A Phase 3, Double-Blind, Placebo-controlled Study of Quizartinib Administered in Combination With Induction and Consolidation Chemotherapy, and Administered as Continuation Therapy in Subjects 18 to 75 Years Old With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (QuANTUM First)
Phase: PHASE3
Conditions: Acute Myeloid Leukemia, Leukemia
Sponsor: Daiichi Sankyo

 
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CLINICAL STUDY PROTOCOL 
A PHASE 3, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF QUIZARTINIB 
ADMINISTERED IN COMBINATION WITH 
INDUCTION AND CONSOLIDATION 
CHEMOTHERAPY, AND ADMINISTERED AS 
CONTINUATION THERAPY IN SUBJECTS 18 TO 75 
YEARS OLD WITH NEWLY DIAGNOSED FLT3-ITD (+) 
ACUTE MYELOID LEUKEMIA 
 
AC220-A-U302 
 
 
QUIZARTINIB ADVANCEMENT INTO THE NEXT GENERATION OF 
TRIALS FOR UNMET NEEDS IN AML – First-LINE (QuANTUM-First) 
IND/EudraCT NUMBER 74,552/2015-004856-24 
 
 
VERSION 7.0, 26 May 2021 
 
DAIICHI SANKYO INC 
211 Mt. Airy Road 
Basking Ridge, NJ 07920-2311 
United States 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo, Inc. 

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DOCUMENT HISTORY 
 
 
Version Number 
Version Date 
7.0 
26 May 2021 
6.0 
28 Oct 2020 
5.0 
07 Apr 2020 
4.0 
26 Jun 2019 
3.0 
20 Nov 2018 
2.0 
06 Apr 2017 
1.0 
17 Dec 2015 

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SUMMARY OF CHANGES 
Amendment Rationale: 
The main purpose of this amendment is to update the hierarchical order for statistical testing of 
the secondary endpoints based on recent feedback from the United States Food and Drug 
Administration (FDA).   
This amendment is considered to be non-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 because it does not significantly impact the safety or physical/mental integrity of subjects 
nor the scientific value of the study. 
Changes to the Protocol: 
Please refer to the comparison document for protocol Version 7.0 (dated 26 May 2021) versus 
Version 6.0 (dated 28 Oct 2020) for actual changes in-text.  The Summary of Changes below is a 
top-line summary of major changes in the current AC220-A-U302 clinical study protocol 
(Version 7.0) by section. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (section numbers and/or paragraph/bullet numbers) refer to the current protocol version, 
which incorporates the items specified in this Summary of Changes. 
Minor edits, such as updates to language that do not alter original meaning, update to version 
numbering, formatting, change in font color, deletions of unused references, additions of new 
references, corrections to typographical errors, use of abbreviations, moving verbiage within a section 
or table, change in style, or changes in case, are not noted in the table below. 
 
Section # and Title 
Description of Change 
Brief Rationale 
Synopsis, Statistical Analyses 
11.4.1.2 Secondary Efficacy 
Analyses 
Changed the statistical testing 
order of the secondary endpoints 
and clarified that the EFS 
analysis which uses the IRC 
assessment will be based on the 
EFS definition in new health 
authority Guidances.63,72  
Updated based on recent FDA 
recommendation. 
3.1. Overall Design 
Figure 3.2, days of cytarabine 
dosing corrected 
Correction 
17.1.1. Schedule of Events – 
Induction Phase 
Table 17.3: Schedule of 
Assessment - Induction Phase 
(Cycle 2 with “5+2” regimen) - 
added footnote for EORTC QLQ-
C30 and EQ-5D-5L only to be 
done if it is the last day of the 
Induction Phase for Cycle 2, Day 
28, to match Section 6.2.1.2.2.11. 
Correction 
EFS = event-free survival; EORTC = European Organisation for Research and Treatment of Cancer; EQ-5D-5L  = 
health-related quality of life questionnaire;  IRC = Independent Review Committee; QLQ-C30 = core quality of life 
questionnaire 

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PROTOCOL SYNOPSIS 
EudraCT: 
2015-004856-24 
IND Number: 
74,552 
Protocol Number: 
AC220-A-U302 
Investigational Product: 
Quizartinib 
Active Ingredient(s) / INN: 
Quizartinib dihydrochloride / Quizartinib 
Study Title: 
A Phase 3, Double-Blind, Placebo-controlled Study of 
Quizartinib Administered in Combination with Induction and 
Consolidation Chemotherapy, and Administered as Continuation 
Therapy in Subjects 18 to 75 Years Old with Newly Diagnosed 
FLT3-ITD (+) Acute Myeloid Leukemia (QuANTUM-First) 
Study Phase: 
Phase 3 
Indication Under Investigation: Newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-internal 
tandem duplication (ITD) (+) acute myeloid leukemia (AML) 
Study Objectives: 
Primary Objective: 
The primary objective is to compare the effect of quizartinib 
versus placebo (administered with standard induction and 
consolidation chemotherapy, then administered as continuation 
therapy for up to 36 cycles) on the primary endpoint of overall 
survival (OS) in subjects with newly diagnosed AML with 
FLT3-ITD mutations. 
Secondary Objectives: 
The secondary objectives are to: 
 Compare the following in subjects treated with quizartinib 
versus placebo (administered with standard induction and 
consolidation chemotherapy, then administered as 
continuation therapy for up to 36 cycles): 
 Event-free survival (EFS) 
 Composite complete remission rate (CRc = complete 
remission (CR) + CR with incomplete neutrophil or 
platelet recovery [CRi]) after Induction; 
 Percentage of subjects achieving CRc with FLT3-ITD 
minimal or measurable residual disease (MRD) 
negativity after Induction; 

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 Complete remission (CR) rate after Induction; 
 Percentage of subjects achieving CR with FLT3-ITD 
MRD negativity after Induction. 
 Further characterize the safety profile of quizartinib 
administered with standard induction and consolidation 
chemotherapy, then administered as continuation therapy for 
up to 36 cycles. 
 Assess the pharmacokinetics (PK) of quizartinib and its 
metabolite (AC886). 
Exploratory Objectives: 
The exploratory objectives are to: 
 Evaluate the following in subjects treated with quizartinib 
versus placebo (administered with standard induction and 
consolidation chemotherapy, then administered as 
continuation therapy for up to 36 cycles): 
 Relapse-free survival (RFS); 
 Duration of complete remission (CR); 
 CR rate at end of first Induction Cycle; 
 CRc rate at the end of first Induction Cycle; 
 Rate of CR with partial hematologic recovery (CRh) 
after Induction (only for Independent Review 
Committee [IRC] assessment of response); 
 Rate of morphologic leukemia-free state (MLFS) after 
Induction (only for IRC assessment of response); 
 RFS in subjects who enter the Continuation Phase, after 
achieving CRc in Induction; 
 Transplantation rate;  
 Heath care resource utilization; 
 Impact on subject reported quality of life (QoL) and 
symptoms, as assessed by European Organisation for 
Research and Treatment of Cancer (EORTC) core 
quality of life questionnaire (QLQ-C30); 
 Change in general health status measured by 
EQ-5D-5L. 
 Assess the population PK (PopPK) of quizartinib and 
exposure-response relationship for QT interval corrected 
with Fridericia’s formula (QTcF) including assessment 

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post-anthracycline administration, and clinical response 
measures. 
 Assess the pharmacodynamics and biomarkers of 
quizartinib. 
Study Design: 
This is a Phase 3, randomized, double-blind, placebo-controlled, 
global study to compare the effect of quizartinib versus placebo 
(administered with standard induction and consolidation 
chemotherapy, then administered as continuation therapy for up 
to 36 cycles) on the primary endpoint of OS in subjects with 
newly diagnosed AML with FLT3-ITD mutations. 
Randomization will be stratified based on: 
 Region (North America, Europe, and Asia/Other Regions)  
 Age (<60 years old, ≥60 years old) 
 White blood cell (WBC) count at the time of diagnosis of 
AML (<40×109/L, ≥40×109/L) 
Study Phases: 
Induction Phase (up to 2 cycles) 
Cycle 1 
Cycle 1, Day 1 is defined as the start date of the chemotherapy 
infusions. 
Cytarabine (cytosine arabinoside) 100 mg/m2/day 
(200 mg/m2/day allowed if institutional or local standard) will 
be administered by continuous intravenous (IV) infusion for a 
total of 7 days, starting on Day 1 and ending on Day 8. 
One of the following anthracycline regimens (investigator’s 
choice) will be administered: 
Daunorubicin 60 mg/m2/day IV infusion on Days 1, 2, and 3; or 
Idarubicin 12 mg/m2/day IV infusion on Days 1, 2, and 3. 
Subjects will be randomized on Day 7.  If necessary, 
Randomization may be performed later (eg, Days 8 to 10) to 
allow time for addressing electrolyte abnormalities, QTcF 
prolongation, etc.  
Quizartinib/placebo will be administered orally once daily for 14 
days.  Dosing should start after the end of the cytarabine 
infusion, normally on Day 8.  If quizartinib/placebo 
administration cannot begin as scheduled, the start of dosing 
may be delayed, but best efforts should be made to start within 3 
days of Randomization if possible.  If quizartinib/placebo cannot 

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be started within 3 days of Randomization, please contact the 
Medical Monitor.  The dose will be 40 mg/day.  For subjects 
concomitantly receiving a strong cytochrome P450 (CYP) 3A4 
inhibitor, the dose will be reduced from 40 mg/day to 20 
mg/day.  If quizartinib/placebo is interrupted, missed doses will 
not be made up. 
On Day 21 (window Day 21 to Day 28), a bone marrow aspirate 
specimen (or a core biopsy specimen if aspirate cannot be 
obtained) will be collected for local and central pathology.  If 
this bone marrow does not provide an accurate assessment of 
response, the bone marrow aspiration will be repeated upon 
count recovery or Day 56 ( 3 days), whichever occurs first.  
Subjects with ≥ 5% blasts after Cycle 1 may receive a second 
cycle of Induction, if appropriate. 
Cycle 2 
For Cycle 2 of Induction, investigators may choose to administer 
1 of the following: 
“7+3” chemotherapy regimen, defined as 7 days of continuous 
IV infusion of cytarabine 100 mg/m2/day (200 mg/m2/day 
allowed if institutional or local standard) plus 3 days of 
anthracycline (the same anthracycline must be used throughout 
the Induction phase); OR 
“5+2” chemotherapy regimen, defined as 5 days of continuous 
IV infusion of cytarabine 100 mg/m2/day (200 mg/m2/day 
allowed if institutional or local standard) plus 2 days of 
anthracycline (the same anthracycline must be used throughout 
the Induction phase). 
Quizartinib/placebo will be administered orally once daily for 14 
days.  Dosing will start following the end of the cytarabine 
infusion, normally on Cycle 2, Day 8 or Cycle 2, Day 6, 
depending on the chemotherapy regimen selected by the 
investigator (ie, “7+3” or “5+2”, respectively).  If 
quizartinib/placebo administration cannot begin as scheduled, 
the start of dosing may be delayed, but best efforts should be 
made to begin as soon as possible.  If quizartinib/placebo is 
interrupted, missed doses will not be made up. 
Collection of a bone marrow aspirate specimen (or a core biopsy 
specimen if aspirate cannot be obtained) and assessment of 
response will be done according to the same schedule as in 
Cycle 1.  

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Consolidation Phase  
Subjects who achieve a CR or CRi at the end of the Induction 
Phase will enter the Consolidation Phase.  The following are the 
options for consolidation therapy: 
 treatment with quizartinib/placebo plus cytarabine (4 cycles, 
if tolerated); or 
 allogeneic hematopoietic stem cell transplantation (HSCT); 
or 
 treatment with quizartinib/placebo plus cytarabine, followed 
by allogeneic HSCT. 
Cytarabine will be given on Days 1, 3, and 5 for a total of 
6 doses.  The cytarabine regimen will be:  
 for subjects <60 years old: cytarabine 3.0 g/m2 IV infusion, 
every 12 hours; or  
 for subjects ≥60 years old: cytarabine 1.5 g/m2 IV infusion, 
every 12 hours. 
Quizartinib/placebo will be administered orally once daily for 14 
days, starting on Day 6.  If quizartinib/placebo administration 
cannot begin as scheduled, the start of dosing may be delayed, 
but best efforts should be made to begin as soon as possible.  
The dose will be 40 mg/day.  For subjects concomitantly 
receiving a strong cytochrome CYP3A4 inhibitor, the dose will 
be reduced from 40 mg/day to 20 mg/day.  If quizartinib/placebo 
is interrupted, missed doses will not be made up. 
A bone marrow aspirate specimen (or a core biopsy specimen if 
aspirate cannot be obtained) will be collected for local and 
central pathology in the first and last cycles of Consolidation, 
upon count recovery from Day 21 to Day 56. 
Allogeneic Hematopoietic Stem Cell Transplantation  
Subjects are permitted to undergo allogeneic HSCT between the 
end of the Induction Phase and the start of the Continuation 
Phase.  Under certain circumstances, subjects meeting necessary 
criteria may undergo allogeneic HSCT for consolidation within 
the first 3 months of the Continuation Phase (see 
Section 6.2.2.2). 
For subjects who undergo allogeneic HSCT, treatment with 
quizartinib/placebo should be discontinued 7 days before the 
start of a conditioning regimen.  Subjects may begin 
continuation therapy 30 to 180 days after the allogeneic HSCT.  

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Sites should follow their local procedures for allogeneic HSCT 
conditioning and recovery.  
From the time of allogeneic HSCT up through the end of the 
allogeneic HSCT period, the investigator will contact the 
transplant unit every 4 weeks for follow-up information.  Once 
the subject is able, the subject will return to the clinic for site 
visits every 4 weeks. 
Continuation Phase (up to 36 cycles):  
Following consolidation therapy, subjects will enter the 
Continuation Phase if they meet the inclusion criteria.  In 
addition, per investigator discretion, subjects who have achieved 
CR or CRi following Induction but are unable to receive 
consolidation therapy will be permitted to enter the Continuation 
Phase if they meet the inclusion criteria. 
During the Continuation Phase subjects will be treated with 
quizartinib/placebo once daily for up to 36 cycles.  Continuation 
therapy will begin after induction or consolidation therapy, 
including allogeneic HSCT, and will continue until relapse, start 
of nonprotocol specified AML treatment, death, unacceptable 
toxicity, study close, or completion of 36 cycles, whichever 
occurs first. 
Quizartinib/placebo will be administered orally once daily 
starting on Day 1, with no breaks in dosing between cycles.  If 
quizartinib/placebo is interrupted, missed doses will not be made 
up. 
The starting dose will be 30 mg.  For subjects receiving a strong 
CYP3A4 inhibitor concomitantly, the starting dose will be 20 
mg/day. 
On Cycle 1, Day 16, the dose will be increased from 30 mg/day 
to 60 mg/day (from 20 mg/day to 30 mg/day for subjects 
receiving a strong CYP3A4 inhibitor) if the average QTcF of the 
triplicate electrocardiograms (ECGs) is ≤450 ms on Cycle 1, 
Day 15.  If the dose of quizartinib/placebo is not able to be 
increased on Cycle 1, Day 16, the dose may be increased on 
Cycle 2, Day 2 if the average QTcF of the triplicate ECGs is 
≤450 ms on Cycle 2, Day 1.  Once the dose is increased to 
60 mg/day, the subject may continue on this dose as long as 
dose reduction is not needed. 
Subjects will have their blood counts monitored every 4 weeks 
and will have a bone marrow exam every 12 weeks for 48 weeks 
and then every 24 weeks until week 96. 

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Long-Term Follow-up Phase 
The Long-Term Follow-up Phase begins upon completion of 36 
cycles of quizartinib/placebo in the Continuation Phase or 
permanent discontinuation of quizartinib/placebo in any phase.  
After completion of the 30 day safety visit, long-term follow-up 
visits will be performed as follows: 
 Every 4 weeks for subjects who have not had an EFS event; 
 Every 12 weeks for subjects who have had an EFS event. 
Study Duration: 
The total duration of subject participation will be until death, 
withdrawal of consent, the subject becomes lost to follow-up, or 
study closure, whichever occurs first.  Subjects will be followed 
for EFS and OS events after completion of induction and 
consolidation therapy whether or not the subject receives 
continuation therapy. 
The total duration of treatment with quizartinib/placebo will be 
up to 42 cycles (inclusive of Induction, Consolidation, and 
Continuation Phases). 
The OS analysis will be performed: 
 When the target 287 OS events are observed and a minimum 
of 24 months has elapsed since the last subject was 
randomized. 
 If the target 287 OS events are not achieved by 24 months 
since the last subject was randomized, then the analysis will 
be performed at a maximum of 30 months after the last 
subject is randomized. 
All other efficacy analyses will be performed at the same time as 
the OS analysis. 
The primary completion date is the date when the final OS 
analysis (up to a maximum of 30 months after the last subject is 
randomized) has been completed.  All subjects still on treatment 
and continuing to derive benefit from study drug at the primary 
completion date will continue to follow the study schedule of 
assessments until the overall End of Study is reached. 
Overall End of Study will occur when: 
 all subjects have discontinued treatment and discontinued 
long-term survival follow-up or have died  
 an alternative study becomes available, for subjects 
continuing to derive benefit from treatment with quizartinib, 
where the study drug is offered to these subjects 

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 the study is discontinued by the Sponsor for other reasons 
(eg, administrative, program-level or class-related) 
The subject’s EOS is the date of their last study visit/contact. 
Study Centers and Location: 
This study will be conducted in approximately 250 study sites 
worldwide. 
Subject Eligibility Criteria: 
Inclusion Criteria: 
Subjects must satisfy all of the following criteria to be 
randomized: 
1. Must be competent and able to comprehend, sign, and date 
an Ethics Committee or Institutional Review Board 
approved Informed Consent Form (ICF) before 
performance of any study-specific procedures or tests; 
2. ≥18 years or the minimum legal adult age (whichever is 
greater) and ≤75 years (at Screening); 
3. Newly diagnosed, morphologically documented primary 
AML or AML secondary to myelodysplastic syndrome or a 
myeloproliferative neoplasm based on the World Health 
Organization (WHO) 2008 classification (at Screening); 
4. Eastern Cooperative Oncology Group performance status 
0-2 (at Screening); 
5. Presence of FLT3-ITD activating mutation in bone marrow 
(allelic ratio of ≥3% FLT3-ITD/total FLT3); 
6. Subject is receiving standard "7+3" induction 
chemotherapy regimen as specified in the protocol;  
7. Adequate renal function defined as: 
a. Creatinine clearance rate >50 mL/min, as calculated with 
the modified Cockcroft Gault equation; 
8. Adequate hepatic function defined as: 
a. Total serum bilirubin ≤1.5 × ULN unless the subject 
has documented Gilbert’s syndrome or the increase is 
related to increased unconjugated (indirect) bilirubin 
due to hemolysis; 
b. Serum alkaline phosphatase, aspartate transaminase and 
alanine transaminase ≤2.5 × ULN; 
9. Serum electrolytes within the institution’s normal limits: 
potassium, calcium (total calcium, calcium corrected for 
serum albumin in case of hypoalbuminemia, or ionized 
calcium) and magnesium.  If outside of the institution’s 

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normal range, subject will be eligible when electrolytes are 
corrected; 
10. If a woman of childbearing potential, must have a negative 
serum pregnancy test upon entry into this study and must 
be willing to use highly effective birth control upon 
enrollment, during the treatment period and for 6 months 
following the last dose of investigational drug or 
cytarabine, whichever is later.  A woman is considered of 
childbearing potential following menarche and until 
becoming postmenopausal (no menstrual period for a 
minimum of 12 months) unless permanently sterile 
(undergone a hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy); 
11. If male, must be surgically sterile or willing to use highly 
effective birth control upon enrollment, during the 
treatment period, and for 6 months following the last dose 
of investigational drug or cytarabine, whichever is later. 
Exclusion Criteria: 
Subjects who meet any of the following criteria are not 
eligible to be randomized: 
1. Diagnosis of acute promyelocytic leukemia (APL), French-
American-British classification M3 or WHO classification 
of APL with translocation, t(15;17)(q22;q12), or BCR-
ABL positive leukemia (ie, chronic myelogenous leukemia 
in blast crisis); subjects who undergo diagnostic workup for 
APL and treatment with all-trans retinoic acid (ATRA), but 
who are found not to have APL, are eligible (treatment with 
ATRA must be discontinued before starting induction 
chemotherapy). 
2. Diagnosis of AML secondary to prior chemotherapy or 
radiotherapy for other neoplasms; 
3. Prior treatment for AML, except for the following 
allowances: 
a. Leukapheresis; 
b. Treatment for hyperleukocytosis with hydroxyurea; 
c. Cranial radiotherapy for central nervous system (CNS) 
leukostasis; 
d. Prophylactic intrathecal chemotherapy; 
e. Growth factor/cytokine support; 
4. Prior treatment with quizartinib or other FLT3-ITD 
inhibitors; 

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5. Prior treatment with any investigational drug or device 
within 30 days prior to Randomization (within 2 weeks for 
investigational or approved immunotherapy) or currently 
participating in other investigational procedures; 
6. History of known CNS leukemia, including cerebrospinal 
fluid positive for AML blasts; lumbar puncture is 
recommended for subjects with symptoms of CNS 
leukemia to rule out extramedullary CNS involvement; 
7. History of other malignancies, except adequately treated 
non-melanoma skin cancer, curatively treated in-situ 
disease, or other solid tumors curatively treated with no 
evidence of disease for at least 2 years; 
8. Uncontrolled or significant cardiovascular disease, 
including any of the following: 
a. Bradycardia of less than 50 beats per minute, unless the 
subject has a pacemaker; 
b. QTcF interval >450 ms; 
c. Diagnosis of or suspicion of long QT syndrome 
(including family history of long QT syndrome); 
d. Systolic blood pressure ≥180 mmHg or diastolic blood 
pressure ≥110 mmHg; 
e. History of clinically relevant ventricular arrhythmias 
(eg, ventricular tachycardia, ventricular fibrillation, or 
Torsade de Pointes); 
f. History of second (Mobitz II) or third degree heart 
block (subjects with pacemakers are eligible if they 
have no history of fainting or clinically relevant 
arrhythmias while using the pacemaker); 
g. History of uncontrolled angina pectoris or myocardial 
infarction within 6 months prior to Screening; 
h. History of New York Heart Association Class 3 or 4 
heart failure; 
i. Left ventricular ejection fraction (LVEF) ≤45% or less 
than the institutional lower limit of normal per multi-
gated acquisition scan (MUGA) or echocardiogram 
done within 30 days prior to randomization; 
j. Complete left bundle branch block; 
9. Active acute or chronic systemic fungal, bacterial, or viral 
infection not well controlled by antifungal, antibacterial or 
antiviral therapy; 
10. Known active clinically relevant liver disease (eg, active 
hepatitis B, or active hepatitis C)  

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11. Known history of human immunodeficiency virus (HIV).  
Subjects should be tested for HIV prior to Randomization if 
required by local regulations or EC; 
12. History of hypersensitivity to any excipients in the 
quizartinib/placebo tablets; 
13. Females who are pregnant or breastfeeding;  
14. Otherwise considered inappropriate for the study by the 
investigator. 
Dosage Form, Dose and Route 
of Administration: 
Quizartinib is supplied to the Study Center as 20 mg and 30 mg 
tablets.  Each 20 mg tablet contains 20 mg quizartinib 
dihydrochloride (17.7 mg free base), and each 30 mg tablet 
contains 30 mg quizartinib dihydrochloride (26.5 mg free base). 
Placebo tablets will match the appearance of quizartinib 20 mg 
and 30 mg tablets. 
The quizartinib 20 mg and matching placebo are white, film-
coated, round tablets.  The quizartinib 30 mg and matching 
placebo are yellow, film-coated, round tablets. 
Quizartinib/placebo is packaged in high density polyethylene 
bottles, containing 30 tablets each, with child-resistant caps.  
Study Endpoints: 
Efficacy 
The primary efficacy endpoint is OS. 
Overall survival is defined as the time from randomization until 
death from any cause. 
Secondary efficacy endpoints (ie, secondary outcome measures) 
are: 
 Event-free survival is defined as the time from 
Randomization until the date of the earliest of any of the 
following:  
 Refractory disease (or treatment failure) which is 
determined at the end of the Induction Phase; 
 Relapse after CR or CRi; 
 Death from any cause at any time during the study. 
 Composite complete remission rate which is the percentage 
of subjects achieving CR or CRi after Induction; 
 Percentage of subjects achieving CRc with FLT3-ITD MRD 
negativity below a certain cutoff after Induction.  Minimal 
or measurable residual disease is the presence of a small 

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number of leukemic cells in the bone marrow of patients 
with AML below the level of detection using conventional 
morphologic assessment. The FLT3-ITD MRD assay by 
Next Generation Sequencing will be used to detect and 
quantify residual FLT3-ITD mutations. 
 Complete remission rate, which is the percentage of subjects 
achieving CR after Induction; 
 Percentage of subjects achieving CR with FLT3-ITD MRD 
negativity following induction therapy. 
Exploratory efficacy endpoints are: 
 RFS is the time from randomization, for subjects who 
achieve CR or CRi in the Induction Phase, until documented 
relapse or death from any cause, whichever comes first; 
 Duration of CR is the time from the first documented CR 
until documented relapse or death from any cause, 
whichever comes first; 
 CR rate at the end of the first Induction cycle is the 
percentage of subjects who achieved CR after 1 Cycle of 
Induction;  
 CRc rate at the end of the first Induction cycle is the 
percentage of subjects whose best response is CR or CRi at 
the end of first Induction cycle; 
 CRh rate is the percentage of subjects achieving CRh after 
Induction (only for IRC assessment of response); 
 MLFS rate is the percentage of subjects achieving MLFS 
after Induction (only for IRC assessment of response); 
 RFS in subjects who enter the Continuation Phase is the 
time from randomization, for subjects who achieve CR or 
CRi in the Induction Phase, until relapse or death from any 
cause, whichever comes first; 
 Transplantation rate is the percentage of subjects undergoing 
allogeneic HSCT directly following protocol treatment with 
no intervening AML therapy (excluding conditioning 
regimens); 
 Subject reported QoL and symptoms as assessed with the 
EORTC QLQ-C30 Questionnaire; 
 General health status assessed using EuroQol (EQ-5D-5L) 
Questionnaire; 

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 Healthcare resource utilization. 
Pharmacokinetics 
 PK concentration for quizartinib and its metabolite (AC886) 
and PopPK analysis results. 
 For PK-ECG-Biomarker Substudy: PK concentrations and 
PK parameters (area under the concentration versus time 
curve [ng•h/mL] from the time 0 to 24 hours [AUC0-24], 
maximum plasma concentration [Cmax], minimum plasma 
concentration [Cmin], and time to maximum plasma 
concentration [Tmax]) for quizartinib and AC886; 
Pharmacodynamic 
 FLT3-ITD autophosphorylation activity in an ex vivo 
plasma inhibitory activity (PIA) assay. 
Biomarker 
 FLT3-ITD MRD (results will not be available until the end 
of the study).  
 Mutations in the kinase and juxtamembrane domains of 
FLT3-ITD and other mutations known to be associated with 
AML or myeloid diseases (eg, CEBPA, DNMT3A, IDH1, 
IDH2, Kit, NPM1, and NRAS), determined with bone 
marrow or whole blood samples. 
Planned Sample Size: 
The target sample size will be approximately 536 subjects, 
randomized in a 1:1 ratio to receive quizartinib/placebo: 
administered with standard induction and consolidation 
chemotherapy, then administered as continuation therapy for up 
to 36 cycles.  
Statistical Analyses: 
Efficacy Analyses 
Efficacy analyses will be performed on the Intent-to-treat (ITT) 
Analysis Set and Per-protocol Analysis Set.  All other efficacy 
exploratory analyses will be performed based on ITT Analysis 
Set and availability of assessment. 
The efficacy analyses will be performed according to the 
treatment groups assigned at Randomization. 
Overall survival is the primary efficacy endpoint for this study. 
Comparison of distribution of OS between treatment groups will 
be made using a stratified log-rank test with the 3 stratification 
factors used in randomization at a 2-sided 5% significance level. 
The median OS will be calculated based on Kaplan-Meier 

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estimates and the corresponding 95% confidence interval (CI) 
will be calculated using the method provided by Brookmeyer 
and Crowley. 
The OS analysis will be performed: 
 When the target 287 OS events are observed and a minimum 
of 24 months has elapsed since the last subject was 
randomized. 
 If the target 287 OS events are not achieved by 24 months 
since the last subject was randomized, then the analysis will 
be performed at a maximum of 30 months after the last 
subject is randomized. 
For the secondary analyses, comparison of distribution of EFS 
between the 2 treatment groups will be made using a stratified 
log-rank test with the 3 stratification factors used in 
randomization.  The distribution function of EFS will be 
estimated using the Kaplan-Meier method.  EFS will be 
analyzed based on the response assessment by the Independent 
Review Committee (IRC).  EFS will also be analyzed based on 
the investigator’s response assessment as one of the sensitivity 
analyses to be performed. 
Comparisons of CR rate, rate of subjects achieving CR with 
FLT3-ITD MRD negativity, CRc rate, and rate of subjects 
achieving CRc with FLT3-ITD MRD negativity between 
treatment groups will be made using a Cochran-Mantel-
Haenszel test with the 3 stratification factors used in 
randomization. 
To control for the family-wise type I error rate for the primary 
and secondary efficacy endpoints, a serial hierarchically ordered 
gatekeeping strategy will be employed.  The primary assessment 
of OS in the ITT Analysis Set will be evaluated first, and if 
significant at a 2-sided alpha of 0.05, a statistical evaluation of 
EFS by IRC, based on the EFS definition in the Guidances,63,72 
will be performed in the ITT Analysis Set.  After EFS 
evaluation, the order of other secondary endpoints to be tested 
will be CR rate, rate of subjects achieving CR with FLT3-ITD 
MRD negativity, CRc rate, and rate of subjects achieving CRc 
with FLT3-ITD MRD negativity.  Testing will stop once 1 test 
in the sequence fails to be statistically significant. 
Exploratory efficacy analyses of RFS will be analyzed using the 
Kaplan-Meier method for subjects achieving CRc. 

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RFS in subjects who enter the Continuation Phase will be 
summarized similarly as RFS. 
Duration of CR will be analyzed similarly as RFS. 
Rate of allogeneic HSCT, rate of CR at end of first Induction 
cycle, rate of CRc at end of first Induction cycle, rate of CRh 
after Induction, and rate of MLFS after Induction will be 
analyzed and CI will be provided. 
Pharmacokinetic Analyses 
For the PK-ECG-Biomarker Substudy: PK parameters of 
quizartinib and its metabolite (AC886) will be estimated for 
subjects who have sufficient plasma concentrations available.  
Standard non-compartmental analysis will be estimated for 
subjects with sufficient intense PK data available for the 
following PK parameters: AUC0-24, Cmax, Cmin, Tmax, and 
accumulation ratio and parent/metabolite ratio at Day 8 and Day 
21 during Cycle 1 of Induction.  
Plasma concentrations and PK parameters will be summarized 
using descriptive statistics by treatment group and by treatment 
phase when appropriate.  
Population PK modeling will be performed for quizartinib and 
its metabolite (AC886) and details will be provided in a separate 
PopPK report. 
Pharmacodynamic Analyses 
A subject is said to have achieved full inhibition at a certain PIA 
assessment visit if the corresponding PIA value is >90%.  
Number and percentage of subjects achieving full inhibition will 
be provided for the quizartinib group.  Summary statistics will 
be provided for the quizartinib group in the Pharmacodynamic 
Analysis Set. 
Biomarker Analyses 
Number and percentage of subjects expressing different AML 
associated mutations will be summarized by treatment groups. 
FLT3-ITD allelic ratio will be summarized and presented by 
treatment groups. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set.  
For safety analyses, subjects will be analyzed according to 
actual treatment received.  Safety analyses include frequency 
and severity of treatment-emergent adverse events (TEAEs). 

