed 
using the samples. 


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CHAPTER 4 
4. PARTICIPANT REGISTRATION, ENROLLMENT AND EVALUATION 
4.1. Approaching Participants, Eligibility Screening and Obtaining Consent 
Potential participants will be approached for this study after the decision to proceed with 
transplantation is made and a suitable donor is identified.  The principal investigator or 
designee at each study site will evaluate participant eligibility. Informed consent will be 
obtained via a signature on the IRB or IEC approved consent form prior to performing study 
specific procedures and within 84 days before the start of the pre-transplant conditioning 
regimen.  Once the participant has provided and signed consent, the participant will be 
enrolled in the screening segment of Advantage eClinical and assigned a participant 
identification number.  After consent, a BM aspirate and biopsy will be obtained.  The 
pre-transplant conditioning regimen must begin ≤ 30 days after this biopsy.  The first 2 cc of 
BM aspirate will be collected and sent to the central laboratory for assessment of MRD.  The 
remainder of the aspirate and the core biopsy will be used to confirm ongoing remission prior 
to transplant.  Aspirate is required and BM biopsy in addition is preferred. If aspirate is 
unobtainable (e.g., dry tap), BM biopsy is required. Once CR and other eligibility criteria 
(per Section 2.3.1.1) are confirmed, the participant will be registered through the Advantage 
eClinical system. 
4.2. Determination of Eligibility for Randomization 
Beginning on day 30 and no later than day 90 after the first infusion of hematopoietic cells, 
the study site principal investigator or designee will determine if the participant is eligible to 
begin the study drug per criteria in Section 2.3.2.  The recommendation is for participants to 
start as soon as medically able after HCT with a recommended window of randomization at 
days 30 to 45 after HCT.  Also note that a repeat BM aspirate and biopsy is required after 
engraftment to ensure that the participant remains in CR.  If eligibility is confirmed, the 
participant is randomized and begins study drug within 24 hours of randomization.  
4.3. Randomization Procedure 
Participants will be randomized using the IRT system.  Upon successful completion of the 
enrollment form, the confirmation of randomization will be displayed.  
Participants will be stratified by: 1) conditioning regimen intensity (myeloablative vs reduced 
intensity/non-myeloablative), 2) time from day 0 of HCT to randomization (30-60 days vs 
61-90 days), and 3) presence or absence of or unknown MRD on pre-HCT BM aspirate (most 
recent aspirate should be used).  Conditioning regimen intensity is defined using the 
CIBMTR Guidelines39 (APPENDIX L). The conditioning regimen used for stratification may 
be adjudicated by the protocol chairs and protocol officer according to the Conditioning 
Regimen Adjudication Charter or the regimen does not appear in APPENDIX L or follow its 
guidance.  


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4.4. Participant Evaluations 
4.4.1. Pre-transplant Evaluations and Requirements 
The following observations will be made < 30 days before initiating the pre-transplant 
conditioning regimen and prior to registration: (unless otherwise specified). 
1. Medical and Disease History (including documented FLT3/ITD mutation positive status 
from original diagnosis)  
2. Physical examination, including vital signs (blood pressure), height and weight  
3. Karnofsky performance status score (APPENDIX F) 
4. HCT-specific Comorbidity Index score (APPENDIX G)  
5. CBC and white blood cell count (WBC) with differential.  CBC includes hemoglobin, 
hematocrit and platelets.  WBC with differential includes relative and ANCs, relative and 
absolute lymphocyte counts and blasts 
6. Liver functions and blood chemistries: sodium, potassium, chloride, bicarbonate, albumin, 
blood urea and/or blood urea nitrogen, glucose, serum creatinine, magnesium, phosphate, 
calcium, TBL, alkaline phosphatase (ALP), AST, ALT and CK.  The corrected calcium 
will be calculated in the CRF 
7. Thyroid function: thyroid stimulating hormone (TSH) and free thyroxine (T4) 
8. Estimated creatinine clearance, using the Cockcroft-Gault formula and actual body weight 
9. Infectious disease markers (may be performed < 42 days before the start of the 
pre-transplant conditioning regimen): cytomegalovirus (CMV) antibody, Hepatitis panel 
(HepB surface antigen, HepB core antibody, HepC antibody). Additional markers may be 
performed according to local standard.  If any of the hepatitis B tests are positive, then a 
hepatitis B virus (HBV) DNA test is required 
10. ECG (may be performed < 42 days before the start of the pre-transplant conditioning 
regimen). 12-lead ECGs will be recorded in triplicate (3 separate ECGs, 10 minutes resting 
prior to first ECG and at least 5 minutes apart per time point) and transmitted electronically 
for central reading. The mean QTcF of the triplicate ECG tracings from central read must 
be used for eligibility, all final treatment decisions and AE reporting.  
11. Echocardiogram or multigated acquisition scan (as per standard of care) for LVEF (may 
be performed < 84 days before the start of the pre-transplant conditioning regimen) 
12. Pulmonary function tests, including DLCO and/or FEV1 (may be performed < 84 days 
before the start of the pre-transplant conditioning regimen) 
13. Pregnancy test (serum hCG) for women of childbearing potential as defined in 
Section 2.3.1.1 (must be performed < 7 days prior to the start of the pre-transplant 
conditioning regimen) 
14. HQL assessments (FACT-BMT, FACT-Leu and EQ-5D-5L) 


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4.4.2. Pre-transplant Bone Marrow Aspirate and Biopsy 
After the participant signs consent and prior to registration, a BM aspiration and/or biopsy is 
performed in order to: 
1. Obtain first 2 cc of BM aspirate sample for analysis of MRD 
2. Obtain 5 cc (or per institutional requirement) BM aspirate and/or biopsy to confirm CR. 
Aspirate is required and BM biopsy in addition is preferred. If aspirate is unobtainable 
(e.g., dry tap), BM biopsy is required. 
The BM aspirate and/or biopsy are to be performed < 30 days prior to the start of the 
pre-transplant conditioning regimen. Details on the MRD laboratory sample collection will be 
detailed in the Laboratory Manual(s).  
Once this BM biopsy confirms CR and all other eligibility is confirmed, the participant can be 
registered. 
4.4.3. Evaluations after Transplant and Prior to Randomization 
The following evaluations to determine eligibility for randomization to maintenance therapy 
or establish baseline at randomization, will be done after engraftment and ≤ 14 days prior to 
randomization (unless otherwise specified).   
1. Medical and Disease History. Details on conditioning regimen, HCT, and engraftment will 
also be collected. 
2. Physical examination, including vital signs (blood pressure), and weight 
3. Triplicate ECG. Central read for ECG is used for eligibility. It is advised that the ECG is 
scheduled at least 3 days prior to the planned randomization date. 
4. Karnofsky performance status score (APPENDIX F) 
5. CBC and WBC with differential. CBC includes hemoglobin, hematocrit and platelets.  
WBC with differential includes relative and ANCs, relative and absolute lymphocyte 
counts and blasts. 
6. Liver functions and blood chemistries: sodium, potassium, chloride, bicarbonate, albumin, 
blood urea and/or blood urea nitrogen, glucose, serum creatinine, magnesium, phosphate, 
calcium, TBL, ALP, AST, ALT and CK 
7. Thyroid function: TSH and free T4 
8. Pregnancy test (serum hCG) for women of childbearing potential as defined in 
Section 2.3.1.1 (must be < 72 hours before randomization) 
9. BM evaluation:  BM aspirate for MRD and BM aspirate and/or biopsy for confirmation 
of CR (may be completed < 30 days before randomization). For confirmation of CR, 
aspirate is required and BM biopsy in addition is preferred. If aspirate is unobtainable 
(e.g., dry tap), a BM biopsy is required. 
10. Formal assessment of acute and chronic GVHD (APPENDIX I) 


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11. Infection assessment 
12. Concomitant medication review 
13. HQL (FACT-BMT, FACT-Leu and EQ-5D-5L) 
4.4.4. Evaluations during Treatment 
Upon initiation of study drug, weekly laboratory monitoring, toxicity assessment and GVHD 
assessment is required for the first 4 weeks.  Monitoring and assessment is then required once 
every month for the following 5 months of treatment and then once every 2 months for the 
second 6 months of treatment, and then every 3 months for the second year of treatment. 
Unscheduled visits and laboratory monitoring may occur as needed.  Participants who 
discontinue treatment early will have assessments performed according to the month 24 visit, 
with the exception of BM aspiration and/or biopsy, which will continue to be performed 
according to institutional standard of care through first relapse.  If a participant discontinues 
for relapse, an End of Treatment (EOT) MRD sample is not required. 
The following required observations are performed after initiation of maintenance therapy. 
These evaluations will occur at all study visits (unless otherwise specified). Please also 
refer to Table 4. 
1. Physical examination including vital signs (blood pressure) and weight 
2. Triplicate ECG. If the mean triplicate QTcF on day 8 has increased > 30 ms compared to 
the mean triplicate QTcF of the pre-randomization ECG with no other known etiology, 
then a confirmatory ECG will be performed on day 9. If the day 9 mean triplicate QTcF 
also shows an increase of > 30 ms compared to that of the pre-randomization ECG, then 
dose reduction by 1 dose level should be considered. 
3. Karnofsky performance status score (APPENDIX F) 
4. CBC and WBC with differential.  CBC includes hemoglobin, hematocrit and platelets.  
WBC with differential includes relative and ANCs, relative and absolute lymphocyte 
counts and blasts.  
5. Liver functions and blood chemistries: sodium, potassium, chloride, bicarbonate, albumin, 
blood urea and/or blood urea nitrogen, glucose, serum creatinine, magnesium, phosphate, 
calcium, TBL, ALP, AST, ALT and CK.  The corrected calcium will be calculated in the 
eCRF. 
6. Thyroid function: TSH and free T4 
7. Pregnancy test (serum hCG) for women of childbearing potential to be performed 
8. BM evaluation: a BM aspirate for MRD and a BM aspirate and/or biopsy for disease 
evaluation. For disease evaluation, a BM aspirate is required and BM biopsy in addition is 
preferred. If aspirate is unobtainable (e.g., dry tap), a BM biopsy is required. An MRD 
sample is not required at EOT if a participant discontinues treatment due to relapse. 
Documentation to support relapse diagnosis must be submitted to the Blinded Endpoint 
Adjudication Committee. Relapse documentation will be dependent on the type of relapse 
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tissue biopsy reports, and cerebrospinal fluid analysis reports. BM will be collected at the 
following time points after randomization:  
a. 3 months ± 1 week  
b. 6 months ± 1 week  
c. 12 months ± 2 weeks 
d. 18 months ± 4 weeks 
e. 24 months ± 4 weeks 
9. AE/serious adverse event (SAE) assessment 
10. Symptom-driven acute and chronic GVHD assessment. Information on acute and chronic 
GVHD will be collected at all study visits. 
11. Infection assessment 
12. Concomitant medication review 
13. HQL (FACT-BMT, FACT-Leu and EQ-5D-5L) at day 29, and at 3, 6, 12, 18 and 24 months 
after randomization 
14. Resource Utilization: Beginning at randomization through EOT details on antibiotic use, 
medications used for AEs, hospitalizations and emergency department visits will be 
collected. 
15. Pharmacokinetic samples for gilteritinib will be collected on treatment day 8 predose, day 
15 predose, day 29 predose and predose at every subsequent treatment visit in the ongoing 
treatment period (within 0.5 hour before drug administration). Details on laboratory sample 
collection will be detailed in the Laboratory Manual. 
16. If disease recurs, a sample of PB or BM aspirate, whichever is available, should be sent to 
the reference lab for detection of FLT3 mutations as detailed in the Laboratory Manual. 
Information on subsequent AML therapies will be collected. 


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4.4.5. Evaluations after Treatment 
Participants who complete treatment, or who discontinue early from treatment, will continue 
to be followed for relapse (if not yet occurred) and survival assessments.  A 30-day follow-up 
(+ 7 days) will be conducted for safety follow-up and a long-term follow-up will be 
conducted every 3 months for relapse and survival contact.  The 30-day follow-up will start 
at the participant’s EOT visit; long-term follow-up starts 3 months after the participant’s 
EOT visit.  Additional contacts may be required for data sweeps.  The following observations 
are required after study drug has been discontinued.  
1. Safety follow-up at the 30-day follow-up only.  
2. Disease evaluation according to institutional standard of care until relapse. If disease 
recurs, a sample of PB or BM aspirate, whichever is available, should be sent to the 
reference lab for detection for FLT3 mutations as detailed in the Laboratory Manual. 
Information on first disease relapse including laboratory results and reports will be 
collected. Documentation to support relapse diagnosis must be submitted to the Blinded 
Endpoint Adjudication Committee. Relapse documentation will be dependent on the type 
of relapse and may include but is not limited to the following: bone marrow biopsy 
reports, flow cytometry reports, tissue biopsy reports, and cerebrospinal fluid analysis 
reports. Information on subsequent AML therapies will be collected. 
3. Contact for Relapse and Survival – every 3 months (± 2 weeks) after the EOT visit for up 
to 5 years after the last participant is randomized if RFS is statistically significant but OS 
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Footnotes: 
a. Randomization to occur 30 – 90 days after start date of HCT. Day 1 of the treatment period is defined as the date of randomization. Study drug should begin within 24 hours of 
randomization 
b. Participants who discontinue treatment early will have assessments performed according to the month 24 visit, with the exception of BM aspirate and/or biopsy, which will 
continue to be performed according to the time points in Section 4.4.4 through relapse. An EOT MRD sample is not required if the participant discontinues treatment due to 
relapse. 
c. Informed consent must be obtained within 84 days prior to the start of the pre-transplant conditioning regimen. 
d. Results of FLT3 mutation local testing do not affect eligibility at this time point as participants will be in CR.  The documentation of an FLT3-ITD mutation in the past will satisfy 
eligibility criteria.  Additionally, medical history will include any abnormality that occurs until randomization. 
e. Infectious disease markers to include CMV Ab, HepB sAg, HepB Core Ab, HepC Ab. Additional markers may be performed per local standard. If any of the HepB tests is 
positive, then an HBV DNA test is required.  
f. CBC includes hemoglobin, hematocrit and platelets. WBC with differential includes relative and ANCs, relative and absolute lymphocyte counts and blasts.  Serum chemistry 
includes sodium, potassium, chloride, bicarbonate, albumin, blood urea and/or blood urea nitrogen, creatinine, glucose, calcium, phosphate, magnesium, and creatine kinase.  
Liver function tests include AST, ALT, ALP and total bilirubin. TFTs include TSH and free T4. The corrected calcium will be calculated in the CRF. 
g. WOCBP must have a negative serum pregnancy test. Pre-registration pregnancy test must be performed ≤ 7 days prior to the start of the pre-transplant conditioning regimen and 
within 72 hours of randomization. 
h. Pre-randomization BM aspirate may be performed ≤ 30 days prior to randomization.  
i. Aspirate is required and BM biopsy in addition is preferred. If aspirate is unobtainable (e.g., dry tap), a BM biopsy is required. 
j. 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). The mean QTcF of the 
triplicate ECG tracings based on central reading will be used for eligibility, all final treatment decisions and AE reporting. It is advised that the ECG be scheduled at least 3 days 
prior to the planned randomization date.  
k. If the mean triplicate QTcF on day 8 has increased > 30 ms compared to the mean triplicate QTcF of the pre-randomization ECG with no other known etiology, then a 
confirmatory ECG will be performed on day 9. If the day 9 mean triplicate QTcF also shows an increase of > 30 ms compared to that of the pre-randomization ECG, then dose 
reduction by 1 dose level should be considered.    
l. PFTs and MUGA or Echo may be performed up to 84 days prior to the start of the pre-transplant conditioning regimen. 
m. AEs and SAEs will be collected from the time of randomization through 30 days after the last dose of study drug.  In addition, investigators should report any SAE that occurs 
after consent and prior to randomization that is assessed as related to invasive study-related procedures apart from the HCT, as well as any SAEs assessed as related to study drug 
that happen after the 30-day follow-up period. 
n. Health-related quality of life questionnaires include FACT-BMT, FACT-Leu and EQ-5D-5L. 
o. Pharmacokinetic samples for gilteritinib will be collected within 0.5 hours before drug administration. 
p. Documentation to support morphological relapse diagnosis must be submitted to the Blinded Endpoint Adjudication Committee. Relapse documentation will be dependent on the 
type of relapse and may include but is not limited to: bone marrow biopsy reports, flow cytometry reports, tissue biopsy reports, and cerebrospinal fluid analysis reports. 
 
Footnotes continued on next page 


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Please note the following allowed windows for visits/assessments listed in the table above:  
Day 8, 15, 22 and 29: ± 1 business day 
Months 2-6:  ± 1 week 
Months 8, 10, 12 are ± 2 weeks 
Months 15, 18, 21, 24: ± 4 weeks 
30-day follow-up: + 7 days 
Every 3 months follow-up: ± 2 weeks 
The monthly visits refer to the end of each month – i.e., Month 2 occurs at the end of the 2nd month of treatment, etc. 
 


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4.4.6. Evaluations for Non-Randomized Participants  
For participants who registered, but are not randomized, the reason for not proceeding to 
randomization will be recorded in Advantage eClinical.  
4.4.7. Evaluations for Participants who are Randomized but do not Start Study Drug  
Participants who are randomized but do not start therapy must only be followed for relapse 
and survival according to the long-term follow-up instructions in Table 4. 
4.5. Data Reporting 
4.5.1. Criteria for Forms Submission  
Forms that are not entered into Advantage eClinical within the specified time will be 
considered delinquent.  A missing form will be requested either until the form is entered into 
the Advantage eClinical and integrated into the Data Coordinating Center’s (DCC) master 
database, or until an exception is granted and entered into the Missing Form Exception File. 
4.5.2. Reporting Participant Death 
If a participant death occurs during the SAE collection period (see Section 4.6), information 
must be entered into Advantage eClinical within 24 hours of knowledge of the participant’s 
death. If a participant death occurs during the long-term follow-up period, information must 
be entered into Advantage eClinical according to the standard entry timelines. If the cause of 
death is unknown at that time, it does not need to be recorded at that time.  However, once 
the cause of death is determined, the form must be updated in Advantage eClinical. 
4.6. AE Reporting 
AE reporting requirements are summarized below and further information regarding AEs is 
described in APPENDIX K.  AEs and SAEs will be collected from the time of randomization 
through 30 days after the last dose of study drug.  In addition, investigators should report any 
SAE that occurs after consent and prior to randomization that is assessed as related to 
invasive study-related procedures apart from the HCT, as well as any SAEs assessed as 
related to study drug that happens after the 30 day follow-up period. All AEs are to be 
followed up until resolved, judged to be no longer clinically significant, or until they become 
chronic to the extent that they can be fully characterized. 
4.6.1. Definition of AEs 
An AE is defined as any untoward medical occurrence in a participant 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.  


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GVHD and infection are collected on separate CRFs because they are separate endpoints. 
Events of GVHD and infection are not to be reported as AEs for this study unless they meet 
one of the following: 
● 
Meet one or more of the SAE criteria in Section 4.6.2 and be related to study drug 
● 
Result in death between the first dose of study medication through 30 days after the last 
dose of study drug (inclusive), regardless of relationship to study drug. 
Some countries may have additional local requirements for reporting events 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 reported via the web-based electronic data capture system, Advantage eClinical 
accordingly. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets 1 of the 
following criteria: 
● 
Induces clinical signs or symptoms. 
● 
Requires active intervention. 
● 
Requires interruption or discontinuation of study medication. 
● 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
See APPENDIX J for detailed information on monitoring and assessment of liver 
abnormalities. 
4.6.2. Definition of SAEs 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes: 
● 
Death 
● 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the participant at immediate risk of death.  
It does not include an AE that, had it occurred in a more severe form, might have caused 
death) 
● 
Persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
● 
Congenital anomaly or birth defect 
● 
Requires 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 that may not be immediately life-threatening or result 
in death/hospitalization, but may jeopardize the participant or may require intervention to 
prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations. These events, including those that may result in 


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disability/incapacity, should also be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of drug 
dependency or drug abuse. 
For this study, GVHD and infection are only to be reported as SAEs if one of the following 
conditions is met: 1) the event is both related to study drug and also meets the definition of 
SAEs above, or 2) the event results in death that occurs within 30 days after the last dose of 
study drug. 
AML relapse will not be reported as an AE/SAE term unless it is the cause of a death that 
occurs between the first day of study drug though 30 days after the last dose of study drug 
(inclusive). 
Special situations related to the medicinal products administered to the participant as part of 
the study (e.g., study drug) 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) 
● 
Occupational exposure to the medicinal product(s) 
● 
Medication error involving the medicinal product(s) (with or without participant exposure 
to the Sponsor medicinal product, e.g., name confusion) 
● 
Off-label use 
● 
Lack of effect 
● 
Exposure via breast milk 
● 
(Suspicion of) transmission of an infectious agent 
● 
Drug-drug interaction 
All serious events and special situations noted above must be reported through the expedited 
AE reporting system via Advantage eClinical and must be reported within 24 hours of 
knowledge of the event. If there are network outages, a paper copy of the AE form must be 
completed and emailed to 1506safety@emmes.com to initiate Sponsor review. Once the 
system is available, the event information must be entered into the system.   
The Sponsor also has a list of events for gilteritinib classified as “important medical events”. 
If an AE is considered to be an event per this classification as an “important medical event”, 
additional information on the event may be requested and the event will be requested to be 
reported through the expedited AE reporting system via Advantage eClinical. In the event an 
AE is classified as an “important medical event”, the determination of serious and reporting 
through the expedited AE reporting system is per the opinion of the investigator. 
4.6.2.1. 
SAE Reporting in Japan 
For Japan, the investigator or sub-investigator must also 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 


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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. 
Fax the JUTOKUNA YUUGAIJISHOU HOUKOKUSHO to the CRO: 
PAREXEL International  
Global Monitoring Operations  
Fax: 03-6888-3348 
The investigator or sub-investigator must also report the event in Advantage eClinical. The 
minimal identifiable information must be reported within 48 hours of awareness, followed by 
full information within 5 business days of awareness. 
4.6.3. Criteria for Causal Relationship to the Study Drug 
AEs that fall under either "Possible" or "Probable" should be defined as "AE whose 
relationship to the study drugs could not be ruled out". Table 5 lists the causal relationship to 
the study drug and the criteria for the causal relationship.   
Table 5 
Criteria for Causal Relationship 
Causal 
Relationship 
to the Study 
Drug 
Criteria for Causal Relationship 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study 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 study 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 study drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals and which follows a clinically 
reasonable response on re-administration (re-challenge) or withdrawal (de-
challenge). 
 
