Conditions: Leukemia, Myeloid, Acute
Keywords: FLT3-ITD Positive refractory or relapsed acute myeloid leukemia Hematology malignancy Developmental Phase II
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is a Phase 2, multi-center, open-label study to evaluate the efficacy, safety and pharmacokinetics of quizartinib monotherapy in Japanese subjects with FLT3-ITD positive refractory or relapsed acute myeloid leukemia.

Detailed description:

Arms:
arm 1: Participants who received an initial dose of 30 mg/day of quizartinib and, if no QT prolongation, the dose escalated to 60 mg/day at Day 15. arm 2: Participants who received a CYP3A4 strong inhibitor received an initial dose of 20 mg/day of quizartinib and, if no QT prolongation, the dose escalated to 30 mg/day at Day 15.

Interventions: intervention 1: Quizartinib
Intervention descriptions: intervention 1: Quizartinib was orally administered once daily every morning. Treatment with quizartinib was administered in 28-day cycles and continued until the discontinuation criteria for treatment were met.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Confidential 
 
 
 
 
 
Clinical Study Protocol 
A Phase 2 Open-label, Single-arm Study of Quizartinib 
(AC220) Monotherapy in Japanese Patients with FLT3-ITD 
Positive Refractory or Relapsed Acute Myeloid Leukemia 
 
 
AC220-A-J201 
 
 
 
Version 1.2, 19 May 2017 
 
 
Daiichi Sankyo Co., Ltd. 
 
 
Confidential Information 
Information contained in this document is proprietary to Daiichi Sankyo Co., Ltd.  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 
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an authorized representative of Daiichi Sankyo Co., Ltd. 


 
 
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PROTOCOL SYNOPSIS 
Protocol number: 
AC220-A-J201 
Investigational 
product: 
Quizartinib 
Active ingredient/ 
r-INN: 
AC220/quizartinib 
Study title: 
A Phase 2 Open-label, Single-arm Study of Quizartinib 
(AC220) Monotherapy in Japanese Patients with FLT3-ITD 
Positive Refractory or Relapsed Acute Myeloid Leukemia 
Phase of 
development: 
Phase 2 
Indication under 
investigation: 
Acute myeloid leukemia (AML) 
Study objectives: 
<Primary objective> 
To evaluate the composite complete remission (CRc) rate 
(defined as the proportion of patients whose best response is 
complete remission [CR], CR with incomplete platelet recovery 
[CRp], or CR with incomplete hematological recovery [CRi]) 
after treatment with quizartinib as multiple-dose monotherapy 
in Japanese patients with FMS-like tyrosine kinase 3 internal 
tandem duplication (FLT3-ITD) positive relapsed or refractory 
AML. 
 
<Secondary objectives> 
• 
To evaluate the best response with quizartinib 
• 
To evaluate the response rate with quizartinib 
• 
To evaluate the overall survival with quizartinib 
• 
To evaluate the event-free survival with quizartinib 
• 
To evaluate the leukemia-free survival with quizartinib 
• 
To evaluate the transplantation rate with quizartinib 
• 
To evaluate the safety of quizartinib 
• 
To evaluate the pharmacokinetics of quizartinib 
• 
To evaluate quizartinib-related biomarkers 
 


 
 
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<Type of study objectives> 
Efficacy, safety, and pharmacokinetics 
Study design: 
Type of study: Interventional 
Type of intervention: Pharmaceutical drugs 
Type of proposed indications: Treatment 
Study design: Single arm (two-stage design) 
<Stage 1> 
Concerning the 25 patients included in the efficacy analysis 
set, the study will be terminated both if CR, CRp, or CRi 
(CRc) is achieved in 3 or fewer patients (the treatment will be 
determined to be ineffective), or if CR, CRp, or CRi (CRc) is 
achieved in 11 or more patients (the treatment will be 
determined to be effective).  Meanwhile, if CRc is achieved 
in 4 to 10 patients, registration of patients will be continued 
until 41 patients are included in the efficacy analysis set 
(addition of 16 patients in Stage 2). 
<Stage 2> 
Concerning the 41 patients included in the efficacy analysis 
set, if CRc is achieved in 15 or more patients, the treatment is 
determined to be effective (rejection of the null hypothesis). 
Level of blinding: Open-label 
Type and presence/absence of comparator: Not applicable 
Presence/absence of add-on to standard therapy: Not applicable 
Planned study 
period: 
01 Dec 2016 to 31 Mar 2019 
Study centers and 
location: 
Refer to Attachment 1. 
Subject eligibility 
criteria: 
1) Provision of written informed consent for participation in 
the study. 
2) Patients aged 20 years or older when consent is obtained. 
3) Primary AML patients or AML patients with a history of 
myelodysplastic syndrome (MDS). 
4) AML patients who have first relapsed within 6 months after 
achieving remission with initial remission induction 