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Adverse events to be included in summary tables will be 
restricted to TEAEs. 
Descriptive statistics will be provided for the clinical laboratory 
results and changes from baseline by scheduled time of 
evaluation and by treatment group including end of treatment 
visit as well as for the maximum and minimum post-baseline 
values. 
Abnormal clinical laboratory results will be graded according to 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03, if applicable.  A shift 
table, presenting by treatment group the 2-way frequency 
tabulation for baseline and the worst post-baseline value 
according to the CTCAE grade, will be provided for clinical 
laboratory tests.  Abnormal clinical laboratory test results 
deemed of clinical significance or of Grade 3 or 4 will be listed. 
Descriptive statistics will be provided for the vital signs 
measurements and changes from baseline by scheduled time of 
evaluation and by treatment group including end of treatment 
visit as well as for the maximum and minimum post-baseline 
values. 
Electrocardiogram parameters will be summarized using 
descriptive statistics for actual values and for changes from 
baseline by treatment group by scheduled time of evaluation 
including end of treatment visit as well as for the maximum 
post-baseline values.  QTcF will be considered as the primary 
correction method to assess QT corrected (QTc) interval. 
The number and percentage of subjects with QT/QTc interval 
values meeting the criteria will be tabulated (eg, QTcF ≤450 ms, 
>450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms) and QTcF 
maximum changes from baseline (>30 and >60 ms) over all 
posttreatment evaluations will be summarized.  
Electrocardiogram data will also be presented in the data 
listings.  Unless otherwise stated, baseline will be the last 
measurement before first dose of quizartinib/placebo. 
Physical examination findings will be listed for the Safety 
Analysis Set. 
Blood transfusion data will be summarized by treatment group 
and treatment phases. 
Concomitant medications will be coded using the World Health 
Organization drug dictionary (most recent version).  Number 
and percentage of subjects taking concomitant medications will 

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be summarized by ATC2 class and preferred term and presented 
by treatment group. 
Subgroup analyses of AEs will be performed if appropriate 
using subgroups defined in the Statistical Analysis Plan (SAP). 
Health Economics and Outcome Research 
The patient-reported outcomes (EORTC QLQ-C30, EQ-5D) and 
the health resource utilization data will be assessed based on a 
separate analysis plan.  The plan will provide details of the 
descriptive and comparative statistical analyses. 

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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................33 
1. 
INTRODUCTION ...........................................................................................................36 
1.1. 
Background ......................................................................................................................36 
1.1.1. 
Investigational Product ....................................................................................................36 
1.1.1.1. Name ................................................................................................................................36 
1.1.1.2. Description ......................................................................................................................36 
1.1.1.3. Intended use under investigation .....................................................................................36 
1.1.1.4. Nonclinical studies ..........................................................................................................36 
1.1.1.5. Clinical Experience .........................................................................................................36 
1.2. 
Study Rationale ...............................................................................................................41 
1.2.1. 
Selection of ≥3% FLT3-ITD Allelic Ratio as Cutoff for Study Eligibility .....................42 
1.2.2. 
Selection of Chemotherapy Regimens ............................................................................42 
1.2.3. 
Rationale for Quizartinib Dose Selection ........................................................................43 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................................................46 
2.1. 
Study Objectives ..............................................................................................................46 
2.1.1. 
Primary Objective ............................................................................................................46 
2.1.2. 
Secondary Objectives ......................................................................................................46 
2.1.3. 
Exploratory Objectives ....................................................................................................46 
2.2. 
Study Hypothesis .............................................................................................................47 
3. 
STUDY DESIGN ............................................................................................................48 
3.1. 
Overall Design .................................................................................................................48 
3.1.1. 
Study Duration .................................................................................................................49 
3.2. 
Discussion of Study Design .............................................................................................50 
3.2.1. 
Treatment Groups ............................................................................................................50 
3.2.2. 
Study Phases ....................................................................................................................50 
3.2.2.1. Induction Phase (up to 2 cycles) ......................................................................................50 
3.2.2.2. Consolidation Phase ........................................................................................................51 

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3.2.2.3. Continuation Phase (up to 36 cycles) ..............................................................................52 
3.2.2.4. Long Term Follow-up Phase ...........................................................................................53 
4. 
STUDY POPULATION ..................................................................................................54 
4.1. 
Inclusion Criteria .............................................................................................................54 
4.1.1. 
Inclusion Criteria – Randomization .................................................................................54 
4.1.2. 
Inclusion Criteria – Consolidation Phase ........................................................................55 
4.1.3. 
Inclusion Criteria – Continuation Phase ..........................................................................55 
4.2. 
Exclusion Criteria ............................................................................................................55 
5. 
STUDY TREATMENT(S) ..............................................................................................57 
5.1. 
Assigning Subjects to Treatments and Blinding .............................................................57 
5.1.1. 
Treatment Group(s) .........................................................................................................57 
5.1.2. 
Method of Treatment Allocation .....................................................................................57 
5.1.3. 
Blinding ...........................................................................................................................57 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................57 
5.2. 
Study Drugs .....................................................................................................................57 
5.2.1. 
Quizartinib .......................................................................................................................57 
5.2.2. 
Placebo ............................................................................................................................58 
5.2.3. 
Description ......................................................................................................................58 
5.2.4. 
Labeling and Packaging ..................................................................................................58 
5.2.5. 
Preparation .......................................................................................................................58 
5.2.6. 
Storage .............................................................................................................................58 
5.2.7. 
Drug Accountability ........................................................................................................58 
5.3. 
Standard Chemotherapy ..................................................................................................59 
5.4. 
Administration .................................................................................................................59 
5.4.1. 
Induction Phase (up to 2 cycles) ......................................................................................59 
5.4.2. 
Consolidation Phase ........................................................................................................61 
5.4.3. 
Continuation Phase (up to 36 cycles) ..............................................................................61 
5.5. 
Control Treatment ...........................................................................................................62 
5.6. 
Quizartinib/Placebo Dose Reductions and Dosing Interruptions ....................................62 
5.6.1. 
QTcF Prolongation - Dose Interruptions and Reductions ...............................................63 
5.6.1.1. Managing QTc Prolongation ...........................................................................................64 
5.6.2. 
Non-Hematologic Toxicity ..............................................................................................65 

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5.6.2.1. Hepatic Events and Liver Enzyme Elevation ..................................................................65 
5.6.2.2. Sweet’s Syndrome (Acute Febrile Neutrophilic Dermatosis) .........................................66 
5.6.2.3. Pyoderma Gangrenosum .................................................................................................66 
5.6.2.4. Differentiation Syndrome ................................................................................................67 
5.6.3. 
Myelosuppression (Continuation Phase) .........................................................................67 
5.6.4. 
Strong CYP3A4 Inhibitors – Dose Modifications ...........................................................68 
5.7. 
Method of Assessing Treatment Compliance ..................................................................68 
5.8. 
Prior and Concomitant Medications ................................................................................68 
5.8.1. 
Prior Medication ..............................................................................................................68 
5.8.2. 
Concomitant Medication (Drugs and Therapies) ............................................................68 
5.8.2.1. Supportive Care ...............................................................................................................69 
5.8.3. 
Prohibited Concomitant Medications ..............................................................................69 
5.8.4. 
Prior and Concomitant Nondrug Treatment and Procedures ..........................................70 
5.8.5. 
Previous and Concomitant Transfusions .........................................................................70 
5.8.6. 
Previous Radiotherapy .....................................................................................................70 
5.8.7. 
Hematopoietic Stem Cell Transplantation Treatment .....................................................70 
5.9. 
Subject Withdrawal/Discontinuation ...............................................................................70 
5.9.1. 
Reasons for Permanent Discontinuation of Study Drug..................................................70 
5.9.1.1. Long-Term Follow-up of Subjects after Permanent Discontinuation of Study 
Drug .................................................................................................................................71 
5.9.2. 
Withdrawal from Study ...................................................................................................71 
5.9.2.1. Withdrawal of Consent from Study Participation ...........................................................71 
5.9.2.2. Subjects Lost to Follow-up ..............................................................................................72 
6. 
STUDY PROCEDURES .................................................................................................73 
6.1. 
Screening (Days -7 to 6) ..................................................................................................73 
6.1.1. 
Overview of Screening ....................................................................................................73 
6.1.2. 
Screening Procedures ......................................................................................................73 
6.2. 
Treatment Period .............................................................................................................75 
6.2.1. 
Induction Phase (up to 2 cycles) ......................................................................................75 
6.2.1.1. Cycle 1 .............................................................................................................................75 
6.2.1.2. Cycle 2 .............................................................................................................................82 
6.2.2. 
Consolidation Phase ........................................................................................................93 
6.2.2.1. Consolidation Chemotherapy (4 Cycles, if Tolerated) ....................................................93 

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6.2.2.2. Allogeneic Hematopoietic Stem Cell Transplantation (up to 180 Days After 
Transplant Date) ............................................................................................................102 
6.2.3. 
Continuation Phase (up to 36 cycles) ............................................................................104 
6.2.3.1. Continuation Therapy ....................................................................................................106 
6.2.3.2. Allogeneic Hematopoietic Stem Cell Transplantation ..................................................114 
6.3. 
End of Treatment (+ 7 Days) .........................................................................................114 
6.4. 
Long-Term Follow-up Phase .........................................................................................115 
6.4.1. 
Safety Follow-up Visit ..................................................................................................115 
6.4.2. 
Long-Term Follow-up Visits .........................................................................................115 
6.4.2.1. Long-Term Follow-up Visits for Subjects Who Have Not Had an EFS Event 
(Refractory/Relapse) ......................................................................................................116 
6.4.2.2. Long-Term Follow-up Visits for Subjects Who Have Had an EFS Event 
(Refractory/Relapse) ......................................................................................................117 
7. 
EFFICACY ASSESSMENTS .......................................................................................118 
7.1. 
Primary Efficacy Endpoint ............................................................................................118 
7.2. 
Secondary Efficacy Endpoints ......................................................................................118 
7.3. 
Exploratory Efficacy Endpoints ....................................................................................119 
7.4. 
Appropriateness of Selected Efficacy Endpoints ..........................................................119 
7.5. 
Independent Review Committee ...................................................................................121 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS .........................122 
8.1. 
Pharmacokinetic (PK) Endpoint(s) ................................................................................122 
8.1.1. 
Sparse PK Sampling (Induction, Consolidation, and Continuation Phases) .................122 
8.1.2. 
PK-ECG-Biomarker Substudy (Induction Phase) .........................................................123 
8.2. 
Pharmacodynamic Endpoint(s) .....................................................................................123 
8.3. 
Biomarker Endpoint(s) ..................................................................................................124 
8.4. 
Immunogenicity .............................................................................................................125 
8.5. 
Pharmacogenomic Analysis ..........................................................................................125 
8.5.1. 
Genomic or Genetic Analysis ........................................................................................125 
9. 
SAFETY EVALUATION AND REPORTING ............................................................126 
9.1. 
Adverse Event Collection and Reporting ......................................................................126 
9.2. 
Events of Special Interest ..............................................................................................127 
9.2.1. 
QTc Prolongation, Torsades de Pointes, and Other Ventricular Arrhythmias ..............127 
9.2.2. 
Combined Elevations of Aminotransferases and Bilirubin ...........................................127 

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9.3. 
Adverse Event ...............................................................................................................127 
9.3.1. 
Definition of Adverse Event ..........................................................................................127 
9.3.2. 
Serious Adverse Event ..................................................................................................128 
9.3.3. 
Severity Assessment ......................................................................................................128 
9.3.4. 
Causality Assessment ....................................................................................................129 
9.3.5. 
Action Taken Regarding Study Drug(s) ........................................................................129 
9.3.6. 
Other Action Taken for Event .......................................................................................129 
9.3.7. 
Adverse Event Outcome ................................................................................................130 
9.4. 
Safety Reporting –Procedure For Investigators ............................................................130 
9.5. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................131 
9.6. 
Exposure In Utero During Clinical Studies ...................................................................131 
9.7. 
Clinical Laboratory Evaluations ....................................................................................132 
9.8. 
Vital Signs .....................................................................................................................132 
9.9. 
Electrocardiograms ........................................................................................................132 
9.10. 
Physical Examinations ...................................................................................................132 
9.11. 
Other Examinations .......................................................................................................132 
10. 
OTHER ASSESSMENTS .............................................................................................133 
10.1. 
Health Economics and Outcome Research ....................................................................133 
10.1.1. Patient-Reported Outcomes ...........................................................................................133 
10.2. 
Health Economic Assessments ......................................................................................134 
11. 
STATISTICAL METHODS .........................................................................................135 
11.1. 
Analysis Sets .................................................................................................................135 
11.2. 
General Statistical Considerations .................................................................................135 
11.3. 
Study Population Data ...................................................................................................136 
11.4. 
Statistical Analysis ........................................................................................................136 
11.4.1. Efficacy Analyses ..........................................................................................................136 
11.4.1.1. Primary Efficacy Analyses ............................................................................................136 
11.4.1.2. Secondary Efficacy Analyses ........................................................................................136 
11.4.1.3. Exploratory Efficacy Analyses ......................................................................................137 
11.4.1.4. Sensitivity and Supplementary Analyses ......................................................................137 
11.4.1.5. Subgroup Analyses ........................................................................................................137 
11.4.2. Pharmacokinetic/Pharmacodynamic Analyses ..............................................................138 

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11.4.2.1. Pharmacokinetic Analyses .............................................................................................138 
11.4.2.2. Pharmacodynamic Analyses ..........................................................................................138 
11.4.2.3. Biomarker Analyses ......................................................................................................138 
11.4.3. Safety Analyses .............................................................................................................139 
11.4.3.1. Adverse Event Analyses ................................................................................................139 
11.4.3.2. Clinical Laboratory Evaluation Analyses ......................................................................139 
11.4.3.3. Vital Sign Analyses .......................................................................................................140 
11.4.3.4. Electrocardiogram Analyses ..........................................................................................140 
11.4.3.5. Transfusion ....................................................................................................................140 
11.4.3.6. Physical Examination Analyses ....................................................................................140 
11.4.3.7. Prior and Concomitant Medications ..............................................................................140 
11.4.3.8. Safety Subgroup Analyses .............................................................................................140 
11.4.4. Health Economics and Outcomes Research Data Analysis ..........................................140 
11.4.5. Data Review by Data Monitoring Committee ...............................................................140 
11.5. 
Sample Size Determination ...........................................................................................141 
11.6. 
Statistical Analysis Process ...........................................................................................141 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................142 
12.1. 
Monitoring and Inspections ...........................................................................................142 
12.2. 
Data Collection ..............................................................................................................142 
12.3. 
Data Management ..........................................................................................................142 
12.4. 
Study Documentation and Storage ................................................................................143 
12.5. 
Record Keeping .............................................................................................................143 
13. 
FINANCING AND INSURANCE ................................................................................145 
13.1. 
Finances .........................................................................................................................145 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................145 
14. 
PUBLICATION POLICY .............................................................................................146 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................147 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance .........................................147 
15.2. 
Subject Confidentiality ..................................................................................................147 
15.3. 
Informed Consent ..........................................................................................................147 
15.4. 
Regulatory Compliance .................................................................................................148 
15.5. 
Protocol Deviations .......................................................................................................148 

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15.6. 
Supply of New Information Affecting the Conduct of the Study .................................149 
15.7. 
Protocol Amendments ...................................................................................................149 
15.8. 
Study Termination .........................................................................................................149 
15.9. 
Data Monitoring Committee ..........................................................................................149 
15.10. 
Independent Review Committee ...................................................................................150 
15.11. 
Steering Committee .......................................................................................................150 
15.12. 
Address List ...................................................................................................................150 
16. 
REFERENCES ..............................................................................................................151 
17. 
APPENDICES ...............................................................................................................157 
17.1. 
Schedule of Events ........................................................................................................157 
17.1.1. Schedule of Events – Induction Phase ...........................................................................158 
17.1.2. Schedule of Events – Consolidation Phase ...................................................................165 
17.1.2.1. Schedule of Events – Allogeneic Hematopoietic Stem Cell Transplantation ...............167 
17.1.3. Schedule of Events – Continuation Phase .....................................................................168 
17.1.4. Schedule of Events – Long-Term Follow-up Phase ......................................................171 
17.2. 
Highly Effective Methods of Birth Control ...................................................................172 
17.3. 
Standard Chemotherapy ................................................................................................172 
17.3.1. Cytarabine ......................................................................................................................172 
17.3.2. Daunorubicin .................................................................................................................172 
17.3.3. Idarubicin Hydrochloride ..............................................................................................172 
17.4. 
QT Prolonging Medications and CYP3A4 Inhibitors/Inducers ....................................173 
17.4.1. Potential QT/QTc Prolonging Drugs .............................................................................173 
17.4.2. CYP3A4 Inhibitors and Inducers ..................................................................................175 
17.5. 
Electrocardiograms ........................................................................................................177 
17.5.1. Electrocardiogram Monitoring Guidelines ....................................................................178 
17.5.2. Electrocardiogram Collection Times .............................................................................178 
17.5.3. PK-ECG-Biomarker Substudy (Induction Phase) .........................................................179 
17.6. 
Eastern Cooperative Oncology Group Performance Status Scale .................................180 
17.7. 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 454 .....................................................................................................................180 
17.8. 
Response Criteria ...........................................................................................................181 
17.9. 
Graft-Versus-Host Disease Grading and Scoring ..........................................................182 
17.10. 
Modified Cockcroft Gault Equation ..............................................................................184 

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17.11. 
Clinical Laboratory Determinations ..............................................................................184 
17.11.1. Corrected Calcium Formula for Eligibility ...................................................................185 
17.12. 
Product Complaints .......................................................................................................186 
17.13. 
EORTC QLQ-C30 .........................................................................................................187 
17.14. 
EQ-5D-5L ......................................................................................................................189 
 

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LIST OF TABLES 
Table 1.1: Summary of the Efficacy Findings Across all 5 Daily Doses Studied in the 
Phase 2 Program .........................................................................................................37 
Table 1.2: Summary of the QTcF Findings Across all 5 Daily Doses Studied in the 
Phase 2 Program .........................................................................................................38 
Table 5.1: Guidelines for Quizartinib/Placebo Dose Reductions and Dosing 
Interruptions ................................................................................................................63 
Table 8.1: Sparse PK Sampling for Quizartinib and its Metabolite (AC886) During 
Induction – Cycle 1 (All Subjects Not in the PK-ECG-Biomarker Substudy) .........122 
Table 8.2: Sparse PK Sampling for Quizartinib and its Metabolite (AC886) During 
Consolidation – Cycle 1 (All Subjects) ....................................................................122 
Table 8.3: Sparse PK Sampling for Quizartinib and its Metabolite (AC886) During 
Continuation – Cycles 1 and 2 (All Subjects) ..........................................................123 
Table 8.4: PK-ECG-Biomarker Substudy: PK Time Points for Quizartinib and its 
Metabolite (AC886) During the Induction Phase (Cycle 1 Only) ............................123 
Table 8.5: PK-ECG-Biomarker Substudy: Time Points for PIA Samples ................................124 
Table 17.1: Schedule of Assessment - Induction Phase (Cycle 1 with “7+3” 
chemotherapy regimen) ............................................................................................158 
Table 17.2: Schedule of Assessment - Induction Phase (Cycle 2 with “7+3” 
chemotherapy regimen) ............................................................................................161 
Table 17.3: Schedule of Assessment - Induction Phase (Cycle 2 with “5+2” regimen) .............163 
Table 17.4: Schedule of Assessment – Consolidation Chemotherapy (4 Cycles, if 
tolerated) ...................................................................................................................165 
Table 17.5: Schedule of Events – Allogeneic Hematopoietic Stem Cell Transplantation ..........167 
Table 17.6: Schedule of Activities and Assessments - Continuation Therapy (up to 36 
cycles) .......................................................................................................................168 
Table 17.7: Schedule of Activities and Assessments for Long-Term Follow-up Phase 
(through the end of the study, ie, all EFS events achieved) .....................................171 
Table 17.8: Potential QT/QTc Prolonging Drugs ........................................................................173 
Table 17.9: CYP3A4 Inhibitors ...................................................................................................175 
Table 17.10: CYP3A4 Inducers ................................................................................................176 
Table 17.11: Schedule of Electrocardiograms – Induction Phase .............................................179 
Table 17.12: Schedule of Electrocardiograms – Consolidation Phase......................................179 
Table 17.13: Schedule of Electrocardiograms - Continuation Phase ........................................179 
Table 17.14: PK-ECG-Biomarker Substudy: ECG Time Points Associated with PK 
Sampling During the Induction Phase (Cycle 1 Only) .............................................180 

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Table 17.15: Response Criteria .................................................................................................181 
Table 17.16: Acute Graft-Versus-Host Disease Grading and Staging ......................................182 
Table 17.17: Percent Body Surfaces .........................................................................................182 
Table 17.18: Organ Scoring of Chronic Graft-Versus-Host Disease ........................................183 
Table 17.19: Clinical Laboratory Analytes ...............................................................................185 
 

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LIST OF FIGURES 
Figure 3.1: Study Summary ..........................................................................................................48 
Figure 3.2: Study Design Schematic (Screening to Treatment Period) ........................................49 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ΔQTcF 
Change from baseline in QTcF 
AE 
Adverse event 
ALT 
Alanine transaminase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil counts  
APL 
Acute promyelocytic leukemia 
AST 
Aspartate transaminase  
ATRA 
All-trans retinoic acid 
AUC 
Area under the concentration versus time curve (ng•h/mL) 
AUC0-24 
Area under the concentration versus time curve (ng•h/mL) from the time 0 to 
24 hours 
AUC0-inf 
Area under the concentration-versus-time curve (ng•h/mL) from the time of 
dosing extrapolated to infinity, calculated as: AUC0-inf = AUClast + 
Clast/λz 
BSA 
Body surface area 
CI 
Confidence interval 
Cmax 
Maximum plasma concentrations  
Cmin 
Minimum plasma concentration 
CNS 
Central nervous system 
CR 
Complete remission 
CRc 
Composite complete remission 
CRh 
Complete remission with partial hematologic recovery 
CRi 
Complete remission with either incomplete neutrophil or platelet recovery  
CRO 
Contract research organization 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DISS 
Drug-induced sweet’s syndrome 
DLI 
Donor lymphocyte infusion 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 

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ABBREVIATION 
DEFINITION 
EDC 
Electronic data capture 
EFS 
Event-free survival 
EIU 
Exposure in utero 
EORTC 
European Organisation for Research and Treatment of Cancer  
EOT 
End of treatment 
EQ-5D-5L 
Descriptive system of health-related quality of life states consisting of five 
dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which can take one of five responses.  The 
responses record five levels of severity (no problems/slight 
problems/moderate problems/severe problems/extreme problems) within a 
particular EQ-5D dimension. 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase 3 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice  
G-CSF 
Granulocyte-colony stimulating factor 
GVHD 
Graft-versus-host disease 
HDPE 
High density polyethylene  
HIV 
Human immunodeficiency virus  
HR 
Hazard ratio 
HRQoL 
Health-Related Quality of Life 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
INN 
International Non-proprietary Name 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITD 
Internal tandem duplication 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system  
IV 
Intravenous 
IXRS 
Interactive web/voice response system 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLFS 
Morphologic leukemia-free state 

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ABBREVIATION 
DEFINITION 
MRD 
Minimal or measurable residual disease 
ms 
Millisecond 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
OS 
Overall survival 
P-gp 
P-glycoprotein 
PIA 
Plasma inhibitory activity  
PK 
Pharmacokinetic 
PopPK 
Population pharmacokinetics 
PPS 
Per-protocol analysis set 
PRO 
Patient-reported outcome 
QLQ-C30 
Core quality of life questionnaire 
QoL 
Quality of life 
QTc 
QT interval corrected 
QTcF 
QT interval corrected with Fridericia’s formula 
RFS 
Relapse-free survival 
RTK 
Receptor tyrosine kinase 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total serum bilirubin  
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal  
UV 
Ultraviolet 
WBC 
White blood cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 

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were relapsed or refractory to salvage therapy or relapsed after HSCT.  In Cohort 1, the 
composite complete remission (CRc) rate was 57% in FLT3-ITD (+) subjects with a median 
survival of 25.3 weeks.2,4  Cohort 2 showed a CRc rate of 46% in FLT3-ITD (+) subjects with a 
median survival of 24.0 weeks.2 Importantly, 35% of Cohort 2 FLT3-ITD (+) subjects were 
bridged to HSCT.5  
The maximum tolerated dose (MTD) determined in the Phase 1 study, CP0001, was 200 mg 
continuous daily dosing.3  However, in the Phase 2 Study (AC220-002) 35% of subjects 
experienced Grade 3 QT prolongation at the 200 mg dose and therefore the dose was reduced.  A 
single case of Grade 4 QT prolongation, Torsades de Pointes, was reported in the AC220-002 
Study in a subject with pneumonia, atrial fibrillation, taking concomitant medications known to 
cause QT prolongation.6  No deaths related to QT prolongation have been reported.2 
A Phase 2b Study (2689-CL-2004) was subsequently conducted, which enrolled 76 subjects with 
FLT3-ITD (+) AML randomized to 60 mg or 30 mg daily, to examine efficacy and toxicity at 
these lower doses.  Both males and females were randomized at each dose.  The study showed 
that the CRc rate was similar at both lower doses and to that observed in the earlier Study 
AC220-002 (Table 1.1).7  QT prolongation was dose-dependent and was substantially reduced at 
the lower doses (Table 1.2). 
Table 1.1: 
Summary of the Efficacy Findings Across all 5 Daily Doses Studied in the 
Phase 2 Program 
Study 
2689-CL-2004 
AC220-002 
Quizartinib Dose 
30 mg 
(N=38) 
60 mg 
(N=38) 
90 mg 
(N=57) 
135 mg 
(N=67) 
200mg 
(N=12) 
CRc rate 
47% 
47% 
47% 
45% 
42% 
Partial Remission rate 
13% 
24% 
25% 
28% 
50% 
CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=CR with incomplete neutrophil 
recovery; CRp=CR with incomplete platelet recovery  
Source: Russell N, Tallman MS, Goldberg S, et al. Abstract 187 (Table 8)7 

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Table 1.2: 
Summary of the QTcF Findings Across all 5 Daily Doses Studied in the 
Phase 2 Program 
Study 
2689-CL-2004 
AC220-002 
Quizartinib Dose 
30 mg 
(N=38) 
60 mg 
(N=36)a 
90 mg 
(N=57) 
135 mg 
(N=67) 
200 mg 
(N=12) 
Maximum value of QTcF (ms) 
>480 to ≤500 (Grade 2) 
5% 
14% 
21% 
13% 
33% 
>500 (Grade 3) 
5% 
3% 
21% 
15% 
42% 
Maximum change in QTcF from baseline (ms) 
≤30  
50% 
44% 
9% 
9% 
0% 
>30  to ≤60 
47% 
36% 
46% 
51% 
8% 
>60 
5% 
19% 
46% 
39% 
92% 
QTcF=QT interval corrected with Fridericia’s formula 
a Two subjects in the 60 mg/day group were randomized but never treated with quizartinib 
Source: Schiller G, Tallman MS, Goldberg S, et al8 
Common adverse events (AEs) observed in the Phase 1 and 2 studies included gastrointestinal 
disorders (nausea, diarrhea, and vomiting), hematologic disorders (anemia, neutropenia, and 
thrombocytopenia), febrile neutropenia, fatigue, and QT prolongation.  Although hematologic 
toxicity is associated with underlying disease, safety reports from Study AC220-002 in AML 
indicate delayed recovery or continued suppression of absolute neutrophil counts (ANC) and 
platelets as a consequence of continued treatment with quizartinib.2 
1.1.1.5.1. Clinical Pharmacology 
The tablet formulation, which will be used in Phase 3 studies, exhibited comparable relative 
bioavailability to the solution formulation which was administered in the earlier Phase 1 and 2 
studies.  In a relative bioavailability study (AC220-014) in fasting, healthy volunteers and oral 
administration of a single 60 mg dose (2x30 mg tablets) of quizartinib, the median time to 
maximum plasma concentration (Tmax) was 4 (minimum, 2; maximum; 8) hours for quizartinib 
and 8 (minimum, 4; maximum; 48) hours for AC886 (the major active metabolite of quizartinib, 
with similar potency to the parent molecule, quizartinib).  The geometric mean (coefficient of 
variation [CV] %) terminal half-life was 64.9 (75%) hours and 53.5 (40%) hours for quizartinib 
and AC886, respectively.  Quizartinib and AC886 showed dose-proportional increases in area 
under the concentration versus time curve (ng•h/mL) (AUC) and maximum plasma 
concentrations (Cmax) over the tested dose range of 30 to 90 mg.2 
Following a single-oral dose of [14C]-quizartinib, 76.3% of total radioactivity was recovered in 
feces with only 1.6% recovered in urine 14 days after dosing (AC220-006).  Excretion of 
radioactivity was still ongoing at study completion at Day 14, mainly in feces.  AC886 was the 
only major circulating metabolite and is formed by cytochrome P450 (CYP3A4).2 
In a Phase 2b study, 2689-CL-2004, in which AML subjects receiving multiple doses of 
quizartinib at 30 mg/day or 60 mg/day, steady-state was reached by Day 15 for both quizartinib 
and AC886, consistent with the terminal half-life of approximately 3 days observed in healthy 