4.6.4. Criteria for Defining the Severity of an AE  
AEs, including abnormal clinical laboratory values, will be graded using the CTCAE 
guidelines (version 4.03).  The items that are not stipulated in the CTCAE version 4.03 will 
be assessed according to the criteria below in Table 6 and entered into the web-based 
electronic data capture system, Advantage eClinical. 
 
 


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Table 6 
Definition for Severity of an AE 
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 the AE  
4.6.5. Criteria for Defining Expectedness 
For the purposes of regulatory reporting, expected SAEs are those that are listed in the 
Investigational Brochure.  
4.6.6. AE Reporting Guidelines  
AEs must be reported regardless of whether a relationship exists between the AE and the use 
of the study drug.  
From the time of screening until randomization, only deaths should be reported during this 
time frame on the appropriate event-driven CRF in Advantage eClinical. In addition, 
investigators should report any SAE that occurs after consent and prior to randomization that 
is assessed as related to invasive study-related procedures apart from the HCT. From the time 
of randomization through 30 days after the end of study drug, non-serious AEs are required 
to be reported via event-driven forms in Advantage eClinical. SAEs, irrespective of the 
attribution of the event to the study drug/procedure/treatment, will be reported through the 
expedited AE reporting system via Advantage eClinical, and will be graded according to the 
CTCAE Version 4.03. SAEs must be reported within 24 hours of knowledge of the event.  
The National Heart, Lung and Blood Institute (NHLBI) Data and Safety Monitoring Board 
will receive summary reports of all unexpected SAEs in an expedited manner and a summary 
of all adverse experiences at least twice yearly. 
For this study, GVHD and infection are only to be reported as SAEs if one of the following 
conditions is met: 1) the event is both related to study drug and also meets the definition of 
SAEs above, or 2) the event results in death that occurs within 30 days after the last dose of 
study drug. 
AML relapse will not be reported as an AE/SAE term unless it is the cause of a death that 
occurs between the first day of study drug though 30 days after the last dose of study drug 
(inclusive). 
4.6.7. Monitoring of Common SAEs 
Common SAEs are those events anticipated to occur in the study population independent of 
drug exposure.  SAEs classified as “common” are provided in APPENDIX K Common SAEs 
for reference. The list does NOT change reporting obligations or prevent the need to report an 
SAE as detailed above. The purpose of this list is to provide events reported as SAEs that 


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may not require expedited reporting to the regulatory authorities based on the classification 
of “common SAEs.” Investigators must report individual occurrences of these events as 
stated in Section 4.6.5. 
Any changes to this list or changes in frequency of the events will be communicated to the 
participating investigational sites.  
4.6.8. Procedure in Case of Pregnancy 
If a female participant becomes pregnant during the study dosing period or within 6 months 
from the discontinuation of dosing or partner of a male participant becomes pregnant during 
the study dosing period or within 127 days from the discontinuation of dosing, the 
investigator should report the information through the expedited AE reporting system via 
Advantage eClinical.  The expected date of delivery or expected date of the end of the 
pregnancy, last menstruation, estimated conception date, pregnancy result, neonatal data and 
other related information will be requested.  If a participant becomes pregnant during the 
study dosing period, the study drug will be discontinued. 
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. Additional information regarding the 
outcome of a pregnancy (which is categorized as an SAE) is mentioned below. 
● 
“Spontaneous abortion” includes miscarriage, abortion and missed abortion 
● 
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug 
● 
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by 
the investigator 
● 
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at 
the birth 
● 
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
Information will be collected at the time of delivery/birth and 6 months and 12 months after 
birth.  
4.6.9. Emergency Procedures and Management of Overdose 
In the event of suspected gilteritinib (ASP2215) overdose, the participant should receive 
supportive care and monitoring. The Sponsor Medical Monitor or Study Chair should be 
contacted. 
 


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CHAPTER 5 
 
5. STATISTICAL CONSIDERATIONS 
5.1. Study Design and Objectives 
The study is a double-blind, placebo-controlled, randomized Phase III, multi-center trial 
comparing gilteritinib as maintenance therapy vs placebo, in FLT3/ITD AML participants in 
first morphologic CR who are undergoing an HCT.  Randomization will start between days 
30 and 90 after HCT, after the participant has engrafted.  The target number of participants 
randomized is 346, 173 for each arm.  To account for an anticipated 35% dropout between 
enrollment (at transplant) and randomization post-transplant, 532 participants are expected to 
enroll at the time of transplant in order to get the targeted number randomized.   
5.1.1. Accrual 
It is estimated that approximately 2 years (24 months) of accrual will be necessary to enroll 
the targeted sample size. 
5.1.2. Randomization 
Participants will be randomized at a ratio of 1:1 between the treatment arm and the placebo 
arm using permuted blocks of random sizes.  Randomization will be stratified by the 
conditioning regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time 
from transplant to randomization (30-60 days vs 61-90 days), and the presence of MRD 
(present vs absent/unknown) based on the pre-transplant BM aspirate.   
5.1.3. Primary Endpoint 
The primary endpoint is RFS, treated as a time to event outcome.  The primary analysis will 
be performed using the intent-to-treat principle so that all randomized participants will be 
included in the analysis.  Morphological relapse or death will be considered failures for this 
endpoint, which will be adjudicated by a blinded endpoint review committee. The Blinded 
Endpoint Review Committee will assess relapse according to the Blinded Endpoint Review 
Committee Charter.  
5.1.4. Primary Hypothesis 
The primary null hypothesis is that there is no difference in RFS between the treatment arm 
and placebo.  Using a hazard ratio (HR) to denote the RFS primary endpoint for the treatment 
arm compared to the placebo, the primary hypotheses are:  
H0: 
HR = 1 vs Ha: HR  ≠ 1  
This hypothesis will be tested at a 0.05 significance level.   
5.1.5. Duration of Follow-up 
All participants may remain on treatment for up to 24 months (730 days) following the 
initiation of study drug. The primary analysis will occur 2.5 years after the last participant 
was randomized or when approximately 122 events have been observed for the primary 
endpoint, whichever occurs first. If RFS is not statistically significant or both RFS and OS 


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are statistically significant at the primary analysis, the study, including follow-up, will be 
stopped. If RFS is statistically significant but OS is not statistically significant at the primary 
analysis, participants will be followed for relapse and survival for a total of 5 years after the 
last participant is randomized.  
For an individual participant, study duration will last for 2.5 to 5.5 years if the RFS is not 
statistically significant or if both the RFS and OS are statistically significant at the primary 
analysis; otherwise, study duration for an individual participant will last up to 5 to 8 years. 
5.1.6. Definition of Analysis Populations 
5.1.6.1. 
Efficacy Analysis Population 
The intention-to-treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized.  Participants who are 
randomized but do not start therapy will not be replaced. 
5.1.6.2. 
Safety Analysis Population 
The safety analysis population will serve as the population for all summaries of the safety 
data.  The safety analysis population consists of all participants who took at least 1 dose of 
study drug (gilteritinib or placebo).  Participants will be analyzed based on the actual 
treatment received. 
5.1.6.3. 
Pharmacokinetic Analysis Population 
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 participants may be 
excluded from the PKAS at the discretion of the pharmacokineticist. Any formal definitions 
for exclusion of participants or time-points from the PKAS will be documented in the 
Classification Specifications. 
5.2. Sample Size and Power Considerations 
The primary analysis will be done using stratified log-rank tests, with the randomization 
factors used as stratification variables.  RFS in the control group is assumed to be 67% at 
1 year, 59% at 2 years, and 55% at 3 years, based on CIBMTR data on patients with 
FLT3/ITD mutation transplanted in CR1 who were alive and progression free at 60 days. A 
total of 122 events provide 85% power to detect a HR of 0.57 (corresponding to a 15% 
difference in 2 year RFS) with two-sided significance level of 0.05.  This assumes that the 
survival function in the control group has piecewise constant hazard functions in each 
interval, that the treatment arm has proportional hazards with a HR of 0.57, and maximum 
follow-up of 3 years (Note that CIBMTR data indicates that very few events occur after 3 
years so there is little benefit in longer follow-up).  Assuming approximately 2 years of 
accrual and 5% drop out rate per year, 346 participants need to be enrolled to ensure a high 
likelihood of obtaining 122 events.   


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It is estimated that approximately 103 RFS events will be observed after 2.5 years from the 
last participant randomized.  This will provide approximately 78.6% power with two-sided 
significance level of 0.05.  Note that the exact number of RFS events and corresponding 
power will be specified in the finalized SAP for the primary analysis. 
An O’Brien-Fleming type alpha-spending function will be utilized to control the overall 
2-sided 0.05 significance level for the OS primary and final analyses.40  Similar to RFS, it is 
estimated that approximately 83 and 100 OS events will be observed after 2.5 and 5 years 
from the last participant randomized, respectively.  Based on the information fraction of 0.83 
(83/100), the study will provide approximately 55% power at the primary analysis with 
2-sided p-value boundary of 0.0278 and approximately 69.9% power at the final analysis 
with 2-sided p-value boundary of 0.042 under the assumption of an HR of 0.6 for OS.  Note 
that the exact number of OS events at the primary analysis and a better predicted number of 
OS events at the final analysis will be specified in the finalized SAP for the primary analysis. 
The exact number of OS events at the final analysis and adjusted p-value boundary based on 
the actual information fraction used at the primary analysis will be specified in the finalized 
SAP for the final analysis. 
5.3. Interim Analysis and Stopping Guidelines 
Policies and composition of the DSMB are described in the DSMB Charter and the 
study-specific DSMB Charter Addendum. RFS with immature data may be participant to 
overestimation; the data are not robust and is rarely reproducible when more mature data are 
available. For this reason, early evaluation may lead to stopping the trial too early, and 
therefore the DSMB will not stop the trial due to differences in RFS. Toxicity, AEs, and 
other safety endpoints will be monitored regularly and reported to the DSMB at each 
meeting. 
5.3.1. Guidelines for Safety Monitoring 
Monitoring of a key safety endpoint will be conducted monthly, and if rates significantly 
exceed preset thresholds, the NHLBI will be notified so that the DSMB can be advised.  The 
stopping guideline serves as trigger for consultation with the DSMB for additional review 
and are not formal “stopping rules” that would mandate automatic closure of study 
enrollment. 
The key safety endpoint for this study is mortality.  The rate of mortality will be monitored 
up to 90 days post-randomization separately in each of the two treatment arms.  At least three 
events must be observed in order to trigger review.  The expected probability of mortality 
within 90 days post randomization among FLT3+ AML patients who are alive without 
progression at day 60 post-transplant is ≤ 15%, based on CIBMTR data.  Each month, the 
null hypothesis that the 90-day mortality rate is less than or equal to 15% is tested.  An 
extension of the sequential probability ratio test (SPRT) for censored exponential data will be 
used for monitoring, as described in greater detail below and in APPENDIX E. 
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations for a treatment arm.  The SPRT can be represented graphically.  At each 


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monthly interim analysis, the total time on study in months (x axis) is plotted against the total 
number of endpoints (y axis) (e.g., participants experiencing death).  The continuation region 
of the SPRT is defined by two parallel lines.  Only the upper boundary will be used for 
monitoring to protect against excessive 90-day mortality.  If the graph falls above the upper 
boundary, the SPRT rejects the null hypothesis, and concludes that there are more events than 
predicted by the observed time on study.  Otherwise, the SPRT continues until enrollment 
reaches the maximum of 173 participants per arm. 
This procedure assumes a censored exponential distribution for the time until death during 
the first 90 days, and censors follow-up time after 90 days.  Only deaths that occur on or 
before the participant has been followed for 90 days are counted.  Total time on study is 
computed as time from randomization to death, or to 90 days, whichever comes first, 
summed for all participants on study. 
The usual measures of performance of an SPRT are the error probabilities  and  of 
rejecting H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected 
sample size E(N|i).  The tests to be used in this protocol were developed from the following 
SPRT:   
A SPRT contrasting 15% versus 25% 90-day rate of mortality results in decision 
boundaries with a common slope of 0.073 and an upper intercept of 4.251, with 
nominal type I and II errors of 7.5% and 15%, respectively.  
The actual operating characteristics of the truncated test, shown in Table 7, were determined 
in a simulation study that assumed uniform accrual of 173 individuals over a 24-month time 
period, and exponential time to failure after randomization.   
Table 7 
Operating Characteristics of Sequential Testing Procedure from a 
Simulation Study with 10000 Replications 
DAY 90 MORTALITY 
True 90-Day Rate 
15% 
20% 
25% 
Probability Reject Null 
0.047 
0.427 
0.901 
Mean Month Stopped 
26.2 
21.0 
12.5 
Mean # Endpoints in 90 Days 
25.2 
26.9 
19.8 
Mean # Participants Enrolled 
168.5 
139.0 
87.9 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 5% 
of the time when the true 90-day mortality rate is 15%, and 90% of the time when the rate is 
25%.  This corresponds to a type I error rate of  = 0.05 and a type II error rate of  = 0.1.  
When the true 90-day mortality rate is 25%, on average, the DSMB will be consulted 
12 months after opening, when 20 events have been observed in 88 participants. 
5.4. Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all participants.  
Characteristics to be examined are: age, gender, race/ethnicity (if available), performance 


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status, MRD status, CMV status, HCT-specific comorbidity index, time from diagnosis to 
transplantation, time from CR to randomization, time from transplant to randomization, 
donor type, conditioning regimen and intensity, graft type, HLA matching, GVHD 
prophylaxis regimen, presence of GVHD prior to randomization, treatment used for GVHD, 
and time to ANC recovery.   
5.5. Analysis Plan 
5.5.1. Participant Disposition 
The number and percentage of all participants who receive any study drug, who complete the 
study, and who discontinue the study prematurely, will be reported per treatment group, 
along with reasons for discontinuation. 
5.5.2. Analysis of the Primary Endpoint 
The primary outcome of the trial is RFS from the time of randomization, treated as a time to 
event variable. Participants going off study drug without prior documentation of a RFS event 
will continue to be followed for RFS, and this additional follow-up will be included in the 
primary analysis. Participants without a RFS event but lost to follow-up will be censored at 
last date of follow-up. The primary analysis will be conducted 2.5 years after the last 
participant was randomized or when approximately 122 RFS events have been observed for 
the primary endpoint, whichever occurs first.  RFS will be compared between groups in the 
ITT population using the stratified log-rank test, stratified on conditioning regimen intensity, 
time from transplant to randomization, and pre-transplant MRD status.  The HR, along with 
confidence intervals, will be estimated from a stratified Cox model with treatment as a 
covariate, and using the same strata variables.  Kaplan-Meier estimates of RFS will also be 
described for each group, along with confidence intervals at 1, 2, and 3 years.  In order to 
evaluate the robustness of the primary endpoint analysis of RFS, several sensitivity analyses 
will be performed.  The first sensitivity analysis is the same as the primary analysis except 
that it censors at the last disease assessment without relapse when relapse or death is 
documented after more than one missed disease assessment, regardless of whether 
participants have early terminated the study treatment or have taken subsequent AML 
therapies  This sensitivity analysis will be conducted using the same methods as for the 
primary endpoint.  A sensitivity analysis will also be conducted to assess whether any 
random imbalances in the intensity of preparative regimen or the planned GVHD prophylaxis 
affected the RFS outcome, by adding these variables as covariates into the stratified Cox 
model.  Finally, the proportional hazards assumption for the Cox model using graphical 
methods and time-dependent covariates will be assessed and if there is evidence that this 
assumption is violated, adjusted RFS curves will be generated, and adjusted RFS 
probabilities will be compared between the groups at 2 and 3 years.  Additional details 
regarding RFS events, primary analysis and sensitivity analyses are provided in the SAP. 


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5.5.3. Analysis of Secondary Endpoints 
5.5.3.1. 
Overall Survival 
OS will be a key secondary endpoint, with explicit control of the type I error rate through a 
gatekeeper approach.  Formal significance testing of OS will be conducted if the RFS 
comparison is statistically significant.  Otherwise, survival analyses will be considered 
exploratory.  Primary analysis for OS will be performed when the primary analysis for RFS is 
statistically significant at 2-sided α = 0.05.  If the primary analysis for RFS is statistically 
significant while the primary analysis for OS is not statistically significant, a final analysis 
for OS will occur 5 years after the last participant was randomized.   
OS curves from time of randomization will be estimated using the Kaplan-Meier estimator 
applied to the ITT population, and compared between treatment groups using the stratified 
log-rank test, with the same strata variables as for the primary endpoint.  The HR, along with 
confidence intervals, will be estimated from a stratified Cox model with treatment group as a 
covariate.  Surviving participants will be censored at the last known alive date. 
Additional analyses assessing the impact of crossover after unblinding on OS will be 
performed.  Details of these analyses will be provided in the SAP. 
5.5.3.2. 
Non-relapse Mortality (NRM) 
Incidence of NRM will be estimated using the cumulative incidence function, treating 
relapse/progression as a competing risk.  Incidence of NRM will be compared between the 
treatment arms using a Fine and Gray model, adjusting for strata variables of conditioning 
regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time from 
transplant to randomization, and pre-transplant MRD status.   
5.5.3.3. 
Relapse 
Incidence of relapse will be estimated using cumulative incidence function, treating death in 
remission as a competing risk.  Incidence of relapse/progression will be compared between 
the treatment arms using a Fine and Gray model, adjusting for strata variables of conditioning 
regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time from 
transplant to randomization, and pre-transplant MRD status. 
5.5.3.4. 
Event-free Survival (EFS) 
EFS will be estimated using the Kaplan-Meier estimator applied to the ITT population, and 
compared between treatment groups using the stratified log-rank test, with the same strata 
variables as for the primary endpoint.  The HR, along with confidence intervals, will be 
estimated from a stratified Cox model with treatment group as a covariate. The reason for 
participants starting new therapies, and the types of new therapies given will be described in 
each arm. EFS considers discontinuation of study drug or initiation of an anticancer treatment 
to be an event.   
5.5.3.5. 
Acute GVHD of Grades II-IV and III-IV 
Cumulative incidence of new onset aGVHD or worsening in the grade of aGVHD at the time 
of randomization by one point (e.g., grade II aGVHD at the time of randomization, 


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progressing to grade III or more after randomization) will be estimated from the time of 
randomization using the cumulative incidence function, treating death prior to aGVHD as the 
competing risk.  Cumulative incidence of aGVHD will be compared between treatment arms 
using a Fine and Gray model, adjusting for strata variables of conditioning regimen intensity 
(myeloablative vs reduced intensity/non-myeloablative), time from transplant to 
randomization, and pre-transplant MRD status. An additional analysis will be performed 
treating death and relapse without documentation of an aGVHD event as a competing risk. 
5.5.3.6. 
Chronic GVHD  
Cumulative incidence of new onset chronic GVHD from the time of randomization or 
worsening in the grade of chronic GVHD at the time of randomization by one point (e.g., 
mild chronic GVHD at the time of randomization, progressing to moderate or severe chronic 
GVHD after randomization) will be estimated using the cumulative incidence function, 
treating death prior to chronic GVHD as the competing risk.  Cumulative incidence of 
chronic GVHD will be compared between treatment arms using a Fine and Gray model, 
adjusting for strata variables of conditioning regimen intensity (myeloablative vs reduced 
intensity/non-myeloablative), time from transplant to randomization, and pre-transplant MRD 
status.  
5.5.3.7. 
Infection  
The number of infections and the number of participants experiencing infections will be 
tabulated by type of infection, CTCAE grade and time period after transplant. The 
cumulative incidence of CTCAE grade 3 to 5 infections, treating death (grade 5) as a 
competing event, will be compared among the treatment arms using Gray’s test. 
5.5.3.8. 
Relative Dose Intensity 
Relative Dose Intensity is defined as the percentage of the planned number of doses of study 
drug which are actually taken by the participant. Descriptive statistics for study drug dose 
intensity will be presented for the safety population by treatment group. 
5.5.3.9. 
Extent of Exposure 
Exposure to treatment, measured by the duration of treatment in number of months, will be 
summarized by treatment group using the safety population.  The number and proportion of 
participants with dose reduction and dose interruption will be tabulated. 
5.5.3.10. Safety and Tolerability 
5.5.3.10.1. Adverse Events  
All AEs recorded on treatment including within 30 days from the last study treatment will be 
summarized. AEs will be categorized by System Organ Class (SOC) and preferred term (PT) 
using the MedDRA dictionary and will be graded according to the CTCAE version 4.03. 
The number and percent of participants experiencing 1 or more AE(s) will be summarized by 
treatment group, SOC and PT. The number and percentage of participants with at least 
1 grade 3 or higher AE will be summarized by treatment group, SOC and PT.  