 
 
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therapy or those who are refractory to all therapies given 
prior to the start of the study and failed to achieve 
remission.  The initial remission induction therapy must 
be a regimen containing at least 1 cycle of standard-dose 
treatment with anthracyclines or mitoxantrone.  It is not 
taken into consideration whether they have hematopoietic 
stem cell transplant (HSCT) or not. 
• 
Definition of refractory to treatment 
• 
Patients who have less than 50% reduction in bone 
marrow blasts and have failed to achieve CR, CRp, 
or CRi after 1 cycle of treatment. 
• 
Patients who have failed to achieve CR, CRp, or 
CRi after 2 cycles of treatment. 
• 
Definition of first relapse (within 6 months after 
achieving remission) 
• 
Patients who have achieved CR, CRp, or CRi after 
initial remission induction therapy and have 
relapsed within 6 months.  It is not taken into 
consideration whether they have received 
consolidation therapy, maintenance therapy, or 
HSCT or not. 
• 
The duration of remission is defined as the day of 
the bone marrow test when CR, CRp, or CRi was 
confirmed or the day of HSCT to the day of the 
bone marrow test when relapse was confirmed or 
the day of reappearance of leukemic blasts in the 
peripheral blood. 
5) Patients with mutations of the FLT3-ITD gene in bone 
marrow or peripheral blood. 
* A specimen for the FLT3-ITD mutation test will be 
submitted to Navigate BioPharma Services, Inc. (Navigate 
BioPharma), the central laboratory, to test mutations in the 
FLT3-ITD gene.  However, patients who have been 
confirmed to be FLT3-ITD positive in the FLT3-ITD 
testing previously performed at another testing company or 


 
 
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the central laboratory, SRL Inc., may be assessed for 
eligibility for the study without waiting for the result of 
measurement at Navigate BioPharma. 
6) Eastern Cooperative Oncology Group performance status 
(ECOG PS) score 0 to 2 (refer to “Appendix 2”). 
7) Patients in whom the intervals listed below can be achieved 
between the last dose or application of prior therapy and the 
first dose of the study drug in the study: 
• 
Cytotoxic drugs (excluding hydroxycarbamide used for 
the purpose of controlling the increase in white blood 
cells): 2 weeks 
• 
Non-cytotoxic drugs: at least 5 × the half-life of the 
drug 
8) Laboratory test results obtained within 14 days before 
registration meet all of the following requirements: 
Laboratory Parameter 
Requirement 
AST 
≤ 2.5 times the upper limit of the 
institutional reference range 
ALT 
≤ 2.5 times the upper limit of the 
institutional reference range 
Total bilirubin 
≤ 1.5 times the upper limit of the 
institutional reference range 
Serum creatinine 
≤ 1.5 times the upper limit of the 
institutional reference range  
(or estimated glomerular filtration rate 
[eGFR]* ≥ 25 mL/min/1.73 m2) 
Serum K 
Within the institutional reference range** 
Serum Mg 
Within the institutional reference range** 
Serum Ca (corrected for albumin) 
Within the institutional reference range** 
* eGFR (mL/min/1.73 m2)  194 × serum creatinine 1.094 × age 0.287 (× 0.739 for 
females) 
** Patients with electrolytes outside the institutional reference range will be 
eligible if these values are corrected upon retesting following any necessary 
supplementation. 
 
9) Patients who can receive quizartinib orally. 
 
<Exclusion criteria> 
1) Diagnosis of acute promyelocytic leukemia. 
2) Patients who developed AML in association with prior 
chemotherapy or radiotherapy given to treat another 
malignant tumor than AML (patients with treatment-related 


 
 