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1.1.1.5.2. Combination Studies with Induction Chemotherapy 
Study 2689-CL-0005 is a Phase 1, open-label, multiple-dose, dose-escalation study in patients 
with newly diagnosed AML [FLT3-ITD (+) or FLT3-ITD (-)].  The treatment and follow up 
phases of the study has been completed. 
The dose escalation was conducted using a modified 3+3 design, where 6 subjects were enrolled 
at each dose level.  The subjects were given cytarabine 200 mg/m2 × 7 days and daunorubicin 
60 mg/m2 × 3 days (7+3) for Induction and high dose intermittent cytarabine 3 g/m2 every 
12 hours on Days 1, 3, and 5 for Consolidation.  Quizartinib was administered daily for either 
7 or 14 days, starting at Day 4 of induction and/or consolidation chemotherapy.  Subjects were 
allowed to proceed directly to a stem cell transplant after achieving a response or receive further 
quizartinib as maintenance therapy after Consolidation if they were not transplant eligible.  Three 
dose levels were tested; 60 mg × 7 days, 60 mg × 14 days, and 40 mg × 14 days.  Through 
May 31, 2013 18 subjects were enrolled in the study.  The median age of subjects was 43 years 
(minimum, 22; maximum, 60).  Of the 18 subjects, 16 had the FLT-ITD mutation.  At 60 mg × 
7 days, one of the 6 subjects had a dose limiting toxicity (DLT, grade 3 hyponatremia).  At 
60 mg × 14 days, 2 of the 6 subjects had a DLT (Grade 3 QT corrected [QTc] prolongation and 
Grade 4 pericarditis) which exceeded the pre-specified criteria so 40 mg × 14 days was then 
explored.  At 40 mg × 14 days, 1 of the 6 subjects had a DLT (Grade 3 constrictive pericarditis).  
The most common (20%) treatment-related AEs were nausea (42%), diarrhea (32%), anemia 
(26%), febrile neutropenia (26%), neutropenia (21%), fatigue (21%), pyrexia (21%) and 
thrombocytopenia (21%).  The most common (10%) Grade 3 or 4 treatment-related AEs were 
febrile neutropenia (26%), thrombocytopenia (21%) anemia (21%), neutropenia (21%), 
leucopenia (16%), and nausea (11%).  The maximum tolerated dose was identified as 40 mg for 
14 days or 60 mg for 7 days.2,9 
The AML18 pilot quizartinib dose-escalation study was an investigator-sponsored study 
conducted in the UK that enrolled newly diagnosed (FLT3 [+] and FLT3 [-]) AML patients 
greater than 60 years old.1  Quizartinib was administered with standard chemotherapy comprised 
daunorubicin, cytarabine, and etoposide.10 
Six cohorts with escalating doses of quizartinib (60 mg, 90 mg or 135 mg based on doses used in 
the Phase 2 AC220-002 study with quizartinib) for 7 or 14 days were planned.  If 60 mg was not 
tolerated dose de-escalation to 40mg for 7 or 14 days was allowed.  Because of the presumed 
increased sensitivity in females to QTc prolongation, each cohort required a minimum of 
3 females.  The day of safety evaluation was on completion of the chemotherapy in course 2. 
Fifty-five subjects with a median age of 69 years (minimum, 62; maximum, 87) were enrolled, of 
whom 48 were evaluable.  Four subjects were FLT3-ITD (+).  Thirteen subjects (4 males, 
9 females) entered Cohort 1 (60 mg for 7 days).  No DLTs were seen in males but 3 DLTs 
occurred in females (all grade 4:1 cardiac (myocardial infarction), 1 hypokalemia; 1 mucositis) 
so this cohort exceeded tolerability for females. 8 subjects (all males) entered Cohort 2 (60 mg 
for 14 days) where 4 DLTs (all grade 3; 3 QTc prolongation, 1 appetite loss) were seen, so this 
cohort exceeded tolerability for males.10  In the 40 mg for 14 day cohort, there was 1 DLT 
(hematological) of 5 evaluable males and 0 of 8 evaluable females had a DLT. 
Induction death (death within 30 days) occurred in 3/46 (6.5%) evaluable patients.  Complete 
remission (CR) was achieved in 33/42 (79%; including all 4 FLT3-ITD [+]) of subjects evaluable 

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for CR.  Overall median time to neutrophil and platelet count recovery (neutrophils to 
1000/mm3; platelets to 100,000/mm3) was prompt (28 and 22 days post Course 1; 22 and 19 days 
post Course 2, respectively).  No subjects received stem cell transplantation.  
Based on data from these 2 clinical studies, quizartinib is predicted to be tolerated and provide 
sufficient clinical benefit administered in subjects as 40 mg dose once daily for 14 days. 
1.1.1.5.3. Maintenance Study: 2689-CL-0011 in AML 
Allogeneic transplant has become an accepted standard of care for consolidating newly 
diagnosed FLT3-ITD AML subjects in first remission.10, 11, 12  An ongoing Phase 1 study of 
quizartinib as maintenance therapy in subjects with AML who have been treated with an 
allogeneic HSCT (2689-CL-0011) has enrolled 13 subjects with AML in morphologic remission 
(<5% bone marrow blasts) during first or second remission following an allogeneic HSCT.1  
These subjects were identified as FLT3-ITD (+) at diagnosis, and after recovery of blood counts 
post-HSCT were treated with doses of 40 mg/day (n=7) and 60 mg/day (n=6) of quizartinib.13 
Preliminary data has shown that both doses are well tolerated and the median number of cycles 
administered was 18.12  One patient relapsed on study drug (Cycle 1).  One patient had Grade 2 
graft-versus-host disease (GVHD) on quizartinib.  There was no Grade 3 QTcF prolongation.  
Preliminary results showed that all 13 subjects had experienced at least 1 treatment-emergent AE 
(TEAE); diarrhea (62%), fatigue (54%), nausea (54%), vomiting (54%), GVHD in skin (38%), 
neutropenia (38%), anemia (31%), dry eye (31%), dysgeusia (31%), peripheral edema (31%), 
pyrexia (31%), and upper respiratory tract infection (31%) were reported in more than 3 subjects 
each.  Three subjects discontinued treatment due to AEs: Grade 4 possibly-related neutropenia; 
Grade 3 not related hemolytic anemia; and Grade 2 possibly related corneal epithelium defect.2,13  
Per study protocol, further dose escalation to 90 mg/day was allowed but based on data from the 
2689-CL-2004 study examining 30 mg and 60 mg/day doses and showing a high level of clinical 
activity with reduced QT prolongation compared to higher doses, it was decided that no further 
dose escalation was desirable.8  These data indicate that quizartinib can be safely administered as 
maintenance therapy after HSCT with promising early efficacy data. 
1.2. 
Study Rationale 
FLT3 is a transmembrane tyrosine kinase that belongs to the Class III split-kinase domain family 
of RTKs.  FLT3 is expressed in AML cells in approximately 90% of patients and stimulates 
survival and proliferation of leukemic blasts.14, 15  Moreover, FLT3 is mutated in 30% of AML 
cases.16, 17  The 2 types of mutations found in AML include ITDs (24%) and point mutations in 
the activation loop (approximately 7%).2, 16  Patients with FLT3-ITD mutations have a worse 
prognosis when treated with conventional chemotherapy compared with patients with wild-type 
FLT3 due to a higher relapse rate.18  No FLT3 inhibitors have been approved for AML due to 
limited clinical utility with lack of durable responses when administered as single agents.19, 20  
Initial studies with the next generation quizartinib are encouraging based on a high response rate 
when administered as monotherapy.  However acute myeloid leukemia is a polyclonal disease 
and patients with FLT3-ITD mutated AML may experience greater clinical benefit when 
quizartinib is administered in combination with standard chemotherapy.17  In addition to FLT3, 
quizartinib inhibits c-KIT stem cell factor CD117 which is expressed in more than 70% of AML.  
Furthermore, KIT mutations occur in more than 40% of core binding factor leukemias.21  In 

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addition, KIT mutations are evident in Runt-related transcription factor 1/ runt-related 
transcription factor 1; translocated to, 1-(+) AML.22, 23 
Results from the Phase 1 2689-CL-0005 and AML18 studies of quizartinib in combination with 
standard induction and/or consolidation therapy for subjects with newly diagnosed FLT3-ITD 
(+) AML showed that quizartinib at the doses of 40 mg for 14 days can be safely administered 
with induction and/or consolidation chemotherapy.  In addition, the majority of FLT3-ITD (+) 
subjects achieved CR.  The data from Study 2689-CL-0011 indicate that quizartinib can be 
safely administered as maintenance after HSCT with promising early efficacy data with only 1 of 
13 FLT3-ITD (+) patients experiencing disease relapse.13  These findings serve as the basis for 
studying combination of quizartinib with chemotherapy and subsequent continuation treatment 
following consolidation chemotherapy or HSCT in subjects with newly diagnosed AML with 
FLT3-ITD mutations. 
1.2.1. 
Selection of ≥3% FLT3-ITD Allelic Ratio as Cutoff for Study Eligibility 
In previous Phase 2 studies with quizartinib, subjects with an allelic ratio of FLT3-ITD to total 
FLT3 of >10% were defined as ITD(+).  Analysis of “ITD(-)” subjects from Study AC220-002 
showed that those subjects with a low level (≤10%) of the ITD mutation had similar response 
rates to positive (>10%) subjects, while those with no detectable ITD mutation (<0.3%) had 
lower response rates.  Therefore, for the ongoing QuANTUM-R Phase 3 study of relapsed and 
refractory AML subjects and for this QuANTUM-First study the cutoff will be reduced to ≥3% 
based on the limit of quantitation for the clinical diagnostic assay.  The lower ITD ratio for 
eligibility will allow those subjects with a reliably detectable and quantifiable ITD mutation to be 
enrolled and to determine the potential benefit from quizartinib. 
1.2.2. 
Selection of Chemotherapy Regimens 
The National Comprehensive Cancer Network (NCCN) Guidelines (Version 1.2015) for 
induction chemotherapy for AML include a 3-day administration of an anthracycline (idarubicin 
12 mg/m2 or daunorubicin 45 mg /m2 to 90 mg /m2) plus 7 days of standard dose cytarabine 
(cytosine arabinoside) (“7+3” chemotherapy regimen).24, 25, 26  
Anthracycline (idarubicin 12 mg/m2 or daunorubicin 45 mg /m2 to 90 mg /m2) is administered as 
a short intravenous (IV) infusion or bolus daily for 3 days (Days 1 to 3).  The dose of cytarabine 
is usually 100 mg/m2 to 200 mg/m2, administered as a continuous IV infusion daily for 7 days 
(Days 1 to 7).24 
Depending on age and patient selection about 70 to 80 percent of patients achieve a CR with 
idarubicin or daunorubicin based induction therapy.27, 28  Most remissions come after a single 
course.  Until recently, daunorubicin had been commonly administered at a dose of 45 mg/m2; 
however, randomized studies suggest that higher doses of daunorubicin (eg, 60 mg/m2 to 
90 mg/m2 per day) are more effective and no more toxic than 45 mg/m2.  A Phase 3 trial of 
657 adults (17 to 60 years old) with untreated AML randomly assigned induction therapy with 
7 days of continuous IV infusion cytarabine (100 mg/m2 per day) plus 3 once-daily doses of 
daunorubicin at 45 mg/m2 or 90 mg/m2.  Compared to the 45 mg/m2 daunorubicin dose, patients 
assigned to the 90 mg/m2 dose had a higher CR rate (71% versus 57 %), a longer median overall 
survival (OS), 24 versus 16 months) and similar rates of severe (grade 3/4/5) AEs.28  A similar 

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randomized trial in older adults (>60 years) also reported higher CR rates with 90 mg/m2 
daunorubicin compared with 45mg/m2 (52% versus 35%).29 
However, in another trial (AML17), 1206 adults with untreated AML or high-risk 
myelodysplastic syndrome were randomly assigned induction therapy with cytarabine 
(100 mg/m2 every 12 hours on Days 1 to 10 inclusive) plus daunorubicin at a dose of either 
90 mg/m2 or 60 mg/m2 on Days 1, 3, and 5.25 All patients received a second Induction course 
that included daunorubicin 50 mg/m2 on days 1, 3, and 5.  There was no overall difference in CR 
rate.  The 60 day mortality was increased in the 90 mg/m2 arm (10% versus 5%), which resulted 
in no difference in overall 2 year survival (59% versus 60%).25 
The proposed Induction regimen for QuANTUM-First is the standard “7+3” regimen with the 
choice of daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 on Days 1 to 3 combined with 
cytarabine 100 mg/m2 (200 mg/m2 if institutional or local standard) on Days 1 to 7.  
The NCCN Guidelines (Version 1.2015) for post-remission chemotherapy for AML include 
consolidation with high-dose cytarabine.  The NCCN recommended high dose cytarabine is 2 to 
3 g/m2 (1 to 1.5 g/m2 for subjects ≥60 years of age) administered as an IV infusion every 
12 hours on Days 1, 3, and 5 for a total of 6 doses.24  European Leukemia Net recommendations 
suggest using high dose cytarabine as a consolidation therapy in clinical trials only.30  
However, there is no clear consensus recommendation for a Consolidation cytarabine regimen 
for FLT3 (+) patients.  The NCCN recommends enrolling FLT3 (+) patients into a clinical trial.24 
European LeukemiaNet recommendations suggest to use HSCT as a consolidation for patients 
with FLT3-ITD who are 18-60 years old and to use “modest” dose of cytarabine for 
consolidation in patients over age of 60.30  
The proposed consolidation regimen for QuANTUM-First is cytarabine 3 g/m2 twice daily for 
subjects <60 years old and 1.5 g/m2 twice daily for subjects ≥60 years old and on Days 1, 3, and 
5.  The dose of cytarabine has been defined as 3 g/m2 based on data from the CALGB study in 
which cytarabine doses of 100 mg/m2 or 400 mg/m2 for 5 days or 3 g/m2 twice daily on Days 1, 
3, and 5 were compared.31  The 3 g/m2 dose was found to have superior disease free survival 
compared to the lower doses.31  
1.2.3. 
Rationale for Quizartinib Dose Selection 
During the Induction Phase and Consolidation Phase subjects will receive quizartinib 40 mg or 
matching placebo, once daily for 14 days per cycle, immediately following standard 
chemotherapy.  The 40 mg dose was selected based on the results of Study 2689-CL-0005 and 
the investigator initiated AML18 pilot study.  In these studies quizartinib 40 mg × 14 days was 
identified as the MTD, when given in addition to standard chemotherapy in newly diagnosed 
AML subjects older than 60 years. 
In addition to the clinical data, the quizartinib dose of 40 mg following chemotherapy is 
supported by data from pharmacodynamic assays.  The in vitro PIA measures the ability of 
plasma taken at various times before and after dosing with quizartinib to inhibit signaling in 
FLT3-ITD (+) cell lines.  The inhibitory activity demonstrated in this assay has been found to 
correlate with clinical response to different FLT3 inhibitors.19  Plasma inhibitory activity data 
from the Phase 2b (2689-CL-2004) studies demonstrated that 30 mg is the minimum dose for 
complete and rapid inhibition of FLT3-ITD signaling in this assay.32  However, there are several 

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compensatory mechanisms, such as increases in FLT ligand and direct cell to cell contact 
between blast cells and stromal cells that reduce the effectiveness of FLT3 inhibitors and protect 
leukemic blasts from apoptosis.33, 34  Therefore it is important to administer a dose above the 
minimum to ensure complete and durable inhibition of the target, particularly when quizartinib is 
administered for only 14 days and not continuously as with monotherapy studies. 
Data from Study AC220-015, which examined the effect of strong and moderate CYP3A4 
inhibitors on quizartinib PK in human volunteers, indicate that concomitant ketoconazole, a 
strong CYP3A4 inhibitor, will increase AUC0-inf approximately 2-fold, and concomitant 
fluconazole, a moderate CYP3A4 inhibitor, will increase quizartinib AUC0-inf approximately 
1.2-fold.2  Additionally, predicted quizartinib Cmax at steady state after repeat daily dosing will 
increase approximately 2.0-fold and 1.2-fold, respectively, with concomitant ketoconazole and 
fluconazole.  Subjects who begin treatment with a strong CYP3A4 inhibitor while receiving 
quizartinib will be required to be reduced from 40 mg/day to 20 mg/day.  If the strong CYP3A4 
inhibitor is discontinued, the dose of quizartinib can be resumed at the regularly scheduled dose.  
No dose reduction of quizartinib is required when subjects are coadministered a moderate or 
weak CYP3A4 inhibitor.  If quizartinib/placebo is interrupted, missed doses will not be made up. 
Quizartinib has been shown to be a P-glycoprotein (P-gp) substrate based on in vitro studies.  
However, clinical data suggest that P-gp plays a minimal role in the absorption or clearance of 
quizartinib.  Based on the mass balance study, quizartinib appears to be highly absorbed into 
enterocytes and has minimal renal excretion (AC220-006).  Inhibition of P-gp/CYP3A4 by 
ketoconazole resulted in a small change (eg, <20%) in absorption of quizartinib (AC220-015).  
Therefore no dose adjustment is required when quizartinib is coadministered with a P-gp 
inhibitor. 
The potential of quizartinib and AC886 to inhibit cytarabine metabolism was examined in human 
liver S9.  Pooled human liver S9 was incubated with cytarabine (50 μM) in the presence of 
6 concentrations of quizartinib or AC886 (0.1, 0.3, 1, 3, 10, and 30 μM) for 15 minutes at 
37°C.  At the end of the incubation period the reactions were terminated and samples were 
analyzed for ara-U, a metabolite of cytarabine.  Gemcitabine was used as a positive control 
inhibitor of cytarabine metabolism by cytidine deaminase.  Based on these data, quizartinib does 
not inhibit cytarabine metabolism (up to 30 μM for parent and metabolite). 
The quizartinib concentration relationship to QTcF prolongation (ΔQTcF) was evaluated by 
incorporating circadian rhythm with PK and ECG data collected from Study 2689-CL-2004 into 
a non-linear mixed effect model.  The covariates evaluated were quizartinib and AC886 plasma 
concentrations and sex.  QTcF changes with circadian rhythm and is linearly dependent on 
quizartinib plasma concentrations.  AC886 plasma concentrations and sex are not significant 
covariates for the QTcF prolongation.  This model was used to predict QTcF prolongation at 
steady state geometric mean Cmax normalized to 40 mg.  The analysis predicted that 
administration of 40 mg/day quizartinib with dose reduction to 20 mg/day for the subjects on 
strong CYP3A4 inhibitors resulted in the upper 90% CI of ΔQTcF less than 17 ms.  These results 
suggest that the proposed quizartinib dose regimen has acceptable risk of QT prolongation based 
on the International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) E14 Guidance stating: “Drugs that prolong the mean 
QT/QTc interval by >20 ms have a substantially increased likelihood of being proarrhythmic.”35 

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During the Continuation Phase, subjects will receive study drug, quizartinib 30 mg or matching 
placebo, once daily, starting on Day 1, with no breaks between cycles.  Study drug dosage will 
be increased on Day 16 to 60 mg once daily for subjects where QTcF is maintained ≤450 ms and 
study drug is tolerated.  This escalating dose schedule based on QTcF interval at drug 
steady-state is the same as that in the ongoing QuANTUM-R Study.  The 30 mg and 60 mg 
doses were chosen, based on the results of Study 2689-CL-2004.  In that study quizartinib 30 mg 
or 60 mg, was given to subjects with FLT3-ITD (+) AML, and 60 mg was identified as the target 
dose as it showed rapid and durable inhibition of FLT3 phosphorylation on pharmacodynamic 
assay.  Additional dose adjustments for toxicity including myelosuppression and administration 
of strong CYP3A4 inhibitors from 30 mg/day to 20 mg/day, or 60 mg/day to 30 mg/day, are 
included.  If quizartinib/placebo is interrupted, missed doses will not be made up.  Once the dose 
is increased to 60 mg/day, the subject may continue on this dose as long as dose reduction is not 
needed. 

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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective is to compare the effect of quizartinib versus placebo (administered with 
standard induction and consolidation chemotherapy, then administered as continuation therapy 
for up to 36 cycles) on the primary endpoint of overall survival (OS) in subjects with newly 
diagnosed AML with FLT3-ITD mutations. 
2.1.2. 
Secondary Objectives 
The secondary objectives are to: 
 Compare the following in subjects treated with quizartinib versus placebo 
(administered with standard induction and consolidation chemotherapy, then 
administered as continuation therapy for up to 36 cycles): 
 Event-free survival (EFS) 
 Composite complete remission rate (CRc = CR + CR with incomplete neutrophil 
or platelet recovery [CRi]) after Induction;  
 Percentage of subjects achieving CRc with FLT3-ITD minimal or measurable 
residual disease (MRD) negativity after Induction; 
 Complete remission (CR) rate after Induction; 
 Percentage of subjects achieving CR with FLT3-ITD MRD negativity after 
Induction. 
 Further characterize the safety profile of quizartinib administered with standard 
induction and consolidation chemotherapy, then administered as continuation therapy 
for up to 36 cycles. 
 Assess the pharmacokinetics (PK) of quizartinib and its metabolite (AC886). 
2.1.3. 
Exploratory Objectives 
The exploratory objectives are: 
To evaluate the following in subjects treated with quizartinib versus placebo (administered with 
standard induction and consolidation chemotherapy, then administered as continuation therapy 
for up to 36 cycles): 
 Relapse-free survival (RFS); 
 Duration of CR; 
 CR rate at the end of first Induction Cycle;  
 CRc rate at the end of first Induction Cycle; 

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 Rate of CR with partial hematologic recovery (CRh) after Induction (only for 
Independent Review Committee [IRC] assessment of response); 
 Rate of morphologic leukemia-free state (MLFS) after Induction (only for IRC 
assessment of response); 
 RFS in subjects who enter the Continuation Phase, after achieving CRc in Induction; 
 Transplantation rate; 
 Healthcare resource utilization; 
 Impact on subject reported quality of life (QoL) and symptoms, as assessed by 
European Organisation for Research and Treatment of Cancer (EORTC) core quality 
of life questionnaire (QLQ-C30); 
 Change in general health status measured by EQ-5D-5L. 
To assess the population PK (PopPK) of quizartinib and exposure-response relationship for 
QTcF including assessment of post-anthracycline administration, and clinical response measures; 
To assess the pharmacodynamics and biomarkers of quizartinib. 
2.2. 
Study Hypothesis 
Quizartinib will prolong OS in subjects ≥18 and ≤75 years old with newly diagnosed AML with 
FLT3-ITD mutations when administered with standard induction and consolidation 
chemotherapy, then administered as continuation therapy for up to 36 cycles. 

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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, global study to compare the 
effect of quizartinib versus placebo (administered with standard induction and consolidation 
chemotherapy, then administered as continuation therapy for up to 36 cycles) on the primary 
endpoint of OS in subjects with newly diagnosed AML with FLT3-ITD mutations.  The study 
duration is described in Section 3.1.1. 
This study will be conducted in approximately 250 study sites worldwide. 
The target sample size will be approximately 536 subjects.  Randomization will be done in a 
1:1 ratio into the 2 treatment groups (quizartinib or placebo).  Randomization will be stratified 
based on: 
 Region (North America, Europe, Asia/Other Regions) 
 Age (<60 years old, ≥60 years old) 
 White blood cell (WBC) count at the time of diagnosis of AML (<40×109/L, 
≥40×109/L) 
The study design consists of 4 consecutive phases (Induction, Consolidation, Continuation, 
Long-Term Follow-up) as outlined in Section 3.2.2 and shown in Figure 3.1.  Figure 3.2 shows 
the study design from Screening into the Treatment Period. 
Figure 3.1: 
Study Summary 
Consolidation 
Phasea (includes 
transplant periodb) 
Induction 
Phasea 
Continuation 
Phasea 
Long-term  
Follow-up Phase 
   
Quizartinib / placebo administration   
Quizartinib / placebo 
permanently discontinued 
Each phase has a specific visit schedule 
Visit / follow up schedule 
• Subjects who have not had 
an EFS event: Q 4 Weeks 
• Subjects who have had an 
EFS event – Q 12 Weeks 
Follow all randomized subjects for EFS and overall survival 
 
EFS=event-free survival; Q=every 
a Subjects who permanently discontinue quizartinib/placebo in the Induction, Consolidation, or Continuation Phases 
will enter the Long-Term Follow-up Phase. 
b During transplant period, quizartinib/placebo interrupted and subjects followed for relapse and survival status.  

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Figure 3.2: 
Study Design Schematic (Screening to Treatment Period)  
Newly 
Diagnosed 
AML ≥ 18 
and ≤ 75 y.o. 
FLT3-ITD 
mutant
Treatment Period
Cytarabinea
(Days 1 – 7)
Anthracyclinea
(Days 1 – 3)
Quizartinib
(QD Days 8 – 21)
Cytarabinea
(Days 1 – 7)
Anthracyclinea
(Days 1 – 3)
Placebo
(QD Days 8 – 21)
Cytarabinea
(Days 1, 3, & 5)
Quizartinib
(QD Days 6 – 19)
Cytarabinea
(Days 1, 3, & 5)
Placebo
(QD Days 6 – 19)
Quizartinib
(QD)
Placebo
(QD)
Inductiona 
(up to 2 Cycles)
Randomization – Cycle 1 
Day 7 (+3 days)
Consolidation 
(with chemotherapy and or 
allogeneic HSCT)
Continuation 
(up to 36 cycles)
OS = primary endpoint
 
AML=acute myeloid leukemia; FLT3=FMS-like tyrosine kinase 3; ITD=internal tandem duplication; OS = overall 
survival; QD=once a day; y.o. =years old 
a During Induction Cycle 2 investigators may choose to administer the “7+3” chemotherapy regimen, or the "5+2" 
chemotherapy regimen, and quizartinib/placebo will therefore start on Day 8 or Day 6, respectively. 
3.1.1. 
Study Duration 
The total duration of subject participation will be until death, withdrawal of consent, lost to 
follow-up, or study closure, whichever occurs first.  Subjects will be followed for EFS and OS 
events after completion of induction and consolidation therapy, whether or not the subject 
receives continuation therapy.  Close and uniform follow up is essential to determine the timing 
of relapse in each treatment arm. 
The total duration of treatment with quizartinib/placebo will be up to 42 cycles (inclusive of 
Induction, Consolidation, and Continuation Phases). 
The OS analysis will be performed: 
 When the target 287 OS events are observed and a minimum of 24 months has 
elapsed since the last subject was randomized. 
 If the target 287 OS events are not achieved by 24 months since the last subject was 
randomized, then the analysis will be performed at a maximum of 30 months after the 
last subject is randomized. 

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All other efficacy analyses will be performed at the same time as the OS analysis. 
The primary completion date is the date when the final OS analysis (up to a maximum of 
30 months after the last subject is randomized) has been completed.  All subjects still on 
treatment and continuing to derive benefit from study drug at the primary completion date will 
continue to follow the study schedule of assessments until the overall End of Study is reached. 
Overall End of Study will occur when: 
 all subjects have discontinued treatment and discontinued long-term survival 
follow-up or have died  
 an alternative study becomes available, for subjects continuing to derive benefit from 
treatment with quizartinib, where the study drug is offered to these subjects 
 the study is discontinued by the Sponsor for other reasons (administrative, 
program-level or class-related) 
The subject’s EOS is the date of their last study visit/contact. 
3.2. 
Discussion of Study Design 
3.2.1. 
Treatment Groups 
Subjects will be randomized to the quizartinib group or placebo group. 
3.2.2. 
Study Phases 
In the Induction, Consolidation, and Continuation Phases, each cycle will be 28 days in duration.  
Additional time is allowed for recovery of blood counts, if needed, in the Induction or 
Consolidation Phases. 
Subjects in remission following the Induction or Consolidation Phases will have their blood 
counts monitored at least every 4 weeks and will have a bone marrow aspirate specimen (or a 
core biopsy specimen if aspirate cannot be obtained) collected every 12 weeks for the first 
48 weeks, followed by every 24 weeks for the next 48 weeks, until relapse or 96 weeks have 
passed, whichever occurs first.  For more details see the bone marrow aspirate specimen 
collection in Section 6.2.3 and Section 6.4.2.1.1. 
3.2.2.1. 
Induction Phase (up to 2 cycles) 
During the Induction Phase subjects will be treated with quizartinib plus the cytarabine and 
anthracycline regimen or placebo plus the cytarabine and anthracycline regimen.  Subjects are 
permitted to receive up to 2 cycles of induction chemotherapy.   
Cycle 1 
Subjects will begin the cytarabine and anthracycline regimen on Day 1.  Cytarabine will be 
administered by continuous intravenous (IV) infusion for a total of 7 days, starting on Day 1 and 
ending on Day 8.  The anthracycline will be administered on Days 1, 2, and 3. 
Subjects will be randomized on Day 7.  If necessary, Randomization may be performed later 
(eg, Days 8 to 10) to allow time for addressing electrolyte abnormalities, QTcF prolongation, etc.  

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Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing should start 
following the end of the cytarabine infusion, normally on Day 8.  If quizartinib/placebo 
administration cannot begin as scheduled, the start of dosing may be delayed, but best efforts 
should be made to start within 3 days of Randomization if possible.  If quizartinib/placebo 
cannot be started within 3 days of Randomization, please contact the Medical Monitor.  If 
quizartinib/placebo is interrupted, missed doses will not be made up. 
On Day 21 (window Day 21 to Day 28), a bone marrow aspirate specimen (or a core biopsy 
specimen if aspirate cannot be obtained) will be collected for local and central pathology.  If this 
bone marrow does not provide an accurate assessment of response, the bone marrow procedure 
will be repeated upon count recovery or Day 56 (±3 days), whichever occurs first.  Subjects with 
≥ 5% blasts at the end of Cycle 1 may receive a second cycle of Induction, if appropriate.  At the 
investigator’s discretion, to allow for blood counts to recover or other reasons, the second 
Induction cycle may start up to 60 days after Day 1 of the first Induction cycle. 
Cycle 2 
Subjects will begin the cytarabine and anthracycline regimen on Day 1.  It is recommended to 
wait at least 7 days after the last dose of quizartinib/placebo in Cycle 1 of Induction before 
starting Cycle 2 of Induction, since quizartinib has a long elimination half-life and there are no 
data on the safety of administering anthracycline within 7 days following quizartinib 
administration.  For Cycle 2 of Induction, investigators may choose to administer a “7+3” or 
“5+2” regimen. 
Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing will start 
following the end of the cytarabine infusion, normally on Cycle 2, Day 8 or Cycle 2, Day 6, 
depending on the chemotherapy regimen selected by the investigator (ie, “7+3” or “5+2”, 
respectively).  If quizartinib/placebo administration cannot begin as scheduled, the start of dosing 
may be delayed, but best efforts should be made to begin as soon as possible.  If 
quizartinib/placebo is interrupted, missed doses will not be made up. 
On Day 21 (window Day 21 to Day 28), a bone marrow aspirate specimen (or a core biopsy 
specimen if aspirate cannot be obtained) will be collected for local and central pathology.  If this 
bone marrow does not provide an accurate assessment of response, the bone marrow procedure 
will be repeated upon count recovery or Day 56 ( 3 Days), whichever occurs first.  Subjects 
with ≥ 5% blasts at the end of Cycle 1 may receive a second cycle of Induction, if appropriate.  
At the investigator’s discretion, to allow for blood counts to recover or other reasons, the first 
cycle of Consolidation may start up to 60 days after Day 1 of the last Induction cycle. 
See Section 5.4.1 for specific treatment administration requirements during the Induction Phase, 
and Section 6.2.1, Table 17.1, Table 17.2 and Table 17.3 for all procedures to be done during the 
Induction Phase. 
3.2.2.2. 
Consolidation Phase  
Subjects who achieve a CR or CRi at the end of the Induction Phase will enter the Consolidation 
Phase.  The following are the options for consolidation therapy: 
 Treatment with quizartinib/placebo plus cytarabine (4 cycles, if tolerated); or 
 Allogeneic HSCT; or 

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 Treatment with quizartinib/placebo plus cytarabine followed by allogeneic HSCT. 
Cytarabine will be administered by IV infusion every 12 hours on Days 1, 3, and 5 for a total of 
6 doses.  Quizartinib/placebo will be administered orally once a day from Day 6 to Day 19 
(14 days).  If quizartinib/placebo is interrupted, missed doses will not be made up. 
Each cycle in the Consolidation Phase will be 28 days in duration.  The subjects will receive 
4 cycles of consolidation therapy, if tolerated.  At the investigator’s discretion, to allow for blood 
counts to recover, the subsequent Consolidation cycle may start up to 60 days after Day 1 of the 
previous cycle. 
A bone marrow aspirate specimen (or a core biopsy specimen if aspirate cannot be obtained) will 
be collected for local and central pathology in the first and last cycles of Consolidation, upon 
count recovery from Day 21 to Day 56. 
See Section 4.1.2 for eligibility criteria to proceed into the Consolidation Phase, Section 5.4.2 for 
specific treatment administration requirements during the Consolidation Phase, and Section 6.2.2 
and Table 17.4 for all procedures to be done during the Consolidation Phase. 
3.2.2.2.1. Allogeneic Hematopoietic Stem Cell Transplantation  
Allogeneic HSCT is one of the options for consolidation therapy, either alone or following 
consolidation treatment with cytarabine and quizartinib/placebo.  Allogeneic HSCT that is 
performed for other reasons, eg, molecular relapse, will be considered nonprotocol-specified 
AML therapy, and the subject will be discontinued from quizartinib/placebo but will continue to 
be followed for outcome data. 
In general, subjects are permitted to undergo allogeneic HSCT between the end of the Induction 
Phase and the start of the Continuation Phase.  Under certain circumstances, a subject may 
undergo allogeneic HSCT for consolidation within the first 3 months of the Continuation Phase 
(see Section 6.2.2.2).   
The investigator will be responsible to contact the transplant center on a regular basis to collect 
required data.  Once the subject is able, the subject will return to the clinic for site visits every 
4 weeks.  See Section 6.2.2.2 and Table 17.5 for details. 
For subjects who undergo allogeneic HSCT, treatment with quizartinib/placebo should be 
discontinued 7 days before the start of a conditioning regimen.  Subjects may begin continuation 
therapy anytime between 30 to 180 days after the allogeneic HSCT.  The site should follow their 
local procedures for allogeneic HSCT conditioning and recovery. 
Subjects are not permitted to undergo autologous HSCT at any time during the study.  Subjects 
who undergo autologous HSCT will be discontinued from quizartinib/placebo but will continue 
to be followed for outcome data. 
3.2.2.3. 
Continuation Phase (up to 36 cycles) 
Following consolidation therapy, subjects will enter the Continuation Phase if they meet the 
inclusion criteria (see Section 4.1.3).  In addition, per investigator discretion, subjects who have 
achieved CR or CRi following Induction, but who are unable to receive consolidation therapy, 
will be permitted to enter the Continuation Phase if they meet the inclusion criteria. 