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Distribution of the maximum severity (grade) and treatment-related AEs will be summarized 
by treatment group, SOC and PT. Distribution of SAEs, discontinuations due to AE and 
deaths on study will be presented for each treatment group. 
Additional summary tables will be generated for the following population subsets: 
participants with SAEs including deaths, participants 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. 
5.5.3.10.2. Laboratory Assessments  
Clinical laboratory evaluations (including serum chemistry, LFTs, thyroid tests, hematology) 
and their changes from baseline will be summarized by treatment using descriptive statistics. 
Clinically significant abnormalities in laboratory values will be presented for each treatment. 
Shift tables will present shift from baseline to worst grade for selected variables using the 
CTCAE grade and laboratory reference range indicator. Frequency of participants with 
laboratory values outside normal range will be generated in addition to tabulation of worst 
toxicity grade. 
5.5.3.10.3. Physical Examination  
All clinically significant abnormal findings will be recorded as medical history, AEs, 
infection or GVHD and graded using either CTCAE guidelines or according to standard 
criteria for GVHD. 
5.5.3.10.4. Electrocardiograms 
The 12-lead ECG results will be summarized by treatment group and time point. Overall 
ECG interpretation will be summarized for each time point. A shift analysis table showing 
shifts from baseline in overall ECG (normal, abnormal) will be provided. ECG parameters 
and their change from baseline will be summarized by treatment group using descriptive 
statistics. 
5.5.3.11. Karnofsky Performance Status Scores 
Karnofsky performance status scores will be summarized by treatment group and visit. 
5.5.3.12. Post- transplant MRD Status 
The cumulative incidence of detection of MRD in participants who are MRD undetectable 
prior to randomization will be described in each group and compared between treatment arms 
using Gray’s test; death without detection of MRD will be treated as a competing risk.  
Similarly, the time until eradication of MRD in participants who have detectable MRD prior 
to randomization will also be described and compared between treatment arms using Gray’s 
test; death without eradication of MRD will be treated as a competing risk. 


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5.5.4. Analysis of Exploratory Endpoints 
5.5.4.1. 
Health-Related Quality of Life (HQL) 
HQL will be measured on day -30, day -14, day 29, month 3, month 6, month 12, month 18 
and EOT (month 24) using three instruments: the FACT-BMT, FACT-Leu, and EQ-5D-5L.  
HQL at each time point will be summarized using simple descriptive statistics (mean, SD) 
and simple comparisons between treatment arms will be performed using t-tests. 
EQ-5D-5L VAS will be summarized by treatment group using descriptive statistics (mean, 
standard deviation, minimum, maximum and median) on ITT.  Additionally, change from 
baseline will be calculated as the post-baseline score minus the baseline score and 
summarized in the same way.  Analysis of covariance (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.  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 ITT.  
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 factors. 
FACT-BMT score will be summarized by treatment group using descriptive statistics (mean, 
standard deviation, minimum, maximum and median) on ITT.  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 factors. 
Additional exploratory analyses of resource utilization, participant reported outcomes 
(FACT-BMT, FACT-Leu) and health outcome (EQ-5D-5L) will be performed and the details 
will be included in a separate Patient Reported Outcome Statistical Analysis Plan. 
Minimal clinically important differences (MCIDs) will also be predefined in the separate 
Patient Reported Outcome Statistical Analysis Plan.  
5.5.4.2. 
Healthcare Resource Utilization 
Descriptive analyses of healthcare resource utilization will be conducted for antibiotic use, 
medication for AEs, and hospitalization including the total and average number and duration 
of hospitalizations. Additional analyses may be performed and reported separately. 
Resource utilization counts including duration of hospital stays, duration of medications and 
duration of antibiotic use will be summarized by treatment group using descriptive statistics 
(mean, standard deviation, minimum, maximum and median) on ITT. The difference between 
treatment groups will be tested with ANOVA while controlling of stratification factors. 


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5.5.4.3. 
GRFS 
aGRFS, cGRFS and GRFS will be analyzed on the ITT in the same manner as RFS. 
5.5.4.4. 
Subgroup Analysis 
Subgroup analyses will be conducted for RFS for each of the following variables: 
pre-transplant MRD status at enrollment, MRD status at randomization, CR status prior to 
randomization, time from transplant to randomization, age, gender, region, incidence of 
FLT3 mutation at relapse, conditioning regimen intensity, cytogenic risk factor and GVHD 
prophylaxis. Interaction tests between treatment group and subgroup will be conducted 
within a Cox proportional hazards regression model with treatment, subgroup, and a 
treatment*subgroup interaction term.  A forest plot will be used to show the HR for each 
subgroup. 
5.5.4.5. 
Gilteritinib Plasma Pharmacokinetics 
Gilteritinib plasma concentrations will be summarized by treatment, visit, and time point (in 
hours). 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. 
5.5.5. Handling of Missing Data, Outliers, Visit Windows and Other Information 
As a general principle, no imputation of missing data will occur during analysis. Exceptions 
are the start and stop dates of AEs and concomitant medication. The imputed dates will be 
used to determine whether an AE is/is not treatment-emergent or a medication is/is not 
concomitant. Listings of the AEs and concomitant medications will present the actual partial 
dates; imputed dates will not be shown.  
The definition for windows to be used for analyses by visit, if applicable, will be outlined in 
the statistical analysis plan (SAP). 
 


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APPENDIX A 
HUMAN SUBJECTS 
 


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APPENDIX A 
HUMAN SUBJECTS 
 
1. Participant Consent 
A conference will be held with the participant, and family if available, to discuss this study 
and alternative treatments available for the treatment of the underlying disease.  The 
conference will be conducted by the Principal Investigator or other designated physician.  
Potential risks associated with the study treatments should be discussed as objectively as 
possible.  Consent will be obtained using an IRB/IEC-approved consent. 
The Sponsors will provide a template of the consent form to each center.  Each center will 
customize the template according to their local requirements and submit it for review by the 
local IRB or IEC.  The delegated clinical research organizations and APGD will verify the 
adequacy of the consent forms prior to submission to the IRB or IEC.  Each center must 
provide evidence of IRB or IEC approval. 
2. Confidentiality 
Confidentiality will be maintained by masking individual names and assigning a participant 
identifier code.  The code relaying the participant’s identity with the identifier (ID) code will 
be kept separately at the center.  The ID code will be transmitted to the network. 
3. Participation of Women and Minorities and Other Populations 
Women and ethnic minorities and other populations will be included in this study.  Accrual 
of women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of AML 
in these groups.  Centers will be notified if their rates differ significantly from those expected 
and asked to develop appropriate recruitment strategies. 
 


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APPENDIX B 
INVESTIGATOR’S SIGNATURE 
 


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APPENDIX B 
INVESTIGATOR’S SIGNATURE 
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Trial of 
the FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following 
Allogeneic Transplant for Patients with FLT3/ITD AML 
BMT CTN PROTOCOL 1506 
ASTELLAS PROTOCOL 2215-CL-0304 
Version 4.0, August 19, 2022 
Protocol History: 
Version 1.0 23Sep2016 
Version 1.1 [JP] Nonsubstantial Amendment 1 dated 09Nov2016 
Version 1.1 [FR] Nonsubstantial Amendment 2 dated 03Nov2016 
Version 1.1 [UK] Nonsubstantial Amendment 3 dated 20Mar2017 
Version 1.1 [DE] Nonsubstantial Amendment 4 dated 03May2017 
Version 1.2 [FR] Nonsubstantial Amendment 5 dated 19Jul2017 
Version 2.0 Substantial Amendment 1 dated 20Nov2017 
Version 2.1 Nonsubstantial Amendment 6 dated 19Feb2018 
Version 2.2 [UK] Nonsubstantial Amendment 7 dated 28Feb2018 
Version 3.0 Substantial Amendment 2 dated 15Mar2019 
I have read all pages of this clinical study protocol. I agree to conduct the study as outlined in the 
protocol and to comply with all the terms and conditions set out therein. I confirm that I will 
conduct the study in accordance with ICH GCP guidelines and applicable local regulations. I will 
also ensure that subinvestigator(s) and other relevant members of my staff have access to copies of 
this protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions 
of these documents. 
Principal Investigator: 
 
 
Signature: 
 
 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C 
OPERATIONAL AND ADMINISTRATIVE 
CONSIDERATIONS 
 


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APPENDIX C 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
1. 
Clinical Study Quality Control 
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 transcribe data (including laboratory values, if applicable) in the electronic 
case report form (eCRF) in a timely manner after the participant visit unless otherwise noted.  
The BMT CTN DCC will be reviewing form submission regularly and will follow-up to 
assure data is submitted promptly.  
The investigator or site designee is responsible for ensuring that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. 
The monitor will verify a subset of the data in the eCRFs with source documents and confirm 
that there are no inconsistencies between them. 
Study Documentation 
Study documentation includes, but is not limited to, all CRFs, workbooks, source documents, 
monitoring logs and appointment schedules, sponsor-investigator correspondence, and signed 
protocol and amendments, IRB/IEC correspondence and approved current and previous 
consent forms and signed participant consent forms. 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study.  The original recording of an observation should be retained as the source document. If 
the original recording of an observation is the electronic record, that will be considered the 
source. 
Clinical Study Monitoring 
The Sponsors or delegated CROs are responsible for monitoring the clinical study to ensure 
that the participant’s human rights, safety and well-being are protected, that the study is 
properly conducted in adherence with 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 Sponsors or delegated CROs are 
responsible for assigning study monitor(s) to this study for proper monitoring.  The protocol 
will be monitored in accordance with planned monitoring procedures. 
Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CROs as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records and documentation when they 


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are requested by the Sponsor monitors and auditors, the IRB/IEC or regulatory authorities. 
The confidentiality of the participant's identities shall be well protected consistent with local 
and national regulations when the source documents are subject to direct access. 
Quality Assurance 
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that the trial is conducted and data are generated, documented, 
recorded and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s). 
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, CRFs and source documents. Direct access to these documents will be required 
by the auditors.  
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 participants. The investigator 
should not implement any deviation from or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study participants.  
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 participant who:  
● 
Entered into the study and did not satisfy entry criteria. 
● 
Developed withdrawal criteria during the study and was not withdrawn from the study. 
● 
Received the wrong treatment or incorrect dose.  
● 
Received excluded concomitant treatment.  
When a deviation from the protocol is identified for an individual participant, the investigator 
or designee must ensure the Sponsor or designee is notified. The Sponsor or designee will 
follow up with the investigator, as applicable, to assess the deviation and the possible impact 
to the safety and/or efficacy of the participant to determine participants continuation in the 
study.  
If a deviation impacts the safety of a participant, 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. 


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NOTE:  Other deviations outside of the categories defined above that require reporting to the 
IRB/IEC in accordance with local requirements will be reported, as applicable.  
The following is specific to investigational sites in Japan: 
Deviations from the Protocol and Other Actions Taken to Avoid Life-Threatening Risks 
to Participants 
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the participants. When the investigator does not follow the protocol in 
order to avoid urgent risks for participants, 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. 
2. 
Ethics and Protection of Participant Confidentiality 
Institutional Review Board/Independent Ethics Committee/Competent Authorities 
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent and all other forms of participant information related to the 
study (e.g., advertisements used to recruit participants) and any other necessary documents be 
reviewed by an IRB/IEC.  The IRB/IEC will review the ethical, scientific and medical 
appropriateness of the study before it is conducted. IRB/IEC approval of the protocol, 
informed consent and participant information and/or advertising, as relevant, will be obtained 
prior to the authorization of drug shipment to a study site. 
Any substantial amendments to the protocol will require IRB/IEC approval 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., SUSAR 
and any additional reports required by local regulations) to the IRB/IEC of any changes that 
affect the conduct of the study and/or increase the risk to participants.  Written 
documentation of the submission to the IRB/IEC should also be provided to the Sponsor. 
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IRB/IEC 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. 


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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.  
Informed Consent of Participants 
Participant Information and Consent 
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding this study. Prior to any study-related screening 
procedures being performed on the participant, the informed consent statement will be 
reviewed and signed (Specific to investigational sites in Japan: place a personal seal), and 
dated by the participant 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) informed consent 
form (ICF) will be given to the participant and the original will be placed in the participant’s 
medical record. An entry must also be made in the participant’s dated source documents to 
confirm that informed consent was obtained prior to any study-related procedures and that 
the participant 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. 
Supply of New and Important Information Influencing the Participant’s Consent and 
Revision of the Written Information 
The investigator or his/her representative will immediately inform the participant orally 
whenever new information becomes available that may be relevant to the participant’s 
consent or may influence the participant’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 participant’s medical records and must document whether the participant is willing to 
remain in the study or not. 
The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
participant on all updated ICFs throughout their participation in the study. The investigator or 
his/her designee must re-consent participants 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 participant 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 participant and the original 
will be placed in the participant’s medical record. An entry must be made in the participant’s 
records documenting the reconsent process. 


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The following items 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 Act on Securing Quality, Efficacy and Safety 
of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene 
Therapy Products, and Cosmetics, in compliance with Article 80-2 Paragraph 6 of the 
Pharmaceutical Affairs Law, the Sponsor should inform all 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 participants, in compliance with the 
information provided above [Supply of New and Important Information Influencing the 
Participant’s Consent and Revision of the 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, these 
documents should be sent to the IRB. 
Participant Confidentiality 
Individual participant 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 participant to the participant's physician or to other 
appropriate medical personnel responsible for the participant's well-being. 
The Sponsor affirms the participant's right to protection against invasion of privacy. Only a 
participant identification number and/or initials will identify participant 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 (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e., HIPAA). 
3. 
Administrative Matters 
Arrangement for Use of Information 
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 Astellas. 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 Sponsors 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 


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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. 
Documents and Records Related to the Clinical Study 
The investigator will archive all study data (e.g., Participant 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 investigational 
new drug (IND). The Sponsor will notify the site/investigator if the NDA/Marketing 
Authorisation 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. 
The investigator and Sponsor will mutually agree upon the storage format for the retention of 
electronic data 
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 participant to direct access and should be 
provided upon request from the Sponsor or regulatory authorities. 
The head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until the 
date defined in 1. or 2. below, whichever comes later. 
1. Approval date of marketing of the test drug (if development of the drug is stopped, until 
three years after the decision to discontinue development is notified) 
2. Until three years after discontinuation or termination of the study.) 
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. 


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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 participant 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. 
Insurance of Participants 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. 
The following paragraph is specific to investigational sites in Japan: 
If a participant 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 participant 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 participant 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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APPENDIX D 
NEW YORK HEART ASSOCIATION  
CLASSIFICATION OF CARDIAC DISEASE 
 


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APPENDIX D 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE 
 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, 
e.g., no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
 
Source: The Criteria Committee of the New York Heart Association. (1994). Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston: Little & Co. 1994;253–56. 
 
 


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APPENDIX E 
DERIVATION OF A SEQUENTIAL TEST STATISTIC 
FOR CENSORED EXPONENTIAL DATA 
 


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APPENDIX E 
DERIVATION OF A SEQUENTIAL TEST STATISTIC 
FOR CENSORED EXPONENTIAL DATA 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,
f
be the density function for random variable X.  According to Neyman and Pearson, 
the most powerful test of 
o
H

=
:
0
 versus
1
1 :

=
H
 decides in favor of 
1
H  or 
0
H
if 
c
Ln 
 or 
c
Ln 
, respectively, where 

=
n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1


is the likelihood ratio, and 
c is determined to have the size .  When the sample size is not fixed in advance, further 
improvement is possible by using Wald’s Sequential Probability Ratio Test (SPRT).  The 
SPRT continues to sample as long as 
A
L
B
n 

 for some constant 
A
B

1
, stops sampling 
and decides in favor of 
1
H as soon as 
A
Ln 
, and stops sampling and decides in favor of 
0
H
as soon as 
B
Ln 
. 
 
The usual measures of performance of such a procedure are the error probabilities 

and of 
rejecting 
0
H when 
0

=
, and of accepting 
0
H when 
1
=
, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j 

.  Wald and Wolfowitz showed that among all tests, sequential 
or not, for which 


)
reject 
(
Pr
0
0
H
 and 


)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, 
j=0,1, the SPRT with error probabilities 

 and minimizes 
)
(
0 N
E
 and 
)
(
1 N
E
.  If, in 
addition, the 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function 
)
,
( 
x
f
, with monotone likelihood ratio in 
)
(x

, then any SPRT for testing 
0
against 
)
(
0
1


 
has non-decreasing power function.  
 
For the SPRT with error probabilities 

and , the SPRT boundaries are given approximately 
by 

/)
1( −
=
A
 and 
)
1
/(


−
=
B
.  The operating characteristics of the SPRT are given by 
)
/(
)
1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O
−
−
=
 where 
)
(
h
is the non-trivial solution to the equation 

=1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.   
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(




z
E
B
O
A
O
N
E
+
−
=
provides the average sample 
number for an arbitrary .  The sample size distribution is very highly skewed, 
2
)]
(
[
)
(
N
E
N
Var

.  Thus we will consider a truncated test with maximum sample size of 
0
N  
and simulate to obtain the operating characteristics of the test. 


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Derivation of the SPRT for Censored Exponential Survival Times 
 
Suppose that we wish to construct a sequential test for the composite null hypothesis that the 
rate of overall mortality at an early time point t is less than or equal to p0 versus the 
alternative hypothesis that it is greater than or equal to p0.  Let us assume that the survival 
times, 
nT
T
T
,...,
,
2
1
, are i.i.d. with exponential density function 
T
e
T
f



−
=
)
,
(
.  Although an 
exponential model may not fit well for overall mortality, it usually provides a reasonable 
model over a short time frame for modeling toxicity, so in all discussion below we assume 
that exponential survival times are censored at time point t. In the exponential 
parameterization, a t-day survival rate of p0 translates into a mean survival of µ0=-t/ln(1-p0) 
(rate parameter 
=
0
-ln(1-p0)/t).  
 
The SPRT is derived with reference to a simple null and alternative hypothesis for the rate 
parameter, in this case, 
0 :
o
H


=
  versus
1
1 :

=
H
 .  The log-likelihood ratio for the 
exponential in the presence of censoring is 
1
0
1
0
1
0
log
( ;
)
log
( ,
)
(log( )
log(
))
(
)
n
n
n
i
i
i
i
i
i
f x
f x
d
T






−
=
−
−
−



, where d is the number of 
events.   The SPRT can be represented graphically when plotting the number of deaths (d) on 
the y axis against the total time on study 
n
i
iT  on the x axis.  The continuation region in 
terms of d is bounded by two parallel lines given by 
1
0
1
0
1
0
1
0
1
0
1
0
(
)
(
)
log( )
log( )
(log
log
)
(log
log
)
(log
log
)
(log
log
)
n
n
i
i
i
i
B
A
T
d
T




















−
−
+


+








−
−
−
−










 
with common slope 
1
0
1
0
(
)/ (log
log
)




−
−
, and intercepts 
1
0
log
/ (ln
ln
)
A


−
 and 
1
0
log
/ (ln
ln
)
B


−
, for the upper and lower bounds, respectively.  For monitoring purposes, at 
an interim analysis calendar time point s, suppose that d(s) events have occurred and that the 
total time on study is 
( )
n
i
i
T s

.The cumulative number of events d(s) is plotted on the y axis 
against the total time on study,
( )
n
i
i
T s

.  When this graph crosses the upper boundary, the null 
hypothesis is rejected. In practice, monitoring will be scheduled monthly after the start of 
enrollment to the study.   
A truncated version of the SPRT can be obtained by specifying a maximum sample size. We 
truncate the SPRT by declaring that if the test has failed to terminate after the maximum 
sample size, that the null hypothesis will be accepted.  Since the probability that the 
untruncated SPRT would reject the null at the maximum sample size is negligible, it makes 
little difference how the final boundary value is selected, and this rule is chosen for 


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simplicity. The operating characteristics of this proposed truncated SPRT for censored 
exponential data can be estimated by simulation. 