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AML).  However, this shall not apply to patients with a 
history of MDS. 
3) History of malignant tumor within 5 years before 
registration. 
* However, participation of the following patients in the 
study is allowed. 
• 
Curatively treated skin cancer other than malignant 
melanoma, carcinoma in situ, or cervical carcinoma in 
situ (The time to onset of AML is not considered when 
the standard therapy has been completed.) 
• 
Prostate cancer without local recurrence or progression 
(any of the cases in which hormonal therapy has been 
initiated, the tumor has been surgically removed, or the 
lesion has disappeared with radiotherapy) 
4) Persistent, symptomatic Grade 2 or more severe 
non-hematological toxicity (excluding alopecia) from prior 
therapy. 
5) Patients with graft-versus-host disease (GVHD) that is 
clinically significant or requiring treatment, those who need 
to start treatment for GVHD, those requiring intensified 
treatment for GVHD within 21 days before registration, or 
those with Grade 2 or more severe clinically significant or 
irreversible non-hematological toxicity related to HSCT. 
6) History of or current symptomatic central nervous system 
involvement with clinical symptoms. 
7) Disseminated intravascular coagulation, or other clinically 
significant coagulation abnormalities. 
8) Prior treatment with quizartinib or prior participation in any 
clinical study of quizartinib. 
9) Prior treatment with other FLT3 inhibitors (sorafenib or 
other FLT3 inhibitors under development) (This does not 
include midostaurin.) 
10) Extensive surgery within 28 days before registration. 
11) Radiation therapy within 28 days before registration. 
12) History of or current cardiovascular disease as specified 


 
 
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below: 
• 
QT corrected for heart rate using Fridericia’s method 
(QTcF) interval of 450 ms or longer, determined as the 
average of three central electrocardiogram (ECG) 
measurements taken within 14 days before registration 
• 
Heart rate of 50 beats/min or lower, determined as the 
average of three central ECG measurements taken 
within 14 days before registration (excluding patients 
with a cardiac pacemaker) 
• 
Previous, current, or suspected long QT syndrome, or a 
family history of congenital long QT syndrome 
• 
History of life-threatening ventricular arrhythmia, such 
as ventricular tachycardia, ventricular fibrillation, or 
torsades de pointes 
• 
Second or third degree heart block (This shall not 
apply to patients who have second or third degree heart 
block, but who have a cardiac pacemaker and have 
never experienced syncope or arrhythmia before.) 
• 
History of myocardial infarction within 6 months 
before registration 
• 
History of uncontrolled angina pectoris within 6 
months before registration 
• 
Class III or more severe congestive heart failure 
according to “Appendix 3 New York Heart Association 
(NYHA) Functional Classification” 
• 
Left ventricular ejection fraction (LVEF) below 45% or 
the lower limit of the institutional reference range 
• 
Uncontrolled hypertension 
• 
Complete left or right bundle branch block 
13) Active infection that is not well controlled with 
antibacterial, antifungal, or antiviral therapy. 
14) Active liver disease (hepatitis B, hepatitis C, etc.) 
15) Tested positive for human immunodeficiency virus (HIV) 
antibody within 120 days before registration. 
16) Women of childbearing potential, or their male partners 


 
 
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who are unable or unwilling to practice appropriate 
contraception using effective contraceptive methods (eg, 
barrier contraceptives combined with spermicides, 
intrauterine device) for the entire study period and 3 
months after the last dose of the study drug. 
 
Women of non-childbearing potential (postmenopausal 
women with no menses for at least 2 years and women who 
have undergone hysterectomy etc. at least 1 month before 
registration) may be registered in the study. 
 
Male patients may not donate their sperm during the period 
from 14 days before registration to 105 days after the last 
dose of the study drug.  Female patients may not donate 
their eggs during the period from 14 days before 
registration to 12 weeks after the last dose of the study 
drug. 
17) Women found to be pregnant by a pregnancy test 
performed within 14 days before registration. 
18) Women who may need to breastfeed during the study 
period and for 25 days after the last dose of the study drug. 
19) Patients who are otherwise considered ineligible for the 
study in the opinion of the investigators (investigator or 
subinvestigator). 
Dosage form, dose 
and route of 
administration: 
<Dosage form> 
White film-coated tablets, each of which contains 20 mg 
AC220, or yellow film-coated tablets, each of which contains 
30 mg AC220. 
 
<Regimen> 
Quizartinib will be administered at an initial dose of 30 mg/day.  
For patients receiving strong cytochrome P450 (CYP) 3A4 
inhibitors, an initial dose of 20 mg/day will be used.  
Quizartinib will be orally administered once daily every 
morning.  Treatment with quizartinib will be administered in 


 
 
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28-day cycles and continued until the withdrawal criteria are 
met. 
If a patient vomits after taking a dose of the study drug, a 
replacement dose may not be given on the same day. 
A patient who did not take the study drug at the usual hour of 
dosing (eg, forgot to take the dose) will be allowed to take the 
missed dose within 10 hours after the usual hour of dosing (for 
example, if the patient usually takes the drug at 7:00 or 8:00, 
he/she may take it by 17:00 or 18:00).  In this case, the next 
dose of the study drug on the following day should be taken at 
least 12 hours after the time when the last dose was taken.  If 
the patient does not take the missed dose by 10 hours after the 
usual hour of dosing, he/she should not take the study drug on 
that day and resume taking the drug on the following day.  The 
patient may not take two doses at once on the day when the 
drug is resumed. 
 