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During the Continuation Phase subjects will be treated with quizartinib/placebo once daily for up 
to 36 cycles.  Continuation therapy will begin after induction or consolidation therapy, including 
allogeneic HSCT, and will continue until relapse, start of nonprotocol specified AML treatment, 
death, unacceptable toxicity, study close, or completion of 36 cycles, whichever occurs first. 
The cycles during the Continuation Phase will be 28 days each, with no breaks in dosing 
between cycles.  If quizartinib/placebo is interrupted, missed doses will not be made up. 
Subjects will have their blood counts monitored at least every 4 weeks and will have a bone 
marrow exam every 12 weeks for 48 weeks and then every 24 weeks until week 96. 
See Section 4.1.3 for eligibility criteria to proceed into the Continuation Phase, Section 5.4.3 for 
specific treatment administration requirements during the Continuation Phase, and Section 6.2.3 
and Table 17.6 for all procedures to be done during the Continuation Phase. 
3.2.2.4. 
Long Term Follow-up Phase 
Subjects who complete 36 cycles of quizartinib/placebo in the Continuation Phase or 
permanently discontinue quizartinib/placebo in the Induction, Consolidation, or Continuation 
Phases will enter the Long-term Follow-up Phase, as detailed in Section 6.4.2. 

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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria  
4.1.1. 
Inclusion Criteria – Randomization 
Subjects must satisfy all of the following criteria to be randomized: 
1. Must be competent and able to comprehend, sign, and date an Ethics Committee (EC)- or 
Institutional Review Board (IRB)- approved Informed Consent Form (ICF) before 
performance of any study-specific procedures or tests; 
2. ≥18 years or the minimum legal adult age (whichever is greater) and ≤75 years (at 
Screening); 
3. Newly diagnosed, morphologically documented primary AML or AML secondary to 
myelodysplastic syndrome or a myeloproliferative neoplasm, based on the World Health 
Organization (WHO) 2008 classification (at Screening);36  
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see 
Appendix 17.6 for descriptions) (at the time the subject signs their first informed consent 
form); 
5. Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of ≥3% 
FLT3-ITD/total FLT3) (Section 6.1.2); 
6. Subject is receiving standard “7+3" induction chemotherapy regimen as specified in the 
protocol (see Section 5.4.1 for required anthracycline and cytarabine doses);  
7. Adequate renal function defined as: 
a. Creatinine clearance >50 mL/min, as calculated with the modified Cockcroft Gault 
equation (Appendix 17.9); 
8. Adequate hepatic function defined as: 
a. Total serum bilirubin (TBL) ≤1.5 × upper limit of normal (ULN) unless the subject 
has documented Gilbert’s syndrome or the increase is related to increased 
unconjugated (indirect) bilirubin due to hemolysis; 
b. Serum alkaline phosphatase, aspartate transaminase (AST) and alanine transaminase 
(ALT) ≤2.5 × ULN; 
9. Serum electrolytes within the institution’s normal limits: potassium, calcium (total 
calcium, calcium corrected for serum albumin in case of hypoalbuminemia 
[Section 17.11.1], or ionized calcium) and magnesium.  If outside of the institution’s 
normal range, subject will be eligible when electrolytes are corrected; 
10. If a woman of childbearing potential, must have a negative serum pregnancy test upon 
entry into this study and must be willing to use highly effective birth control 
(Appendix 17.2) upon enrollment, during the treatment period and for 6 months 
following the last dose of investigational drug or cytarabine, whichever is later.  A 
woman is considered of childbearing potential following menarche and until becoming 

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postmenopausal (no menstrual period for a minimum of 12 months) unless permanently 
sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy); 
11. If male, must be surgically sterile or willing to use highly effective birth control 
(Appendix 17.2) upon enrollment, during the treatment period, and for 6 months 
following the last dose of investigational drug or cytarabine, whichever is later. 
4.1.2. 
Inclusion Criteria – Consolidation Phase 
Subjects must satisfy all of the following criteria to start the Consolidation Phase and receive 
consolidation therapy: 
1. Achieved CR or CRi (as defined in Table 17.15), based on local laboratory results, at the 
end of the Induction Phase; 
2. Able to begin Consolidation Phase within 60 days of Day 1 of the last Induction Cycle. 
4.1.3. 
Inclusion Criteria – Continuation Phase 
Subjects must satisfy all of the following criteria to start the Continuation Phase and receive 
continuation therapy: 
1. Subject does not have active acute, or ≥ Grade 3 GVHD  
2. Subject has not initiated therapy for active GVHD (prophylaxis is allowed) within 
21 days; 
3. Confirmed <5% of blasts based on the most recent bone marrow aspirate, based on the 
local laboratory results, performed within 28 days prior to Cycle 1 Day 1 of continuation 
therapy; 
4. Absolute neutrophil count (ANC) >500/mm3 and platelet count >50,000/mm3 without 
platelet transfusion support within 24 hours prior to Cycle 1 Day 1 of continuation 
therapy; 
5. Able to begin Continuation Phase within 60 days of Day 1 of the last Consolidation cycle 
received or within 180 days after allogeneic HSCT (ie, stable after transplant). 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible to be randomized: 
1. Diagnosis of acute promyelocytic leukemia (APL), French-American-British 
classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or 
BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis); subjects 
who undergo diagnostic workup for APL and treatment with ATRA, but who are found 
not to have APL, are eligible (treatment with ATRA must be discontinued before starting 
induction chemotherapy). 
2. Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms; 
3. Prior treatment for AML, except for the following allowances: 
a. Leukapheresis; 

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b. Treatment for hyperleukocytosis with hydroxyurea; 
c. Cranial radiotherapy for central nervous system (CNS) leukostasis; 
d. Prophylactic intrathecal chemotherapy; 
e. Growth factor/cytokine support;  
4. Prior treatment with quizartinib or other FLT3-ITD inhibitors; 
5. Prior treatment with any investigational drug or device within 30 days prior to 
Randomization (within 2 weeks for investigational or approved immunotherapy) or 
currently participating in other investigational procedures; 
6. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts; 
lumbar puncture is recommended for subjects with symptoms of CNS leukemia to rule 
out extramedullary CNS involvement; 
7. History of other malignancies, except adequately treated non-melanoma skin cancer, 
curatively treated in-situ disease, or other solid tumors curatively treated with no 
evidence of disease for at least 2 years; 
8. Uncontrolled or significant cardiovascular disease, including any of the following: 
a. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker; 
b. QTcF interval >450 ms; 
c. Diagnosis of or suspicion of long QT syndrome (including family history of long QT 
syndrome); 
d. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg; 
e. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, 
ventricular fibrillation, or Torsade de Pointes); 
f. History of second (Mobitz II) or third degree heart block (subjects with pacemakers 
are eligible if they have no history of fainting or clinically relevant arrhythmias while 
using the pacemaker); 
g. History of uncontrolled angina pectoris or myocardial infarction within 6 months 
prior to Screening; 
h. History of New York Heart Association Class 3 or 4 heart failure; 
i. Left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower 
limit of normal per multi-gated acquisition scan (MUGA) or echocardiogram done 
within 30 days prior to randomization; 
j. Complete left bundle branch block; 
9. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled 
by antifungal, antibacterial or antiviral therapy; 
10. Known active clinically relevant liver disease (eg, active hepatitis B, or active 
hepatitis C)  
11. Known history of human immunodeficiency virus (HIV).  Subjects should be tested for 
HIV prior to Randomization if required by local regulations or EC; 
12. History of hypersensitivity to any excipients in the quizartinib/placebo tablets; 
13. Females who are pregnant or breastfeeding;  
14. Otherwise considered inappropriate for the study by the investigator. 

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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s) 
Subjects will be randomized to either the quizartinib group or the placebo group. 
5.1.2. 
Method of Treatment Allocation 
Subjects will be randomized into 1 of the 2 treatment groups (quizartinib or placebo) in a 
1:1 ratio.  The randomization will be stratified by age, region, and WBC count at the time of 
diagnosis of AML.  Randomization will be managed through an Interactive Web/Voice 
Response System (IXRS). 
5.1.3. 
Blinding 
This study has a double-blind design.  Quizartinib is supplied as 20 mg and 30 mg tablets.  
Placebo is supplied as tablets that match the appearance of the quizartinib 20 mg and 30 mg 
tablets.  Neither the subjects nor any of the investigators, sponsor, or contract research 
organizations (CROs) will be aware of the treatments received.  
An independent biostatistician, not otherwise part of the sponsor study team, will generate the 
randomization schedule. 
5.1.4. 
Emergency Unblinding Procedure 
In the case of an emergency where, in the opinion of the investigator, the study treatment 
assignment must be unblinded in order to evaluate further a course of medical treatment, it is 
required that the investigator discuss the case with the Medical Monitor, but the discussion may 
occur after unblinding if the subject requires emergency treatment. (Contact information – refer 
to the study reference materials). 
In the event of unblinding, information about the treatment assignment must be restricted to 
designated Study Center staff/personnel that are providing immediate care to the subject.  Any 
documentation of the treatment assignment must be maintained separately (ie, a secured file).  
The information must not be included in the subject’s primary source files to ensure the 
treatment assignment will remain blinded to the Sponsor and study personnel not involved with 
the subject’s immediate care. 
5.2. 
Study Drugs 
5.2.1. 
Quizartinib 
Quizartinib is supplied to the Study Center as 20 mg tablets or 30 mg tablets.  Each 20 mg tablet 
contains 20 mg quizartinib dihydrochloride (17.7 mg free base), and each 30 mg tablet contains 
30 mg quizartinib dihydrochloride (26.5 mg free base). 
All packages are shipped at conditions depicted on the product label.  A temperature monitoring 
device will accompany every shipment to the Study Center from the Depot with instructions 
included within the shipment on how to process. 

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5.2.2. 
Placebo 
Placebo is supplied to the Study Center as tablets matching the appearance of quizartinib 20 mg 
tablets and 30 mg tablets.  All packages are shipped at conditions depicted on the product label.  
A temperature monitoring device will accompany every shipment to the Study Center from the 
Depot with instructions included within the shipment on how to process. 
5.2.3. 
Description 
The quizartinib and matching placebo will be supplied as round film-coated 20 mg (white) and 
30 mg (yellow) tablets. 
5.2.4. 
Labeling and Packaging 
Double-blind study drug (quizartinib or matching placebo) will be provided in labeled high 
density polyethylene (HDPE) bottles.  Each bottle will have a child-resistant cap and contain 
30 tablets.  The bottle label will include all information required by national and local 
regulations. 
5.2.5. 
Preparation 
Double-blind study drug (quizartinib or matching placebo) will be provided to Study Centers as 
fully prepared HDPE bottles.  Bottles will be individually numbered.  Assignment of bottles to 
subjects will be done via the IXRS. 
There is no additional preparation required for quizartinib or matching placebo.  Additional 
instructions for the handling of quizartinib/placebo will be provided in the study pharmacy 
manual. 
5.2.6. 
Storage 
Double-blind study drug supplies (quizartinib or matching placebo) must be stored appropriately 
in a locked cabinet/room with limited and controlled access under the recommended storage 
conditions.  The required storage conditions are provided in the pharmacy manual. 
NOTE: If storage conditions go outside of the recommended storage conditions, the Study 
Center must not dispense the affected supplies (affected supplies should be placed in 
quarantine per IXRS requirements).  Proper notification processes must be followed 
immediately after receipt of quizartinib/placebo identified as having a temperature 
excursion. 
5.2.7. 
Drug Accountability 
When a drug shipment is received, the investigator or designee will check the amount and 
condition of the drug. 
In addition, the investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment.  This process is also documented on the Shipment Temperature 
Record and Excursion Reporting Form that is included with each shipment. 
A Drug Accountability Record must be kept current and must contain the dates and quantities of 
study drug (quizartinib/placebo) received and any other medications supplied by the sponsor, the 

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subject’s identification number and/or initials or supply number (as applicable), the date and 
quantity of quizartinib/placebo dispensed and remaining (in tablets), as well as the initials of the 
dispenser. 
At the end of the study, or as directed, all quizartinib/placebo supplies, including unused, 
partially used, or empty containers, will either be destroyed at the site or be returned to a 
designee as instructed by Sponsor.  Quizartinib/placebo will be returned or destroyed locally 
only after the study monitor has completed a final inventory to verify the quantity to be returned.  
The return of quizartinib/placebo must be documented and the documentation included in the 
shipment.  At the end of the study, a final reconciliation statement of quizartinib/placebo must be 
completed by the investigator or designee and provided to the Sponsor.  Unused supplies of 
quizartinib/placebo may be destroyed by the investigator when approved in writing by Sponsor 
and Sponsor has received copies of the study center’s drug handling and disposition standard 
operating procedures and it is assured that the sponsor will receive copies of the certificate of 
destruction which is traceable to the quizartinib/placebo tablets.  Destruction of study drug at the 
Study Center is preferred. 
5.3. 
Standard Chemotherapy 
Subjects will receive commercially available cytarabine (cytosine arabinoside) and anthracycline 
(daunorubicin or idarubicin). 
Refer to the cytarabine and anthracycline package insert or appropriate local (ie, country 
specific) labeling for detailed description of administration and potential risks associated with 
cytarabine and anthracycline.  
Dose adjustments for renal and hepatic function are permitted per local package insert, labeling, 
or institutional guidelines. 
5.4. 
Administration 
This section describes the administration of double-blind study drug (quizartinib or matching 
placebo) as well as induction and consolidation chemotherapy. 
Quizartinib/placebo can be taken either with or without food.  Subjects should be encouraged to 
take quizartinib/placebo at the same time every day (for example, the morning) to encourage 
compliance.  If the subject omits to take quizartinib in the morning, it may be taken later in the 
day (until midnight); otherwise the dose is considered missed.  If the subject vomits after taking 
quizartinib/placebo, no replacement dose should be given.  If quizartinib/placebo is interrupted, 
missed doses will not be made up.  Do not double the dose of quizartinib/placebo the next day if 
a dose was missed. 
If quizartinib/placebo administration cannot begin as scheduled, the start of dosing may be 
delayed in each cycle.  If delayed, best efforts should be made to begin administration of 
quizartinib/placebo as soon as possible. 
5.4.1. 
Induction Phase (up to 2 cycles) 
Subjects are permitted to receive up to 2 cycles of induction chemotherapy.  Subjects with 
≥5% blasts, per the Cycle 1 Days 21 to 28 bone marrow (or a later bone marrow if the Days 21 to 

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28 bone marrow does not allow for an accurate assessment of response), may receive a second 
cycle of induction chemotherapy, if appropriate.  
Cycle 1 
Cycle 1, Day 1 is defined as the start date of the chemotherapy infusions. 
Cytarabine (cytosine arabinoside) 100 mg/m2/day (200 mg/m2/day allowed if this is the 
institutional or local standard) will be administered by continuous IV infusion for a total of 
7 days, starting on Day 1 and ending on Day 8. 
One of the following anthracycline regimens (investigator’s choice) will be administered: 
 Daunorubicin 60 mg/m2/day IV infusion on Days 1, 2, and 3; or 
 Idarubicin 12 mg/m2/day IV infusion on Days 1, 2, and 3. 
Subjects will be randomized on Day 7.  If necessary, Randomization may be performed later 
(eg, Days 8 to 10) to allow time for addressing electrolyte abnormalities, QTcF prolongation, etc.  
Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing should start 
following the end of the cytarabine infusion, normally on Day 8.  If quizartinib/placebo 
administration cannot begin as scheduled, the start of dosing may be delayed, but best efforts 
should be made to start within 3 days of Randomization if possible.  If quizartinib/placebo 
cannot be started within 3 days of Randomization, please contact the Medical Monitor.  The dose 
will be 40 mg/day (2 × 20 mg tablets).  For subjects concomitantly receiving a strong CYP3A4 
inhibitor, the dose will be reduced from 40 mg/day to 20 mg/day (Section 5.6.4).  If 
quizartinib/placebo is interrupted, missed doses will not be made up. 
Cycle 2 
At the investigator’s discretion, to allow for blood counts to recover or other reasons, the second 
Induction cycle may start up to 60 days after Day 1 of the first Induction cycle.  It is 
recommended to wait at least 7 days after the last dose of quizartinib/placebo in Cycle 1 of 
Induction before starting Cycle 2 of Induction, since quizartinib has a long elimination half-life 
and there are no data on the safety of administering anthracycline within 7 days following 
quizartinib administration. 
For Cycle 2 of Induction, investigators may choose to administer 1 of the following: 
 “7+3” chemotherapy regimen, defined as 7 days of continuous IV infusion of 
standard dose cytarabine plus 3 days of anthracycline (the same anthracycline must be 
used throughout the Induction phase); OR 
 “5+2” chemotherapy regimen, defined as 5 days of continuous IV infusion of 
standard dose cytarabine plus 2 days of anthracycline (the same anthracycline must be 
used throughout the Induction Phase). 
Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing will start 
following the end of the cytarabine infusion, normally on Cycle 2, Day 8 or Cycle 2, Day 6, 
depending on the chemotherapy regimen selected by the investigator (ie, “7+3” or “5+2”, 
respectively).  If quizartinib/placebo administration cannot begin as scheduled, the start of dosing 
may be delayed, but best efforts should be made to begin as soon as possible.  The dose will be 

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40 mg/day.  For subjects concomitantly receiving a strong CYP3A4 inhibitor, the dose will be 
reduced from 40 mg/day to 20 mg/day.  If quizartinib/placebo is interrupted, missed doses will 
not be made up. 
5.4.2. 
Consolidation Phase  
Cytarabine will be given on Days 1, 3, and 5.  The cytarabine regimen will be: 
 for subjects <60 years old: cytarabine 3.0 g/m2 by IV infusion, every 12 hours for a 
total of 6 doses; or  
 for subjects ≥60 years old: cytarabine 1.5 g/m2 by IV infusion, every 12 hours for a 
total of 6 doses. 
Subjects who are unable to tolerate a full cycle of consolidation chemotherapy are not required to 
complete the full cycle of chemotherapy in any cycle during the Consolidation Phase (4 Cycles, 
if tolerated). 
Quizartinib/placebo will be administered orally once daily for 14 days starting on Day 6.  If 
quizartinib/placebo dosing cannot begin as scheduled, the start of dosing may be delayed but best 
efforts should be made to begin as soon as possible.  The dose will be 40 mg/day (2 × 20 mg 
tablets).  The dose will be reduced from 40 mg/day to 20 mg/day (1 × 20 mg tablet) when 
subjects are concomitantly receiving strong CYP3A4 inhibitors (Section 5.6.4).  If 
quizartinib/placebo is interrupted, missed doses will not be made up. 
5.4.3. 
Continuation Phase (up to 36 cycles) 
Quizartinib/placebo continuation therapy will begin after induction or consolidation therapy 
(including allogeneic HSCT) upon blood count recovery ANC >500/mm3 and platelet count 
>50,000/mm3 without a platelet transfusion within 24 hours of drawing blood samples).  
Quizartinib/placebo will be administered orally once daily starting on Day 1, with no breaks in 
dosing between cycles.  If quizartinib is interrupted, missed doses will not be made up.  
Quizartinib/placebo continuation therapy will continue for up to 36 cycles after induction or 
consolidation, (as defined in Section 3.2.2.3) until: relapse, start of nonprotocol specified AML 
treatment, death, unacceptable toxicity, study close, or completion of 36 cycles, whichever 
occurs first. 
The dose of quizartinib/placebo on Cycle 1, Days 1 to 15 will be 30 mg (1 × 30 mg tablet) orally 
once daily.  On Cycle 1, Day 16, the dose will be increased to 60 mg/day (2 × 30 mg tablets) if 
the average QTcF of the triplicate ECGs is ≤450 ms on Cycle 1, Day 15.  Once the dose is 
increased to 60 mg/day, the subject may continue on this dose as long as dose reduction is not 
needed. 
For subjects concomitantly receiving a strong CYP3A4 inhibitor, the dose of quizartinib/placebo 
on Cycle 1, Days 1 to 15 will be 20mg (1 × 20mg tablet) orally once daily.  On Cycle 1, Day 16, 
the dose will be increased to 30mg/day (1 × 30mg tablets) if the average QTcF of the triplicate 
ECG is ≤450 ms on Cycle 1, Day 15. 
If the dose of quizartinib/placebo is not able to be increased on Cycle 1, Day 16, the dose may be 
increased on Cycle 2, Day 2 if the average QTcF of the triplicate ECG is ≤450 ms on Cycle 2, 
Day 1. 

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Subjects who permanently discontinued quizartinib/placebo because they completed 12 cycles of 
continuation therapy (as required in protocol Versions 1.0 and 2.0) may be restarted at the 
discretion of the investigator after discussion with the Medical Monitor.  Subjects who restart 
therapy will receive double-blind continuation therapy in the same treatment group (quizartinib 
or placebo) to which they were randomized. 
5.5. 
Control Treatment 
The control treatment will be placebo tablets matching the appearance of quizartinib 20 mg and 
30 mg tablets. 
5.6. 
Quizartinib/Placebo Dose Reductions and Dosing Interruptions 
The following are reasons for quizartinib/placebo dose reduction or dosing interruption: 
 Adverse event: QTcF prolongation, other non-hematologic toxicities, or 
myelosuppression;  
 Concomitant administration of a strong CYP3A4 inhibitor  
See Table 5.1 for guidance on dose reductions and interruptions of quizartinib/placebo during the 
Induction, Consolidation, and Continuation Phases. 
The dose of quizartinib/placebo will not be reduced lower than 30 mg/day in any phase of the 
study (not lower than 20 mg/day for subjects receiving strong CYP3A4 inhibitors). 
If quizartinib/placebo is interrupted, doses will not be made up. 

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Table 5.1: 
Guidelines for Quizartinib/Placebo Dose Reductions and Dosing 
Interruptions 
Induction Phase 
Full Dose 
AE, no concomitant 
strong CYP3A4 
inhibitor 
Concomitant strong 
CYP3A4 inhibitora 
AE and concomitant 
strong CYP3A4 
inhibitora 
40 mg/day 
30 mg/day 
20 mg/day 
Interruptb 
AE=adverse event; CYP = cytochrome P450 
a 
See Section 5.6.4 regarding increasing dose of study drug immediately after stopping strong CYP3A4 inhibitors. 
b See Section pertaining to AE (Section 5.6.1, Section 5.6.2, or Section 5.6.3) for duration of interruption, missed 
doses will not be made up. 
Consolidation Phase 
Full Dose 
AE, no concomitant 
strong CYP3A4 
inhibitor 
Concomitant strong 
CYP3A4 inhibitora 
AE and concomitant 
strong CYP3A4 
inhibitora 
40 mg/day 
30 mg/day 
20 mg/day 
Interruptb 
AE=adverse event; CYP = cytochrome P450 
a 
See Section 5.6.4 regarding increasing dose of study drug immediately after stopping strong CYP3A4 inhibitors. 
b See Section pertaining to AE (Section 5.6.1, Section 5.6.2, or Section 5.6.3) for duration of interruption, missed 
doses will not be made up. 
Continuation Phase 
 
Full Dose 
AE, no 
concomitant 
strong CYP3A4 
inhibitor 
Concomitant 
strong CYP3A4 
inhibitora 
AE and 
concomitant 
strong CYP3A4 
inhibitora 
Days 1-15 
30 mg/day 
Interrupt 
20 mg/day 
Interruptb 
Day 16 onward 
60 mg/day 
40 mg/dayc 
30 mg/dayd 
20 mg/daye 
AE=adverse event; CYP = cytochrome P450 
a See Section 5.6.4 regarding increasing dose of study drug immediately after stopping strong CYP3A4 inhibitors. 
b See Section pertaining to AE (Section 5.6.1, Section 5.6.2, or Section 5.6.3) for duration of interruption, missed 
doses will not be made up. 
c Can be further reduced to 30 mg/day, if necessary 
d Can be further reduced to 20 mg/day, if necessary  
e Can be interrupted if necessary. 
5.6.1. 
QTcF Prolongation - Dose Interruptions and Reductions 
Subjects taking quizartinib/placebo who experience QTcF prolongation >480 ms should be 
managed according to the guidelines below.  For all episodes of QTc prolongation, regardless of 
grade, check electrolyte (potassium, calcium, and magnesium) levels and correct any 
abnormalities.  If possible, stop any medications that may prolong the QT interval. 
QTcF >480 ms ≤500 ms 
 The dose of quizartinib/placebo will be reduced one level without interruption of 
dosing. 

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 Following dose reduction, the quizartinib/placebo dose may be resumed at the 
previous level in the next cycle if the QTcF has decreased to within 30 ms of baseline 
or <450 ms but subject must be monitored closely for QT prolongation for the first 
cycle at the increased dose.  
QTcF >500 ms 
 Quizartinib/placebo dosing will be interrupted for up to 14 days.  If QTcF returns to 
within 30 ms of baseline or <450 ms within 14 days, quizartinib/placebo 
administration may be resumed at a reduced dose (reduce by one level). 
 If QTcF >500 ms occurs during the Induction or Consolidation Phases, and if no 
cause other than quizartinib/placebo can be identified, then during the Continuation 
Phase, the dose of quizartinib/placebo cannot be escalated to 60 mg/day. 
Recurrent QTcF>500 ms 
 Permanently discontinue quizartinib/placebo if QTcF >500 ms recurs despite 
appropriate dose reduction and correction/elimination of other risk factors (eg, serum 
electrolyte abnormalities, concomitant QT prolonging medication) 
QTcF >500 ms or >60 ms change from baseline, and Torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of serious arrhythmia 
 Quizartinib/placebo dosing will be permanently discontinued. 
5.6.1.1. 
Managing QTc Prolongation 
Electrolytes (potassium, calcium, and magnesium) should be checked and supplementation given 
to correct any values outside the institution’s normal range.  If an electrolyte abnormality is 
identified, subjects should be monitored more frequently until levels normalize.  Appropriate 
management should include ECG monitoring, reduction of serum electrolyte losses, replacement 
of electrolyte stores, and evaluation and treatment of associated toxicities. 
Subjects should be monitored for the presence of hypokalemia at least 3 times per week during 
the Induction and Consolidation Phases of the study (see Section 6.2.1, Section 6.2.2.1, 
Section 17.1.1, and Section 17.1.2 for further details).  If hypokalemia occurs, oral or IV 
potassium supplementation should be administered, as clinically indicated, and serial potassium 
level monitoring should be performed until potassium levels normalize.  In addition, the 
underlying cause of hypokalemia should be investigated to prevent further episodes, if possible.  
If Grade 3 hypokalemia occurs (potassium 3 mmol/L), IV potassium replacement, close subject 
follow-up, continuous ECG monitoring, and serial potassium level monitoring every 2 to 4 hours 
until recovery to Grade 1 should be considered. 
Subjects should also be monitored for the presence of concomitant hypomagnesemia and 
hypocalcemia (using the institution’s normal ranges) and, if present, then replacement therapy 
should be initiated.  In addition, the underlying cause of these electrolyte abnormalities should be 
investigated to prevent further episodes, if possible. 
Concomitant medications should be reviewed to identify and, if appropriate, discontinue any 
medication with known QT prolonging effects (Table 17.8). 

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Subjects who experience >480 ms QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved. 
5.6.2. 
Non-Hematologic Toxicity  
The following guidelines should be followed for subjects who develop Grade 3 or 4 
non-hematologic toxicity that is at least possibly related to quizartinib/placebo and persisting 
>48 hours without improvement to ≤ Grade 2 or without waiting 48 hours if in the investigator’s 
judgment the AE poses a serious risk to the subject: 
 Dosing will be interrupted for up to 28 days. 
 If toxicity improves to ≤ Grade 1 within 28 days, treatment may be resumed at the 
previous dose. 
 If toxicity improves to ≤ Grade 2 within 28 days, treatment may be resumed at a 
reduced dose (1 level). 
 If toxicity does not improve/resolve within 28 days, then quizartinib/placebo will 
be discontinued. 
5.6.2.1. 
Hepatic Events and Liver Enzyme Elevation 
Elevation of liver enzymes that meet the criteria below should be investigated and the cause 
identified when possible: 
 ALT >8 × ULN; or  
 AST or ALT >5 × ULN for more than two weeks; or 
 ALT or AST >3 × ULN, but not reaching the limits in the above criteria, in 
combination with clinical symptoms suggestive of hepatitis; or 
  ALT or AST >3 × ULN with TBL >2 × ULN. 
Once the cause of liver enzyme elevation is identified, remove or treat the contributing cause.  If 
the above criteria are met and the elevation is considered to be related or possibly related to 
quizartinib/placebo, then quizartinib/placebo dosing should be interrupted. 
Liver enzyme level testing will be repeated at least weekly, or more frequently, based on degree 
of hepatic laboratory abnormality.  If the liver enzyme levels return to baseline levels, 
quizartinib/placebo may be resumed at the full dose.  If toxicity does not improve/resolve within 
28 days, then quizartinib/placebo will be discontinued. 
Upon resumption of quizartinib/placebo, if liver enzyme elevations recur, treatment may be 
resumed at a reduced dose following return to baseline levels. 
5.6.2.1.1. Liver Safety Monitoring and Evaluations 
Any subject who temporarily interrupts or permanently discontinues quizartinib/placebo due to 
confirmed liver enzyme abnormalities and/or jaundice in the absence of a known cause, must 
have an evaluation to determine the cause of the event.  