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APPENDIX F 
KARNOFSKY PERFORMANCE STATUS SCALE 
 


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APPENDIX F 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of 
disease. 
Able to carry on normal activity 
and to work. No special care 
needed. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Care for self, unable to carry on normal 
activity or to do work. 
Unable to work. Able to live at 
home, care for most personal 
needs. A varying amount of 
assistance needed. 
60 
Requires occasional assistance but is able to 
care for most of his needs. 
50 
Requires considerable assistance and 
frequent medical care 
40 
Disabled, requires special care and 
assistance. 
Unable to care for self. Requires 
equivalent of institutional or 
hospital care. Disease may be 
rapidly progressing. 
 
30 
Severely disabled, hospitalization indicated, 
although death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
Source: Karnofsky DA, Abelman WH, Craver LF, Burchenal JH. The use of the nitrogen mustards in the palliative 
treatment of carcinoma. Cancer. 1948;1(4):634-56. 
 


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APPENDIX G 
HCT – SPECIFIC COMORBIDITY INDEX SCORE 
 


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APPENDIX G 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
Comorbidities 
Definition 
Score 
Migraine/headache 
 
0 
Osteoporosis 
 
0 
Osteoarthritis 
 
0 
Hypertension 
 
0 
Gastrointestinal 
Including inflammatory bowel disease 
0 
Mild pulmonary 
DLCO and/or FEV1 > 80% or Dyspnea on moderate activity 
0 
Mild renal 
Serum creatinine 1.2-2 mg/dL 
0 
Endocrine 
 
0 
Bleeding 
 
0 
Coagulopathy 
Deep venous thrombosis or pulmonary embolism 
0 
Asthma 
 
0 
Arrhythmia 
 
1 
Myocardial 
Coronary artery disease, congestive heart failure, history of 
medically documented myocardial infarction, EF  50% 
1 
Mild hepatic 
Chronic hepatitis, bilirubin > ULN to 1.5 x ULN, or AST/ALT > 
ULN to 2.5 x ULN 
1 
Cerebro-vascular accident 
History of transient ischemic attack or cerebro-vascular accident 
1 
Morbid obesity 
 
1 
Diabetes 
Requiring treatment 
1 
Depression/anxiety 
 
1 
Infection 
Requiring continuation of treatment after day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia rheumatica 
2 
Moderate pulmonary 
DLCO and/or FEV1 66% - 80% or 
Dyspnea on slight activity 
2 
Peptic ulcer 
Patients who have required treatment 
2 
Moderate-severe renal 
Serum creatinine > 2 mg/dl, on dialysis, or prior renal 
transplantation 
2 
Valvular heart disease 
Except mitral valve prolapse 
3 
Prior solid tumor 
Requiring treatment with chemotherapy 
3 
Moderate-severe hepatic 
Liver cirrhosis, Bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN 
3 
Severe pulmonary 
DLCO and/or FEV1 ≤ 65% or 
Dyspnea at rest or requiring oxygen 
3 
Total score is the sum of all comorbidities present at time of transplantation. 
AST: aspartate aminotransferase; ALT; alanine aminotransferase; CTD: connective tissue disease; DLCO: 
diffusing capacity of the lung for carbon monoxide; EF: ejection fraction; FEV1: forced expiratory volume in 
1 second; HCT: hematopoietic cell transplantation; RA: rheumatoid arthritis; SLE: systemic lupus 
erythematosus; ULN: upper limit of normal.  
Source: Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-specific comorbidity 
index: a new tool for risk assessment before allogeneic HCT. Blood. 2015:106(8):2912-9. 


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APPENDIX H 
LIST OF EXCLUDED AND PRECAUTIONARY 
MEDICATIONS 
 


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APPENDIX H 
LIST OF EXCLUDED AND PRECAUTIONARY MEDICATIONS 
The following list describes medications and foods that are common strong inhibitors of 
CYP3A and these drugs should be avoided unless the drugs are considered absolutely 
essential for the care of the participant. This list should not be considered all inclusive. 
Consult individual drug labels for specific information on a compound’s propensity to inhibit 
CYP3A.  If there are concerns or questions about concomitant use of any drugs listed below, 
discussion with the co-chairs and protocol officer is strongly encouraged. 
Strong CYP3A Inhibitors 
Drug Type 
Generic Drug Name 
Human Immunodeficiency Virus Protease 
Inhibitors 
Indinavir 
Nelfinavir 
Lopinavir 
Ritonavir 
Saquinavir 
Food/Juice 
Grapefruit juice 
Others 
Boceprevir 
Telaprevir 
Clarithromycin 
Telithromycin 
Conivaptan 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Nefazodone 
CYP: cytochrome P450 
Source: Table 4 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf 
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. The 
following 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 
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 Targeting Sigma (non-specific) Receptor (sigma R) 
Treatment with concomitant drugs that target non-sigma specific receptor are to be avoided 
with the exception of drugs that are considered absolutely essential for the care of the 
participant. 
No list of drugs that target sigma non-specific receptor is provided.  Please consult individual 
drug labels for specific information on whether a compound targets sigma non-specific 
receptors. 
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. 


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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/mood stabilizer 
Thioridazine 
Mesoridazine 
Chlorpromazine 
Prochlorperazine 
Trifluoperazine 
Fluphenazine 
Perphenazine 
Pimozide 
Risperidone 
Ziprasidone 
Lithium 
Haloperidol 
Tricyclic/tetracyclic antidepressants  
Amitriptyline 
Desipramine 
Doxepin 
Dosulepin hydrochloride 
Imipramine 
Maprotiline 
Selective serotonin and norepinephrine 
reuptake inhibitors (SSNRIs) antidepressants  
Venlafaxine 
Macrolide antibiotics 
Azithromycin 
Erythromycin 
Clarithromycin 
Dirithromycin 
Roxithromycin 
Tulathromycin 
Fluoroquinolone antibiotics 
Moxifloxacin 
Gatifloxacin 
Table continued on next page 


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Drug Type 
Generic Drug Name 
Azole antifungals  
Ketoconazole 
Fluconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Antimalarials 
Amodiaquine 
Atovaquone 
Chloroquine 
Doxycycline 
Halofantrine 
Mefloquine  
Proguanil 
Primaquine 
Pyrimethamine 
Quinine 
Sulphadoxine 
Antiprotozoals 
Pentamidine 
Antiemetics 
Droperidol 
Dolasetron 
Granisetron 
Ondansetron 
Antiestrogens 
Tamoxifen 
Immunosuppressants 
Tacrolimus 


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APPENDIX I 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE 
AND CHRONIC GRAFT-VERSUS-HOST DISEASE 
 


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APPENDIX I 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE  
AND CHRONIC GRAFT-VERSUS-HOST DISEASE 
 
1. 
Acute graft-versus-host disease (GVHD) organ staging 
 
Stage 
Skin 
Liver (bilirubin) 
GI (stool output per 
day) 
0 
No rash 
< 2 mg/dL 
(< 34.2 µmol/L) 
< 500 ml/day  
1 
Maculopapular rash < 
25% BSA 
 2 to 3 mg/dL 
(34.2 to 51.3 µmol/L) 
500 to < 1000 ml/day or  
persistent nausea 
2 
Maculopapular rash 25 – 
50% BSA 
 > 3 to 6 mg/dL 
(> 51.3 to 102.6 
µmol/L) 
1000 to 1500 ml/day 
3 
Maculopapular rash > 
50% BSA 
> 6 to15 mg/dL 
(> 102.6 to 256.5 
µmol/L) 
>1500 ml/day 
4 
Generalized erythroderma 
plus bullous formation 
> 15 mg/dL 
(> 256.5 µmol/L) 
Severe abdominal pain 
with or without ileus 
BSA: body surface area; GI: gastrointestinal; GVHD: graft-versus-host disease 
 
Grade 
Skin 
Liver (bilirubin) 
GI (Stool output/day) 
I 
Stage 1–2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
- 
Stage 2–3 or 
Stage 2–4 
IV 
Stage 4 or 
Stage 4 
- 
GI: gastrointestinal 
Source: modified from Jacobsohn DA, Vogelsang GB.  Acute graft versus host disease. Orphanet J Rare Dis. 
2007;2:35. doi:10.1186/1750-1172-2-35 
 
 


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2. 
Grading of Chronic Graft-Versus-Host Disease (National Institutes of Health 
Criteria) 
 
 
 


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Source: Jagasia MH, Hildegard TG, Arora M, et al. National Institutes of Health Consensus Development 
Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging 
Working Group Report. Biology of blood and marrow transplantation.  Biol Blood Marrow Transplant. 2015 
March;21(3): 389–401.e1. doi:10.1016/j.bbmt.2014.12.001.  
 
 


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3. 
Categories of Acute and Chronic Graft-Versus-Host Disease  
 
Categories of Acute and Chronic Graft-Versus-Host Disease 
Category 
Time of Symptoms 
after HCT 
Presence of Acute 
GVHD Features 
Presence of 
Chronic GVHD 
Features* 
Acute GVHD 
 
 
Classic acute GVHD 
≤ 100 d 
Yes 
No 
Persistent, recurrent or late-onset 
acute GVHD 
>100 d 
Yes 
No 
Chronic GVHD 
 
 
Classic chronic GVHD 
No time limit 
No 
Yes 
Overlap syndrome 
No time limit 
Yes 
Yes 
D: day; GVHD: graft-versus-host disease; HCT: hematopoietic cell transplant 
*As defined in Section 4 (below) 
 
Source: Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health 
consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis 
and Staging Working Group report. Biol Blood Marrow Transplant. 2005;11:945–56. [PubMed: 16338616] 


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4. 
Signs and Symptoms of Chronic Graft-Versus-Host Disease 
Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic GVHD) 
Distinctive (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis 
of Chronic GVHD) 
Other Features* 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
Skin 
Poikiloderma 
Depigmentation 
Sweat impairment 
Erythema 
 
Lichen planus-like 
features 
 
Ichthyosis 
Maculopapular 
rash 
 
Sclerotic features 
 
Keratosis pilaris 
Pruritus 
 
Morphea-like 
features 
 
Hypopigmentation 
 
 
Lichen sclerosis-
like features 
 
Hyperpigmentation 
 
Nails 
 
Dystrophy 
 
 
 
 
Longitudinal ridging, 
splitting, or brittle 
features 
 
 
 
 
Onycholysis 
 
 
 
 
Pterygium unguis 
 
 
 
 
Nail loss (usually 
symmetric; affects most 
nails)† 
 
 
Scalp and 
body hair 
 
New onset of scarring or 
nonscarring scalp 
alopecia (after recovery 
from 
chemoradiotherapy) 
Scaling, 
papulosquamous lesions 
Thinning scalp hair, 
typically patchy, 
coarse, or dull (not 
explained by 
endocrine or other 
causes) 
 
 
 
 
Premature gray hair 
 
Mouth 
Lichen-type 
features 
Xerostomia 
 
Gingivitis 
 
Hyperkeratotic 
plaques 
Mucocele 
 
Mucositis 
 
Restriction of 
mouth opening 
from sclerosis 
Mucosal atrophy 
Pseudomembranes† 
Ulcers† 
 
Erythema 
Pain 
Eyes 
 
New onset dry, gritty, or 
painful eyes‡ 
Photophobia 
 
 
 
Cicatricial conjunctivitis 
‡Keratoconjunctivitis 
sicca‡ 
Confluent areas of 
punctate keratopathy 
Periorbital 
hyperpigmentation 
 
Table continued on next page 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic GVHD) 
Distinctive (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis 
of Chronic GVHD) 
Other Features* 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
 
 
 
Blepharitis 
(erythema of the 
eyelids with edema) 
 
Genitalia 
Lichen planus-like 
features 
Erosions† 
 
 
 
Vaginal scarring 
or stenosis 
Fissures† 
 
 
 
 
Ulcers† 
 
 
GI tract 
Esophageal web 
Strictures or 
stenosis in the 
upper to mid third 
of the esophagus† 
 
Exocrine pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
 
 
 
 
Weight loss 
 
 
 
 
Failure to thrive 
(infants and 
children) 
Liver 
 
 
 
Total bilirubin, 
alkaline 
phosphatase > 2 × 
ULN† 
 
 
 
 
ALT or AST 
> 2 × ULN† 
Lung 
Bronchiolitis 
obliterans 
diagnosed with 
lung biopsy 
Bronchiolitis obliterans 
diagnosed with PFTs 
and radiology‡ 
 
BOOP 
Muscles, 
fascia, joints 
Fasciitis 
Joint stiffness or 
contractures 
secondary to 
sclerosis 
Myositis or 
polymyositis‡ Myositis 
or polymyositis‡ 
Edema 
Muscle cramps 
Arthralgia or 
arthritis 
 
Hematopoieti
c and immune 
 
 
Thrombocytopenia 
 
 
 
 
Eosinophilia 
 
 
 
 
Lymphopenia 
 
 
 
 
Hypo- or 
hypergammaglobuli
nemia 
 
 
 
 
Autoantibodies 
(AIHA and ITP) 
 
Table continued on next page 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic GVHD) 
Distinctive (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis 
of Chronic GVHD) 
Other Features* 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
Other 
 
 
Pericardial or pleural 
effusions 
 
 
 
 
Ascites 
 
 
 
 
Peripheral 
neuropathy 
 
 
 
 
Nephrotic syndrome 
 
 
 
 
Myasthenia gravis 
 
 
 
 
Cardiac conduction 
abnormality or 
cardiomyopathy 
 
Abbreviations: AIHA: autoimmune hemolytic anemia; ALP: alkaline phosphatase; ALT: alanine 
aminotransferase; AST: aspartate aminotransferase; BOOP: bronchiolitis obliterans-organizing pneumonia; 
GVHD: graft-versus-host disease; ITP: idiopathic thrombocytopenic purpura; PFTs: pulmonary function tests; 
ULN: upper limit of normal. 
* Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed. 
† In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
‡ Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 
 
Source: Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health 
consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis 
and Staging Working Group report. Biol Blood Marrow Transplant. 2005;11:945–56. [PubMed: 16338616] 
 
 
 
 


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APPENDIX J 
LIVER SAFETY MONITORING AND ASSESSMENT 
 


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APPENDIX J 
LIVER SAFETY MONITORING AND ASSESSMENT 
Any participant enrolled in a clinical study with active drug therapy and reveals an increase 
of serum aminotransferases to > 3 × upper limit of normal (ULN; to > 5 × ULN in 
participants with liver metastases) or total bilirubin (TBL) > 2 × ULN, should undergo 
detailed testing for liver enzymes (including at least alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase [ALP] and TBL). Testing should be 
repeated within 48-72 hours of notification of the test results.  Participants should be asked if 
they have any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
  
ALT or AST 
 
TBL 
Moderate 
> 3 x ULN (in participants without liver 
metastases), > 5 x ULN (in participants with 
liver metastases) 
or 
> 2 x ULN 
 
 
 
 
Severe† 
> 3 x ULN 
and 
> 2 x ULN 
In addition, the participant should be considered to have severe hepatic abnormalities for any 
of the following: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases) 
● 
ALT or AST > 3 × ULN and International normalization ratio (INR) > 1.5 (If INR 
testing is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests.  The site should complete the Liver Abnormality-
CRF (LA-CRF) or appropriate document.  Participants 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 participant 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 an SAE.  
The Sponsor should be contacted and informed of all participants 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.  New-onset 
diseases should be recorded as “AEs” in Advantage eClinical. Symptoms are recorded on 
the LA-CRF.  Illnesses and conditions such as hypotensive events and decompensated 
cardiac disease that may lead to secondary liver abnormalities should be noted.  
Nonalcoholic steatohepatitis is seen in obese hyperlipoproteinemic and/or diabetic 
participants and may be associated with fluctuating aminotransferase levels. The 
investigator should ensure that the medical history form captures any illness that predates 
study enrollment that may be relevant in assessing hepatic function. 
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the eCRF. Information on alcohol, other substance use and diet 
should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the participant’s history, other testing may be appropriate including: 
o acute viral hepatitis (A, B, C, D, E or other infectious agents) 
o ultrasound or other imaging to assess biliary tract disease 
o other laboratory tests including PT or INR, direct bilirubin 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Discontinuation 
In the absence of an explanation for increased LFTs, such as viral hepatitis, preexisting or 
acute liver disease, presence of liver metastases or exposure to other agents associated with 
liver injury, the participant may be discontinued from the study. The investigator may 
determine that it is not in the participant’s best interest to continue study enrollment. 
Discontinuation of treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in participants without liver metastases) 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN and TBL > 2 × ULN (in participants with liver metastases) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a participant with moderate or severe hepatic laboratory 
tests is not possible, drug should be discontinued.   


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


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COMMON SERIOUS ADVERSE EVENTS 
 


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APPENDIX K 
COMMON SERIOUS ADVERSE EVENTS 
The purpose of this appendix is to outline those serious AEs that commonly occur in the 
study population. The events listed below require reporting through the expedited AE 
reporting system via Advantage eClinical.   
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied. The list does NOT change the reporting obligations or prevent the 
need to report an AE meeting the definition of an SAE. The purpose of this list is to 
identify some events reported as SAEs which may not require expedited reporting to the 
regulatory authorities based on the classification of “common SAEs.”  
For expedited safety reporting, single occurrences of the following events may be excluded 
from expedited reporting to regulatory agencies according to local requirements. If aggregate 
analysis of these events indicate they occur more frequently with study drug, an expedited 
safety report may be submitted to regulatory agencies. 


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Serious Adverse Events Caused by Active AML/Transplant 
Grades Usually 
Observed with 
Active 
AML/Transplant 
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 
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 


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Serious Adverse Events Caused by Active AML/Transplant 
Grades Usually 
Observed with 
Active 
AML/Transplant 
Table continued on next page 
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 - 4 
Hypertrophied gums 
0 - 1 
Hyperuricemia 
0 - 1 
Hypokalemia 
0 - 2 
Hypotension 
0 - 2 
Hypoxia 
0 - 3 
INR increased 
0 - 1 
Lactate dehydrogenase increased 
0 - 2 
Malaise 
0 - 2 
Multiorgan failure 
0 - 5 
Nausea 
0 - 2 
Oral dysesthesia 
0 - 2 
Petichiae 
0 - 2 
Pruritus 
0 - 3 
Skin and subcutaneous tissue disorders 
0 - 3 
Transient ischemic attacks 
0 - 2 
Tumor lysis syndrome 
3 - 5 
Vasculitis 
0 - 5 
Vomiting 
0 - 2 
Weight loss 
0 - 2 
AE: adverse event; AML: acute myeloid leukemia; GVHD: graft-versus-host disease; INR: international 
normalization ratio 


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APPENDIX L 
CHARACTERIZATION OF CONDITIONING REGIMENS 
 


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APPENDIX L 
CHARACTERIZATION OF CONDITIONING REGIMENS 
 
Myeloablative Conditioning (MAC)* 
Reduced Intensity/Non-Myeloablative 
Conditioning (RIC/NMA) 
 MAC regimens are defined as regimens 
containing: 
• Total body irradiation (TBI) ≥ 5 Gy 
single dose or ≥ 8 Gy fractionated, or 
• Busulfan > 8 mg/kg PO or 6.4 mg/kg 
IV (total dose), or 
• Treosulfan > 30000 mg/m2 (or 
> 30 g/m2), or 
• Melphalan > 150 mg/m2, or 
• Thiotepa ≥ 10 mg/kg. 
 Any regimen that does not meet criteria to 
be defined as MAC regimen will be 
characterized as RIC/NMA 
MAC: myeloablative conditioning; NMA: non-myeloablative; RIC: reduced intensity conditioning; TBI: total 
body irradiation 
*New agents, dosing or regimens that are developed during the study that may be considered myeloablative and 
are not documented in the protocol will be documented in the conditioning regimen adjudication charter and 
will be included in the next available protocol amendment. 


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APPENDIX M 
CORRELATIVE LABORATORY STUDIES 
 


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APPENDIX M 
CORRELATIVE LABORATORY STUDIES 
The correlative laboratory studies for this clinical trial are directed at several goals.  The first 
goal is to re-test the diagnostic specimens with a FLT3-ITD companion diagnostic test, in the 
event a companion diagnostic is essential for the safe and effective use of ASP2215.  A 
related, second goal will be to determine the diagnostic FLT3 mutant-to-wild type allelic 
ratio in as many participants as possible and correlate that result with trial endpoints.   A third 
goal is to assess the correlation of a standardized assay for minimal residual disease (MRD) 
with survival and relapse. These results could inform future study designs of FLT3 inhibitors. 
A fourth goal will be to correlate the presence or absence (at diagnosis or during therapy) of 
AML-associated mutations (such as NPM1) with trial endpoints. A fifth goal will be to assess 
FLT3 mutation status at the time of relapse. 
As detailed in the Informed Consent document, all participants in this study will have the 
opportunity to give consent to allow the trial investigators and their designated affiliates 
access to any diagnostic material (BM aspirate or blood, or DNA or RNA derived therefrom) 
available.  It is recognized that diagnostic material may be available for only a subset of 
participants.  The diagnostic material will be used to 1) compare with the results of local 
testing for a FLT3/ITD mutation; 2) estimate the FLT3/ITD mutant-to-wild type allelic ratio 
present at diagnosis; and 3) assay for the presence of AML-associated mutations (for 
example, DNMT3a, NPM1).  Those diagnostic samples that are already stored at 
Invivoscribe will not be available for central banking with the BMT CTN as they are the 
property of Invivoscribe (which maintains a policy of keeping such samples for a 15 year 
period). 
Bone marrow aspirates will be collected prior to allogeneic transplant and at designated time 
points following transplant as detailed in the protocol (Table 4; Schedule of Assessments).  
During the BM aspirate procedure, the first pull (approximately 2 mL) of the marrow aspirate 
will be specifically collected and shipped to the Reference Laboratory (Invivoscribe).  The 
aspirate material will be used to assay for MRD using a next-generation sequencing (NGS)-
based test.  The results of this MRD assay represent a key secondary endpoint of this trial, 
and will be correlated with relapse and survival endpoints. 
Specimens collected for MRD will be stored at the reference laboratory until completion of 
the study (and all designated correlative lab studies or bridging studies if required by 
regulatory authorities), and then samples from North American participants will be 
transferred to the BMT CTN for storage and possible future use by designated investigators. 
 


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APPENDIX N 
REFERENCES 
 


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APPENDIX N 
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37. Cella D, Jensen SE, Webster K, 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. 
38. Cheson, BD, Bennet JM, Kopecky KJ, et al. Revised Recommendation of the 
Internatinal Working Group for Diagnsosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J of Clin Oncology. 2003;21(24)4642-49. 
39. Bacigalupo A, Ballen K, Rizzo D, et al: Defining the Intensity of Conditioning 
Regimens: Working Definitions. Biol Blood Marrow Transplant. 2009;15:1628-35.  
40. Gordon Lan K.K. and DeMets D. L. Discrete Sequential Boundaries for Clinical Trials. 
Biometrika. 1983;70(3):659–663. 
 

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STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 21 Feb 2023 
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Trial of the FLT3 
Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant 
for Patients with FLT3/ITD AML
ISN/Protocol: 2215-CL-0304
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.


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Table of Contents 
1 
INTRODUCTION ·················································································· 8 
2 
FLOW CHART AND VISIT SCHEDULE ···················································· 8 
3 
STUDY OBJECTIVES AND DESIGN ························································· 9 
3.1 
Study Objectives ··············································································· 9 
3.1.1 
Primary Objective ········································································ 9 
3.1.2 
Secondary Objectives ···································································· 9 
3.1.3 
Exploratory Objectives: ·································································· 9 
3.2 
Study Design ··················································································· 10 
3.3 
Randomization ················································································· 11 
4 
SAMPLE SIZE····················································································· 11 
5 
ANALYSIS SETS ················································································· 14 
5.1 
Intent-to-Treat Analysis Set (ITT) ·························································· 14 
5.2 
Safety Analysis Set (SAF) ··································································· 14 
5.3 
Pharmacokinetics Analysis Set (PKAS) ···················································· 14 
6 
ANALYSIS VARIABLES ······································································· 15 
6.1 
Efficacy Endpoints ············································································ 15 
6.1.1 
Primary Efficacy Endpoint ····························································· 15 
6.1.2 
Secondary Efficacy Endpoints ························································· 17 
6.1.3 
Exploratory Endpoints ·································································· 22 
6.2 
Safety Variables ··············································································· 24 
6.3 
Pharmacokinetic Variables ··································································· 25 
6.4 
Other Variables ················································································ 26 
7 
STATISTICAL METHODOLOGY ··························································· 27 
7.1 
General Considerations ······································································· 27 
7.2 
Study Population ·············································································· 28 
7.2.1 
Disposition of Participants ····························································· 28 
7.2.2 
Protocol Deviations ····································································· 28 
7.2.3 
Demographic and Other Baseline Characteristics ··································· 28 
7.2.4 
Previous and Concomitant Medications ·············································· 29 
7.2.5 
Prior AML Therapy ····································································· 29 
7.2.6 
New Anti-Leukemic Therapy ·························································· 29 


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7.3 
Study Drugs ···················································································· 30 
7.3.1 
Exposure ·················································································· 30 
7.3.2 
Relative Dose Intensity ································································· 30 
7.4 
Analysis of Efficacy ·········································································· 31 
7.4.1 
Analysis of Primary Endpoint ························································· 31 
7.4.2 
Analysis of Secondary Endpoints ····················································· 32 
7.4.3 
Analysis of Exploratory Endpoints ···················································· 36 
7.5 
Analysis of Safety ············································································· 37 
7.5.1 
Adverse Events ·········································································· 37 
7.5.2 
Infection ·················································································· 39 
7.5.3 
Clinical Laboratory Evaluation ························································ 39 
7.5.4 
Vital Signs ················································································ 40 
7.5.5 
Electrocardiograms (ECGs) ···························································· 41 
7.5.6 
Pregnancies ··············································································· 42 
7.5.7 
Karnofsky Performance Status Scores ················································ 42 
7.6 
Analysis of PK ················································································· 42 
7.7 
Analysis of Pharmacodynamics ····························································· 43 
7.8 
Subgroups of Interest ········································································· 43 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 44 
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 44 
7.10.1 
Missing Data ············································································· 44 
7.10.2 
Outliers ··················································································· 46 
7.10.3 
Visit Windows ··········································································· 46 
7.10.4 
Blinding··················································································· 46 
7.10.5 
Pooling of Strata ········································································· 47 
8 
DOCUMENT REVISION HISTORY ························································· 48 
9 
REFERENCES ···················································································· 53 
10 
APPENDICES ····················································································· 54 
10.1 
Appendix 1: Key Contributors and Approvers ············································ 54 
10.2 
Appendix 2: Search Strategy for Adverse Events of Interest ···························· 57 
 
 
 


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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 Gilteritinib 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BERC 
Blinded endpoint review committee 
BMI 
Body Mass Index 
BM 
Bone marrow 
BMT 
Bone marrow transplant 
BMT-CTN 
Bone Marrow Transplant Clinical Trial Network 
BSA 
Body surface area 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CMH 
Cochran-Mantel-Haenszel 
CMV 
Cytomegalovirus 
CR 
Complete remission 
CR1 
First complete remission 
CS 
Classification Specifications 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DLI 
Donor lymphocyte infusion 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture  
EFS 
Event-free survival 
EQ-5D-5L 
EuroQol Group-5 dimension-5 level  
FACT-BMT 
Functional Assessment of Cancer Therapy-Bone Marrow Transplant 
FACT-G 
Functional Assessment of Cancer Therapy-General 


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Abbreviations 
Description of abbreviations 
FACT-Leu 
Functional Assessment of Cancer Therapy-Leukemia 
FLT3 
FMS-like tyrosine kinase 
FPI 
First participant in 
GI 
Gastrointestinal 
GRFS 
GVHD-free relapse-free survival 
GVHD 
graft-versus-host disease 
H 
High 
HSCT 
Hematopoietic stem cell transplant 
HLA 
Human Leucocyte Antigen 
HQL 
Health-related quality of life 
IAP 
Interim Analysis Plan 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IPCW 
Inverse probability of censoring weights 
IRT 
Interactive Response Technology 
ISN 
International Study Number 
ITD 
Internal tandem duplication 
ITT 
Intent-to-treat analysis set 
IU/L 
International units/liter 
L 
Low 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
Min 
Minute 
mL 
Milliliter 
mmHg 
millimeters of mercury 
MOP 
Manual of procedures 
MRD 
Minimal residual disease 
msec 
Milliseconds 
MUGA 
Multigated acquisition scan 
N 
Number 
 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NGS 
Next-generation sequencing 
NHLBI 
National Heart, Lung, and Blood Institute 
NR 
Non-Response 
NRM 
Non-relapse mortality 
OS 
Overall Survival 
PB 
Peripheral blood 
PCR 
Polymerase chain reaction 
PD 
Protocol Deviation 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 


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Abbreviations 
Description of abbreviations 
PT 
Preferred Term 
QTc 
QT interval corrected for heart rate 
QTcF 
Fridericia-corrected QT interval 
RBC 
Red blood cell 
R-IWG 
Revised International Working Group 
RDI 
Relative Dose Intensity 
RFS 
Relapse-free survival 
RMST 
Restricted mean survival time 
RPFST 
Rank-preserving structural failure time method 
RR 
Interval between 2 consecutive r waves on an ECG 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
ULN 
Upper limit of normal 
US 
United States 
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 participant has 
been enrolled, the clinical trial protocol applies to the participant. 
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 participant and continues until the last 
assessment after completing administration of the test drug or comparative 
drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a participant signing consent until just before the test drug 
or comparative drug (sometimes without randomization) is given to a 
participant. 
Randomization 
The process of assigning trial participants 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 participants for enrollment 
in a trial. 
Screen failure 
Potential participant who did not meet 1 or more criteria required for 
participation in a trial. 
Study period 
Period of time from the first site initiation date to the last site completing 
the study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.  
The final SAP will be approved prior to the primary database lock.  
If there are any changes from the planned analyses in the final version of the SAP that impact 
the statistical analyses, then they will be documented in the Clinical Study Report (CSR).  
2 
FLOW CHART AND VISIT SCHEDULE 
Flow Chart 
 
 
AML: acute myeloid leukemia; ANC: absolute neutrophil count; BM: bone marrow; CR1: first morphologic 
complete remission; FLT3: FMS-like tyrosine kinase 3; GVHD: graft-versus-host disease; HSCT: 
hematopoietic stem cell transplant; ITD:  internal tandem duplication; MRD: minimal residual disease. 


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Refer to Table 4 of the protocol for the schedule of assessments. 
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 participants with 
FLT3/ITD AML in CR1 who undergo HSCT and are randomized to receive gilteritinib or 
placebo beginning after the time of engraftment for a two year period. 
3.1.2 
Secondary Objectives 
The key secondary objective is to compare overall survival (OS) in participants treated with 
gilteritinib as maintenance therapy after HSCT compared to those treated with placebo. 
Additional secondary objectives are the following: 
● 
To determine the safety and tolerability of gilteritinib after HSCT.    
● 
To compare non-relapse mortality (NRM) and event-free survival (EFS) (where events 
include relapse, death, stopping therapy and administration of donor lymphocyte infusion 
(DLI) or new therapy for suspicion of disease) in participants treated with gilteritinib as 
maintenance therapy after HSCT compared to those treated with placebo. 
● 
To compare 6-month cumulative incidence of grades II-IV and III-IV acute 
graft-versus-host disease (GVHD) and 12-month and 24-month cumulative incidence of 
mild, moderate, and severe chronic GVHD in participants treated with gilteritinib as 
maintenance therapy after HSCT compared to those treated with placebo. 
● 
To examine the effect of pre- and post-transplant MRD on RFS and OS.  
Relationship of minimal residual disease (MRD), as determined using a next-generation 
sequencing (NGS) platform specific to FLT3/ITD mutations, with RFS and OS. 
● 
To compare incidence and severity of infection in participants treated with gilteritinib as 
maintenance therapy after HSCT compared to those treated with placebo.  
3.1.3 
Exploratory Objectives: 
The exploratory objectives are to: 
● 
Examine health-related quality of life (HQL) 
● 
Compare leukemia-specific health-related quality of life (as measured by Functional 
Assessment of Cancer Therapy-Leukemia [FACT-Leu]) in participants treated with 
gilteritinib as maintenance therapy after HSCT compared to those treated with placebo.  
● 
Assess the effect of gilteritinib as maintenance therapy after HSCT compared to those 
treated with placebo on disease- and treatment-related symptoms as well the proximal 
and distal impacts of changes in symptoms (e.g., functioning, and health-related quality 
of life [HQL]) as measured by Functional Assessment of Cancer Therapy – Bone 
Marrow Transplant (FACT-BMT), FACT-Leu and EuroQol Group-5 Dimension –5 
Level (EQ-5D-5L) 
● 
Examine healthcare resource utilization.   


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● 
Estimate the proportion of participants who are willing and able to be randomized to 
maintenance and describe the frequencies of events that preclude randomization. 
● 
Assess gilteritinib pharmacokinetics using population pharmacokinetic modeling. 
● 
Evaluate FLT3 mutation status and other potential genomic and/or other biomarkers that 
may correlate to treatment outcome 
● 
To compare GVHD-free relapse-free survival (GRFS), acute GVHD-free relapse-free 
survival (aGRFS) and chronic GVHD-free relapse-free survival (cGRFS) in participants 
treated with gilteritinib as maintenance therapy after HSCT compared to those treated 
with placebo 
3.2 
Study Design 
The study is a double-blind, placebo-controlled, randomized Phase III, multi-center trial 
comparing gilteritinib as maintenance therapy vs placebo, in FLT3/ITD AML participants in 
first morphologic CR who are undergoing an HSCT.  Randomization will start between days 
30 and 90 after HSCT, after the participant has engrafted.  The target number of participants 
randomized is 346, 173 for each arm.  To account for an anticipated 35% dropout between 
registration and randomization, 532 participants are expected to register at the time of 
transplant in order to get the targeted number randomized. The trial will be conducted at 
approximately 200 centers in North America, Europe, South America, Central America, 
Asia/Pacific and rest of world. 
This trial will have a three-step enrollment process: 
● 
Screening segment will occur after informed consent is signed 
● 
Registration will occur prior to HSCT after all registration eligibility criteria are met 
● 
Randomization will occur after HSCT once the participant is ready to begin the study 
drug and after all randomization eligibility criteria are met 
After engraftment, participants will undergo a BM aspirate and/or biopsy to ensure continued 
CR status (Engraftment is defined as absolute neutrophil count (ANC) ≥ 500 cells/μL and 
platelets ≥ 20000/μL  on 3 consecutive measurements (each occurring at least 1 day apart)). 
The participant must not have had a platelet transfusion within 7 days prior to the first 
measurement. BM aspirate and/or biopsy must be performed ≤ 30 days prior to 
randomization and can be repeated if necessary to meet the 30 day requirement. Aspirate is 
required and BM biopsy in addition is preferred. If aspirate is unobtainable (e.g., dry tap), 
BM biopsy is required. Once aspirate and/or biopsy confirm continued morphological CR 
status, participants can then proceed to randomization. 
Randomization should occur anytime between days 30 to 90 after day zero (the day of 
allograft infusion) of HSCT.  BM aspirate and/or biopsy after engraftment after HSCT must 
be done to confirm ongoing remission and must be performed ≤ 30 days prior to 
randomization.  Please note that the recommended window to randomize participants is 
between 30 to 45 days after HSCT, but the protocol allows randomization up to day +90 after 
HSCT. Study drug should be started within 24 hours of randomization. Day 1 of the 
treatment period is defined as the date of randomization. Study drug will be administered on 


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an outpatient basis but may be continued in the inpatient setting if participants require 
inpatient evaluation. No investigational or commercial agents or therapies other than study 
drug may be administered with the intent to treat the participant’s malignancy. 
Randomized participants will return to the clinic for study visits while on study drug for up to 
24 months (730 days) after initiation of study drug.  
The primary analysis will occur 2.5 years after the last participant is randomized (i.e., the 
data cutoff date is 07Jan2023) or when approximately 122 events have been observed for the 
primary endpoint, whichever occurs first.  If RFS is not statistically significant or both RFS 
and OS are statistically significant at the primary analysis, the study including follow-up, will 
be stopped.  If RFS is statistically significant but OS is not statistically significant at the 
primary analysis, participants will be followed for relapse and survival for a total of 5 years 
after the last participant is randomized.  
For an individual participant, study duration will last for 2.5 to 5.5 years if the RFS is not 
statistically significant or if both the RFS and OS are statistically significant at the primary 
analysis; otherwise, study duration for an individual participant will last up to 5 to 8 years.  
3.3 
Randomization 
Randomization and study drug assignment will be performed via Interactive Response 
Technology (IRT).  Prior to the initiation of the study treatment, the site staff will contact the 
IRT in order to determine the randomly assigned treatment.  Specific procedures for 
randomization through the IRT are contained in the study procedures manual. 
Participants will be randomized at a ratio of 1:1 between the treatment arm and the placebo 
arm using permuted blocks of random sizes.  Randomization will be stratified by 
conditioning regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time 
from transplant to randomization (30-60 days vs 61-90 days), and the presence of MRD 
(present vs absent/indeterminate) based on the pre-transplant BM aspirate. Date of 
randomization is the date the participant is randomized in IRT. 
4 
SAMPLE SIZE 
The primary analysis will be done using stratified log-rank tests, with the randomization 
factors used as stratification variables.  RFS in the control group is assumed to be 67% at 
1 year, 59% at 2 years, and 55% at 3 years, based on CIBMTR data on participants with 
FLT3/ITD mutation transplanted in CR1 who were alive and progression free at 60 days. A 
total of 122 events provides 85% power to detect a HR of 0.57 (corresponding to a 15% 
difference in 2-year RFS) with two-sided significance level of 0.05.  This assumes that the 
survival function in the control group has piecewise constant hazard functions in each 
interval, that the treatment arm has proportional hazards with a HR of 0.57, and maximum 
follow up of 3 years (Note that CIBMTR data indicates that very few events occur after 
3 years so there is little benefit in longer follow up).  Assuming approximately 2 years of 
accrual and 5% drop out rate per year, 346 participants need to be randomized to ensure a 
high likelihood of obtaining 122 events. 


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As of February 15, 2023, 103 RFS events by BERC were observed after 2.5 years from the 
last participant randomized (i.e., the data cutoff date is 07Jan2023).  This will provide 
approximately 78.6% power with two-sided significance level of 0.05.  
 




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As February 15, 2023, 86 OS events were observed after 2.5 years from the last participant 
randomized (i.e., the data cutoff date is 07Jan2023).  It is predicted the study would have 
100 OS events by 5 years after the last participant randomized and the actual observed 
number of OS events may be slightly different from 100. In such case, the study will use 
100 OS events to calculate the information fraction to calculate the p-value boundary at the 
primary analysis. O’Brien-Fleming type alpha-spending function [Lan & DeMets, 1983] will 
be utilized to control the overall 2-sided 0.05 significance level for the OS primary and final 
analyses as shown in Table 1. For example, with 86 observed OS events at the primary 
analysis and 104 observed OS events at the final analysis, the study has 57.0% power and 
71.3% power to detect a difference in OS between gilteritinib and placebo with the 
assumption of HR=0.6 at the 2-sided p-value boundary of 0.0313 for the primary analysis and 
adjusted 2-sided p-value of 0.0393 per Wassmer and Brannath (2016) for the final analysis, 
respectively.  
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. 
Intent-to-Treat Analysis Set (ITT) will be used for efficacy and biomarker analysis.  Safety 
Analysis Set (SAF) will be used for the analyses of safety variables. Pharmacokinetic 
Analysis Set (PKAS) will be used for pharmacokinetic analyses.  The data from all 
randomized participants will be included in the data tables, listings, and figures.   
5.1 
Intent-to-Treat Analysis Set (ITT) 
The intent-to-treat analysis set (ITT) will consist of all participants who are randomized and 
will be used for efficacy analyses.  Participants will be included in the treatment group to 
which they are randomized. Participants who are randomized but do not start therapy will not 
be replaced. 
The ITT 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 consists of all participants who took at least 1 dose of study drug 
(gilteritinib or placebo). Participants 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 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 sampling and the date and time of PK 
sampling is known. Additional participants may be excluded from the PKAS at the discretion 
of the pharmacokineticist.  