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Evaluation may include the following depending on the clinical situation: 
 Medical history and physical exam, including focus on medications and substances 
used: alcohol, acetaminophen, azole antifungals, change in medication dosages, new 
medications added, over the counter medication use and recreational drug use.  Check 
for change in diet or use of dietary supplements; 
 Abdominal ultrasound; 
 Hepatitis A, B, C, and E screening (anti-hepatitis A virus immunoglobulin M, 
hepatitis B surface antigen, anti-hepatitis C virus plus viral titer, and evaluation for 
Hepatitis E), antinuclear antibody and anti-Smith antibody, cytomegalovirus, Epstein 
Barr virus; 
 Additional evaluations as deemed appropriate by the investigator to exclude other 
causes of liver enzyme and bilirubin elevations; 
 All laboratory results, including local laboratory reference ranges are to be recorded. 
5.6.2.2. 
Sweet’s Syndrome (Acute Febrile Neutrophilic Dermatosis) 
Sweet's syndrome can be idiopathic, malignancy associated, or drug induced.37  The incidence of 
drug-induced Sweet’s syndrome (DISS) following FLT3 inhibitor monotherapy is approximately 
10% during the treatment period in the setting of relapsed/refractory AML.38  DISS is unlikely to 
occur in the setting of concurrent cytoreduction with traditional chemotherapy due to suppression 
of terminal differentiation of FLT3-ITD myeloblasts and associated clinical manifestations.  
Diagnostic criteria for DISS include abrupt onset of painful erythematous plaques or nodules, 
pyrexia >38°C, temporal relationship between drug ingestion and clinical presentation, 
temporally related resolution of lesions after drug withdrawal or treatment with systemic 
corticosteroids, and histopathologic evidence of a dense neutrophilic infiltrate without evidence 
of leukocytoclastic vasculitis.  Cardiac, pulmonary, and upper airway neutrophil infiltration can 
present as life-threatening emergencies.37  
The symptoms of neutrophilic dermatosis can generally be managed with systemic corticosteroid 
administration.  Other first-line systemic treatments for Sweet's syndrome include potassium 
iodide and colchicine.37  The interruption or discontinuation of quizartinib is usually not 
required38, 39 and discussion with the Medical Monitor is optional.  However, for advanced 
Grade 3 or 4 toxicities the decision to continue, interrupt or discontinue quizartinib therapy must 
be made by the investigator based on the individual subject’s condition, taking into account the 
risks and benefits of continuing quizartinib/placebo therapy, and in consultation with the Medical 
Monitor. 
5.6.2.3. 
Pyoderma Gangrenosum  
Pyoderma gangrenosum is characterized by multiple cutaneous ulcers with mucopurulent or 
hemorrhagic exudate.40  This sterile neutrophilic dermatosis is known to occur in association 
with malignancy, infection, autoimmune disorders and drugs, eg, tyrosine kinase inhibitors.41  
There is no diagnostic test, since it is a diagnosis of exclusion.  Extracutaneous manifestations of 
this neutrophilic dermatosis are reported somewhat less commonly than with Sweet’s syndrome.  

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As with Sweet’s Syndrome, the symptoms of neutrophilic dermatosis can generally be managed 
with systemic and/or topical corticosteroid administration, and discussion with the Medical 
Monitor is optional.40  More severe cases may require immunosuppressive or 
immunomodulatory agents.  For advanced Grade 3 or 4 toxicities, the decision to continue, 
interrupt or discontinue quizartinib therapy must be made by the investigator based on the 
individual subject’s condition, taking into account the risks and benefits of continuing 
quizartinib/placebo therapy, and in consultation with the Medical Monitor. 
5.6.2.4. 
Differentiation Syndrome 
Quizartinib can cause terminal differentiation of AML blast cells in patients with relapsed or 
refractory disease, which may be associated with the development of differentiation syndrome 
and may be life-threatening or fatal if not treated. 
Symptoms of differentiation syndrome are dyspnea, fever, peripheral edema, hypotension, 
weight gain, pleuro-pericardial effusion, acute renal failure, musculoskeletal pain, and 
hyperbilirubinemia.  Less commonly, differentiation syndrome might present with pulmonary 
hemorrhage or acute febrile neutrophilic dermatosis.  Please refer to the current Quizartinib IB 
for additional details on differentiation syndrome.2 
It is important to promptly recognize the signs and symptoms of differentiation syndrome and 
implement appropriate treatment.  Subjects with suspected differentiation syndrome should 
promptly start treatment with systemic glucocorticoids and hemodynamic monitoring until 
improvement. 
Please refer to Section 5.6.2 for guidance on quizartinib dose interruption and/or reduction. 
5.6.3. 
Myelosuppression (Continuation Phase)  
In the Continuation Phase, the dose of quizartinib/placebo may be reduced at the investigator’s 
discretion if: 
 The subject enters the Continuation Phase with hematologic recovery (CR or CRi 
[ANC ≥1000/mm3 and/or platelet count is ≥100,000/mm3]) and the platelet count 
becomes <100,000/mm3 and/or ANC is 1000/mm3 or;  
 The subject enters the Continuation Phase without hematologic recovery (ANC 
>500/mm3 and <1000/mm3 and/or platelet count >50,000/mm3 and <100,000/mm3 
without transfusion support) and the subject has been on continuation therapy for 
≥8 weeks. 
The dose of quizartinib/placebo may be reduced stepwise from 60 mg/day to 40 mg/day to 
30 mg/day.  For subjects experiencing myelosuppression requiring dose reduction while taking a 
dose of 30 mg/day (20 mg/day in subjects receiving a strong CYP3A4 inhibitor), dosing will be 
interrupted. 

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5.6.4. 
Strong CYP3A4 Inhibitors – Dose Modifications 
For subjects receiving a concomitant strong CYP3A4 inhibitor, the dose of quizartinib/placebo 
will be reduced as follows:  
 Induction and Consolidation Phases: The dose of quizartinib/placebo will be reduced 
from 40 mg/day to 20 mg/day. 
 Continuation Phase: The dose of quizartinib/placebo will be reduced from 30 mg/day 
to 20 mg (eg, Cycle 1, Days 1 to 15), or from 60 mg to 30 mg (Day 16 onward). 
Once the strong CYP3A4 inhibitor is discontinued, the dose of quizartinib/placebo will be 
resumed at the full dose (Table 5.1) when the inhibitor is withdrawn.  No washout is required 
for the strong CYP3A4 inhibitor before increasing the dose of quizartinib/placebo back to 
the full dose.  
No dose reduction is required when subjects are coadministered a moderate or weak CYP3A4 
inhibitor.  See Table 17.9 for a list of strong CYP3A4 inhibitors. 
5.7. 
Method of Assessing Treatment Compliance 
The following measures will be employed to ensure treatment compliance. 
 In the Induction Phase, all subjects in this study will commence therapy as hospital 
inpatients and oral quizartinib/placebo will be administered under nursing 
supervision. 
 Subjects discharged from the hospital with quizartinib/placebo during the 
Consolidation and Continuation Phases shall return as noted in the Schedule of 
Events for each Phase, Table 17.4 and Table 17.6, respectively, and compliance will 
be assessed by the returned tablet count. 
5.8. 
Prior and Concomitant Medications 
5.8.1. 
Prior Medication  
All medications received by subjects within 28 days prior to Randomization will be recorded as 
prior medications. 
5.8.2. 
Concomitant Medication (Drugs and Therapies) 
Concomitant medications and therapies include all prescription, over-the-counter, and herbal 
remedies. 
Information on concomitant medications will be collected from Randomization through 30 days 
after the last dose of quizartinib/placebo (does not apply to the allogeneic HSCT period until the 
subject is able to return to the site, see Section 6.2.2.2).  However, information on subsequent 
anti-leukemic treatments will be collected throughout the Long-Term Follow-up Phase.  Data 
collected will include medication name, indication, dose, start date, and stop date. 
If a subject experiences nausea and/or vomiting after the first dose of quizartinib/placebo, the 
subject should receive antiemetics as clinically indicated prior to and after administration of 

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quizartinib/placebo.  If a subject vomits after quizartinib/placebo dosing, a replacement dose of 
quizartinib/placebo will not be administered. 
Dexamethasone or an equivalent ophthalmic steroid preparation (0.1% ophthalmic solution, 
starting 12 hours before and for 24 - 48 hours after completion of cytarabine), or Isotears may be 
used to prevent conjunctival and corneal pain. 
Menstruating females may receive Depo-Provera or another suppressant of menses during the 
entire course of this protocol.  Suppression of menses should be continued until the platelet count 
is ≥50,000/mm3 without transfusion support. 
5.8.2.1. 
Supportive Care 
During the Induction Phase, growth factors (granulocyte-colony stimulating factor [G-CSF]) 
may be considered for subjects who are septic and who have a life-threatening infection, 
according to the Institutional standard of care. 
Growth factors (G-CSF) may be administered during the Consolidation Phase.  Growth factors 
(G-CSF) and pegylated G-CSF must be stopped 7 and 14 days, respectively, prior to the bone 
marrow aspiration in the absence of an urgent medical need for continuing G-CSF 
administration. 
Antibiotics (eg, quinolone), antifungals, and antivirals may be used as standard of care for the 
prevention or treatment of infections.  See Section 5.6.4 for dose requirements if these 
medications are strong CYP3A4 inhibitors. 
5.8.3. 
Prohibited Concomitant Medications 
Subjects may not receive concomitant chemotherapy, immunotherapy, radiotherapy, transplant, 
or any ancillary therapy for AML that is not specified in the protocol, or that is considered to be 
investigational (ie, used for non-approved indications(s) and in the context of a research 
investigation) while on quizartinib/placebo.  See Section 4.2 (exclusion criterion 3) for permitted 
prior therapy.  Donor lymphocyte infusion (DLI) after allogeneic HSCT is permitted. 
Medications associated with QT/QTc prolongations are prohibited and are detailed in 
Appendix 17.4.  Exceptions are made for antibiotics, antivirals, and antifungals that are used as 
standard of care for the prevention or treatment of infections or if the investigator believes that 
beginning therapy with a potentially QTc-prolonging medication (such as anti-emetic) is vital to 
an individual subject’s care while on study.  In that case, additional ECG monitoring will be 
performed at the commencement of such a medication or from when there is an increase in its 
dosage.  See Section 5.6.1 for guidelines on monitoring and managing QTc prolongation. 
Strong CYP3A4 inhibitors should be avoided if possible but may be given with a corresponding 
dose reduction for quizartinib/placebo.  There are no restrictions for moderate or weak CYP3A4 
inhibitors (See Table 17.9).  
Strong or moderate CYP3A4 inducers must not be used. 
If quizartinib is co-administered with drugs that are substrates of P-gp, increased concentrations 
of the substrate drugs are possible and caution should be exercised. 

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5.8.4. 
Prior and Concomitant Nondrug Treatment and Procedures 
All nondrug treatments and procedures received by subjects within 28 days prior to 
Randomization through 30 days after the last dose of quizartinib/placebo will be recorded (does 
not apply to the allogeneic HSCT period until the subject is able to return to the site, see 
Section 6.2.2.2). 
5.8.5. 
Previous and Concomitant Transfusions 
All transfusions received by subjects within 28 days prior to Randomization through 30 days 
after the last dose of quizartinib/placebo will be recorded (does not apply to the allogeneic HSCT 
period until the subject is able to return to the site, see Section 6.2.2.2). 
5.8.6. 
Previous Radiotherapy 
All radiotherapy received by subjects within 28 days prior to Randomization will be recorded. 
5.8.7. 
Hematopoietic Stem Cell Transplantation Treatment  
The conditioning regimen, donor type, and procedures used during the allogeneic HSCT period 
will be recorded.  
Donor lymphocyte infusion after allogeneic HSCT is permitted. 
5.9. 
Subject Withdrawal/Discontinuation 
5.9.1. 
Reasons for Permanent Discontinuation of Study Drug 
Quizartinib/placebo will be permanently discontinued for any of the following reasons: 
 Adverse Event: 
 Intolerable AE related to quizartinib/placebo, including Grade 4 QTcF 
prolongation;  
 Any clinical AE or abnormal laboratory test result indicating, in the investigator’s 
opinion, that continued quizartinib/placebo dosing is not in the subject’s best 
interest; 
 Death; 
 Refractory disease, as defined in Section 7.2;  
 Relapse, as defined in Section 7.2; 
 Institution of nonprotocol specified AML therapy (prophylactic intrathecal therapy 
and DLI are permitted); 
 Pregnancy (see Section 9.6); 
 Withdrawal by subject (from study drug).  NOTE: A subject’s decision to 
discontinue study drug is not the same as complete withdrawal from the study.  If a 
subject decides to stop study drug, the investigator should discuss with the subject 

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that he or she will remain in the study (ie, continue with study visits and assessments, 
including EFS/OS follow-up); 
 Study Terminated by Sponsor. 
Investigators should contact the Medical Monitor if they want to permanently discontinue 
quizartinib/placebo for reasons other than those listed above.  Permanent discontinuations of 
quizartinib/placebo including the reason should be recorded. 
In case of questions regarding continuation of quizartinib/placebo, the investigator should 
consult with the Medical Monitor. 
5.9.1.1. 
Long-Term Follow-up of Subjects after Permanent Discontinuation of Study 
Drug 
The Long-Term Follow-up Phase begins upon completion of 36 cycles of quizartinib/placebo in 
the Continuation Phase or permanent discontinuation of quizartinib/placebo in any phase.  See 
Section 6.4 for details on long-term follow-up requirements. 
5.9.2. 
Withdrawal from Study  
The total duration of subject participation in the study will be until one of the following occurs: 
 Subject death; 
 Study closure or termination;  
 Subject withdrawal of consent from study participation (see Section 5.9.2.1); or 
 Subject lost to follow-up (see Section 5.9.2.2).  
If a subject is withdrawn from the study, the investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of last 
treatment and the reason for withdrawal. 
All subjects who are withdrawn from the study should complete protocol-specified withdrawal 
procedures. 
5.9.2.1. 
Withdrawal of Consent from Study Participation 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has the 
right to withdraw consent from study participation at any time and for any reason without 
prejudice to his or her future medical care by the investigator or at the Study Center. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation: 
 Attendance at study visits per protocol; 
 Study personnel contacting the subject by telephone (may be quarterly, bi-annually, 
annually, or only at end of study); 
 Study personnel contacting an alternative person (eg, family member, spouse, partner, 
legal representative, physician, or other healthcare provider); 

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 Trial personnel accessing and reviewing the subject’s medical information from 
alternative sources (eg, doctor’s notes, hospital records).  
If the subject refuses all of the above methods of follow-up, the investigator should personally 
speak to the subject to ensure the subject understands all of the potential methods of follow-up.  
If the subject continues to refuse all potential methods of follow up, the investigator will 
document this as a withdrawal of consent in the medical record and in the case report form. 
For subjects who withdraw consent as define above, study personnel will use local, regional, and 
national public records (in accordance with local law) to monitor vital status.  
5.9.2.2. 
Subjects Lost to Follow-up 
The investigator will make every effort not to have any subjects Lost to Follow-up.  If a subject 
is potentially Lost to Follow-up (eg, missed study visits, unable to be contacted by phone), the 
investigator will make every effort to contact the subject before the subject is declared Lost to 
Follow-up (see Study Operations Manual for details).  Once the Study Center has exhausted and 
documented all actions, the investigator should contact the study monitor for additional guidance 
and alternative options. 
Subjects will not be classified as Lost to Follow-up unless all actions have been exhausted and 
documented. 

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6. 
STUDY PROCEDURES 
A tabular summary of the visit schedule for the study is provided in Appendix 17.1. 
During the various phases of the study a bone marrow aspirate will be required.  If the aspirate is 
not sufficient or not feasible to obtain, then a core biopsy specimen may be obtained.  In 
addition, if an unscheduled bone marrow examination is performed during any phase of the 
study, an aspirate specimen must be shipped to both the local and central laboratories for 
assessment and a blood sample should be obtained for hematology. 
The FLT3-ITD MRD assessment is for the purposes of this study and results will therefore not 
be available until after the end of the study. 
Laboratory reports with all local laboratory results from samples collected in all phases for 
hematology, serum chemistry (including potassium monitoring as well as hypomagnesemia and 
hypocalcemia), and coagulation are to be sent to the central laboratory for data entry. 
Throughout the treatment period, urine or serum pregnancy tests are to be done at monthly 
intervals for women of childbearing potential (as defined in Section 4.1.1). 
6.1. 
Screening (Days -7 to 6) 
6.1.1. 
Overview of Screening 
Subjects with newly diagnosed, morphologically documented AML (Section 4.1.1) will be 
screened.  The Screening period is the time from 7 days prior to the start of induction 
chemotherapy up to the day of Randomization.  It is anticipated that subjects will recently have 
had some or all of the screening tests done as part of routine care outside the auspices of this 
study.  Results of these tests done as part of routine care may be used to qualify the subject (see 
timing requirements in Section 6.1.2).  The subject does not need to repeat recently completed 
procedures/tests for study qualification. 
Written informed consent must be obtained before any study-specific procedure is performed, 
including sending a bone marrow aspirate specimen (done as routine care) to the central 
laboratory for assessment of FLT3-ITD activating mutation.  A separate screening ICF may be 
used to obtain consent to send the sample to the central laboratory, if desired.  
Full documentation for the qualifying test results is required, including those done as part of 
routine care outside the auspices of this study. 
6.1.2. 
Screening Procedures 
The following activities and/or assessments will be performed at/during Screening: 
 Review the subject's demographics, medical and AML disease history, including 
cytogenetic risk classification42, and results of tests done as part of routine care and 
compare against the eligibility criteria (see Section 4) for randomization; 
 Have the subject sign the ICF (must be done before any study-specific procedures are 
performed); 
 Obtain subject identification number; 

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 Send a bone marrow aspirate specimen (obtained prior to the start of chemotherapy in 
the first Induction cycle) to the central laboratory for assessment of morphology and 
FLT3-ITD activating mutation. 
 If an aspirate specimen is not available: 
 Obtain a peripheral blood sample (obtained prior to the start of chemotherapy 
in the first Induction cycle) for assessment of FLT3-ITD activating mutation 
and send to the central laboratory. 
 If core biopsy is available, send to the central laboratory for assessment of 
morphology.  If not, send aspirate slides (if available) to the central laboratory 
for assessment of morphology 
 Collect results of the following tests (results of most recent tests done as part of 
routine care within 7 days prior to the start of induction chemotherapy may be used to 
qualify the subject): 
 Physical examination (Section 9.10);  
 Vital signs (blood pressure, pulse rate, respiratory rate, and temperature), height, 
weight, and body surface area (BSA); 
 12-lead ECG (does not need to be performed on the study-supplied ECG 
machine); 
 MUGA or echocardiogram performed within 30 days prior to Randomization 
(subjects must have LVEF >45%); if not done as part of routine care, a MUGA or 
echocardiogram must be done and LVEF must be >45%; 
 Laboratory tests (Table 17.19): 
o Hematology; 
o Chemistry; 
o Coagulation; 
o Urinalysis; 
o HIV (if required by local regulations) 
 For women of childbearing potential (as defined in Section 4.1.1) document the 
results of a negative serum pregnancy test (if not performed as a part of routine 
care within 14 days of Randomization, must be performed with the results 
available prior to Randomization); 
 Copies of de-identified local pathology report from the bone marrow aspirate for 
submission to IRC; 
 Assess and record the subject’s ECOG performance status; 
 Record all serious AEs (SAEs) related to any study procedure experienced by the 
subject since the initial ICF (FLT3-ITD Screening if applicable or Main Study) was 
signed and up to the day of Randomization; 
 Record any treatments (drug and nondrug) given for SAEs related to a study 
procedure.  

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6.2. 
Treatment Period 
6.2.1. 
Induction Phase (up to 2 cycles) 
A specimen from all protocol-specified bone marrow aspirates (or a core biopsy specimen if 
aspirate cannot be obtained) must be sent to both the local and central laboratories for 
assessment.  In addition, if an unscheduled bone marrow examination is performed, an aspirate 
specimen must be sent to both the local and central laboratories for assessment, and results of the 
local hematology will be collected. 
Monitoring for the presence of hypokalemia should be performed at least 3 times per week 
during the Induction Phase and treatment instituted to maintain potassium within normal limits.  
Subjects should also be monitored for the presence of concomitant hypomagnesemia and 
hypocalcemia (per institution’s normal ranges) and corrected if clinically indicated.  See 
Section 5.6.1.1 for further details.  The results are to be submitted to the central laboratory. 
Response will be assessed based on the local laboratory results using the response criteria in 
Table 17.15. 
6.2.1.1. 
Cycle 1 
For the purpose of the study procedures and the schedule of events, Day 1 is defined as the first 
day of the first cycle of administration of induction chemotherapy. 
Refer to the schedule of events for list of assessments and procedures to be performed in Cycle 1 
of Induction (Table 17.1). 
Randomization 
Subjects will be randomized on Day 7.  If necessary, Randomization may be performed later 
(eg, Days 8 to 10) to allow time for addressing electrolyte abnormalities, QTcF prolongation, etc.  
The investigator will contact the IXRS to randomize the subject and to assign 
quizartinib/placebo.  
Subjects must be diagnosed as FLT3-ITD (+) in order to be randomized.  Subjects will be 
randomized based on the FLT3-ITD central laboratory result, unless the FLT3-ITD central 
laboratory result is not available by Day 8, in which case the subjects may be randomized based 
on the FLT3-ITD local laboratory result.  However, in all cases a bone marrow aspirate specimen 
(or blood sample taken before start of chemotherapy treatment if bone marrow aspirate specimen 
not available) must be sent for central determination of FLT3-ITD status. 
In the cases where subjects have been randomized and the FLT3-ITD local and central laboratory 
results are discordant, the subjects will continue with quizartinib/placebo dosing. 
6.2.1.1.1. Cycle 1, Day 7 (Window of Days 7 to 10) 
 Once FLT3-ITD (+) confirmed, explain all study procedures, risks, and benefits to the 
subject; review the Main Study ICF with the subject; this may be done sooner than 
Day 7; answer all of the subject’s questions; have the subject sign and date the most 
current approved version of the ICF.  Subjects must receive a copy of their ICF; 

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 Confirm that the subject continues to meet all of the inclusion criteria and none of the 
exclusion criteria (see Section 4); 
 Perform triplicate 12-lead ECG (must be obtained at least 1 minute apart), after the 
subject has been fully supine for 10 minutes.  Triplicate ECGs must be obtained at 
least 1 minute apart; 
 If QTcF >450 ms (average of triplicate): 
o Contact the central ECG laboratory and request an expedited reading; 
o Electrolytes (potassium, calcium, and magnesium) should be checked and any 
values outside the institution’s normal range should be corrected; 
o Concomitant medications should be reviewed to identify and, if appropriate, 
discontinue any medication with known QT prolonging effects (Table 17.8); 
o Perform repeat 12-lead ECG in triplicate.  The QTcF (average of triplicate) 
must be ≤450 ms for randomization.  Contact the central ECG laboratory and 
request an expedited reading.  However, the pre-randomization triplicate ECG 
does not need to be repeated if the QTcF from the local ECG reading is 
>450 ms but the central laboratory reading is ≤450 ms; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Coagulation; 
 Urinalysis; 
 For women of childbearing potential (as defined in Section 4.1.1) perform a serum 
pregnancy test and document the results within 14 days of Randomization (if 
performed in screening, this does not need to be repeated); subjects must have a 
negative result.  Daiichi Sankyo must be notified of any subject who becomes 
pregnant while receiving or within 6 months of discontinuing the quizartinib/placebo 
(refer to Section 9.6); 
 If the subject provides consent, collect pharmacogenomics and proteomic samples 
(blood and buccal swab) before administering quizartinib/placebo; 
 Record all prior medications, nondrug treatments, transfusions, and radiotherapy the 
subject received within 28 days prior to Randomization, and review and document all 
current concomitant medications and transfusions the subject has received at 
Randomization; 
 Record all AEs the subject experienced from Day 1 until the day of Randomization: 
 Record any treatments (drug and nondrug) given for AEs; 
 Access the IXRS to randomize the subject. 

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6.2.1.1.2. Cycle 1, Day 8 (Start of Quizartinib/Placebo Administration) 
Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing will start 
following the end of the cytarabine infusion, normally on Day 8.  If quizartinib/placebo dosing 
cannot begin as scheduled, the start of dosing may be delayed but best efforts should be made to 
begin dosing within 3 days of Randomization, if possible.  If quizartinib/placebo cannot be 
started within 3 days of Randomization, please contact the Medical Monitor.  If 
quizartinib/placebo is interrupted, missed doses will not be made up. 
The following activities and/or assessments will be performed on the first day of dosing, prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG at: -0.5 to 0 hours predose and 2 to 4 hours postdose 
(Table 17.11).  After subjects have been fully supine for 10 minutes record the first of 
the triplicate ECGs.  Triplicate ECGs must be obtained at least 1 minute apart.   
 The predose QTcF (average of triplicate) must be ≤450 ms to proceed with 
administration of the first dose of quizartinib/placebo.  Contact the central ECG 
laboratory and request an expedited reading. However, there is no need to repeat 
the triplicate ECG at -0.5 to 0 hours predose if the QTcF from the local reading is 
450 ms but the central laboratory reading is ≤450 ms. 
 Collect a blood sample for sparse PK sampling at -0.5 to 0 hours predose and 2 to 
4 hours (postdose), see further details in Table 8.1.  Collect PK sample within 
10 minutes after performing the ECG; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Perform 12-lead ECG (triplicate) at: -0.5 to 0 hours predose, 1, 2, 4, and 6 hours 
postdose, (Table 17.14).  After subjects have been fully supine for 10 minutes 
record the first of the triplicate ECGs.  Triplicate ECGs must be obtained at least 
1 minute apart; 
 Collect blood samples for PK sampling at -0.5 to 0 hours predose, 1, 2, 4, and 
6 hours postdose, see further details in Table 8.4.  Collect PK sample within 
10 minutes after performing the last triplicate ECG;  
 Collect blood samples for the PIA assay -0.5 to 0 hours predose and 2 hours 
postdose (Table 8.5), immediately after each respective PK sample collection; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo; the dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 

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6.2.1.1.3. Cycle 1, Days 9 through 14 
The following activities and/or assessments will be performed on Cycle 1, Days 9 through 14, 
unless otherwise noted: 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Perform 12-lead ECG (triplicate) 24 hours after the ECG reading on Day 8, 
Hour 0 (Table 17.14).  After subjects have been fully supine for 10 minutes, 
record the first of the triplicate ECGs.  Triplicate ECGs must be obtained at least 
1 minute apart; 
 Collect a blood sample for PK sampling determination 24 hours after the PK 
sample is collected on Day 8, Hour 0.  See further details in Table 8.4.  Collect 
PK sample within 10 minutes after performing the last triplicate ECG; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.1.4. Cycle 1, Day 15 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 15: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.11).  After subjects 
have been fully supine for 10 minutes, record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling at 2 to 4 hours postdose, see further 
details in Table 8.1.  Collect PK sample within 10 minutes after performing the ECG; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for PK sampling at 2 to 4 hours postdose, see further 
details in Table 8.4.  Collect PK sample within 10 minutes after performing the 
last triplicate ECG;  
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after the PK sample collection; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 

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 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.1.5. Cycle 1, Days 16 through 20 
The following activities and/or assessments will be performed on Cycle 1, Days 16 through 20: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.1.6. Cycle 1, Day 21 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 21, prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform 12-lead ECG (triplicate) 2 to 4 hours postdose (Table 17.11).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling on Day 21 at: 2 to 4 hours postdose, 
see further details in Table 8.1.  Collect PK sample within 10 minutes after the last 
triplicate ECG; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Perform 12-lead ECG (triplicate) on Day 21 at predose (-0.5 to 0 hours), 1, 2, 4, 
and 6 hours postdose (Table 17.14).  After subjects have been fully supine for 
10 minutes record the first of the triplicate ECGs.  Triplicate ECGs must be 
obtained at least 1 minute apart; 
 Collect blood samples for PK on Day 21 at: predose (-0.5 to 0 hours), 1, 2, 4, and 
6 hours postdose, see further details in Table 8.4.  Collect PK sample immediately 
after performing the last triplicate ECG; 
 Collect a blood sample for the PIA assay 2 hours postdose (Table 8.5), 
immediately after PK sample collection; 
 Review and document all concomitant medications and transfusions the subject has 
received; 

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 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 On Day 21 (window of Day 21 to Day 28):  
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen 
cannot be collected, a core biopsy specimen will be collected and sent to both the 
local and central laboratories;  
o Collect a copy of de-identified local pathology report for submission to IRC; 
 On the day the bone marrow aspirate specimen is collected: 
o Collect and send blood samples to the laboratory for the following tests 
(Table 17.19):  
Hematology: 
▪ If additional hematology tests are performed within 14 days after the bone 
marrow aspirate specimen is collected (and before the end of Induction 
Cycle 1), submit the laboratory reports to Q2 Laboratory);  
Chemistry;  
Coagulation; 
o Conduct a physical examination (Section 9.10); 
o Record vital signs (blood pressure, pulse rate, respiratory rate, and 
temperature); 
 Assess the subject’s response based upon the local laboratory results using the 
Response Criteria (Table 17.15); if an accurate assessment of response cannot be 
made, then a bone marrow aspirate should be repeated upon count recovery or 
Day 56 (3 Days), whichever occurs first. 
6.2.1.1.7. Cycle 1, Day 22 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 22 unless 
otherwise specified: 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Perform 12-lead ECG (triplicate) at: Day 22 at 24 hours (after Hour 0 ECG 
reading on Day 21) (Table 17.14).  After subjects have been fully supine for 
10 minutes record the first of the triplicate ECGs.  Triplicate ECGs must be 
obtained at least 1 minute apart; 
 Collect a blood sample for PK sampling on Day 22 at 24 hours (after Hour 0 PK 
sample collected on Day 21), see further details in Table 8.4.  Collect PK sample 
within 10 minutes after performing the last triplicate ECG; 

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 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.1.1.8. Cycle 1, Day 21 to Day 56 (±3 Days or Count Recovery) 
The following should be performed for subjects for whom there is a plan to perform a repeat 
bone marrow aspirate upon count recovery or at Day 56 ±3 days:  
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
 Collect and send blood samples to the laboratory, at least weekly until counts have 
recovered, for the following tests (Table 17.19): 
 Hematology 
 Chemistry 
6.2.1.1.9. Cycle 1, Day 28 (±3 Days) 
The following activities and/or assessments will be performed on Cycle 1, Day 28: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures on the last day of the Induction Phase; 
 Assess and record the subject’s ECOG performance status; 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.1.1.10. Cycle 1, Day of Repeat Bone Marrow Aspirate (if required; upon count recovery 
or up to Day 56  3 Days) 
The following activities and/or assessments will be performed if a repeat bone marrow is 
required to determine response, upon count recovery or up to Cycle 1, Day 56: 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Record all healthcare resource utilization since the last visit (see Section 10.2) 

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 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology: 
 If additional hematology tests are performed within 14 days before or after the 
bone marrow aspirate specimen is collected (and before the end of Induction 
Cycle 1), submit the laboratory reports to Q2 Laboratory; 
 Coagulation; 
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject based upon the local laboratory results using the Response Criteria 
(Table 17.15); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.1.2. 
Cycle 2 
Subjects with ≥5% blasts, per the final bone marrow in Cycle 1 (local laboratory results), may 
receive a second cycle of induction chemotherapy, if considered appropriate in the judgment of 
the investigator (reason for not administering a second cycle should be documented).  
Assessments and procedures for Cycle 2 Day 1 do not need to be repeated if they were done for 
Cycle 1 within the prior 7 days.  Refer to the schedule of events for the list of assessments and 
procedures to be performed in Cycle 2 of Induction (Table 17.2 and Table 17.3). 
It is recommended to wait at least 7 days after the last dose of quizartinib/placebo in Cycle 1 of 
Induction before starting Cycle 2 of Induction, since quizartinib has a long elimination half-life 
and there are no data on the safety of administering anthracycline within 7 days following 
quizartinib administration. 
6.2.1.2.1. Cycle 2, “7+3” Chemotherapy Regimen 
This section describes the procedures to be followed if the subject receives a “7+3” regimen in 
Cycle 2.  See Section 6.2.1.2.2 for the procedures to be followed if the subject receives a “5+2” 
regimen in Cycle 2. 