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The PKAS is used for all tables, listings and graphical summaries of the PK data.  
6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoint 
The study has intercurrent events like early discontinuation of the study treatment or 
initiation of subsequent AML therapy or missing visit for disease assessment, while the study 
continues to collect relapse and death information regardless of having the intercurrent events 
or not. The study has missing data from discontinuation from the study before relapse due to 
participant withdrawal/lost of follow-up.  
The primary efficacy endpoint is Relapse-free survival (RFS) as assessed by the blinded 
endpoint review committee (BERC). Treatment policy ignoring the intercurrent events is 
used to define the primary efficacy endpoint. For each participant, RFS is defined as the time 
from the date of randomization until the date of documented morphological relapse, or death 
from any cause, whichever occurs first. 
Morphological relapse is defined as documentation of any of the following events: 
● 
Bone marrow blasts ≥ 5% (not attributable to regenerating BM) 
● 
Any circulating blasts (not attributable to regenerating BM or growth factors) 
● 
Presence of extramedullary blast foci per Revised International Working Group (R-
IWG) criteria 
● 
The earliest date of any of the relapse event will be used for RFS.  
For a participant who is not known to have relapse or death, RFS is censored at the date of 
last follow-up for relapse assessment. Last follow-up for relapse assessment date refers to last 
date among the following assessments:  bone marrow aspiration or biopsy, peripheral blood 
assessment of blast, or a follow-up visit where no relapse was indicated. A participant who 
has no post-baseline disease assessment will be censored at the randomization date.   
Only relapses or deaths occurring on or prior to the cutoff date are counted as RFS events.  
Participants with relapses or deaths after the cutoff date will be censored at the last follow-up 
for relapse assessment date on or before cutoff date. 
Alternative definition of RFS will also be used for sensitivity analyses: 
● 
RFS will be defined similarly as above except that a participant is censored at the last 
follow-up for disease assessment when relapse or death is documented after more than 
1 missed disease assessment, considering hypothetical policy for missing visits and 
treatment policy ignoring other intercurrent events. 
● 
RFS will be defined similarly as above except that a participant is censored at the end of 
planned treatment considering on-treatment policy.  
● 
RFS will be defined similarly as above by using investigator assessed relapse. 


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Table 2 
RFS Definition 
 
Primary  
(By BERC) 
Sensitivity 1 
(Missing >1 
assessment) 
Sensitivity 2 
(censored at 
planned EoT) 
Sensitivity 3 
(By investigator) 
Situation  
Event/Censor; 
RFS date 
Event/Censor; 
RFS date 
Event/Censor; 
RFS date 
Event/Censor; 
RFS date 
Death or relapse on 
or before analysis 
cutoff date  
Event; 
Earlier date of relapse 
by BERC or death 
Event; 
Earlier date of 
relapse by BERC 
or death 
 
If relapse after ≥2 
missed assessments 
and patient is alive,  
Censor; 
Last follow-up for 
relapse assessment 
date 
Event; 
Earlier date of 
relapse by BERC 
or death 
 
If relapse or died 
after planned 
EoT,   
Censor; 
Date of planned 
EoT 
Event; 
Earlier date of 
relapse by 
investigator or 
death 
 
 
Death and relapse 
after analysis cutoff 
date  
Censor; 
Last follow-up for 
relapse assessment 
date before cutoff date 
Censor; 
Last follow-up for 
relapse assessment 
date before cutoff 
date 
Censor; 
Last follow-up 
for relapse 
assessment date 
before cutoff date 
Censor; 
Last follow-up for 
relapse 
assessment date 
before cutoff date 
No RFS event 
Censor; 
Last follow-up for 
relapse assessment 
date before cutoff date 
Censor; 
Last follow-up for 
relapse assessment 
date before cutoff 
date 
Censor; 
minimum(Last 
follow-up for 
relapse 
assessment date 
before cutoff 
date, EoT date) 
Censor; 
Last follow-up for 
relapse 
assessment date 
before cutoff date 
No RFS event and 
no disease 
assessment 
Censor; 
Randomization date 
Censor; 
Randomization 
date 
Censor; 
Randomization 
date 
Censor; 
Randomization 
date 
RFS = Date of Event or Censor – Date of Randomization +1 
Date of EoT = last dose date 
 
The additional alternative definition of RFS below will be used for sensitivity analysis to 
assess the impact of Covid-19 if at least 2.5% of the participants are impacted. 
● 
RFS will be defined similarly as the primary definition above except that a participant is 
censored at the last follow-up for relapse assessment if the assessment was delayed or 
missing due to Covid-19. 
● 
RFS will be defined similarly as the primary definition above except that a participant is 
censored at the end of treatment if the reason for treatment discontinuation is due to 
Covid-19. 
● 
RFS will be defined similarly as the primary definition above except that a participant is 
censored at the date of Covid-19 diagnosis or death date due to Covid-19, whichever 
occurs first. 


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● 
RFS will be defined similarly as the primary definition above except that a participant is 
censored at the date of Covid-19 diagnosis or death date due to Covid-19 or at the end of 
treatment if the reason for treatment discontinuation is due to Covid-19 or at the last 
follow-up for relapse assessment if the assessment was delayed or missing due to 
Covid-19, whichever occurs first. 
6.1.2 
Secondary Efficacy Endpoints 
6.1.2.1 Key Secondary Efficacy Endpoint 
● 
Overall survival (OS)  
OS is defined as the time from the date of randomization until the documented date of death 
from any cause per treatment policy by ignoring the intercurrent events.  All events of death 
will be included, regardless of whether the event occurred while the participant is still taking 
study drug or placebo or after the participant discontinue study drug. Participants who are 
still alive at the time of analysis will be censored at the last day known to be alive or at the 
analysis cutoff date, whichever is earlier. Participants who died after the analysis cut-off date 
will be censored at the analysis cut-off date. The date of last known alive is the latest date 
that the participant is confirmed to be alive across the entire database. 
OS (in days) is calculated as:  
(Date of death or known to be alive) – (Date of randomization) +1. 
Table 3 
OS Definition 
Situation  
Date of Event or Censor 
Outcome 
Death before or on analysis cutoff date  
Date of death 
Event 
Death after analysis cutoff date  
Analysis cutoff date 
Censor 
Last known alive is before or on cutoff date 
Last known alive date 
Censor 
Last known alive is after cutoff date 
Analysis cutoff date 
Censor 
OS = Date of Event or Censor – Date of Randomization +1 
The alternative definition of OS below will be used for sensitivity analysis to assess the 
impact of Covid-19 if at least 2.5% of the participants are impacted. 
● 
OS will be defined similarly as the primary definition above except that a participant is 
censored at the end of treatment if the reason for treatment discontinuation is due to 
Covid-19. 
● 
OS will be defined similarly as the primary definition above except that a participant is 
censored at the date of Covid-19 diagnosis or death date due to Covid-19, whichever 
occurs first. 
● 
OS will be defined similarly as the primary definition above except that a participant is 
censored at the date of Covid-19 diagnosis or death date due to Covid-19 or at the end of 
treatment if the reason for treatment discontinuation is due to Covid-19, whichever 
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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, or premature discontinuation of the treatment, or initiation of other anti-leukemic 
treatment, or death from any cause, whichever occurs first.  
See Section 6.1.1 for the definition of relapse. Anti-leukemic treatment is defined as 
hypomethylating agents, chemotherapy, oral anticancer agents, DLI or cellular therapies 
given because of detectable disease (via cytogenetics, flow cytometry or PCR), not meeting 
R-IWG criteria for relapse. 
If a participant experiences relapse or death, the participant 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 participant discontinues the treatment or initiates other anti-leukemic treatment, the 
participant 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 date of start of anti-leukemic treatment, respectively. 
If multiple events occur on the same date, take the order of “relapse”, “death”, “treatment 
discontinuation”, and “initiation of other anti-leukemic treatment”. 
For a participant who is not known to have relapse, death, treatment discontinuation or 
initiation of other anti-leukemic treatment, EFS is censored at the last follow-up for relapse 
assessment or randomization date, whichever occurs last 
Table 4 
EFS Definition 
Situation  
Date of Event or Censor 
Outcome 
Death or relapse or premature discontinuation of 
the treatment, or initiation of other anti-leukemic 
treatment on or before analysis cutoff date  
Date of relapse, death, premature 
discontinuation of treatment or 
initiation of other anti-leukemic 
treatment 
Event 
Death and relapse and premature discontinuation of 
the treatment and initiation of other anti-leukemic 
treatment after analysis cutoff date  
Last follow-up for relapse 
assessment date before cutoff date 
Censor 
No EFS event 
Last follow-up for relapse 
assessment date before cutoff date 
Censor 
No EFS event and no disease assessment 
Randomization date 
Censor 
EFS = Date of Event or Censor – Date of Randomization +1 
● 
Time to Non-Relapse Mortality (NRM) 
Time to NRM is defined similar to RFS (see Section 6.1.1) with event of interest as the 
participants who died without documentation of morphological relapse. Competing event will 
be the documentation of relapse. For a participant who is not known to have relapse or death, 
time to NRM is censored at the date of last follow-up for relapse assessment before cutoff 
date. 


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● 
Time to Relapse 
Time to relapse is defined similar to RFS (see Section 6.1.1) with event of interest as the 
participants who had documentation of morphological relapse. Competing event will be the 
death without documentation of relapse. For a participant who is not known to have relapse 
or death, time to relapse is censored at the date of last follow-up for relapse assessment 
before cutoff date. 
● 
Time to Treatment-Emergent Acute GVHD II-IV 
Time to treatment-emergent acute GVHD II-IV is defined as the time from the date of 
randomization until the date of treatment-emergent acute GVHD II-IV, or 
treatment-emergent death from any cause, whichever occurs first. Participants who are still 
alive and have no acute GVHD event at the time of analysis will be censored at the last day 
of the aGVHD assessment or at the analysis cutoff date, whichever is earlier.  
The event of interest will be the participants who had treatment-emergent acute GVHD II-IV. 
Events include the following: 
● 
Development of new grade II-IV acute GVHD after randomization  
● 
Worsening in the grade of acute GVHD at the time of randomization by one point 
(e.g., grade I acute GVHD at the time of randomization, progressing to grade II or 
more after randomization) 
Competing event will be the treatment emergent death without documentation of acute 
GVHD II-IV event. An additional analysis will be done treating treatment emergent death 
and treatment emergent relapse without documentation of acute GVHD II-IV event as 
competing events. Definition of relapse follows Section 6.1.1.   
Grading of acute GVHD will be derived by consensus grading (Przepiorka 1995) per 
BMT-CTN manual of procedures (MOP). 
● 
The acute GVHD algorithm calculates the grade based on the organ (skin, GI and 
liver) stage and etiology/biopsy reported on the weekly GVHD form.  
● 
If none of the etiologies for skin, upper GI, lower GI, or liver are reported as GVHD, 
then the overall grade is 0 
● 
If multiple etiologies are specified for lower GI or liver, the organ system will be 
downstaged by 1.   
● 
If an upper GI biopsy is negative, upper GI symptoms are downstaged 
● 
If GVHD is not listed as an etiology for upper GI then upper GI symptoms are 
downstaged  
● 
Each organ contributes to the overall grade; while to get an overall grade, it does not 
necessarily need all organ symptoms. Different organ/stage determine different grade. 
 


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Table 5 
Organ Stage for GVHD grading 
Stage 
Skin 
Lower GI 
Upper GI 
Liver 
1 
Maculopapular Rash  
<25% BSA 
Diarrhea 500-999ml/day 
Persistent Nausea, 
Vomiting, or Anorexia 
Bilirubin  
2-3 mg/dl 
2 
Maculopapular Rash  
25-50% BSA 
Diarrhea 1000-1500 
ml/day 
--- 
Bilirubin 
3.1-6 mg/dl 
3 
Maculopapular Rash  
> 50% BSA 
Diarrhea > 1500 ml/day 
--- 
Bilirubin  
6.1-15 
mg/dl 
4 
Generalized Erythroderma  
 > 50% BSA plus  
Bullous Formation and 
Desquamation  
> 5% BSA 
Severe Abdominal Pain 
With or Without Ileus or 
Grossly Bloody Stool 
--- 
Bilirubin  
> 15 mg/dl 
 
Table 6 
Acute GVHD Grade 
Grade 
Skin 
Lower GI 
Upper GI 
Liver 
I 
Stage 1-2 
0 
0 
0 
II 
Stage 3 or 
Stage 1 or 
Stage 1 or 
Stage 1 
III 
--- 
Stage 2-4 
--- 
Stage 2-3 
IV 
Stage 4 
--- 
--- 
Stage 4 
 
● 
Time to Treatment-Emergent Acute GVHD III-IV 
Time to treatment-emergent acute GVHD III-IV is defined as the time from the date of 
randomization until the date of treatment-emergent acute GVHD III-IV, or treatment 
emergent death from any cause, whichever occurs first. Participants who are still alive and no 
treatment-emergent acute GVHD event at the time of analysis will be censored at the last day 
of the aGVHD assessment or at the analysis cutoff date, whichever is earlier.  
The event of interest will be the participants who had treatment-emergent acute  
GVHD III-IV. Event of interest include the following: 
● 
Development of new grade III-IV acute GVHD after randomization  
● 
Worsening in the grade of acute GVHD at the time of randomization by one point 
(e.g., grade II acute GVHD at the time of randomization, progressing to grade III or 
more after randomization) 
Competing event will be the treatment emergent death without documentation of acute 
GVHD III-IV. An additional analysis will be done treating treatment emergent death and 
treatment emergent relapse without documentation of acute GVHD III-IV event as competing 
events. 
● 
Time to Treatment-Emergent Chronic GVHD 


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Time to treatment-emergent chronic GVHD is defined as the time from the date of 
randomization until the date of treatment-emergent chronic GVHD, or treatment emergent 
death from any cause, whichever occurs first. Participants who are still alive and no 
treatment-emergent chronic GVHD event at the time of analysis will be censored at the last 
day of the chronic GVHD assessment or at the analysis cutoff date, whichever is earlier.  
The event of interest will be the participants who had treatment-emergent chronic GVHD. 
Event of interest include the following: 
● 
Development of new mild, moderate or severe chronic GVHD after randomization  
● 
Worsening in the grade of chronic GVHD at the time of randomization by one point 
(e.g. mild chronic GVHD at the time of randomization, progressing to moderate or 
severe chronic GVHD after randomization) 
Competing event will be the treatment emergent death without documentation of chronic 
GVHD. An additional analysis will be done treating treatment emergent death and treatment 
emergent relapse without documentation of chronic GVHD event as competing events. 
● 
Time to Post-Transplant Eradication of MRD 
Time to post-transplant eradication of MRD is defined only on participants with positive 
MRD status at baseline. It is the time from the date of randomization until the eradication of 
MRD, or death from any cause, whichever occurs first. Participants who are still alive at the 
time of analysis will be censored at the last MRD assessment or at the analysis cutoff date, 
whichever is earlier. Participants without post-baseline MRD assessment will be censored at 
the randomization date. 
The event of interest will be the participants who had MRD eradication. Competing event 
will be the death during MRD assessment period without documentation of MRD 
eradication. 
● 
Time to Post-Transplant Detection of MRD 
Time to post-transplant detection of MRD is defined only on participants with negative MRD 
status at baseline. It is the time from the date of randomization until the detection of MRD, or 
death from any cause, whichever occurs first. Participants who are still alive at the time of 
analysis will be censored at the last MRD assessment or at the analysis cutoff date, whichever 
is earlier. Participants without post-baseline MRD assessment will be censored at the 
randomization date. 
The event of interest will be the participants who had positive MRD. Competing event will 
be the death during MRD assessment period without detection of MRD. 
● 
Minimal Residual Disease (MRD) 
MRD will be analyzed by a Sponsor-designated central laboratory.  A peripheral blood 
sample is not acceptable for MRD assessment.  


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FLT3/ITD mutation ratio will be measured in relation to total FLT3. For a participant 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 “Present” if log10-transformed overall FLT3/ITD 
mutation ratio is greater than -4; otherwise, the presence of MRD will be “Absent”. For 
participants with multiple ITD mutations detected, the ratios will be summed. 
Additional absolute cut points (e.g., log10-transformed overall FLT3/ITD to total FLT3 ratio 
of -5, -6, etc.) may be evaluated, as well as the log10 transformed change in FLT3/ITD to total 
FLT3 ratio at each visit compared to baseline. 
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.  
● 
Non-randomization 
These are the participants who were registered but not randomized 
● 
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 designed to measure leukemia-specific signs, symptoms 
and the impact of leukemia on participants.  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.   
● 
Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)  
The FACT-BMT comprised of a general core questionnaire, the Functional Assessment of 
Cancer Therapy-General (FACT-G), which evaluates the HQL of participants receiving 
treatment for cancer, and a transplant-specific module, bone marrow transplant (BMT) 
Concerns, that addresses disease and treatment-related questions specific to BMT.  The 


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FACT-G consists of four subscales developed and normed in cancer participants:  Physical 
Well-being, Social/Family Well-being, Emotional Well-being, and Functional 
Well-being.  Each subscale is positively scored, with higher scores indicating better 
functioning.  The FACT-BMT Total, which is the grand total of all items in the FACT-G and 
BMT modules, will be used as the outcome measure in summarizing the FACT-BMT data. 
● 
Healthcare resource utilization 
Healthcare resource utilization includes hospitalization or emergency department visits 
(duration, underlying reasons, and setting specified: general ward, ICU, etc.), antibiotic use, 
and oral and IV medication for AEs. 
● 
Acute GVHD-free relapse-free survival (aGRFS) 
Time to aGRFS is defined as the time from the date of randomization until the date of 
treatment-emergent acute GVHD III-IV, or morphological relapse (BERC) or death from any 
cause, whichever occurs first. Participants who are still alive and no aGRFS event at the time 
of analysis will be censored at the last follow-up for relapse assessment or at the analysis 
cutoff date, whichever is earlier.  
Treatment-emergent acute GVHD III-IV event is defined as: 
● 
Development of new grade III-IV acute GVHD after randomization  
● 
Worsening in the grade of acute GVHD at the time of randomization by one point (e.g., 
grade II acute GVHD at the time of randomization, progressing to grade III or more after 
randomization) 
● 
Chronic GVHD-free relapse-free survival (cGRFS) 
Time to cGRFS is defined as the time from the date of randomization until the date of 
treatment-emergent chronic GVHD that requires new or additional immunosuppressive 
treatment, or morphological relapse (BERC) or death from any cause, whichever occurs first. 
Participants who are still alive and no cGRFS event at the time of analysis will be censored at 
the last follow-up for relapse assessment or at the analysis cutoff date, whichever is earlier.  
Treatment-emergent chronic GVHD event is defined as: 
● 
Development of new mild, moderate or severe chronic GVHD that requires new or 
additional immunosuppressive treatment after randomization  
● 
Worsening in the grade of chronic GVHD that requires new or additional 
immunosuppressive treatment at the time of randomization by one point (e.g., mild 
chronic GVHD at the time of randomization, progressing to moderate or severe chronic 
GVHD after randomization) 
● 
GVHD-free relapse-free survival (GRFS) 
Time to GRFS is defined as the time from the date of randomization until the date of 
treatment-emergent acute GVHD III-IV, or treatment-emergent chronic GVHD that requires 
new or additional immunosuppressive treatment, or morphological relapse (BERC) or death 
from any cause, whichever occurs first. Participants who are still alive and no GRFS event at 


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the time of analysis will be censored at the last follow-up for relapse assessment or at the 
analysis cutoff date, whichever is earlier.  
Treatment-emergent acute GVHD III-IV event is defined in the aGRFS definition. 
Treatment-emergent chronic GVHD event is defined in the cGRFS definition. 
6.2 
Safety Variables 
Safety endpoints such as AEs, laboratory tests, vital signs, ECGs, physical examination and 
Karnofsky performance status are secondary endpoints of the study. 
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 is marked as an event occurred after the first dose of the 
study drug, then the AE will be considered treatment emergent.  If the AE occurs on 
Day 1 and is marked as an event occurred before the first dose of the study drug, 
then the AE will not be considered treatment emergent.  If a participant 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 7.10.1.  
● 
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 or Important Medical Event (IME).  
● 
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  
Below is a table of the laboratory tests that will be performed during the conduct of the 
study. Refer to the Schedule of Assessments for study visit collection dates.  
Additional laboratory tests should be performed according to institutional standard of 
care.  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. 


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Table 7 
Laboratory Assessments 
Panel/Assessment 
Parameters to be analyzed  
NCI-CTCAE Grading (Hyper/Hypo) 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Red Blood Cell Count (RBC) 
White Blood Cell Count (WBC) 
Platelets 
 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
N/A 
Both 
N/A 
Both 
Hypo 
 
Hypo 
N/A 
N/A 
Both 
N/A 
Biochemistry (fasting) 
Sodium (Na) 
Magnesium (Mg) 
Creatine Phosphokinase (CK) 
Potassium (K) 
Corrected Calcium (CCa) 
Chloride (Cl) 
Phosphate (P) 
Creatinine (Cr) 
Glucose (Gl) 
Blood Urea Nitrogen (BUN) 
Alkaline Phosphatase (ALP) 
Aspartate Aminotransferase (AST) 
Alanine Aminotransferase (ALT) 
Bilirubin Total (TBL)  
Total Protein (TP) 
Albumin (Alb) 
Bicarbonate (HCO3) 
Serum HCG for female participants 
of childbearing potential 
Thyroid Stimulating Hormone (TSH) 
Free Thyroxine (Free T4) 
Both 
Both 
Hyper 
Both 
Both 
N/A 
Hypo 
Hyper 
Both 
N/A 
Hyper 
Hyper 
Hyper 
Hyper 
N/A 
Hypo 
N/A 
N/A 
 
N/A 
N/A 
 
● 
Vital signs (systolic and diastolic blood pressures (mmHg)) 
● 
12-lead electrocardiogram (ECG) 
● 
Karnofsky performance status scores 
6.3 
Pharmacokinetic Variables 
Plasma concentration data of gilteritinib will be used in pharmacokinetic analysis.  
Pharmacokinetic samples for gilteritinib will be collected within 0.5 hours before drug 
administration. 


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6.4 
Other Variables 
● 
Body Mass Index (BMI)  
BMI = weight (kg) / [height (m)]2 
● 
Time from CR to randomization (days) 
Time from CR to randomization = Date of randomization – date of first CR 
● 
Time from transplant to ANC recovery (days)  
Time from transplant to ANC recovery = Date of ANC recovery – date of transplant 
● 
Time from diagnosis to transplantation (days) 
Time from diagnosis to transplantation = Date of transplantation – date of diagnosis + 1 
● 
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 (mg) 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 dose intensity = 120 mg/day  
● 
Relative dose intensity (%) 
Relative dose intensity = dose intensity (mg/day)/planned daily dose (mg/day)*100% 
● 
Previous and concomitant medications 
Previous medication is defined as medication  administered before the date of first 
dosing (exclusive).  
Concomitant medication is defined as medication administered between the date of first 
dose (inclusive) and the date of last dose (inclusive) of study drug.   


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7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
For continuous variables, descriptive statistics will include the number of participants (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 participants with no missing data, 
i.e., will add up to 100%.  
Summaries based on ITT (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 or PKAS will be presented by actual treatment received.   
All statistical comparisons will be made using 2-sided tests at α=0.05 significance level 
unless specifically stated otherwise. All null hypotheses will be of no treatment effect 
difference between gilteritinib and placebo, all alternative hypotheses will be there is 
treatment effect difference between gilteritinib and placebo, unless specifically stated 
otherwise. 
All data processing, summarization, and analyses will be performed using SAS® Version 9. 
4 or higher on Red Hat Enterprise Linux.  Specifications for table, figure, and data listing 
formats can be found in the TLF specifications for this study. 
Study day for safety assessments (e.g., laboratory assessment, onset of adverse events, vital 
signs, etc.) will be calculated in reference to the first dose date. For assessments conducted 
before the first dose, study day will be calculated as (assessment date – first dose date). For 
assessments conducted on or after the first dose, study day will be calculated as (assessment 
date – first dose date + 1). 
Study day for efficacy assessments (bone marrow assessment, overall survival, relapse-free 
survival, etc.) will be calculated in reference to the randomization date. For assessments 
conducted before randomization, study day will be calculated as (assessment date – 
randomization date). For assessments conducted on or after randomization, study day will be 
calculated as (assessment date – randomization date + 1). 
For efficacy evaluation, baseline is defined as the last available measurement from Day -14 
to before randomization. For safety evaluation, baseline is defined as the last available 
measurement from day -14 to before first dose. For MRD assessment, baseline is defined as 
the last available measurement from day -30 to before randomization.  Unless otherwise 
specified, all summaries will be presented by treatment arm. 
For the definition of subgroups of interest please refer to Section 7.8.   


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7.2 
Study Population 
7.2.1 
Disposition of Participants 
The following participant data will be presented: 
● 
Number and percentage of participants with informed consent, discontinued before 
registered, registered, discontinued before randomization, randomized (overall only); 
● 
Number and percentage of randomization failure participants, by primary reason for 
randomization failure for randomization failure participants only;  
For all randomized participants, the following participant data will be presented by treatment 
group: 
● 
Number and percentage of participants in each analysis set; 
● 
Number and percentage of participants who completed or discontinued treatment by 
primary reason for treatment discontinuation;  
● 
Number and percentage of participants who completed the 30-day follow-up evaluation 
by status; 
● 
Number and percentage of participants who completed the long term follow-up 
evaluation  by status. 
7.2.2 
Protocol Deviations 
Protocol deviations (PDs) as defined in the study protocol (Appendix C of the protocol) will 
be assessed for all randomized participants.  The number and percentage of participants 
meeting any criteria will be summarized for each criterion and overall, by treatment group 
and total as well as by study site.  Participants deviating from a criterion more than once will 
be counted once for the corresponding criterion.  Any participants who have more than one 
protocol deviation will be counted once in the overall summary.  A data listing will be 
provided by site and participant. 
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 participants allocated to treatment in each country and site will be 
presented by treatment group.  


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Descriptive statistics for age, weight, body mass index (BMI), height at study entry, time 
from CR to randomization, time to ANC recovery and time from diagnosis to transplantation 
will be presented.  Frequency tabulations for conditioning regimen intensity, time from 
transplant to randomization, pre-transplant MRD status, sex, ethnicity, race, age group, 
Karnofsky performance score (<90 vs >=90), recipient CMV status, donor/recipient CMV 
status, HSCT-specific comorbidity index  (0 vs 1-2, vs >=3), donor type/HLA 
matching(matched sibling, unrelated donor (URD), mismatched URD, related haploidentical, 
or umbilical cord blood), graft type (umbilical cord, BM, PB), prophylaxis regimen, latest 
status of acute GVHD prior to randomization(0-1 vs 2 vs 3-4, yes vs no) and latest status of 
chronic GVHD prior to randomization (yes vs no) and cytogenetic risk 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 ongoing medical conditions, Common Terminology 
Criteria for Adverse Events (CTCAE) grade 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/ingredients (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 
PT/ingredients.  Participants 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 participants who took each 
medication.  
Frequency tabulations for treatment used for GVHD will be presented by treatment group. 
7.2.5 
Prior AML Therapy 
Frequency tabulations of participants with prior AML therapy, regimen, type of treatment, 
prior use of FLT3 inhibitor, and first 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. 
7.2.6 
New Anti-Leukemic Therapy 
Frequency tabulations of participants with new anti-leukemic therapy, regimen, type of 
treatment, best response to therapy and reason for initiating therapy will be presented by 
treatment group. 


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New anti-leukemic therapy will also be summarized by PT by treatment group and presented 
in decreasing order of frequency based on the total number of participants who took each 
medication.  
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 participants 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 20 months 
o at least 20 months, less than 24 months 
o 24 months or more 
o Unknown. 
Counts and percentages of participants in each of these categories will be summarized by 
treatment group for the SAF. 
Listing of participants with dose decrease or interruption will also be provided for SAF. 
7.3.2 
Relative Dose Intensity 
RDI will be examined for participants in the SAF whose total study drug count and first and 
last days of treatment are known. 
RDI will be summarized in two ways for the SAF: 
● 
Descriptive statistics will be presented by treatment arm. 
● 
RDI will be categorized according to the following categories by treatment regimen: 
o 
less than 50% 
o 
at least 50%, less or equal to 80% 
o 
greater than 80% 
o 
Unknown. 


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7.4 
Analysis of Efficacy 
To address multiplicity, a gatekeeping testing strategy will be used for RFS (primary efficacy 
endpoint) and OS (key secondary endpoint). RFS will be tested once at 2-sided significance 
level of 0.05. Only if RFS is significant, will hypothesis testing for OS primary and final 
analyses be performed. An O’Brien-Fleming type alpha-spending function [Lan & DeMets, 
1983] will be utilized to control the overall 2-sided 0.05 significance level for the OS primary 
and final analyses. Other secondary endpoints’ testing will not be multiplicity adjusted.  
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 ITT to compare the RFS as assessed 
by BERC between gilteritinib and placebo. The null and alternative hypotheses for this 
comparison are: 
● 
H01:RFS in the gilteritinib arm is  not different to RFS in the placebo arm 
● 
H11:RFS in the gilteritinib arm is different from RFS in the placebo arm.   
The primary analysis will be performed 2.5 years after the last patient was randomized or 
when approximately 122 RFS events have been observed, whichever occurs first. 
Comparison of gilteritinib and placebo will be tested at 2-sided significance level of 0.05 
The distribution of RFS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between gilteritinib and placebo using log-rank test stratified by 
randomization strata as described in Section 3.3.  In addition, stratified Cox proportional 
hazard model will be used to estimate the hazard ratio and the corresponding 95% confidence 
interval. The same stratification factors will be applied to both the stratified log-rank test and 
the stratified Cox proportional hazards model. The Cox proportional hazard model will be 
included as a sensitivity analysis for testing H01. The stratification factors may be pooled in 
the stratified analysis per Section 7.10.5. 
Kaplan-Meier survival plots will be used to describe the RFS in each treatment group.  Median 
RFS and RFS probabilities at 1, 2 and 3 years with 95% confidence interval will be estimated 
from the Kaplan-Meier plots. 
Median follow-up of RFS estimated from reverse Kaplan-Meier curve will be provided.  
In the event that the MRD status is not available at the time of randomization, participants 
with unknown MRD status will be grouped with negative MRD status for stratification 
purposes. The MRD detection threshold is set to 10-4 (ratio of FLT3-ITD to total FLT3).  The 
presence of MRD will be “Present” if log10-transformed overall FLT3/ITD mutation ratio is 
greater than -4; otherwise, the presence of MRD will be “Absent”. Additional thresholds may 
be explored.  
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: 


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● The primary analysis repeated on the ITT using investigator assessed relapse. 
● The primary analysis repeated on the ITT with the addition of GVHD prophylaxis (CNI 
(CsA or Tac) + MTX +/- Others , CNI (CsA or Tac) + MMF +/- Others , Other) as a 
stratification factor. The stratification factors may be pooled in the stratified analysis per 
Section 7.10.5. 
● 
Unstratified log-rank test and Cox proportional hazards model on the ITT 
● 
Stratified log-rank test and Cox proportional hazards model on the ITT where RFS is 
censored at the last evaluable disease assessment without relapse when relapse or death 
is documented after more than one missed disease assessment. 
● 
Stratified log-rank test and Cox proportional hazards model on the ITT where RFS is 
censored at the end of treatment when participant ended the treatment early 
● If there is a difference in the stratification values between IRT and the CRF, primary 
analysis may be repeated on the ITT using CRF stratification values. 
● 
Restricted mean survival time (RMST) analysis will be used for RFS on the ITT with 
24 months as threshold. Restricted mean survival time will be estimated with its 95% CI.  
Treatment difference of RMST and its 95% CI and the corresponding p-value will be 
provided. 
● 
The primary analysis repeated on the ITT for alternative definitions of RFS taking into 
account the impact of Covid-19, if at least 2.5% of the participants are impacted. 
To investigate non-proportionality between the treatment arms, the LOG(–LOG) survivor 
function versus time curves will be plotted.  The scaled Schoenfeld residuals by time plot will 
be examined for evidence of a non-zero correlation, which indicates non-proportionality. Cox 
models stratified on treatment may be explored given evidence of non-proportional hazards, 
in order to generate adjusted RFS curves by treatment group, which can be compared 
between the groups at 2 and 3 years.   
7.4.2 
Analysis of Secondary Endpoints 
7.4.2.1 Key Secondary Efficacy Analysis 
OS will be a key secondary endpoint, with explicit control of the type I error rate through a 
gatekeeper approach.  Formal significance testing of OS will be conducted if the RFS 
comparison is statistically significant.  Otherwise, survival analyses will be considered 
exploratory.  
Primary analysis for OS will be performed when the primary analysis for RFS is statistically 
significant at 2-sided α = 0.05.  If the primary analysis for RFS is statistically significant 
while the primary analysis for OS is not statistically significant, a final analysis for OS will 
occur 5 years after the last participant was randomized.  
OS will be analyzed on the ITT 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:   


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● 
H02:OS in the gilteritinib arm is not different to OS in the placebo arm 
● 
H12:OS in the gilteritinib arm is different from OS in the placebo arm.  
The hazard ratio of the treatment effect along with 95% confidence interval will be calculated 
by the stratified Cox proportional hazard model. The same stratification factors will be 
applied to both the stratified log-rank test and the stratified Cox proportional hazard model. 
The Cox proportional hazard model will be included as a sensitivity analysis for testing H02. 
The stratification factors may be pooled in the stratified analysis per Section 7.10.5. 
Kaplan-Meier curves will be used to describe the OS in each arm.  Median OS time and OS 
probabilities at 1, 2, 3, 4 and 5 years along with 95% confidence interval will be estimated 
from the Kaplan-Meier curves. 
Median follow-up of OS estimated from reverse Kaplan-Meier curve will be provided. 
For the key secondary endpoint of OS, sensitivity analyses will be performed as below: 
● 
The primary analysis repeated on the ITT with the addition of GVHD prophylaxis (CNI 
(CsA or Tac) + MTX +/- Others , CNI (CsA or Tac) + MMF +/- Others , Other)  as a 
stratification factor. The stratification factors may be pooled in the stratified analysis per 
Section 7.10.5.  
● 
Unstratified log-rank test and Cox proportional hazards model on the ITT  
● If there is a difference in the stratification values between IRT and the CRF, primary 
analysis may be repeated on the ITT using CRF stratification values 
● The primary analysis repeated on the ITT for alternative definitions of OS taking into 
account the impact of Covid-19, if at least 2.5% of the participants are impacted. 
To investigate non-proportionality between the treatment arms, the analyses for RFS as 
assessed by BERC will be carried out for OS. 
Subsequent anti-cancer therapies will be collected and summarized by treatment arm within 
drug class.  Imbalance in the use of subsequent anti-cancer therapy may potentially bias the 
inference in OS.  The following methods may be used to assess the impact of the use of 
subsequent anti-cancer therapy in OS.  
● Censor OS at the last contact date prior to the initiation of subsequent anti-cancer 
therapy 
● Rank-preserving structural failure time method (RPSFT) to correct for confounding 
introduced by the change of treatment including new anti-leukemic therapy. The 
RPSFT model is based on an accelerated failure time model and uses a structural 
assumption of time-proportionality instead of a proportional hazards assumption as 
used in the Cox model 
● Inverse probability of censoring weights (IPCW). 


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7.4.2.2 Other Secondary Efficacy Analysis 
EFS 
EFS will be analyzed in the same manner as RFS in the ITT using the stratified log-rank test 
with the same strata.  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, survival rates at 1, 2 and 3 years if appropriate and 
95% confidence interval will be estimated from the Kaplan-Meier curve. In addition, reason 
for participant starting new therapies and type of new therapies will be summarized. 
NRM 
Incidence of NRM will be estimated using the cumulative incidence function, treating 
relapse/progression as a competing risk.  Incidence of NRM will be compared between the 
treatment arms using a Fine and Gray model, adjusting for strata variables of conditioning 
regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time from 
transplant to randomization, and pre-transplant MRD status.  Cumulative incidence at 1, 2 
and 3 years, subdistribution hazard ratio and its 95% confidence interval will be produced. 
Relapse 
Incidence of relapse will be estimated using cumulative incidence function, treating death 
without relapse as a competing risk.  Incidence of relapse/progression will be compared 
between the treatment arms using a Fine and Gray model, adjusting for strata variables of 
conditioning regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time 
from transplant to randomization, and pre-transplant MRD status. Cumulative incidence at 1, 
2 and 3 years, subdistribution hazard ratio and its 95% confidence interval will be produced.  
Acute GVHD II-IV 
Cumulative incidence of new onset acute GVHD or worsening in the grade of acute GVHD 
at the time of randomization by one point (e.g., grade II acute GVHD at the time of 
randomization, progressing to grade III or more after randomization) will be estimated from 
the time of randomization using the cumulative incidence function, treating treatment 
emergent death prior to acute GVHD II-IV as the competing risk.  Cumulative incidence of 
acute GVHD II-IV will be compared between treatment arms using a Fine and Gray model, 
adjusting for strata variables of conditioning regimen intensity (myeloablative vs reduced 
intensity/non-myeloablative), time from transplant to randomization, and pre- transplant 
MRD status. An additional analysis will be performed treating treatment emergent death and 
treatment emergent relapse without documentation of an acute GVHD event as competing 
risks. Cumulative incidence at 100 and 180 days, subdistribution hazard ratio and its 95% 
confidence interval will be produced.  
Acute GVHD III-IV 
Cumulative incidence of new onset acute GVHD III-IV or worsening in the grade of acute 
GVHD at the time of randomization by one point (e.g., grade III acute GVHD at the time of 
randomization, progressing to grade IV or more after randomization) will be estimated from 


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the time of randomization using the cumulative incidence function, treating treatment 
emergent death prior to acute GVHD III-IV as the competing risk.  Cumulative incidence of 
acute GVHD III-IV will be compared between treatment arms using a Fine and Gray model. 
Cumulative incidence at 100 and 180 days, subdistribution hazard ratio and its 95% 
confidence interval will be produced. An additional analysis will be performed treating 
treatment emergent death and treatment emergent relapse without documentation of an acute 
GVHD event as competing risks. 
Chronic GVHD 
Cumulative incidence of chronic GVHD from the time of randomization will be estimated 
using the cumulative incidence function, treating treatment emergent death prior to chronic 
GVHD as the competing risk.  Cumulative incidence of chronic GVHD will be compared 
between treatment arms using a Fine and Gray model, adjusting for strata variables of 
conditioning regimen intensity (myeloablative vs reduced intensity/non-myeloablative), time 
from transplant to randomization, and pre- transplant MRD status. Cumulative incidence at 
1 and 2 years, subdistribution hazard ratio and its 95% confidence interval will be produced. 
In addition, distribution of maximum grade of chronic GVHD will be tabulated. An 
additional analysis will be performed treating treatment emergent death and treatment 
emergent relapse without documentation of a chronic GVHD event as competing risks. 
Eradication of MRD 
The time until eradication of MRD in participants who have detectable MRD prior to 
randomization will also be described and compared between treatment arms using Gray’s 
test; death during MRD assessment period without eradication of MRD will be treated as a 
competing risk. Cumulative incidence at 1 and 2 years, subdistribution hazard ratio from an 
unadjusted Fine and Gray model, and its 95% confidence interval will be produced. 
Detection of MRD 
The cumulative incidence of detection of MRD in participants who are MRD undetectable 
prior to randomization will be described in each group and compared between treatment arms 
using Gray’s test; death during MRD assessment period without detection of MRD will be 
treated as a competing risk. Cumulative incidence at 1 and 2 years, subdistribution hazard 
ratio and its 95% confidence interval will be produced. 
MRD as prognostic endpoint for RFS and OS  
Subgroup analysis for RFS and OS using pre-HSCT MRD status (present vs 
absent/unknown) and MRD status at randomization (present vs absent) will be performed.  
Additional analysis may be performed to investigate MRD as prognostic endpoint for 
RFS/OS.  


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7.4.3 
Analysis of Exploratory Endpoints 
FLT3/ITD allelic frequencies will be analyzed using the diagnostic specimens when 
available. 
FLT3 mutation status at relapse will be summarized by the number and percentage of 
participants by treatment group on ITT  
Incidence of resource utilization which includes hospitalization (duration, underlying 
reasons, and setting specified: general ward, ICU, etc.), antibiotic use, and medication for 
AEs will be summarized by treatment group on ITT.  The difference between treatment 
groups will be tested using CMH test while controlling of randomization stratification 
factors.  
Resource utilization counts including duration of hospital stays, duration of medications and 
duration of antibiotic use will be summarized by treatment group using descriptive statistics 
(mean, standard deviation, minimum, maximum and median) on ITT. For the duration of 
hospital stays, missing end date will be imputed as the start date if the type of encounter is 
outpatient/day clinic or emergency department visit without admission.  Otherwise, missing 
end date will be imputed using the last dosing date + 7 days. 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 ITT.  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.  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 ITT.  
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 factors. 
FACT-BMT score will be summarized by treatment group using descriptive statistics (mean, 
standard deviation, minimum, maximum and median) on ITT.  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 factors.   
FACT-Leu and FACT-BMT instruments share set of questions for PWB, SWB, EWB, FWB, 
and FACT-G total score and were collected only once.  These parameters will be displayed 
on both FACT-Leu and FACT BMT summary tables. 