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6.2.1.2.1.1. Cycle 2, Day 1 (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2 Day 1 prior to 
cytarabine and anthracycline administration, unless otherwise noted (activities and/or 
assessments performed within 7 days prior to Day 1 do not need to be repeated): 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Weight and BSA (calculated from the height recorded at Screening); 
 Assess and record the subject’s ECOG performance status; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Coagulation; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving quizartinib/placebo 
(refer to Section 9.6); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs since Screening; 
 Administer anthracycline as an IV infusion (refer to Section 5.4.1 for anthracycline 
drug administration); 
 Administer cytarabine as a continuous IV infusion (refer to Section 5.4.1 for 
cytarabine drug administration). 
6.2.1.2.1.2. Cycle 2, Days 2 and 3 (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2 Days 2 and 3: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer anthracycline as an IV infusion (refer to Section 5.4.1 for anthracycline 
drug administration); 

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 Administer cytarabine as a continuous IV infusion (refer to Section 5.4.1 for 
cytarabine drug administration). 
6.2.1.2.1.3. Cycle 2, Days 4 to 7 (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Days 4 to 7: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer cytarabine as a continuous IV infusion (refer to Section 5.4.1 for 
cytarabine drug administration). 
6.2.1.2.1.4. Cycle 2, Day 8 (“7+3” Chemotherapy Regimen) 
Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing will begin after 
the end of the cytarabine infusion, normally on Day 8.  If quizartinib/placebo dosing cannot 
begin as scheduled, the start of dosing may be delayed but best efforts should be made to begin 
dosing as soon as possible.  If quizartinib/placebo is interrupted, missed doses will not be made 
up. 
The following activities and/or assessments will be performed on the day of the start of 
quizartinib/placebo administration (usually Cycle 2, Day 8) prior to quizartinib/placebo 
administration, unless otherwise noted: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG on Day 8 at predose (-0.5 to 0 hours) and 2 to 4 hours 
postdose (Table 17.11).  After subjects have been fully supine for 10 minutes, record 
the first of the triplicate ECGs.  Triplicate ECGs must be obtained at least 1 minute 
apart; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Coagulation; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 

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 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.1.5. Cycle 2, Days 9 through 14 (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Days 9 through 14: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.1.6. Cycle 2, Day 15 (±1 Day) (“7+3” Chemotherapy Regimen)  
The following activities and/or assessments will be performed on Cycle 2, Day 15: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.11).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.1.7. Cycle 2, Days 16 through 20 (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Days 16 through 20: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 

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 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.1.8. Cycle 2, Day 21 (±1 Day) (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Day 21, prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Perform 12-lead ECG (triplicate) 2 to 4 hours postdose (Table 17.11).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 On Day 21 (window of Day 21 to Day 28):  
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen 
cannot be collected, a core biopsy specimen will be collected and sent to both the 
local and central laboratories;  
 Collect a copy of de-identified local pathology report for submission to IRC; 
 On the day the bone marrow aspirate specimen is collected: 
o Collect and send blood samples to the laboratory for the following tests 
(Table 17.19):  
Hematology: 
▪ If additional hematology tests are performed within 14 days after the bone 
marrow aspirate specimen is collected (and before the end of Induction 
Cycle 2), submit the laboratory reports to Q2 Laboratory;  
Chemistry; 
Coagulation; 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and 
temperature); 
 Assess the subject’s response based upon the local laboratory results using the 
Response Criteria (Table 17.15); if an accurate assessment of response cannot be 
made, then a bone marrow aspirate should be repeated upon count recovery or 
Day 56 (3 Days), whichever occurs first. 

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6.2.1.2.1.9. Cycle 2, Day 21 to Day 56 ±3 Days or Count Recovery 
The following should be performed for subjects for whom there is a plan to perform a repeat 
bone marrow aspirate upon count recovery or at Day 56 ±3 days:  
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
 Collect and send blood samples to the laboratory, at least weekly until counts have 
recovered, for the following tests (Table 17.19): 
 Hematology 
 Chemistry 
6.2.1.2.1.10. Cycle 2, Day 28 (±3 Days) (“7+3” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Day 28: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures on the last day of the Induction Phase; 
 Assess and record the subject’s ECOG performance status; 
 Record all healthcare resource utilization since the last visit (see Section 10.2) 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.1.2.1.11. Cycle 2, “7 + 3” Chemotherapy Regimen, Day of Repeat Bone Marrow 
Aspirate (if required; upon count recovery or up to Day 56 ±3 days) 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology: 
 If additional hematology tests are performed within 14 days before or after the 
bone marrow aspirate specimen is collected (and before the end of Induction 
Cycle 2), submit the laboratory reports to Q2 Laboratory; 
 Coagulation; 

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 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject based upon the local laboratory results using the Response Criteria 
(Table 17.15); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.1.2.2. Cycle 2, “5+2” Chemotherapy Regimen 
6.2.1.2.2.1. Cycle 2, Day 1 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Day 1 prior to 
cytarabine and anthracycline administration, unless otherwise noted (activities and/or 
assessments performed within 7 days prior to Day 1 do not need to be repeated): 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Weight and BSA (calculated from the height recorded at Screening); 
 Assess and record the subject’s ECOG performance status; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Coagulation; 
 Urinalysis (only as needed; eg, if renal function has decreased);  
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving quizartinib/placebo 
(refer to Section 9.6); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs since Screening; 

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 Administer anthracycline as an IV infusion (refer to Section 5.4.1 for anthracycline 
drug administration); 
 Administer cytarabine as a continuous IV infusion (refer to Section 5.4.1 for 
cytarabine drug administration). 
6.2.1.2.2.2. Cycle 2, Day 2 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2 Day 2: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer anthracycline as an IV infusion (refer to Section 5.4.1 for anthracycline 
drug administration); 
 Administer cytarabine as a continuous IV infusion (refer to Section 5.4.1 for 
cytarabine drug administration). 
6.2.1.2.2.3. Cycle 2, Days 3 to 5 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Days 3 to 5: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer cytarabine as a continuous IV infusion (refer to Section 5.4.1 for 
cytarabine drug administration). 
6.2.1.2.2.4. Cycle 2, Day 6 (“5+2” Chemotherapy Regimen) 
Quizartinib/placebo will be administered orally once daily for 14 days.  Dosing will start 
following the end of the cytarabine infusion, normally on Day 6.  If quizartinib/placebo 
administration cannot begin as scheduled, the start of dosing may be delayed but best efforts 
should be made to begin dosing as soon as possible.  If quizartinib/placebo is interrupted, missed 
doses will not be made up. 
The following activities and/or assessments will be performed on the Day of the start of 
quizartinib/placebo administration (usually Cycle 2, Day 6), prior to quizartinib/placebo 
administration, unless otherwise noted: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG at: predose (-0.5 to 0 hours) and 2 to 4 hours postdose 
(Table 17.11).  After subjects have been fully supine for 10 minutes record the first of 
the triplicate ECGs.  Triplicate ECGs must be obtained at least 1 minute apart; 

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 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Coagulation; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.2.5. Cycle 2, Days 7 through 12 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Days 7 through 12: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.2.6. Cycle 2, Day 13 (±1 Day) (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Day 13: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.11).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 

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 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.2.7. Cycle 2, Days 14 through 18 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Days 14 through 18: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.2.8. Cycle 2, Day 19 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Day 19, prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform 12-lead ECG (triplicate) 2 to 4 hours postdose (Table 17.11).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.1.2.2.9. Cycle 2, Day 21 (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 2, Day 21 (window of 
Day 21 to Day 28): 
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories;  
 Collect a copy of de-identified local pathology report for submission to IRC; 
 On the day the bone marrow aspirate specimen is collected: 

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 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19):  
Hematology: 
o If additional hematology tests are performed within 14 days after the bone 
marrow aspirate specimen is collected (and before the end of Induction 
Cycle 2), submit the laboratory reports to Q2 Laboratory;  
Chemistry; 
Coagulation; 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Assess the subject’s response based upon the local laboratory results using the 
Response Criteria (Table 17.15); if an accurate assessment of response cannot be 
made, then a bone marrow aspirate should be repeated upon count recovery or Day 56 
(±3 days), whichever occurs first. 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation:  
 Record any treatments (drug and nondrug) given for AEs; 
6.2.1.2.2.10. Cycle 2, Day 21 to Day 56 ±3 Days or Count Recovery 
The following should be performed for subjects for whom there is a plan to perform a repeat 
bone marrow aspirate upon count recovery or at Day 56 ±3 days: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
 Collect and send blood samples to the laboratory, at least weekly until counts have 
recovered, for the following tests (Table 17.19): 
 Hematology 
 Chemistry 
6.2.1.2.2.11. Cycle 2, Day 28 (±3 Days) (“5+2” Chemotherapy Regimen) 
The following activities and/or assessments will be performed on Cycle 1, Day 28: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures on the last day of the Induction Phase; 
 Assess and record the subject’s ECOG performance status; 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 

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 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.1.2.2.12. Cycle 2, “5 + 2” Chemotherapy Regimen, Day of Repeat Bone Marrow 
Aspirate (if required; upon count recovery or up to Day 56 ±3 days) 
 Conduct a physical examination (Section 9.10); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology: 
 If additional hematology tests are performed within 14 days before or after the 
bone marrow aspirate specimen is collected (and before the end of Induction 
Cycle 2), submit the laboratory reports to Q2 Laboratory; 
 Coagulation; 
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject’s response based upon the local laboratory results using the 
Response Criteria (Table 17.15); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.2. 
Consolidation Phase 
6.2.2.1. 
Consolidation Chemotherapy (4 Cycles, if Tolerated) 
At the investigator’s discretion, to allow for blood counts to recover, the Consolidation cycle 
may start up to 60 days after Day 1 of the previous cycle. 
Refer to the schedule of events for the list of assessments and procedures to be performed during 
the Consolidation Phase (Table 17.4). 

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A specimen from all protocol-specified bone marrow aspirates (or a core biopsy specimen if 
aspirate cannot be obtained) must be sent to the central laboratory for assessment.  In addition, if 
an unscheduled bone marrow examination is performed, an aspirate specimen must be sent to 
both the local and central laboratories for assessment and a blood sample should be obtained for 
hematology.  A bone marrow aspirate is collected in Cycle 1 and in the final cycle (eg, in 
Cycle 3 if the subject receives 3 cycles of consolidation therapy).   
During the Consolidation Phase, monitoring for the presence of hypokalemia should be 
performed at least 3 times per week on the days of cytarabine administration.  Potassium levels 
will also be checked when routine chemistry samples tests are being performed.  If hypokalemia 
is identified, potassium should be monitored at least 3 times a week until the levels normalize.  
Subjects should also be monitored for the presence of concomitant hypomagnesemia and 
hypocalcemia (per institution’s normal ranges) and corrected if clinically indicated.  See 
Section 5.6.1.1 for further details.  The results are to be submitted to the central laboratory. 
6.2.2.1.1. Cycle 1, Day 1 
The following activities and/or assessments will be performed on Cycle 1, Day 1 prior to 
cytarabine administration, unless otherwise noted (activities and/or assessments performed 
≤7 days prior to Day 1 do not need to be repeated): 
 Confirm that the subject meets all of the inclusion criteria for the Consolidation Phase 
(see Section 4.1.2); 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Weight and BSA (calculated from the height recorded at Screening); 
 Assess and record the subject’s ECOG performance status; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test and document the results; subjects must have a negative result.  
Daiichi Sankyo must be notified of any subject who becomes pregnant while 
receiving quizartinib/placebo (refer to Section 9.6);  
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 

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 Administer cytarabine 3.0 g/m2 (for subjects <60 years old) or 1.5 g/m2 (for subjects 
≥60 years old) IV every 12 hours. 
6.2.2.1.2. Cycle 1, Day 3 and Day 5 
The following activities and/or assessments will be performed on Cycle 1, Day 3 and Day 5: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
 Administer cytarabine 3.0 g/m2 (for subjects <60 years old) or 1.5 g/m2 (for subjects 
≥60 years old) IV every 12 hours. 
6.2.2.1.3. Cycle 1, Day 6 (+2 days) (Start of Quizartinib/Placebo) 
Quizartinib/placebo will be administered orally once daily for 14 days, starting on Day 6.  If 
quizartinib/placebo administration cannot begin as scheduled, the start of dosing may be delayed, 
but best efforts should be made to begin as soon as possible.  If quizartinib/placebo is 
interrupted, missed doses will not be made up. 
The following activities and/or assessments will be performed on Cycle 1, Day 6, prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG predose (-0.5 to 0 hours) and 2 to 4 hours postdose 
(Table 17.12).  After subjects have been fully supine for 10 minutes record the first of 
the triplicate ECGs.  Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.2;  
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 Review and document all concomitant medications and transfusions the subject has 
received; 

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 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 If the subject is being discharged from the hospital, then dispense quizartinib/placebo.  
Additionally, counsel the subject on the quizartinib/placebo dosing regimen for 
Days 7 to 12, including the total number of tablets to be taken daily, and confirm the 
subject's understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day.  Remind 
subjects that the dose of quizartinib/placebo will be administered at the study site on 
Day 13. 
6.2.2.1.4. Cycle 1, Day 13 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 13: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.12).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect blood samples for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.2. 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
 Collect and send blood samples to the laboratory tests (Table 17.19): 
 Hematology; 
 Chemistry; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 If outpatient, then counsel the subject on the quizartinib/placebo dosing regimen from 
Days 14 through 18, including the total number of tablets to be taken daily, and 
confirm the subject's understanding.  Counsel subjects that quizartinib/placebo may 
be taken with or without food and should be taken at about the same time every day.  
Remind subjects that the dose of quizartinib/placebo will be administered at the study 
site on Day 19. 

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6.2.2.1.5. Cycle 1, Day 19 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 19: 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.12).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.2.  
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance, if they were dispensed quizartinib/placebo bottles upon discharge. 
6.2.2.1.6. Cycle 1, Day 21 to Day 56 ±3 Days or Count Recovery 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
Starting on Day 21, the following assessments should be performed at least weekly until counts 
have recovered: 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology 
 Chemistry 

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The following activities and/or assessments will be performed upon count recovery, or Day 56 
(±3 Days), whichever occurs first:  
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology.  If an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 On the day the bone marrow aspirate specimen is collected: 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
▪ Hematology; 
▪ Chemistry; 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Assess the subject for relapse based on the local laboratory results (see criteria in 
Section 7.2); 
6.2.2.1.7. Cycle 1, Day 28 (±7 Days) 
The following activities and/or assessments will be performed on Cycle 1, Day 28: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
If Cycle 1 is the last Consolidation cycle, see Section 6.2.2.1.14 for details on additional 
assessments. 
6.2.2.1.8. Cycle 2, Cycle 3, and Cycle 4; Day 1 
The following activities and/or assessments will be performed on Day 1 prior to cytarabine 
administration, unless otherwise noted (activities and/or assessments performed ≤7 days prior to 
Day 1 do not need to be repeated): 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Weight and BSA (calculated from the height recorded at Screening); 

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 Assess and record the subject’s ECOG performance status; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test and document the results; subjects must have a negative result.  
Daiichi Sankyo must be notified of any subject who becomes pregnant while 
receiving quizartinib/placebo (refer to Section 9.6);  
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer cytarabine 3.0 g/m2 (for subjects <60 years old) or 1.5 g/m2 (for subjects 
≥60 years old) IV every 12 hours. 
6.2.2.1.9. Cycle 2, Cycle 3, and Cycle 4; Day 3 and Day 5 
The following activities and/or assessments will be performed on Day 3 and Day 5: 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
 Administer cytarabine 3.0 g/m2 (for subjects <60 years old) or 1.5 g/m2 (for subjects 
≥60 years old) IV every 12 hours. 
6.2.2.1.10. Cycle 2, Cycle 3, and Cycle 4, Day 6 (+2 Days) (Start of Quizartinib/Placebo) 
Quizartinib/placebo will be administered orally once daily for 14 days, starting on Day 6.  If 
quizartinib/placebo administration cannot begin as scheduled, the start of dosing may be delayed, 
but best efforts should be made to begin as soon as possible.  If quizartinib/placebo is 
interrupted, missed doses will not be made up. 
The following activities and/or assessments will be performed on Day 6 prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 

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 Perform triplicate 12-lead ECG predose (-0.5 to 0 hours) and 2 to 4 hours postdose 
(Table 17.12).  After subjects have been fully supine for 10 minutes, record the first 
of the triplicate ECGs.  Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day; 
 If the subject is being discharged from the hospital, then dispense quizartinib/placebo.  
Additionally, counsel the subject on the quizartinib/placebo dosing regimen for 
Days 7 to 12, including the total number of tablets to be taken daily, and confirm the 
subject's understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day.  Remind 
subjects that the dose of quizartinib/placebo will be administered at the study site on 
Day 13. 
6.2.2.1.11. Cycle 2, Cycle 3, and Cycle 4; Day 13 (±1 Day) 
The following activities and/or assessments will be performed on Day 13: 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.12).  After subjects 
have been fully supine for 10 minutes, record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect and send blood samples to the laboratory tests (Table 17.19): 
 Hematology; 
 Chemistry; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day; 

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 If outpatient, then counsel the subject on the quizartinib/placebo dosing regimen from 
Days 14 through 18, including the total number of tablets to be taken daily, and 
confirm the subject's understanding.  Counsel subjects that quizartinib/placebo may 
be taken with or without food and should be taken at about the same time every day.  
Remind subjects that the dose of quizartinib/placebo will be administered at the study 
site on Day 19. 
6.2.2.1.12. Cycle 2, Cycle 3, and Cycle 4; Day 19 (±1 Day) 
The following activities and/or assessments will be performed on Day 19: 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.12).  After subjects 
have been fully supine for 10 minutes, record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day; 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance if they were dispensed quizartinib/placebo bottles upon discharge. 
6.2.2.1.13. Cycle 2, Cycle 3, and Cycle 4; Day 28 (±7 Days) 
The following activities and/or assessments will be performed on Day 28: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures (if this is the last day of the Consolidation Phase); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs. 
6.2.2.1.14. Last Consolidation Cycle, Day 21 to Day 56 ±3 Days or Count Recovery 
The following procedures will be done from Day 21 to Day 56 ±3 days or count recovery during 
the last Consolidation cycle before allogeneic HSCT or the start of the Continuation Phase:  

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 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Starting on Day 21, collect weekly until counts have recovered, and send blood 
samples to the laboratory for the following tests (Table 17.19): 
 Hematology; 
 Chemistry; 
The following activities and/or assessments will be performed upon count recovery, or on 
Day 56 (±3 days), whichever occurs first: 
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology.  If an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
On the day the bone marrow aspirate specimen is collected: 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Conduct a physical examination (Section 9.10);  
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Assess the subject for relapse based on the local laboratory results (see criteria in 
Section 7.2). 
6.2.2.2. 
Allogeneic Hematopoietic Stem Cell Transplantation (up to 180 Days After 
Transplant Date) 
Subjects are permitted to undergo allogeneic HSCT after CR or CRi is achieved.  Allogeneic 
HSCT for consolidation may be performed after the Induction Phase, anytime during the 
Consolidation Phase or, if certain criteria are met (see below), within the first 3 months of the 
Continuation Phase.  Refer to the schedule of events for the list of assessments and procedures to 
be performed after allogeneic HSCT (Table 17.5). 
Quizartinib/placebo should be discontinued at least 7 days before the start of a conditioning 
regimen. 
Following the allogeneic HSCT, the investigator will collect the following information from the 
transplant unit: 
 Karnofsky performance status prior to the start of the conditioning regimen; 

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 All conditioning regimens the subject has received; 
 The date and type of transplant the subject has received; 
 The type of donor. 
Additionally, from the time of allogeneic HSCT up through the end of the allogeneic HSCT 
period (up to 180 days after the date of transplant), the investigator will collect the following 
information from the transplant unit every 4 weeks: 
 Determine if the subject has experienced a relapse, based on the available bone 
marrow aspirate and/or biopsy pathology report.  Collect a copy of de-identified local 
pathology report from the bone marrow aspirate for submission to IRC; 
 Review and document the development of acute and chronic GVHD; 
 Record all engraftment failures;  
 Record all transplant related mortality and death for any reason. 
In addition to the above every 4-week follow-up for GVHD following the allogeneic HSCT, 
additional information regarding GVHD (Table 17.16, Table 17.17 and Table 17.18), will be 
collected at the following post-HSCT timepoints: Day 100, 6 months (± 3 months), 12 months 
(± 3 months), 18 months (± 3 months), and 24 months (- 3/+ 6 months).43,44  
Once the subject is able, the subject will return to the clinic for site visits every 4 weeks (see 
Section 6.2.2.2.1). 
A subject is permitted to undergo allogeneic HSCT for consolidation after the start of the 
Continuation Phase if the following criteria are met: 
 When the subject starts the Consolidation Phase, the plan is for the subject to undergo 
HSCT as part of consolidation therapy;  
 A donor is not able to be found during the Consolidation Phase but becomes available 
after the start of the Continuation Phase; 
 The investigator discusses the case with the Medical Monitor; 
 Confirmed <5% of blasts based on the most recent bone marrow aspirate, based on 
the local laboratory results; 
 The transplant is performed within 3 months after Day 1 of continuation therapy. 
For subjects who have an allogeneic HSCT for consolidation within the first 3 months of 
continuation therapy, subjects restart therapy at the cycle they should have been in, had they not 
stopped; eg, if the subject stopped at end of Cycle 2, and were ready to resume therapy 12 weeks 
later (with 28 days per cycle), then the restart cycle would be Cycle 3. 
Any HSCT performed for other reasons, eg, molecular relapse, will be considered 
nonprotocol-specified AML therapy, and the subject will be discontinued from 
quizartinib/placebo but will continue to be followed for outcome data. 
Subjects are not permitted to undergo autologous HSCT at any time during the study.  Subjects 
who undergo autologous HSCT will be discontinued from quizartinib/placebo but will continue 

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to be followed for outcome data.  In addition, the date and type of the transplant, and transplant 
related mortality and death for any reason will be recorded. 
6.2.2.2.1. Post-Allogeneic HSCT Visits (up to 180 Days After Transplant Date) 
This Section describes visits for subjects who have undergone allogeneic HSCT and who are 
able to return to the site for visits, but do not yet meet the eligibility criteria for the Continuation 
Phase (See Section 4.1.3).  Visits will be conducted every 4 weeks. 
The following activities will take place during these visits: 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology (verify peripheral smear is not abnormal and cytopenias do not 
develop); 
 If peripheral smear is abnormal or cytopenias develop, per hematology results, then 
collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen cannot 
be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Evaluate if the subject is eligible for the Continuation Phase; 
 Assess the subject for relapse based on the local laboratory results (see Section 7.2); 
 Review and document all concomitant medications and transfusions the subject has 
received since the subject resumed study visits; 
The following will take place every 12 weeks: 
 Collect a bone marrow aspirate for laboratory analysis and send to both the local and 
central laboratories for assessment of morphology; if an adequate aspirate specimen 
cannot be collected, a core biopsy specimen will be collected and sent to both the 
local and central laboratories 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse (see Section 7.2). 
6.2.3. 
Continuation Phase (up to 36 cycles) 
Following consolidation therapy, subjects will enter the Continuation Phase if they meet the 
inclusion criteria (see Section 4.1.3 Inclusion Criteria – Continuation Phase).  In addition, per 
investigator discretion, subjects who have achieved CR or CRi following Induction but are 
unable to receive consolidation therapy will be permitted to enter the Continuation Phase if they 
meet the inclusion criteria (see Section 4.1.3). 
Subjects will receive quizartinib/placebo for up to 36 cycles (28 days per cycle), with no breaks 
in dosing between cycles.  If quizartinib/placebo is interrupted, missed doses will not be made 
up. 

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Visits will be conducted at the following times: 
 Cycle 1: Days 1, 8, and 15; 
 Cycle 2: Days 1 and 15; 
 Cycles 3 through 36: Day 1. 
Refer to the schedule of events for the list of assessments and procedures to be performed during 
the Continuation Phase (Table 17.6).  
During the Continuation Phase, EORTC QLQ-C30 and EQ-5D-5L assessments will be 
administered every 3 cycles up through Cycle 36 at the following visits: 
 Cycle 1, Day 1 
 Cycle 4, Day 1;  
 Cycle 7, Day 1;  
 Cycle 10, Day 1;  
 Cycle 13, Day 1; 
 Cycle 16, Day 1; 
 Cycle 19, Day 1; 
 Cycle 22, Day 1; 
 Cycle 25, Day 1;  
 Cycle 28, Day 1; 
 Cycle 31, Day 1; 
 Cycle 34, Day 1; 
 Cycle 36, Day 28 (End of Treatment [EOT]). 
During the Continuation Phase, a bone marrow aspirate specimen (or a core biopsy specimen if 
aspirate cannot be obtained) will be collected at the following visits: 
 Cycle 1, Day 1 
 Cycle 4, Day 1 (12 weeks);  
 Cycle 7, Day 1 (24 weeks);  
 Cycle 10, Day 1 (36 weeks);  
 Cycle 13, Day 1 (48 weeks); 
 Cycle 19, Day 1 (72 weeks); 
 Cycle 25, Day 1 (96 weeks). 
An aspirate specimen (or core biopsy specimen if adequate aspirate specimen not available) from 
all protocol-specified bone marrow procedures will be sent to both the local and central 
laboratories for assessment of morphology.  In addition, if an unscheduled bone marrow 

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examination is performed, an aspirate specimen will be sent to both the local and central 
laboratories for assessment and a blood sample should be obtained for local hematology. 
At any time during the Continuation Phase, if relapse is suspected based on abnormal peripheral 
smears or development of cytopenias, collect a bone marrow aspirate specimen for laboratory 
analysis and document results; if an adequate aspirate specimen cannot be collected, a core 
biopsy specimen will be collected.  If a bone marrow aspirate specimen cannot be collected, then 
peripheral blood phenotyping should be performed to confirm that blasts are leukemic.  
Follow-up hematology should be performed after phenotyping.  
6.2.3.1. 
Continuation Therapy 
6.2.3.1.1. Cycle 1, Day 1 
The following activities and/or assessments will be performed on Cycle 1, Day 1, prior to 
quizartinib/placebo administration, unless otherwise noted: 
 Confirm that the subject meets all of the inclusion criteria for the Continuation Phase 
(see Section 4.1.3); 
 For subjects who underwent allogeneic HSCT, collect updated medical history , 
including clinically relevant medical conditions that had onset and resolved during 
HSCT period as well as any medical condition with onset during the HSCT period 
and still ongoing on Day 1 of Continuation (see Section 9.1 for recording AEs during 
HSCT); 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Conduct a physical examination (Section 9.10), including an evaluation for signs and 
symptoms of relapse; 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Weight; 
 Assess and record the subject’s ECOG performance status; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test before study drug administration and document the results; 
subjects must have a negative result.  Daiichi Sankyo must be notified of any subject 
who becomes pregnant while receiving quizartinib/placebo (refer to Section 9.6); 
 Collect a bone marrow aspirate specimen and send to both the local and central 
laboratories for assessment of morphology; if an adequate aspirate specimen cannot 

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be collected, a core biopsy specimen will be collected and sent to both the local and 
central laboratories.  If the last aspirate/biopsy during the Consolidation Phase was 
done ≤7 days prior to Day 1 then collection of the aspirate specimen or core biopsy 
specimen does not need to be repeated; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Dispense a sufficient quantity of quizartinib/placebo to supply the subject until the 
next scheduled visit.  Counsel the subject on the dosing regimen, from Days 1 
through 28, including the total number of tablets to be taken daily, and confirm the 
subject’s understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day; 
 Administer the first dose of quizartinib/placebo. 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.13).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.3; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
6.2.3.1.2. Cycle 1, Day 8 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 8: 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Assess the subject for relapse (see Section 7.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Counsel the subject on the quizartinib/placebo dosing regimen from Days 9 through 
14, including the total number of tablets to be taken daily, and confirm the subject's 

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understanding.  Counsel subjects that quizartinib/placebo may be taken with or 
without food and should be taken at about the same time every day.  Remind subjects 
that the dose of quizartinib/placebo will be administered at the study site on Day 15; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.13).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.3; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
6.2.3.1.3. Cycle 1, Day 15 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 1, Day 15: 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology (can be done monthly after blood counts recovery); 
 Chemistry; 
 Assess the subject for relapse (see Section 7.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance; 
 If the average QTcF of the triplicate ECGs is ≤450 ms on Cycle 1, Day 15, increase 
the dose of quizartinib/placebo for the rest of the Continuation Phase starting on Day 
16, as described in Section 5.4.3;  
 Dispense a sufficient quantity of quizartinib/placebo to supply the subject until the 
next scheduled visit and counsel the subject on the dosing regimen, from Days 16 
through 28, including the total number of tablets to be taken daily, and confirm the 
subject’s understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day.  Remind 

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subjects that the dose of quizartinib/placebo will be administered at the study site on 
Cycle 2, Day 1; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.13).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.3; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
6.2.3.1.4. Cycle 2, Day 1 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 2, Day 1: 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving quizartinib/placebo 
(refer to Section 9.6); 
 Assess the subject for relapse (see Section 7.2); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance; 
 If the dose of quizartinib/placebo was not increased on Cycle 1, Day 16, increase the 
dose of quizartinib/placebo for the rest of the Continuation Phase starting on Cycle 2, 
Day 2 if the average QTcF of the triplicate ECG is ≤450 ms on Cycle 2, Day 1. 

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 Dispense a sufficient quantity of quizartinib/placebo to supply the subject until the 
next scheduled visit and counsel the subject on the dosing regimen, from Days 2 
through 14, including the total number of tablets to be taken daily, and confirm the 
subject’s understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day.  Remind 
subjects that the dose of quizartinib/placebo will be administered at the study site on 
Day 15; 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.13).  After subjects 
have been fully supine for 10 minutes, record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.3; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
6.2.3.1.5. Cycle 2, Day 15 (±1 Day) 
The following activities and/or assessments will be performed on Cycle 2, Day 15: 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology (can be done monthly after blood counts recovery); 
 Chemistry; 
 Assess the subject for relapse (see Section 7.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Counsel the subject on the quizartinib/placebo dosing regimen, from Days 16 through 
28, including the total number of tablets to be taken daily, and confirm the subject's 
understanding.  Counsel subjects that quizartinib/placebo may be taken with or 
without food and should be taken at about the same time every day. 
 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 

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 Perform triplicate 12-lead ECG 2 to 4 hours postdose (Table 17.13).  After subjects 
have been fully supine for 10 minutes record the first of the triplicate ECGs.  
Triplicate ECGs must be obtained at least 1 minute apart; 
 Collect a blood sample for sparse PK sampling within 10 minutes after the last 
triplicate ECG, see further details in Table 8.3; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay 2 to 4 hours postdose (Table 8.5), 
immediately after PK sample collection; 
6.2.3.1.6. Cycle 3, Day 1 (±3 Days) 
The following activities and/or assessments will be performed on Cycle 3, Day 1: 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Perform triplicate 12-lead ECG, fully supine for 10 minutes before the ECG 
(Table 17.13); 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving quizartinib/placebo 
(refer to Section 9.6); 
 Assess the subject for relapse (see Section 7.2); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance  
 Dispense a sufficient quantity of quizartinib/placebo to supply the subject until the 
next scheduled visit and counsel the subject on the dosing regimen, from Days 1 
through 28, including the total number of tablets to be taken daily, and confirm the 
subject’s understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day. 

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 Administer quizartinib/placebo.  The dose may be given with or without food.  It is 
recommended that the dose be given at the same time every day. 
6.2.3.1.7. Cycle 4, Day 1 and Day 1 of Cycle 7, Cycle 10, Cycle 13, Cycle 19, and Cycle 25 
(±3 Days) 
The following activities and/or assessments will be performed: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Perform triplicate 12-lead ECG, fully supine for 10 minutes before the ECG; 
 If subject is included in the PK-ECG-Biomarker Substudy (n = up to 100 subjects): 
 Collect blood samples for the PIA assay anytime postdose (Table 8.5); 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving quizartinib/placebo 
(refer to Section 9.6); 
 Collect a bone marrow aspirate specimen (per schedule in Section 6.2.3) and send to 
both the local and central laboratories for assessment of morphology; if an adequate 
aspirate specimen cannot be collected, a core biopsy specimen will be collected and 
sent to both the local and central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance;  

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 Dispense a sufficient quantity of quizartinib/placebo to supply the subject until the 
next scheduled visit and counsel the subject on the dosing regimen, from Days 1 
through 28, including the total number of tablets to be taken daily, and confirm the 
subject’s understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day. 
6.2.3.1.8. All Other Subsequent Cycles, Day 1 (±3 Days) 
The following activities and/or assessments will be performed on Day 1 of each subsequent 
cycle, unless otherwise specified.  This section covers visits where a bone marrow assessment is 
not being performed, from Cycle 5, Day 1 through Cycle 36, Day 1. 
 On Cycle 16, Day 1; Cycle 22, Day 1; Cycle 28, Day 1; Cycle 31, Day 1; and 
Cycle 34, Day 1: administer the EORTC QLQ-C30 and EQ-5D-5L assessments 
before any other assessments or procedures; 
 Conduct a physical examination (Section 9.10), including an evaluation of the subject 
for signs and symptoms of relapse; 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Record triplicate 12-lead ECG, fully supine for 10 minutes before the ECG; 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving quizartinib/placebo 
(refer to Section 9.6); 
 Assess the subject for relapse (see Section 7.2); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 
 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance;  
 Dispense a sufficient quantity of quizartinib/placebo to supply the subject until the 
next scheduled visit and counsel the subject on the dosing regimen, from Days 1 
through 28, including the total number of tablets to be taken daily, and confirm the 
subject’s understanding.  Counsel subjects that quizartinib/placebo may be taken with 
or without food and should be taken at about the same time every day. 
 On Cycle 36, Day 1, remind subjects to stop taking quizartinib/placebo on Day 28. 

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6.2.3.2. 
Allogeneic Hematopoietic Stem Cell Transplantation 
Refer to Section 3.2.2.2.1 for subjects who are being considered for allogeneic stem cell 
transplantation during the Continuation Phase. 
6.3. 
End of Treatment (+ 7 Days) 
The end of treatment visit is for subjects who complete 36 cycles of continuation therapy or who 
permanently discontinue quizartinib/placebo early.   
Subjects who permanently discontinued quizartinib/placebo because they completed 12 cycles of 
continuation therapy (under Protocol Version 1.0 or 2.0), were restarted on quizartinib/placebo 
and have now completed 36 cycles will need to complete an additional End of Treatment Visit 
once they have permanently discontinued study drug for the second and last time. 
The end of treatment visit should occur within 7 days after the last dose of quizartinib/placebo or 
at the time the decision to discontinue quizartinib/placebo is made, if this is greater than 7 days 
after the last quizartinib/placebo treatment, unless there is a medical condition that prevents 
subjects from completing the visit within this time.  Subjects must complete all end of treatment 
assessments as well as their regularly scheduled evaluations if they are discontinuing during a 
scheduled visit.  The following activities will take place during this visit: 
 Administer the EORTC QLQ-C30 and EQ-5D-5L assessments before any other 
assessments or procedures; 
 Conduct a physical examination (Section 9.10); 
 Record vital signs (blood pressure, pulse rate, respiratory rate, and temperature); 
 Weight; 
 Assess and record the subject’s ECOG performance status; 
 Perform triplicate 12-lead ECG, fully supine for 10 minutes before the ECG; 
 Collect and send blood and urine samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology; 
 Chemistry; 
 Coagulation; 
 Urinalysis (only as needed; eg, if renal function has decreased); 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test.  Daiichi Sankyo must be notified of any subject who becomes 
pregnant while receiving or within 6 months of discontinuing quizartinib/placebo 
(refer to Section 9.6); 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2); 
 Record all healthcare resource utilization since the last visit (see Section 10.2); 

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 Review and document all concomitant medications and transfusions the subject has 
received; 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs;  
 Collect quizartinib/placebo bottles returned by subjects and assess treatment 
compliance, if subject is outpatient. 
6.4. 
Long-Term Follow-up Phase 
The Long-Term Follow-up Phase begins upon completion of 36 cycles of quizartinib/placebo in 
the Continuation Phase or permanent discontinuation of quizartinib/placebo in any phase.  Refer 
to the schedule of events for the list of assessments and procedures to be performed during the 
Long-Term Follow-up Phase (Table 17.7). 
6.4.1. 
Safety Follow-up Visit 
The Safety Follow-up Visit should occur 30 days (+ 7 days) after the last dose of 
quizartinib/placebo, once a subject permanently discontinues or completes the study.  Telephone 
contact with the subject is sufficient unless: the subject has not had an EFS Event or any 
assessment must be repeated for resolution of treatment-related AEs.  The following activities 
will take place during this visit: 
 Assess the subject for relapse (see Section 7.2); 
 For women of childbearing potential (as defined in Section 4.1.1): perform a urine or 
serum pregnancy test; subjects must have a negative result.  Daiichi Sankyo must be 
notified of any subject who becomes pregnant while receiving or within 6 months of 
discontinuing the quizartinib/placebo (refer to Section 9.6); 
 Record all AEs experienced by the subject since the last evaluation: 
 Record any treatments (drug and nondrug) given for AEs; 
 Record subsequent anti-leukemic treatments and their outcomes. 
6.4.2. 
Long-Term Follow-up Visits 
After completion of the Safety Follow-up Visit, the Long-Term Follow-up Visits will be 
performed as follows: 
 Every 4 weeks for subjects who have not had an EFS event; 
 Every 12 weeks for subjects who have had an EFS event. 
If direct contacts are not possible due to withdrawal of consent or the subject becomes lost to 
follow-up, the site must make every effort to collect survival status from public records 
(eg, death certificates) in accordance with local laws.  See Section 5.9.2.1 for further details on 
how subjects will be followed for vital status if they withdraw consent.  
For women of childbearing potential (as defined in Section 4.1.1): perform a urine or serum 
pregnancy test 6 months after the last dose of investigational drug or cytarabine, whichever is 

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later.  Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or 
within 6 months of discontinuing quizartinib/placebo (refer to Section 9.6). 
All subjects will be followed for survival and subsequent anticancer therapy, if available. 
6.4.2.1. 
Long-Term Follow-up Visits for Subjects Who Have Not Had an EFS Event 
(Refractory/Relapse) 
Subjects who have not had an EFS event will be followed every 4 weeks for relapse and survival 
status. 
The following activities will be done every 4 weeks: 
 Collect and send blood samples to the laboratory for the following tests 
(Table 17.19): 
 Hematology (verify peripheral smear is not abnormal and cytopenias do not 
develop); 
 If peripheral smear is abnormal or cytopenias develop, per hematology results, 
then collect a bone marrow aspirate specimen and send to both the local and 
central laboratories for assessment of morphology; if an adequate aspirate sample 
cannot be collected, a core biopsy specimen will be collected and sent to both the 
local and central laboratories; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2); 
 Record subsequent anti-leukemic treatments and their outcomes. 
6.4.2.1.1. Bone Marrow Specimen Collection 
A bone marrow aspirate specimen (or a core biopsy specimen if aspirate cannot be obtained) will 
be collected as noted below, until relapse or 96 weeks have passed, whichever occurs first. 
For subjects who permanently discontinue quizartinib/placebo prior to starting continuation 
therapy and who have not undergone HSCT: 
 Collect a bone marrow aspirate specimen at the end of 12 weeks, 24 weeks, 36 weeks, 
48 weeks, 72 weeks, and 96 weeks from the date of discontinuation of 
quizartinib/placebo and send to both the local and central laboratories for assessment 
of morphology; if an adequate aspirate sample cannot be collected, a core biopsy 
specimen will be collected and sent to both the local and central laboratories. 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2). 

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For subjects who permanently discontinue quizartinib/placebo prior to starting continuation 
therapy and who have undergone HSCT: 
 Collect a bone marrow aspirate specimen during the first site visit following HSCT; 
 If an aspirate/core biopsy specimen was obtained ≤14 days prior to the first site 
visit following HSCT and the specimen is sent to both the local and central 
laboratories, then collection does not need to be repeated at the first site visit 
following HSCT; 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2). 
 Collect a bone marrow aspirate specimen at the end of 12 weeks, 24 weeks, 36 weeks, 
48 weeks, 72 weeks, and 96 weeks from the first site visit following HSCT and send 
to both the local and central laboratories for assessment of morphology; if an 
adequate aspirate sample cannot be collected, a core biopsy specimen will be 
collected and sent to both the local and central laboratories. 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2). 
For subjects who permanently discontinue quizartinib/placebo at any time during the 
Continuation Phase: 
 Continue to collect bone marrow aspirate specimens at the end of 12 weeks, 
24 weeks, 36 weeks, 48 weeks, 72 weeks and 96 weeks from Cycle 1, Day 1 of the 
Continuation Phase.  Send to both the local and central laboratories for assessment of 
morphology; if an adequate aspirate sample cannot be collected, a core biopsy 
specimen will be collected and sent to both the local and central laboratories. 
 Collect a copy of de-identified local pathology report for submission to IRC; 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2). 
For subjects who completed 36 cycles of continuation therapy: 
 Assess the subject for relapse based upon the local laboratory results (see 
Section 7.2). 
6.4.2.2. 
Long-Term Follow-up Visits for Subjects Who Have Had an EFS Event 
(Refractory/Relapse) 
Subjects who have had an EFS event will be followed every 12 weeks for survival status. 
The following activities will take place during long-term follow-up: 
 Record subsequent anti-leukemic treatments.  Record outcomes and remission status 
following subsequent anti-leukemic treatment, if available. 
 Record survival, evaluated by telephone contact. 

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7. 
EFFICACY ASSESSMENTS 
7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is OS.   
Overall survival is defined as the time from Randomization until death from any cause.  Subjects 
alive or lost to follow-up at the time of analysis will be considered censored at the date when 
they were last known to be alive. 
7.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints (ie, secondary outcome measures) are: 
 Event-free survival, which is defined as the time from Randomization until the date of 
the earliest of any of the following (refer to Table 17.15 for definition of response): 
 Refractory disease (or treatment failure) is determined at the end of the Induction 
Phase and defined as: 
o CR or CRi never achieved in the Induction Phase; or 
o Blasts 5% if Auer-rod positive; or 
o Appearance of new or worsening extramedullary disease; 
o For refractory disease, the EFS event date will be set to Day 1 at 
Randomization 
 Relapse after CR or CRi, which is defined as: 
o ≥5% blasts in the bone marrow aspirate and/or biopsy not attributable to any 
other cause; or  
o Reappearance of leukemic blasts in the peripheral blood; and/or 
o New appearance of extramedullary leukemia; or 
o Presence of Auer rods 
 Death from any cause at any time during the study. 
 Composite CR rate which is the percentage of subjects achieving CR or CRi after 
Induction; 
 Percentage of subjects achieving CRc with FLT3-ITD MRD negativity below a 
certain cutoff after Induction.  Minimal or measurable residual disease is the presence 
of a small number of leukemic cells in the bone marrow of patients with AML below 
the level of detection using conventional morphologic assessment. The FLT3-ITD 
MRD assay by Next Generation Sequencing will be used to detect and quantify 
residual FLT3-ITD mutations; 
 Complete remission rate, which is the percentage of subjects achieving CR after 
Induction; 

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 Percentage of subjects achieving CR with FLT3-ITD MRD negativity following 
induction therapy. 
7.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints are: 
 Relapse-free survival (RFS) is the time from randomization, for subjects who achieve 
CR or CRi in the Induction Phase, until documented relapse or death from any cause, 
whichever comes first.  Subjects alive without relapse or lost to follow-up at the time 
of analysis will be considered censored at the date of their last response/relapse 
assessment; 
 Duration of CR is the time from the first documented CR until documented relapse or 
death from any cause, whichever comes first.  Subjects alive without relapse or lost to 
follow-up as of the time of analysis will be censored at the date of their last 
response/relapse assessment; 
 Complete remission rate at the end of the first Induction cycle is the percentage of 
subjects who achieved CR after 1 Cycle of Induction;  
 Composite CR rate at the end of the first Induction cycle is the percentage of subjects 
whose best response is CR or CRi at the end of first Induction cycle; 
 CRh rate is the percentage of subjects achieving CRh after Induction (only for IRC 
assessment of response);  
 MLFS rate is the percentage of subjects achieving MLFS after Induction (only for 
IRC assessment of response); 
 RFS in subjects who enter the Continuation Phase is the time from randomization, for 
subjects who achieve CR or CRi in the Induction Phase, until relapse or death from 
any cause, whichever comes first; 
 Transplantation rate is the percentage of subjects undergoing allogeneic HSCT 
directly following protocol treatment with no intervening AML therapy (excluding 
conditioning regimens); 
 Subject reported QoL and symptoms as assessed with the EORTC QLQ-C30 
Questionnaire; 
 General health status assessed using EuroQol (EQ-5D-5L) Questionnaire; 
 Healthcare resource utilization. 
7.4. 
Appropriateness of Selected Efficacy Endpoints 
The initial goal of therapy for AML is to achieve a CR, given that a CR with currently available 
therapy is requisite, although not sufficient, for a cure.  Complete remission is the most important 
initial response reported in Phase 3 trials because it is the sole outcome currently associated with 
improved survival.  The goal of treatment in AML is to reduce the blasts in the bone marrow to 
below 5% (CR) and return the blood cell counts to normal levels. 

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After chemotherapy, some patients fulfill all of the criteria for CR except for residual 
neutropenia or thrombocytopenia (CRi).  The outcome for these patients does not seem to be 
comparable to that of patients with normalization of all counts, especially for those patients 
during initial therapy for their AML.  This category of response indicates activity of the 
investigational agent.  Patients in CRi might be considered for the transplant.45 
Improvement in EFS has been shown to correlate with increased OS in newly-diagnosed AML 
patients undergoing induction treatment and for AML patients in remission with maintenance 
therapy.  Data from the ECOG E1900 trial, presented at the 2014 American Society of 
Hematology meeting, showed concordance between EFS and OS.46  This randomized, Phase 3 
trial enrolled 657 subjects, 16 to 60 years old, with newly–diagnosed AML.  Subjects were 
randomized to receive daunorubicin 45 mg/m2 or 90 mg/m2 in combination with cytarabine 
followed by consolidation therapy.  
An increase in EFS, which comprises an increased rate of remission, an increased duration of 
remission, or a reduction in early deaths or deaths during remission, is a benefit.  Therefore, EFS 
represents a clinically relevant end point because relapse or treatment failure in AML signifies a 
reduced quality of life and substantial morbidity or mortality resulting either from the use of 
toxic salvage therapies, progressive disease, or both.  For patients with AML who achieve CR 
after induction and consolidation therapy, delaying or preventing relapse is critical to long-term 
survival or cure.47 
Overall survival is precise and easy to measure.  Demonstration of a statistically significant 
improvement in OS can be considered to be clinically significant if the toxicity profile is 
acceptable.  Difficulties in performing and analyzing survival studies include long follow-up 
periods in large trials and subsequent cancer therapy potentially confounding survival analysis.48 
Health-related quality of life (HRQoL) assessment in cancer research has become critical to fully 
evaluate overall treatment effectiveness by also formally including the patient’s perspective as an 
important objective. 
The assessment of patient-reported outcomes (PROs), including HRQoL has become critical to 
fully evaluate overall treatment effectiveness through incorporation of the patient’s perspective.  
Major cancer societies have been supporting its use as a key outcome for more than 2 decades.  
Acute leukemia patients experience significant symptom burden and detrimental impact on 
domains of HRQoL, including physical and emotional well-being, especially in the early course 
of disease.  Intensive therapy may also detrimentally affect PROs.  Fatigue is a particularly 
intense symptom and is significantly inversely correlated with physical and emotional 
functioning.45,49, 50, 51 Accordingly, patient reported symptoms and HRQoL are assessments of 
clinical benefit in acute leukemia.52 
European Organisation for Research and Treatment of Cancer QLQ-C30 is a questionnaire 
developed to assess the QoL of cancer patients, which has been widely used in cancer (including 
leukemia) clinical trials.53  It incorporates five functional scales (physical, role, cognitive, 
emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a number 
of single items assessing additional symptoms commonly reported by cancer patients 
(constipation, diarrhea, sleep and dyspnea), perceived financial impact of the disease and a 
global health status/QoL scale.  

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7.5. 
Independent Review Committee 
An IRC (Section 15.10) will independently review the following events in a blinded manner and 
without any knowledge of the subject’s randomized treatment assignment: 
 During the Induction Phase, the IRC will independently assess the response for each 
bone marrow aspirate (or biopsy, if applicable) sample collected, regardless of 
whether it is the first or second cycle.  If no blood counts are available on the day of 
the bone marrow specimen collection or if blood counts have not recovered on the 
day of the bone marrow specimen collection, blood counts within ± 14 days of the 
bone marrow specimen collection will be used to assess response. 
 During the post-Induction Phases the IRC will independently review data to assess for 
relapse. 
Details about the definitions of the endpoints and IRC processes will be described in the IRC 
charter. 

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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Endpoint(s) 
Blood samples for PK assessments will be collected at multiple time points in the study, as 
outlined in Table 8.1, Table 8.2, Table 8.3, and Table 8.4.  Details for blood sampling, 
processing, storage, and shipment for PK samples will be provided in the study laboratory 
manual. 
8.1.1. 
Sparse PK Sampling (Induction, Consolidation, and Continuation Phases) 
During the Induction Phase (non-PK-ECG-Biomarker Substudy subjects only), blood should be 
collected for plasma quizartinib PK on Cycle 1; -0.5 to 0 hours (predose) on Day 8 and 2 to 
4 hours (postdose) on Day 8, Day 15, and Day 21 per Section 6.2.1 and Table 8.1 within 
10 minutes after the ECG is performed.  
During the Consolidation Phase (all subjects), blood should be collected for plasma quizartinib 
PK on Cycle 1; -0.5 to 0 hours (predose) on Day 6 and 2 to 4 hours (postdose) on Day 6, Day 13, 
and Day 19 per Section 6.2.2 and Table 8.2 within 10 minutes after the ECG is performed.  
During the Continuation Phase (all subjects), blood should be collected for plasma quizartinib 
PK 2 to 4 hours postdose of quizartinib/placebo on Cycle 1; Day 1, Day 8, and Day 15, and 
Cycle 2; Day 1 and Day 15 per Section 6.2.3 and Table 8.3 within 10 minutes after the ECG is 
performed.  
The exact time of each ECG and its corresponding PK sample collection will be recorded.  See 
Appendix 17.5.2 for ECG collection timing. 
Table 8.1: 
Sparse PK Sampling for Quizartinib and its Metabolite (AC886) During 
Induction – Cycle 1 (All Subjects Not in the PK-ECG-Biomarker Substudy) 
Induction Phase 
Cycle 1 
Day 8 
Day 15 
Day 21 
PKa 
PKa 
PKa 
ECG = electrocardiogram; PK = pharmacokinetics 
a Within 10 minutes after the ECG, -0.5 to 0 hours (predose) Day 8 and 2 to 4 hours (postdose) Day 8, Day 15, and 
Day 21. 
 
Table 8.2: 
Sparse PK Sampling for Quizartinib and its Metabolite (AC886) During 
Consolidation – Cycle 1 (All Subjects) 
Consolidation Phase 
Cycle 1 
Day 6 
Day 13 
Day 19 
PKa 
PKa 
PKa 
ECG = electrocardiogram; PK = pharmacokinetics 
a Within 10 minutes after the ECG, -0.5 to 0 hours (predose) on Day 6 and 2 to 4 hours (postdose) on Day 6, Day 
13, and Day 19. 

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Table 8.3: 
Sparse PK Sampling for Quizartinib and its Metabolite (AC886) During 
Continuation – Cycles 1 and 2 (All Subjects) 
Continuation Phase 
Cycle 1 
Cycle 2 
Day 1 
Day 8 
Day 15 
Day 1 
Day 15 
PKa 
PKa 
PKa 
PKa 
PKa 
ECG = electrocardiogram; PK = pharmacokinetics 
a Within 10 minutes after the ECG, which is performed 2 to 4 hours postdose. 
Blood sampling, processing, storage, and shipment instructions are provided in the laboratory 
manual.  Plasma quizartinib and its metabolite (AC886) will be analyzed using validated liquid 
chromatography-tandem mass spectrometry methods. 
8.1.2. 
PK-ECG-Biomarker Substudy (Induction Phase) 
Up to 100 subjects who consent to participation will have intense PK sampling for plasma 
quizartinib concentrations and its metabolite (AC886) at Cycle 1 during the Induction Phase on 
Day 8, Day 15, and Day 21 as shown in Table 8.4, within 10 minutes after the ECG is 
performed.  This will be referred as the “PK-ECG-Biomarker Substudy”.  The predose sample 
should be collected within 0.5 to 0 hours prior to dose.  The 1, 2, 4, and 6 hour post dose samples 
should be taken within ±0.5 hour of nominal time.  The 24 hour post dose samples should be 
taken within ±3 hours of nominal time and before administration of the next dose, when 
applicable. 
Table 8.4: 
PK-ECG-Biomarker Substudy: PK Time Points for Quizartinib and its 
Metabolite (AC886) During the Induction Phase (Cycle 1 Only) 
Induction Cycle 1 
Day 8 (First Day of Quizartinib 
Dosing) 
Day 9 
Day 15 
Day 21 (Last Day of Quizartinib 
Dosing) 
Day 22 
Hour 
Predose 
Hour Postdose 
 
Hour 
Predose 
Hour Postdose 
-0.5 to 0 
1a 
2a 
4a 
6a 
24b 
2 to 4 
-0.5 to 0 
1a 
2a 
4a 
6a 
24c 
ECG = electrocardiogram; PK = pharmacokinetics 
a ±0.5 hour of nominal time 
b ±3 hours of nominal time and before administration of the next dose 
c ±3 hours of nominal time  
8.2. 
Pharmacodynamic Endpoint(s) 
 Inhibition of FLT3-ITD activity in an ex vivo PIA assay 
Up to 100 subjects who are participating in the PK-ECG-Biomarker Substudy will have plasma 
samples collected for testing in an ex vivo PIA assay.  Samples for PIA assessment will be 
collected as described in Section 6.2.1.1, Section 6.2.2.1, Section 6.2.3, and Table 8.5.  When 
collected on the same day as PK sample collection, PIA samples will be collected immediately 
after PK sample collection. 

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Table 8.5: 
PK-ECG-Biomarker Substudy: Time Points for PIA Samples  
Phase 
Induction 
Consolidation 
Continuation 
Cycle 
1 
1 
1 
2 
4 
7 
10 
13 
19 
25 
Day 
8a 
15a 
21a 
6a 
13a 
19a 
1 
8a 
15a 
1 
15a 
1 
1 
1 
1 
1 
1 
Hours 
-0.5 
to 0 
2 
2 to 
4 
2 
2 to 4 
2 to 4 
2 to 4 
anytime postdose 
ECG = electrocardiogram; PIA = plasma inhibitory activity; PK = pharmacokinetics  
a Collect PIA sample immediately after PK sample collection 
8.3. 
Biomarker Endpoint(s) 
In this study, biomarker analyses will be used to investigate the effect of quizartinib at the 
molecular and cellular level as well as to determine how changes in the markers may relate to 
exposure and clinical outcomes.  The required sample collection information should be recorded 
on the electronic case report form (eCRF) page(s) and central laboratory requisition form(s).  
Detailed instructions for the collection, handling, and shipping of biomarker samples are outlined 
in the study laboratory manual. 
 FLT3-ITD MRD by next generation sequencing will be used to detect and quantify 
residual FLT3 ITD mutations.  (Results will not be available until the end of the 
study.) 
For subjects who are in CR or CRi, bone marrow samples from the following visits 
will be analyzed for FLT3-ITD MRD: Screening; End of Induction; Consolidation 
Last Cycle; Post–HSCT; Continuation Cycle 1, Day 1; Continuation Cycle 4, Day 1; 
and EOT (ie, completion of 36 cycles of continuation therapy or early permanent 
discontinuation of quizartinib/placebo). 
 Mutations in the kinase and juxtamembrane domains of FLT3 and other somatic 
mutations known to be associated with AML or myeloid diseases (eg, CEBPA, 
DNMT3A, IDH1, IDH2, Kit, NPM1 and NRAS), determined with bone marrow or 
whole blood samples. 
Bone marrow samples from the following visits will be analyzed for somatic 
mutations: Screening; Continuation Cycle 4, Day 1; and at the time of relapse (as 
defined in Section 7.2). 
 Pharmacodynamic biomarkers will be analyzed with the intent of monitoring the 
anti-tumor impact of treatment with quizartinib.  The following candidate 
pharmacodynamic biomarkers are currently envisaged (other pharmacodynamic 
biomarkers in addition to or in place of these may be considered as suggested by 
updated literature):  FLT ligand; allelic ratio of FLT3-ITD; and flow cytometer 
analysis by using CD33, CD34, CD38, or any other AML or blood cell markers.  
These pharmacodynamic biomarkers will be assessed in bone marrow, blood, RNA, 
or DNA that is left over from samples collected for other tests as described in 
Table 17.1, Table 17.2, Table 17.3, and Table 17.4 using validated assays.  One or 
more of the aforementioned pharmacodynamic biomarkers may also be explored for 
predictive value. 

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 Biomarker samples will be shipped to a central laboratory.  Sample collection, 
preparation, handling, storage, and shipping instructions are provided in the study 
laboratory manual. 
 During the study, in addition to the biomarkers specified above, exploratory research 
may be conducted on any tumor sample.  These studies would extend the search for 
other potential biomarkers relevant to the effects of quizartinib, cancer and/or the 
resistance to treatment.  This may include the development of ways to detect, 
monitor, or treat cancer.  These additional investigations would be dependent upon 
clinical outcome, reagent, and sample availability. 
If the subject agrees, the remaining biomarker samples (bone marrow, blood, or other 
specimens obtained during the study) may be stored for up to 15 years and further 
analyzed to address scientific questions related to quizartinib and/or AML. 
These assessments will be performed as described in Section 6, Table 17.1, Table 17.2, 
Table 17.3, Table 17.4, and Table 17.6. 
8.4. 
Immunogenicity 
Not applicable. 
8.5. 
Pharmacogenomic Analysis 
8.5.1. 
Genomic or Genetic Analysis 
Blood and epithelial oral cell samples will be collected for pharmacogenetic sample banking 
from subjects who have provided a separate informed consent for this part of the study.  
Participation in this part of the study is optional for all subjects.  For those subjects who choose 
to participate, samples will be banked for possible future pharmacogenetic and DNA analysis.  
These samples may be analyzed only for genes suspected to contribute to the safety and efficacy 
of the study medications. 
Samples will be retained until the genetic material has been exhausted or until the Sponsor 
instructs the genotyping contractor to destroy the sample (in accordance with laboratory 
procedures).  During the period of storage, the genetic samples will not be immortalized or sold 
to anyone.  Subjects will have the right to withdraw consent and have their sample destroyed at 
any time. 
For instructions on management of pharmacogenomics samples please refer to the study 
laboratory manual. 