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The completion and compliance rates of the EQ-5D-5L, FACT-BMT, and FACT-Leu will be 
summarized at each visit and overall. Additional exploratory analyses of resource utilization, 
patient reported outcomes (FACT-BMT, FACT-Leu) and health outcome (EQ-5D-5L) will 
be performed and the details will be included in a separate Patient Reported Outcome 
Statistical Analysis Plan. 
aGRFS, cGRFS and GRFS will be analyzed on the ITT in the same manner as RFS using the 
stratified log-rank test with the same strata as described in Section 7.4.1.1.  
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. 
The coding dictionary for this study will be MedDRA.  It will be used to summarize AEs by 
SOC and PT.  AEs will be graded using National Cancer Institute’s Common Terminology 
Criteria for AEs (NCI-CTCAE).  
An overview table to report the number and percentage of participants and an overview table 
to report number of events and events adjusted by patient years of drug exposure will include 
the following details: 
● 
TEAEs, 
● 
Drug-related TEAEs, 
● 
Serious TEAEs, 
● 
Drug-related serious TEAEs, 
● 
TEAEs leading to death, 
● 
Drug-related TEAEs leading to death,  
● 
TEAEs leading to withdrawal of treatment, 
● 
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 participants with TEAEs and the number of events and events 
adjusted by patient years of drug exposure, as classified by SOC and PT will be summarized 
for each treatment group.  Summaries will be provided for: 


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● 
TEAEs 
● 
Drug-related TEAEs,  
● 
Serious TEAEs,  
● 
Drug-related serious TEAEs,  
● 
TEAEs leading to death, 
● 
Drug related TEAEs leading to death, 
● 
TEAEs leading to withdrawal of treatment,  
● 
Drug-related TEAEs leading to withdrawal of treatment,  
● 
TEAE leading to dose reduction, 
● 
Drug related TEAE leading to dose reduction, 
● 
TEAEs leading to dose interruption, 
● 
Drug-related TEAEs leading to dose interruption, 
● 
TEAEs excluding serious adverse events that equal to or exceed a threshold of 10% 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 
● 
Grade 3 or higher TEAEs, 
● 
Drug-related Grade 3 or higher TEAEs. 
The number and percentage of participants 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 participants with TEAE of special interest (AESI), as 
classified by AESI category and PT will be summarized for each treatment group for the 
following: 
● 
TEAE 
● 
Serious TEAE 
● 
TEAE leading to withdrawal of treatment,  
● 
Drug related-TEAE leading to withdrawal of treatment,  
● 
TEAE leading to dose reduction, 
● 
Drug-related TEAE leading to dose reduction,  
● 
TEAE leading to dose interruption, 
● 
Drug-related TEAE leading to dose interruption,  
● 
Grade 3 or higher TEAE,  
● 
Drug-related Grade 3 or higher TEAE 
AE summary tables will include participant counts as opposed to AE counts except for SAE.  
If a participant experiences more than one episode of a particular AE, the participant will be 
counted only once for that AE.  If a participant has more than one AE that codes to the same 
PT, the participant will be counted only once for that PT.  Similarly, if a participant has more 
than one AE within a SOC, the participant will be counted only once in that SOC. 


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The number and percentage of participants 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 
participant count, if a participant has multiple TEAEs with the same SOC or PT, but with 
differing severity grade or relationship, then the participant 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 participant will be counted only once with 
missing severity grade or relationship.  Drug related TEAEs will be presented in a similar 
way by severity grade only. Serious TEAE will be presented in a similar way by relationship 
to study drug. 
The number and percentage of participants with treatment-emergent adverse events of 
interest, as classified by SOC and PT will also be summarized by treatment group and 
overall. The list of adverse events of interest to be summarized may change during the course 
of the study due to ongoing pharmacovigilance.  It will be finalized before the database hard 
lock. 
All AEs, deaths, SAEs and withdrawals due to adverse events will be displayed in listings.  
7.5.2 
Infection 
The number of infections and the number of participants experiencing infections will be 
tabulated by type of infection, severity, and time period after transplant. The cumulative 
incidence of CTCAE grade 3 to 5 infections, treating treatment emergent death without 
infection (grade 5) as a competing event, will be compared between the treatment arms using 
Gray’s test. Participants who are still alive and no infection event at the time of analysis will 
be censored at the end of treatment plus 30 days or at the analysis cutoff date, whichever is 
earlier. 
7.5.3 
Clinical Laboratory Evaluation 
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, will be summarized 
using mean, standard deviation, minimum, maximum and median for each treatment group at 
each visit.  Additionally, a within-participant change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way. Changes in 
laboratory values will be summarized for baseline values versus minimum, maximum and 
last post-baseline values. Plots of median lab values at each scheduled assessment time by 
treatment group may be provided for each laboratory parameter. 
Laboratory results will also be graded using NCI-CTCAE, where possible.  
Parameters that have criteria available for both low and high values, i.e., hypo- and hyper-, 
will be summarized for both criteria. The same participant can be counted for both values if 
the participant has different laboratory values meeting each criterion. NCI-CTCAE grade of 
laboratory evaluations will be summarized by number and percentage of participants for each 
visit. Shift tables of NCI-CTCAE grade change from baseline to worst post-baseline grade 
for selected laboratory parameters will also be presented. The number and percentage of 
participants with grade 3 or 4 laboratory test result will be summarized by treatment group 


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and laboratory parameter (the name of the adverse event associated with the abnormal 
laboratory test result will be presented).  
The list of laboratory parameters to be summarized may change during the course of the 
study due to ongoing pharmacovigilance.  It will be finalized before the database hard lock. 
Laboratory data will be displayed in listings. 
7.5.3.1 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 participant’s worst post-baseline record will 
be used.  
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 participants with potentially clinically significant values in 
liver enzymes and total bilirubin will be presented by treatment group. 
7.5.4 
Vital Signs 
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 participant for each treatment group.  The results of 
vital signs may be displayed in figures. 


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The following potentially clinically significant criteria are defined: 
Vital Sign Variable 
Criteria 
SBP 
≥180 mmHg AND ≥20 mmHg change from baseline 
DBP 
≥105 mmHg AND ≥15 mmHg change from baseline 
7.5.5 
Electrocardiograms (ECGs) 
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 participants 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 participant. 
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 frequency of participants 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.  


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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 participants with 12 lead ECG abnormalities as well as number and 
percent of participants 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.  
 
7.5.6 
Pregnancies 
A detailed listing of all pregnancies will be provided. 
7.5.7 
Karnofsky Performance Status Scores 
Karnofsky performance status scores will be summarized by treatment group and visit. 
Distribution of participants with scores <90, 90-100 will be tabulated by treatment group and 
visit. 
7.6 
Analysis of PK 
PK analysis will be conducted on the PKAS.  
Trough gilteritinib concentrations for a given timepoint will be excluded from the analysis if 
it meets at least one of the following exclusion criteria: 
● 
Discontinuation of study drug prior to day of sample collection.  
● 
Change in dose from 120 mg prior to day of sample collection (For participants that 
return to 120 mg dose, minimum of 14 days of dosing required prior to day of sample 
collection). 
● 
Pause of ≥ 2 days in 14 days prior to day of sample collection (Note for C1D8 sample, 
exclude if pause of ≥ 1 day in 7 days prior to day of sample collection). 
● 
When the time of PK sample collection occurs after dose administration on that day. 
Trough gilteritinib concentrations will be summarized 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. In addition, mean (SD) plot of trough gilteritinib concentration by visit from 0 to 
6 months will be produced. 
ASP2215 Ctrough group is defined based on median ASP2215 Ctrough C1D15 value. If 
individual subject’s Ctrough value is greater or equal to median ASP2215 Ctrough value, then it’s 
defined as high ASP2215 Ctrough, otherwise it is defined as low ASP2215 Ctrough. 
Demographic and other baseline characteristics will be summarized by ASP2215 Ctrough 
C1D15 group using descriptive statistics. 


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KM plot of RFS and separately for OS by median ASP2215 Ctrough C1D15 group will be 
provided. 
Listing of individual participant trough gilteritinib concentration by visit will also be 
provided. Population pharmacokinetic analysis will be performed. Data from this study may 
be pooled with other studies for analysis. Details of this analysis will be specified in a 
separate population pharmacokinetic analysis plan. 
7.7 
Analysis of 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: 
Grouping Variables 
Subgroups 
Age 
< 50 years 
≥ 50 - <60 years 
≥  60 years 
Sex 
Female 
Male 
MRD status at randomization 
Present 
Absent 
Pre-transplant MRD status at 
enrollment from IRT 
Present 
Absent/Indeterminate 
Region 
North America 
Europe 
Asia/Pacific/ Rest of World 
Conditioning regimen intensity 
from IRT 
Myeloablative 
Reduced intensity/non-myeloablative 
GVHD prophylaxis 
CNI (CsA or Tac) + MTX +/- Others  
CNI (CsA or Tac) + MMF +/- Others  
Other 
Time from transplant to 
randomization from IRT 
 30 – 60 days 
61 – 90 days 
Cytogenetic Risk Status 
Favorable 
Intermediate 
Unfavorable 
Other/Unknown 
CR status prior to 
randomization 
CR 
CRp+CRi 
Prior use of FLT3 inhibitor 
Yes 
No 


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Race 
White 
Black or African American 
Asian 
Other/Missing 
HSCT-Specific Comorbidity 
Index 
0 
1-2 
>=3 
Baseline Karnofsky 
Performance Score 
>=90 
<90 
 
Subgroup analysis for incidence of FLT3 mutation at relapse (present/absent) will also be 
provided. 
 
Additional subgroup analysis based on specific regions such as Japan may also be performed. 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Policies and composition of the DSMB are described in the BMT CTN’s Manual of 
Procedures.  No interim efficacy or futility analyses are planned. RFS with immature data 
may be participant to overestimation; the data are not robust and is rarely reproducible when 
more mature data are available. For this reason, early evaluation may lead to stopping the 
trial too early, and therefore the DSMB will not stop the trial due to differences in RFS. 
Toxicity, AEs, and other safety endpoints will be monitored regularly and reported to the 
DSMB at each meeting. 
Monitoring of a key safety endpoint will be conducted monthly, and if rates significantly 
exceed pre-set thresholds, the NHLBI will be notified so that the DSMB can be advised.  The 
stopping guideline serves as trigger for consultation with the DSMB for additional review 
and are not formal “stopping rules” that would mandate automatic closure of study 
enrollment.  Guidelines for safety monitoring is being outlined in Section 5.3.1 of the 
protocol.  
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.10.1 Missing Data  
It should be noted that date conventions were used so that dates could be consistently entered 
through the EDC system.  Dates that were deemed critical had an associated field added so 
that the site could indicate if the day or month was unknown and entered utilizing the 
convention. 
Every effort will be made to resolve incomplete dates for death and disease relapse.  If a 
partial date cannot be resolved, the most conservative imputation methods will be used to 
complete the missing information.  


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For primary endpoint 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.   
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: 
yyyymm 
= 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 
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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7.10.2 Outliers 
All values will be included in the analyses. 
7.10.3 Visit Windows 
Not applicable. Nominal visits will be used in the by visit summary. Values from 
unscheduled visits will be included in the summary of extreme cases (e.g., summary of worst 
post-baseline, summary of minimum post-baseline, summary of maximum post-baseline).  
For efficacy endpoints, all values (scheduled and unscheduled) will be included in the 
analysis.  
7.10.4 Blinding 
This is a double-blind study. Participants will be randomized to receive gilteritinib or placebo 
in a double-blind fashion such that neither the investigator, Sponsor’s study management 
team, clinical staff, nor the participant will know which agent is being administered. The 
randomization number will be assigned based on information obtained from the Interactive 
Response Technology (IRT) system and Advantage eClinicalSM.   
The site and the BERC members will also be blinded to the MRD status used for 
stratification.  
The randomization list and study medication blind will be maintained by the IRT system. The 
Data Safety Monitoring Board (DSMB) will be provided access to the dosing assignment for 
periodic review of the masked data as documented in the DSMB Charter and the study 
specific DSMB Charter Addendum. The DSMB may elect to break the mask. 
The Sponsor may break the treatment code for participants 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 for breaking the codes for all SUSAR cases 
for reporting purposes. 
The treatment code for each randomized participant will be provided by the IRT in the event 
of medical emergency requiring knowledge of the treatment assigned to the participant. The 
time, date, participant 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 participants or other study 
personnel will be made aware of the treatment given to any participant unless a medical 
emergency necessitates such disclosure. 
Unblinding of the study drug should only be considered for participant safety and/or evidence 
of documented morphological relapse contingent upon knowing the blinded study drug 
assignment.  
● 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. 


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● 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. The Astellas Medical 
Monitor must provide approval for unblinding for relapse prior to unblinding. 
The study will be unblinded after database hard lock for the primary analysis. 
7.10.5 Pooling of Strata 
In the RFS, OS and EFS 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 MRD status pre-HSCT, conditioning regimen, 
and time from HSCT to randomization until the issue is resolved or the normal (un-stratified) 
Cox proportional hazard model is applied.  For stratified analysis with GVHD prophylaxis 
regimen as one of the stratification factors, the order of pooling will be MRD status 
pre-HSCT, conditioning regimen, time from HSCT to randomization and GVHD prophylaxis 
regimen. 
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. 


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8 
DOCUMENT REVISION HISTORY 
Version Date 
Changes 
Comment/rationale for change 
1.0 
21-Mar-2017 
NA 
Document finalized 
2.0 
21-Feb-2023 
Changed the term subject to 
participant  
To match the terminology in the 
protocol 
 
 
Section 1 
Updated to clarify the timing of SAP 
finalization. 
 
To match the language from the 
SAP template 
 
 
Section 2  
Flow chart was updated 
 
Table 1 Schedule of Assessments 
was deleted 
 
To match the flow chart in 
protocol version 4 
Schedule of assessment from the 
protocol was referred to ensure 
consistency. 
 
 
Section 3.1.2 – added an objective 
for infection endpoint 
To reflect protocol version 4 
objectives 
 
 
Section 3.1.3 – added an objective 
for FLT3 mutation status, aGRFS, 
cGRFS and GRFS  
To reflect protocol version 4 
objectives 
 
 
Section 3.2 – the text for study 
design was updated  
The timing of the primary and 
final analyses was clarified 
To reflect the changes in the 
study design and the timing of 
the analyses made in protocol 
version 4 
 
 
Section 4 – added the estimated 
statistical power for RFS and OS 
after 2.5 years from the last patient 
randomized. Additionally, the 
estimated power for OS after 5 years 
from the last patient randomized was 
also included. 
To provide the estimated power 
for RFS and OS for primary 
analysis and power for OS for 
final analysis 
 
 
Section 5 – per protocol set was 
deleted.  
In addition, reference to analysis set 
classification meeting was deleted 
Per protocol set will not be used 
for any summaries or analyses 
Analysis sets will be derived 
programmatically, classification 
meeting is not needed 
 
 
Section 5.3 Pharmacokinetics 
Analysis Set (PKAS) definition was 
updated to clarify both dosing 
date/time and sampling date/time 
must be available. 
To clarify the detailed PKAS 
criteria. 
 
 
Section 6.1.1 to clarify the censoring 
rules for RFS is up to follow-up visit 
where no relapse was indicated 
 
To clarify RFS censoring rule 
 
 
 


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Table 1 was updated to include 
different sensitivity analysis for RFS 
 
Alternative definitions for RFS 
accounting for the impact of Covid-
19 were added  
To provide the derivation of 
RFS for different sensitivity 
analyses 
 
Alternative definitions were 
added to assess the impact of 
Covid-19. 
 
 
Section 6.1.2.1:  
Added the definition of last known 
alive date 
 
Alternative definitions for OS 
accounting for the impact of Covid-
19 were added 
To clarify the derivation of last 
known alive date 
 
 
Alternative definitions were 
added to assess the impact of 
Covid-19. 
 
 
Section 6.1.2.2  
Updated the censoring rules for EFS 
 
Added the censoring rule for NRM 
and relapse  
 
 
aGVHD II-IV, aGVHD III-IV and 
cGVHD – modified the censoring 
rule 
 
 
time to MRD eradication and 
detection – modified the censoring 
rule 
To match the censoring rule for 
RFS 
 
To provide details on the 
censoring rules for NRM and 
relapse 
 
To clarify that the censoring rule 
is up to GVHD assessment only 
instead of last known alive date 
 
To clarify that the censoring rule 
is up to MRD assessment only 
instead of last known alive date 
 
 
 
Section6.1.3 – aGRFS, cGRFS and 
GRFS were added as exploratory 
endpoints 
To reflect the addition of these 
endpoints in protocol version 4 
 
 
Section 6.2 and added Section 10.2 to 
clarify Adverse events of special 
safety interest (AESI) searching 
strategy 
To provide details on the search 
strategy for AESI  
 
 
Section 7.1 
Added the statement regarding null 
and alternative hypotheses 
 
 
Computing environment was updated 
 
 
 
 
To clarify the default null and 
alternative hypotheses being 
tested 
 
To reflect the latest SAS version 
we have in the computing 
environment 
 


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Baseline definition of MRD was 
added 
To clarify that MRD assessment 
has a different window for 
baseline derivation 
 
 
Sections 7.2.5 and 7.2.6 were added 
to have summaries for prior AML 
therapy and new ant-leukemic 
therapy 
Prior AML therapy and new 
anti-leukemic therapy will be 
summarized 
 
 
Section 7.2.3 was updated to add 
subgroup of cytogenetic risk status 
for demographics and subgroup 
analysis. 
Cytogenetic risk status will be 
summarized and analyzed  
 
 
Section 7.3.1 
Exposure time categorization was 
updated in months 
 
To change the unit in months 
instead of days 
 
 
Section 7.4 
Detailed description on how to 
address multiplicity was added 
 
Clarified the testing procedure to 
address  multiplicity 
 
 
Section 7.4.1 
Added the timing of the primary 
analysis for RFS 
 
Clarified the stratification factors for 
analysis 
 
Clarified the grouping for GVHD 
prophylaxis 
 
Deleted PPS 
 
Added RMST analysis for RFS 
 
Added sensitivity analysis for RFS 
taking into account Covid-19 impact. 
To clarify the different analyses 
for RFS 
 
 
Section 7.4.2 
Added the timing of the primary 
analysis for OS. 
 
Added the alpha spending for OS 
primary and final analyses 
 
Clarified the stratification factors for 
analysis 
 
Clarified the grouping for GVHD 
prophylaxis 
To clarify the different analyses 
for OS 


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Deleted PPS 
 
Added sensitivity analysis for OS 
taking into account Covid-19 impact. 
 
 
Section 7.4.2.2 
aGVHD II-IV, aGVHD III-IV and 
cGVHD – clarified the definition of 
the event of interest.  In addition, 
both relapse and death were added as 
competing risks 
 
Updated the analysis for MRD as 
prognostic factor 
 
To clarify the analysis for 
aGVHD II-IV, aGVHD III-IV 
and cGVHD 
 
 
 
 
To clarify the analysis for MRD 
as prognostic factor 
 
 
Section 7.4.3 
Added the analyses for aGRFS, 
cGRFS and GRFS 
 
Added the imputation rule for 
duration of hospitalization 
To clarify the analyses to be 
made for the new exploratory 
endpoints aGRFS, cGRFS and 
GRFS 
 
To provide guidance on how to 
compute the duration if end date 
is missing 
 
 
Updated Section 7.5.1 to include 
additional summaries of AEs and AE 
summaries by patient-year 
To clarify the different 
summaries for AE 
 
 
Section 7.5.2 – added the censoring 
rule for participant who did not 
experience infection 
To provide details on the 
censoring rule for infection 
 
 
Updated Section 7.5.3 to add the 
grade 3 and 4 summary for selected 
lab test parameters 
To add new summary for critical 
lab results 
 
 
Updated Section 7.5.5 to add ECG 
abnormalities  
To add new summary for ECG 
abnormalities 
 
 
Section 7.6 
Added the criteria for excluding 
records from the analysis 
 
Added more details on the different 
analysis for PK 
 
To clarify exclusion criteria for 
analysis 
 
To clarify the different analysis 
for PK 
 
 
Section 7.6.8 
Added the following subgroups 
Cytogenetic risk, CR status prior to 
randomization, prior use of FLT3 
inhibitor, race, HSCT-specific 
 
Additional subgroups were 
included in the analyses 


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comorbidity index and baseline 
Karnofsky performance score 
 
 
Updated Section 7.10.4 for handling 
unblinding   
Updated per protocol 
amendment 2 
 
 
Added section 7.10.5 
To clarify the strata pooling 
strategy for efficacy analysis 
 
 
Updated section 10.2 search strategy 
for adverse event of special interest 
To implement updated search 
strategy for adverse event of 
special interest 


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9 
REFERENCES 
Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality 
of life in leukemia: the Functional Assessment of Cancer Therapy--Leukemia (FACT-Leu) 
questionnaire. Value Health. 2012;15:1051-8. 
Cheson BD, Bennett JM, Willman CL, et al. Revised Recommendations of the International Working 
Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 
2003;21(24):4642-4649. 
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) 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika.  
1983;70:659-63. 
Wassmer G and Brannath W, Group Sequential and Confirmatory Adaptive Designs in Clinical 
Trials, 2016 
 








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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