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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Adverse Event Collection and Reporting 
From the initial ICF (FLT3-ITD Screening or Main Study) being signed and up to 
Randomization (Induction phase, Cycle 1 Day 7), all SAEs considered related to study 
procedures by the investigator will be recorded.  For randomized subjects, AEs and SAEs 
occurring between Induction Phase Cycle 1 Day 1 and Day 6 will be recorded retrospectively.  
From Randomization and up to the 30-Day Safety Follow-up Visit, all AEs (see Section 9.3.1 for 
definitions) observed by the investigator or reported by the subject will be recorded, except 
during allogeneic HSCT (see Section 6.2.2.2).  Medical conditions (including clinically 
significant laboratory values/vital signs that are out of range) that were diagnosed or known to 
exist prior to initial ICF will be recorded as part of medical history.  For subjects who undergo 
allogeneic HSCT, medical conditions (including clinically significant laboratory values/vital 
signs that are out of range) that were diagnosed or that occurred after allogeneic HSCT will be 
recorded as post-HSCT medical history.  Any AEs that are unresolved at the time of transitioning 
to conditioning regimen for allogeneic HSCT should be followed up when the subject returns for 
Post-HSCT Visit (see Section 6.2.2.2.1). 
All AEs, SAEs, and events of special interest are to be reported according to the procedures in 
Section 9.4. 
All laboratory results, vital signs, and ECG results or findings should be appraised by the 
investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to quizartinib/placebo discontinuation, dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
subject.  Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit.  Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms.  The investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.3.  The investigator’s assessment must be clearly documented in the Study Center’s 
source documentation with the investigator’s signature. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for pre-existing conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.3.2 for Definitions). 
Refractory disease and relapse (see Section 7.2 for criteria) are study endpoints and 
consequently, refractory disease, relapse, or worsening of AML should not be reported as an 

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AE/SAE.  However, clinical events associated with refractory disease/relapse and its sequelae 
resulting in a serious outcome should be reported as AEs or SAEs.  For deaths, the underlying or 
immediate cause of death should always be reported as an SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to quizartinib/placebo should also be reported and managed as an 
SAE. 
The investigator should follow subjects with AEs until the event has resolved or the condition 
has stabilized.  In case of unresolved AEs, including significant abnormal laboratory values at 
the end of study assessment, these events will be followed until resolution or until they become 
clinically not relevant. 
9.2. 
Events of Special Interest 
9.2.1. 
QTc Prolongation, Torsades de Pointes, and Other Ventricular Arrhythmias 
Subjects who experience >480 ms QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved, as 
described in Section 5.6.1.1. 
QTcF prolongation ≥ Grade 3, either serious or non-serious and whether or not causally related, 
must be recorded as AE or SAE in the Electronic Data Capture (EDC) system within 24 hours of 
awareness of the central ECG laboratory reading, with the investigator’s assessment of 
seriousness, causality, and a detailed narrative.54  The central ECG reading confirming QTcF 
prolongation ≥ Grade 3 is to be recorded in the EDC system. 
9.2.2. 
Combined Elevations of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law case 
[ALT or AST ≥3 × ULN with simultaneous TBL ≥2 × ULN] should always be recorded as an 
AE or SAE within 24 hours of awareness, with the investigator’s assessment of seriousness, 
causality, and a detailed narrative.55 
Subjects will be monitored as described in Section 5.6.2.1.1. 
9.3. 
Adverse Event 
9.3.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.56 
It is the responsibility of investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 

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9.3.2. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more.56 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  Examples include 
allergic bronchospasm, convulsions, and blood dyscrasias or development of drug dependency or 
drug abuse. 
Note: 
 Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE. 
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 
9.3.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI CTCAE:54  
 Grade 1 Mild AE 
 Grade 2 Moderate AE 
 Grade 3 Severe AE 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to AE 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  This is not the same as "seriousness," which is based on patient/event outcome at the 
time of the event.  For example, the NCI CTCAE Grade 4 (life-threatening consequences; urgent 
intervention indicated) is assessed based on unique clinical descriptions of severity for each AE, 
and these criteria may be different from those used for the assessment of AE seriousness.  An AE 

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assessed as grade 4 based on the NCI CTCAE grades may or may not be assessed as serious 
based on the seriousness criteria. 
9.3.4. 
Causality Assessment 
The causal relationship to an AE/SAE will be assessed with consideration to quizartinib/placebo 
on the basis of the investigator’s judgment and the following definitions.  For SAEs only, the 
causal relationship to cytarabine and daunorubicin, if applicable, will also be assessed.  The 
causality assessment must be made based on the available information and can be updated as 
new information becomes available. 
 Related: 
 The AE/SAE follows a reasonable temporal sequence from quizartinib/placebo 
administration (or for SAEs only, from cytarabine or daunorubicin administration) 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE/SAE follows a reasonable temporal sequence from quizartinib/placebo 
administration (or for SAEs only, from cytarabine or daunorubicin 
administration), and is a known reaction to the drug under study or its chemical 
group, or is predicted by known pharmacology. 
 Not Related: 
 The AE/SAE does not follow a reasonable sequence from quizartinib/placebo 
administration (or for SAEs only, from cytarabine or daunorubicin 
administration), or can be reasonably explained by the subject’s clinical state or 
other factors (eg, disease under study, concurrent diseases, and concomitant 
medications). 
9.3.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in quizartinib/placebo dosage was made. 
 Drug Withdrawn: The quizartinib/placebo was permanently stopped. 
 Dose Reduced: The dosage of quizartinib/placebo was reduced. 
 Drug Interrupted: The quizartinib/placebo was temporarily stopped. 
 Dose Increased: The dosage of quizartinib/placebo was increased. 
 Not Applicable: Subject died, quizartinib/placebo had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
9.3.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 

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 Medication required. 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 Other. 
9.3.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
9.4. 
Safety Reporting –Procedure For Investigators 
All AEs, including SAEs and Events of Special Interest, will be reported in the EDC. 
The following types of events should be reported by the investigator in EDC within 24 hours of 
awareness: 
 SAEs (see Section 9.3.2 for definition) 
 QTcF prolongation ≥ Grade 3, either serious or non-serious and whether or not 
causally related (see Section 5.6.1 for additional monitoring details) 
 Hepatic events meeting combination abnormalities [ALT or AST ≥3 × ULN with 
simultaneous TBL ≥2 × ULN] (potential Hy's Law case), both serious and 
non-serious and whether or not causally related (see Section 5.6.2.1 for additional 
monitoring details) 
All events (serious and non-serious) must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the quizartinib/placebo.  Serious events also must 
be reported with investigator’s assessment of causality to cytarabine and daunorubicin, if 
applicable.  A detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided.  Specific or estimated dates of event onset, 
treatment, and resolution should be included when available.  Medical history, concomitant 
medications, and laboratory data that are relevant to the event should also be summarized in the 

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narrative.  For fatal events, the narrative should state whether an autopsy was or will be 
performed, and include the results if available.  Source documents (including medical reports) 
will be retained at the study center and should not be submitted to the Sponsor for SAE reporting 
purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
See study reference materials for contact information for SAE reporting.  Please call the local 
SAE Hotline (see Study Manual) or your study monitor for any questions on SAE reporting. 
9.5. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform investigators and regulatory authorities of any 
Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in other study centers or 
other studies of the investigational drug, as appropriate per local reporting requirements.  Daiichi 
Sankyo and/or CRO will comply with any additional local safety reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
quizartinib/placebo, unless delegated to Daiichi Sankyo, it is the investigator’s responsibility to 
inform the IRB per Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
Central ECs, and the investigator’s responsibility to inform the local EC. 
9.6. 
Exposure In Utero During Clinical Studies 
Women of childbearing potential (as defined in Section 4.1.1) must have negative urine or serum 
pregnancy test results at times specified in the Schedule of Events (Appendix 17.1).  If required 
by local regulations, additional pregnancy testing will be performed.  Follicle stimulating 
hormone (FSH) may be determined as necessary to confirm postmenopausal status.  Serum 
pregnancy tests and FSH will be performed at the local laboratory. 
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or within 
6 months of discontinuing the quizartinib/placebo. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  This information is important for both drug safety and public health 
concerns.  It is the responsibility of the investigator, or designee, to report any pregnancy in a 
female subject using the Exposure In Utero (EIU) Reporting form.  Please contact your study 
monitor to receive the EIU Reporting Form upon learning of a pregnancy.  The investigator 
should make every effort to follow the subject until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  The adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as a SAE (ie, post-partum complications, spontaneous or 
induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted 
fetus), the investigator should follow the procedures for reporting SAEs outlined in Section 9.4. 

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9.7. 
Clinical Laboratory Evaluations 
Clinical laboratory determinations for hematology, blood chemistry, coagulation, and urinalysis 
will be analyzed.  See Table 17.19 for specific analytes. 
9.8. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature will be determined and recorded at the times specified in the study schedule 
(Appendix 17.1). 
9.9. 
Electrocardiograms 
Supine triplicate 12-lead ECGs will be obtained at the times specified in the Schedule of Events 
(Appendix 17.5.2).  Additional ECGs may be obtained at the investigator’s discretion.  If an 
ECG is abnormal then a repeat triplicate ECG must be performed.  
See Section 5.6.1.1 for management of subjects with QTc prolongation.  See Section 5.6.4, 
Section 5.8.3, and Appendix 17.5.1 for ECG monitoring requirements for subject receiving a 
concomitant drug that prolongs QTc or is a CYP3A4 inhibitor. 
9.10. 
Physical Examinations 
A complete physical examination will be performed at Screening and at additional times 
specified in the Schedule of Events (Appendix 17.1).  Whenever possible, the same individual 
will perform subsequent examinations to identify changes from baseline.  Clinically significant 
changes from baseline must be reported as AEs. 
Symptom-directed physical examinations performed during the treatment period will be based on 
the subject’s medical history and AEs, and will include weight determination and a review of 
body systems.  During the Continuation Phase, this will also include an evaluation of signs and 
symptoms of relapse. 
9.11. 
Other Examinations 
Not applicable. 

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10. 
OTHER ASSESSMENTS 
10.1. 
Health Economics and Outcome Research 
10.1.1. 
Patient-Reported Outcomes 
Patient-reported outcomes will be assessed using EORTC QLQ–C30 (Appendix 17.13) and 
EQ-5D-5L (Appendix 17.14). 
 EORTC QLQ–C30 
 EORTC QLQ-C30 incorporates 5 functional scales (physical, role, cognitive, 
emotional, and social), three symptom scales (fatigue, pain, and nausea and 
vomiting), a number of single items assessing additional symptoms commonly 
reported by cancer patients (constipation, diarrhea, sleep, and dyspnea), perceived 
financial impact of the disease and a global health status/QoL scale.  All scores 
are scaled from 0 to 100, with higher scores representing better QoL and fewer 
symptoms.53 
 The QLQ-C30 is the most widely used questionnaire for cancer (including 
leukemia) patients in clinical trials in Europe, and is also used extensively in 
America and throughout the rest of the world.53  The psychometric properties of 
the QLQ-C30 have been well established and the questionnaire was found to 
possess the required standards such as validity (measuring what it is intended to 
measure), reliability (measuring with sufficient precision) and sensitivity (ability 
to detect changes).53  A 10-point difference in a QLQ-C30 domain score is 
generally considered clinically important.57  It has been shown to be sensitive to 
change in patients undergoing cancer treatment (chemotherapy and/or 
radiotherapy).58 
 EQ-5D-5L 
 General health status will be assessed using EQ-5D-5L.  The EQ-5D-5L is a 
6-item generic multi-attribute preference-based health status questionnaire that is 
easy to administer and takes only 1 to 2 minutes to complete.  The questionnaire 
will be used to generate study-specific data for the calculation of quality-adjusted 
life years for economic evaluation. 
 The EQ-5D-5L is in two parts.  The first part comprises five domains (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression) each assessed by 
one item with 5 response options ranging from no problems through profound 
difficulties.  Accordingly, 3125 (5×5×5×5×5) potential health profiles can be 
generated to which public preferences or utilities from published value sets are 
applied, ranging from negative values to 1 (perfect health).59  The second part of 
the EQ-5D-5L is a Visual Analogue Scale on which subjects rate their current 
health, with 0 representing the "worst health you can imagine" and 100 the "best 
health you can imagine." 

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10.2. 
Health Economic Assessments 
The following variables will be collected and recorded to assess healthcare resource utilization 
during the treatment period (excluding the allogeneic HSCT period, when the subject is unable to 
attend site visits): 
 Hospitalizations; 
 Emergency room visits; 
 Skilled nursing facility care; 
 Unscheduled clinic visits; 
 Hospice care; 
 Concomitant medications and procedures. 

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11. 
STATISTICAL METHODS 
11.1. 
Analysis Sets 
All relevant analyses sets are defined as below: 
 Safety Analysis Set will include all subjects who received at least 1 dose of 
quizartinib/placebo. 
 Intent-to-treat (ITT) Analysis Set will include all subjects who are randomized.  
 Per-protocol Analysis Set (PPS) will include all subjects in the ITT Analysis Set who 
have no major protocol deviations that would affect assessment of efficacy endpoints. 
 PK substudy Analysis Set will include all subjects in ITT Analysis Set who 
participated in the PK substudy and received at least 1 dose of quizartinib and had at 
least 1 PK sample. 
 Pharmacodynamic Analysis Set will include all subjects in ITT Analysis Set who 
received at least 1 dose of quizartinib/placebo and had at least 1 predose and 
1 postdose corresponding pharmacodynamic assessment. 
 Biomarker Analysis Set will include all subjects in ITT Analysis Set who received at 
least 1 dose of quizartinib/placebo and had at least one corresponding biomarker 
assessment. 
 EQ-5D-5L and EORTC QLQ-C30 Analysis Set.  The EQ-5D-5L and 
EORTC QLQ-C30 Analysis Set will include all subjects in the ITT Analysis Set who 
complete the relevant EQ-5D-5L and EORTC QLQ-C30 assessment at Screening, at 
least partially in a manner that permits imputation of missing responses posttreatment. 
11.2. 
General Statistical Considerations 
The randomization will be stratified by geographical region (North America, Europe, and 
Asia/Other Regions), Age (<60 years old, ≥60 years old), and WBC count at the time of 
diagnosis of AML (<40×109/L, ≥40×109/L).  
Summary statistics will be presented by treatment group.  For continuous variables, number of 
available observations (n), mean, standard deviation, median, minimum, and maximum will be 
provided.  For categorical variables, the number and percentage in each category will be 
displayed. 
Efficacy analyses will be performed on the ITT Analysis Set and PPS.  Safety analyses will be 
performed using the Safety Analysis Set.  All other efficacy exploratory analyses will be 
performed based on ITT Analysis Set and availability of assessment. 
The efficacy analyses will be performed according to the treatment groups assigned at 
Randomization.  For safety analyses, subjects will be analyzed according to actual treatment 
received. 
Assessments of change from baseline to post-baseline or the ratio of post-baseline to baseline 
will include only those subjects with both baseline and post-baseline measurements.  Baseline 

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will be defined in the SAP.  In general, missing or drop-out data will not be imputed for the 
purpose of data analysis. 
11.3. 
Study Population Data 
Subject disposition will be summarized by treatment group and in total for those defined selected 
Analysis Sets. 
The demographic and baseline characteristics such as baseline ECOG disease status will be 
summarized descriptively by treatment group for the ITT, PPS, and Safety Analysis Sets. 
Quizartinib/placebo exposure (amount and duration), average daily dose and relative dose 
intensity will be summarized using descriptive statistics by treatment group for the Safety 
Analysis Set. 
Medical history will be coded using the latest Medical Dictionary for Regulatory Activities 
(MedDRA) version and summarized by system organ class, preferred term, and presented by 
treatment group. 
11.4. 
Statistical Analysis 
11.4.1. 
Efficacy Analyses 
11.4.1.1. Primary Efficacy Analyses 
Overall survival is the primary efficacy endpoint for this study (see Section 7.1 for the definition 
of OS).   
The primary analysis for OS will be based on the ITT Analysis Set.  Comparison of distribution 
of OS between treatment groups will be made using a stratified log-rank test with the 3 
stratification factors used at randomization at a 2-sided 5% significance level.  The median OS 
will be calculated based on Kaplan-Meier estimates and the corresponding 95% CI will be 
calculated using the method provided by Brookmeyer and Crowley.60  In addition, the stratified 
Cox proportional hazards regression model will be performed to estimate hazard ratio (HR) 
along with the 2-sided 95% CI, and SAS PROC LIFETEST and PROC PHREQ will be used in 
the analysis.61 
11.4.1.2. Secondary Efficacy Analyses 
The analysis for EFS will be based on the ITT Analysis Set.  The distribution of EFS will be 
compared between the 2 treatment groups using a stratified log-rank test with the 3 stratification 
factors used in randomization.  The distribution function of EFS will be estimated using the 
Kaplan-Meier method.  The median EFS along with the 2-sided 95% CIs by Brookmeyer and 
Crowley will be presented by treatment group.60  The stratified Cox proportional hazards 
regression model will be used to estimate the hazard ratio of EFS, along with the 2-sided 
95% CI.   
EFS will be analyzed based on the response assessment by the IRC.  EFS will also be analyzed 
based on the investigator’s response assessment as a sensitivity analysis. 

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The CR rate, rate of subjects achieving CR with FLT3-ITD MRD negativity, CRc rate, and rate 
of subjects achieving CRc with FLT3-ITD MRD negativity will be summarized along with 
95% CI using Clopper-Pearson’s method.62  Comparisons of CR rate, rate of subjects achieving 
CR with FLT3-ITD MRD negativity, CRc rate, and rate of subjects achieving CRc with 
FLT3-ITD MRD negativity between treatment groups will be made using a 
Cochran-Mantel-Haenszel test with the 3 stratification factors used in randomization. 
To control for the family-wise type I error rate for the primary and secondary efficacy endpoints, 
a serial hierarchically ordered gatekeeping strategy will be employed.  The primary assessment 
of OS in the ITT Analysis Set will be evaluated first, and if significant at a 2-sided alpha of 0.05, 
a statistical evaluation of EFS by IRC, based on the EFS definition in the Guidances,63,72 will be 
performed in the ITT Analysis Set.  After EFS evaluation, the order of other secondary endpoints 
to be tested will be CR rate, rate of subjects achieving CR with FLT3-ITD MRD negativity, CRc 
rate, and rate of subjects achieving CRc with FLT3-ITD MRD negativity.  Testing will stop once 
1 test in the sequence fails to be statistically significant. 
11.4.1.3. Exploratory Efficacy Analyses 
Relapse-Free Survival will be analyzed by treatment group using the Kaplan-Meier method for 
subjects achieving CRc. 
RFS in subjects who enter the Continuation Phase will be summarized similarly as RFS. 
Duration of CR will be analyzed similarly as RFS. 
Rate of allogeneic HSCT, rate of CR at end of first Induction cycle, rate of CRc at end of first 
Induction cycle, rate of CRh after Induction (IRC evaluation only), and rate of MLFS after 
Induction (IRC evaluation only) will be summarized by treatment group with point estimate and 
associated 2-sided 95% CI constructed using Clopper-Pearson’s method.62  
Confidence interval presented for exploratory endpoints are provided for summary purpose, not 
inference. 
11.4.1.4. Sensitivity and Supplementary Analyses 
The final set of sensitivity and supplementary analyses will be selected and specified in the SAP. 
11.4.1.5. Subgroup Analyses 
The primary and secondary efficacy endpoints, OS and EFS, will be also analyzed for the 
following subgroups in the ITT Analysis Set: 
 By region: North America, Europe, Asia/Other Regions; 
 By age: <60, 60 to 65, and ≥65years old; 
 By WBC count at the time of diagnosis of AML (<40×109/L, ≥40×109/L); 
 By sex: male and female; 
 By choice of anthracycline: daunorubicin or idarubicin; 
 By race: Caucasian, Black/African American, Asian, Other. 

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The same statistical method employed for the analysis of OS and EFS will be used for the 
planned sub-group analyses. 
11.4.2. 
Pharmacokinetic/Pharmacodynamic Analyses 
11.4.2.1. Pharmacokinetic Analyses 
For the PK-ECG-Biomarker Substudy: pharmacokinetic parameters of quizartinib and its 
metabolites (AC886) will be estimated for subjects who have sufficient plasma concentrations 
available.  Standard non-compartmental analysis will be estimated for subjects with sufficient 
intense PK data available for the following PK parameters: AUC0-24, Cmax, Cmin, Tmax, and 
accumulation ratio and parent/metabolite ratio at Day 8 and Day 21 during Cycle 1 of Induction.  
Plasma concentrations and PK parameters will be summarized using descriptive statistics by 
treatment group and by treatment phase when appropriate.  
Population PK analysis will be conducted to characterize the PK profiles of quizartinib and its 
metabolite (AC886) in the target patient population, including quantification of inter-individual 
variability and identification of potential significant covariates (ie, patients demographics and 
clinical factors) that may affect the PK of quizartinib and its metabolite.  If necessary, PK data 
from this study will be pooled with those from other Phase 1 and 2 studies for the population PK 
modeling.  
The potential relationships between quizartinib PK exposure versus QTcF or clinical response 
measures will be explored by both graphical and modeling approaches. 
Details about the non-compartmental analysis, population PK modeling and exposure-response 
analysis will be provided in separate plans.  The population PK and exposure-response analysis 
results will be reported separately.  In addition, population PK and pharmacodynamic analyses 
may be performed prior to database lock by a third party, unblinded pharmacometrician, who 
will be firewalled from the study team in accordance with the details provided in a separate 
document.  
11.4.2.2. Pharmacodynamic Analyses 
Number and percentage of subjects achieving full inhibition as measured by PIA will be 
summarized for each time point by treatment groups.  A subject is said to have achieved full 
inhibition at a certain PIA assessment visit if the corresponding PIA value is >90%.  Number and 
percentage of subjects achieving full inhibition will be provided for the quizartinib group.  
Summary statistics will be provided for the quizartinib group in the Pharmacodynamic Analysis 
Set. 
11.4.2.3. Biomarker Analyses 
Number and percentage of subjects expressing different AML associated mutations will be 
summarized by treatment group. 
FLT3-ITD allelic ratio will be summarized and presented by treatment groups. 

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11.4.3. 
Safety Analyses 
All safety analyses will be based on the Safety Analysis Set.  Listings will be based on the Safety 
Analysis Set.  
For each safety analysis, baseline will be defined in the SAP.  No inferential statistical analysis is 
planned for safety data, unless otherwise specified.  If the number of subjects with available data 
does not allow for the reliable estimation of variability at a scheduled time point, no summary 
statistics will be presented for that time point, unless otherwise indicated. 
11.4.3.1. Adverse Event Analyses 
Adverse events to be included in summary tables will be restricted to TEAEs.  A TEAE is 
defined as an AE that occur, having been absent before first dose of quizartinib/placebo, or have 
worsened in severity after initiating quizartinib/placebo.  Safety analyses include frequency and 
severity of TEAEs. 
AEs collected more than 30 days after the last dose of quizartinib/placebo will not be considered 
TEAEs unless they are considered drug-related.  If the relationship to drug is missing, the AE is 
considered drug-related. 
AEs will be coded using MedDRA (the latest version) and assigned grades based on NCI 
CTCAE, Version 4.03.  The number and percentage of subjects reporting TEAEs will be 
tabulated by the worst CTCAE grade, system organ class, and preferred term, with a breakdown 
by treatment group.  Similarly, the number and percentage of subjects reporting 
treatment-emergent SAEs will be tabulated by treatment group, as well as TEAEs/SAEs 
considered related to quizartinib/placebo and TEAEs leading to discontinuation of 
quizartinib/placebo, respectively. 
A by-subject AE (including treatment emergent) data listing including, but not limited to, 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to 
quizartinib/placebo will be provided.  Deaths, other SAEs, AESIs and other significant AEs, 
including those leading to permanent discontinuation from quizartinib/placebo, will be listed.  
The AESIs will be re-evaluated periodically and the final list of AESIs will be reflected in the 
final SAP. 
SAEs and nonserious AESIs will be reconciled between the clinical and safety databases.  The 
clinical database will be used to summarize and list the SAEs. 
Subgroup analyses of AEs will be performed if applicable using subgroups defined in the SAP. 
11.4.3.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results and changes from 
baseline by scheduled time of evaluation and by treatment group including end of treatment visit 
as well as for the maximum and minimum post-baseline values. 
Abnormal clinical laboratory results will be graded according to NCI CTCAE Version 4.03, if 
applicable.  A shift table, presenting by treatment group the 2-way frequency tabulation for 
baseline and the worst post-baseline value according to the CTCAE grade, will be provided for 

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clinical laboratory tests.  Abnormal clinical laboratory test results deemed of clinical significance 
or of Grade 3 or 4 will be listed. 
11.4.3.3. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and by treatment group including end of treatment visit 
as well as for the maximum and minimum post-baseline values. 
11.4.3.4. Electrocardiogram Analyses 
Electrocardiogram parameters (PR, RR, QRS, QT, and QTcF) will be summarized by treatment 
group using descriptive statistics for actual values and for changes from baseline by treatment 
group by scheduled time of evaluation including end of treatment visit as well as for the 
maximum post-baseline values.  QTcF will be considered as the primary correction method to 
assess QTc interval. 
The number and percentage of subjects with QT/QTc interval values meeting the criteria will be 
tabulated (eg, QTcF ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms) and QTcF 
maximum changes from baseline (>30 and >60 ms) over all post-treatment evaluations will be 
summarized.  Electrocardiogram data will also be presented in the data listings. 
11.4.3.5. Transfusion 
Blood transfusion data will be summarized by treatment group and treatment phases. 
11.4.3.6. Physical Examination Analyses 
Physical examination findings will be listed for the Safety Analysis Set. 
11.4.3.7. Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(WHODD) (most recent version).  Number and percentage of subjects taking concomitant 
medications will be summarized by ATC2 class and preferred term and presented by treatment 
group. 
11.4.3.8. Safety Subgroup Analyses 
The safety subgroups in the Safety Analysis Set will be identified in the SAP. 
11.4.4. 
Health Economics and Outcomes Research Data Analysis 
The patient-reported outcomes (EORTC QLQ-C30, EQ-5D) and the health resource utilization 
data will be assessed based on a separate analysis plan.  The plan will provide details of the 
descriptive and comparative statistical analyses. 
11.4.5. 
Data Review by Data Monitoring Committee 
A Data Monitoring Committee (DMC) (Section 15.9) will review all data relevant to safety 
(ie, AEs, SAEs, clinical laboratory values, exposure, genotyping, and concomitant medication 
information).  Details will be provided in a separate DMC charter. 

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11.5. 
Sample Size Determination 
The primary endpoint of the study is OS in the ITT Analysis Set. A log-rank test will be applied 
to test the treatment effect between the 2 treatment arms with a 2-sided alpha of 0.05. 
For OS, a plateau effect was observed after 30 months of treatment in the control arm of the 
Midostaurin RATIFY study.64  Therefore, a piecewise exponential model was considered to 
account for the plateau effect. Simulations were carried out to determine the sample size, timing 
of analysis, and power.   
In the RATIFY study, the landmark survival rates of 42% at 30 months and 38% at 60 months in 
FLT3-ITD group were observed in the control arm.65  This translates into a hazard rate of 0.029 
in the first 30 months and 0.003 afterwards in the control arm.  Based on this information, the 
simulation assumes a hazard rate of 0.029 in the first 30 months (from the randomization) and 
0.003 afterwards in the placebo arm, and a HR of 0.7 and 1, respectively, before and after the 
first 30 months between the 2 treatment arms.  This is equivalent to an assumed survival rate of 
54% at 30 months and 50% at 60 months in the quizartinib arm.  
Simulations indicate that about 84% power and 287 events will be obtained to achieve a 
statistically significant difference in OS distribution with approximately 536 subjects by a 
2-sided log-rank test at the 0.05 significance level when OS is analyzed at 24 months after the 
last subject is randomized.   
The OS analysis will be performed: 
 When the target 287 OS events are observed and a minimum of 24 months has 
elapsed since the last subject was randomized. 
 If the target 287 OS events are not achieved by 24 months since the last subject was 
randomized, then the analysis will be performed at a maximum of 30 months after the 
last subject is randomized. 
The sample size derivation is based on the EAST Version 6.3 and simulations were run using 
SAS® Version 9.2.66 
11.6. 
Statistical Analysis Process 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, 
quizartinib/placebo exposure, and prior and concomitant medications.  The SAP will also include 
a description of how missing, unused, and spurious data will be addressed. 
The SAP will be finalized prior to un-blinding to preserve the integrity of the statistical analysis 
and clinical study conclusions. 
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, 
Cary, NC 27513).61 

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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
12.1. 
Monitoring and Inspections 
The CRO monitor and regulatory authority inspectors are responsible for contacting and visiting 
the investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the study (eg, eCRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH good clinical practice (GCP) and local regulations on the conduct of 
clinical research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely.  The frequency of the monitoring visit will vary based on the 
activity at each Study Center.  The monitor is responsible for inspecting the eCRFs and ensuring 
completeness of the study essential documents.  The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the eCRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, GCP and applicable regulations to 
the investigator and will ensure that appropriate action (s) designed to prevent recurrence of the 
detected deviations is taken and documented. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor.  Audit of Study Center facilities (eg, pharmacy, drug 
storage areas, laboratories) and review of study related records will occur in order to evaluate the 
study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  The investigator should respond to audit findings.  In the event that a regulatory 
authority informs the investigator that it intends to conduct an inspection, the Sponsor shall be 
notified immediately. 
12.2. 
Data Collection 
The investigator, sub-investigator, or study staff will enter the data in the eCRF. 
The eCRF completion should be kept current and will be completed, and/or reviewed and 
e-signed by the investigator. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
sponsor. 
To ensure the quality of clinical data across all subjects and Study Centers, a Clinical Data 
Management review will be performed on subject data according to specifications given to CRO.  
Data will be vetted both electronically and manually for eCRFs and the data will be 
electronically vetted by programmed data rules within the application.  Queries generated by 
rules and raised by reviewers will be generated and resolved within the EDC application.  During 

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this review, subject data will be checked for consistency, completeness, and any apparent 
discrepancies. 
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA.  All concomitant medications, prior cancer therapy will 
be coded using WHODD. 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
eCRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date, and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of quizartinib/placebo, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the Study Center (Trial Master File).  
Source documents include all recordings and observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical study.  
These records will be retained in a secure file for the period required by the Study Center’s 
policy.  Prior to transfer or destruction of these records, the Sponsor must be notified in writing 
and be given the opportunity to further store such records. 
12.5. 
Record Keeping 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting copies of source 
documentation (if kept). 

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 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the EC/IRB and the Sponsor. 
 Records related to the quizartinib/placebo (s) including acknowledgment of receipt at 
Study Center, accountability records and final reconciliation and applicable 
correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All essential documentation will be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have lapsed since the 
formal discontinuation of clinical development of the investigational drug.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor.  It is the responsibility of the sponsor to 
inform the investigator/Study Center as to when these documents no longer need to be retained. 
Subject's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
No study document should be destroyed without prior written agreement between Sponsor and 
the investigator.  Should the investigator wish to assign the study records to another party or 
move them to another location, he/she must notify Sponsor in writing of the new responsible 
person and/or the new location. 

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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical study 
agreement.  This agreement will include the financial information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 

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14. 
PUBLICATION POLICY 

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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) for the regions in which the study 
is being conducted. 
15.2. 
Subject Confidentiality 
The investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The investigator must ensure that the subject’s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the investigator. 
In compliance with ICH GCP Guidelines, it is required that the investigator and Study Center 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
15.3. 
Informed Consent  
Before a subject’s participation in the study, it is the investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures are done or any quizartinib/placebo is administered.  Subjects should be given the 
opportunity to ask questions and receive satisfactory answers to their inquiries, and should have 
adequate time to decide whether or not to participate in the study.  The written ICFs should be 
prepared in the local language(s) of the potential subject population. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The ICF and any revision(s) should be approved 
by the EC or IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICFs should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the investigator).  The original signed ICFs 
should be retained in accordance with Study Center policy, and a copy of the signed ICF should 
be provided to the subject.  The date that informed consent was given should be recorded. 
For studies in the US, an additional consent is required for the Health Insurance Portability and 
Accountability Act.  Also, a separate special consent will be required for Pharmacogenomic 
testing for this protocol. 

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15.4. 
Regulatory Compliance 
The study protocol, subject information, and consent form, the IB, any subject written 
instructions to be given to the subject, available safety information, subject recruitment 
procedures (eg, advertisements), information about payments and compensation available to the 
subjects, and documentation evidencing the investigator’s qualifications should be submitted to 
the EC or IRB for ethical review and approval according to local regulations, prior to the study 
start.  The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The investigator and/or CRO must submit and, where necessary, obtain approval from the IEC or 
IRB for all subsequent protocol amendments and changes to the ICFs.  The investigator should 
notify the IEC or IRB of deviations from the protocol or SAEs occurring at the Study Center and 
other AE reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation, and that 
implementation of changes to the initial protocol and other relevant study documents happen 
only after approval by the relevant regulatory bodies. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authorities in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately. 
In addition, the investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the investigator becomes aware of. 
15.5. 
Protocol Deviations 
The investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRBs/IECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject.  Sponsor must be 
notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion criteria, 
dosing, missed study visits) on an expedited basis. 
The investigator, or person designated by the investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or quizartinib/placebo, and had at least 
1 administration of quizartinib/placebo, data should be collected for safety purposes. 
If applicable, the investigator should notify the IEC/ IRB of deviations from the protocol in 
accordance with local procedures. 

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15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all investigators involved in the clinical study, 
IECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IEC/IRB.  The investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICFs. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the investigator by Daiichi Sankyo or the CRO.  Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study centers in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol. 
A local protocol amendment will affect study conduct at a particular Study Center(s) and/or in a 
particular region/country.  Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 
15.8. 
Study Termination 
The sponsor has the right to terminate the study at any time and the study termination may also 
be requested by (a) competent authority/ies. 
Stopping criteria are noted in Section 5.9.2. 
15.9. 
Data Monitoring Committee 
An independent DMC will be created to further protect the rights, safety, and well-being of 
subjects who will be participating in this study by monitoring the progress and results.  The 
DMC will comprise qualified physicians and scientists who are not investigators in the study and 
not otherwise directly associated with the Sponsor. 

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The DMC will periodically review unblinded safety and/or efficacy data in this study.  The 
details about the reviews of the study data and other DMC processes will be described in the 
DMC charter. 
The DMC may recommend modification of the study protocol or study to the Steering 
Committee based on pre-specified rules described in the DMC charter. 
15.10. 
Independent Review Committee 
An IRC will be established to independently review specified study endpoints (see Section 7.5).  
The composition, tasks and detailed operating process of the IRC will be described in detail in 
the IRC charter for this study. 
15.11. 
Steering Committee 
The Steering Committee will be comprised of academic representatives who are experts in the 
field of leukemia and senior representatives from the Sponsor.  The Steering Committee has a 
scientific and clinical advisory function for the study and is not directly involved in operational 
matters.  The responsibilities of the Steering Committee include: 
 Review the protocol, amendments, and any substudies; and  
 Provide guidance on key scientific, medical, strategic, and policy issues;  
15.12. 
Address List 
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
updated in study reference materials.  

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16. 
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