<Criteria for dose increase of the study drug> 
The dose of quizartinib will be increased in accordance with the 
following criteria.  A 12-lead ECG will be measured at least 
once weekly for the first 2 weeks after a dose increase to 
confirm the presence or absence of QTcF prolongation after the 
dose increase.  When doing this, triplicate ECG recordings 
will be obtained. 
 
Assessment criteria for dose increase on Day 16 of Cycle 1 
Patients not concomitantly using strong CYP3A4 inhibitors: 
The dose of quizartinib will be increased to 60 mg/day if all 
QTcF data (determined as the average of three measurements) 
taken by Day 15 of Cycle 1 are 450 ms or shorter. 
 
Patients concomitantly using strong CYP3A4 inhibitors: 
The dose of quizartinib will be increased to 30 mg/day if all 
QTcF data (determined as the average of three measurements) 
taken by Day 15 of Cycle 1 are 450 ms or shorter. 


 
 
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Assessment criteria for dose increase on Day 1 of Cycle 2 
For patients who have not achieved CR, CRp, or CRi after at 
least 1 cycle of treatment with quizartinib and whose condition 
before the decision on dose increase satisfies the following 
requirements, the dose of quizartinib will be increased. 
• 
Absence of Grade 3 or more severe treatment-related 
non-hematological toxicity 
• 
60 ms or shorter increase in QTcF interval from baseline 
• 
Absence of hypoplastic bone marrow upon the decision of a 
dose increase 
 
For patients who have relapsed after achieving CR, CRp, CRi, 
or partial remission (PR), and satisfy the above criteria, the dose 
of quizartinib may be increased.  The dose will be increased to 
60 mg/day if strong CYP3A4 inhibitors are not concomitantly 
used, and to 30 mg/day if strong CYP3A4 inhibitors are 
concomitantly used. 
Study endpoints: 
Primary endpoint: 
CRc rate (composite complete remission rate) 
 
Secondary endpoints: 
• 
Best response 
• 
Response rate 
• 
Overall survival 
• 
Event-free survival 
• 
Leukemia-free survival 
• 
Safety (Adverse events [AEs], laboratory data, vital signs, 
body weight, ECOG PS, 12-lead ECG) 
• 
Pharmacokinetics (plasma concentrations of quizartinib and 
its active metabolite, and pharmacokinetic parameters) 
• 
Biomarkers (plasma inhibitory activity of quizartinib on 
phosphorylated FLT3 and c-Kit proteins) 
Planned sample size: 25 patients for Stage 1, and 16 patients for Stage 2; 41 patients 
in total 


 
 
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Statistical analyses: 
Efficacy evaluation: 
In the efficacy analysis set, frequency tables will be prepared 
for the best response, CRc rate, and response rate (RR: defined 
as the proportion of patients whose best response is CR, CRp, 
CRi, or PR), and the confidence intervals (CIs) will be 
calculated. 
Safety evaluation: 
Safety will be evaluated in the safety analysis set.  Concerning 
AEs that newly appear after the first dose of the study drug or 
that worsen relative to the pre-treatment state, frequency tables 
will be prepared by event (system organ class/preferred term), 
causality with the study drug, and grade according to the 
Common Terminology Criteria for Adverse Events (CTCAE).  
Concerning laboratory data, vital sign measurements, body 
weight, ECOG PS, and 12-lead ECG findings, frequency tables 
or shift tables will be prepared for categorical data, and 
summary statistics will be calculated for quantitative data.  To 
evaluate QT prolongation, summary statistics of QTcF will be 
calculated, and frequency tables will be prepared according to 
the predefined categories. 
Pharmacokinetics: 
In the pharmacokinetic analysis set, summary statistics of the 
plasma concentrations of quizartinib and AC886 will be 
calculated by dose at each time point, and plasma 
concentration-time profiles will be prepared.  Summary 
statistics of pharmacokinetic parameters will be calculated by 
dose at each time point. 
Biomarkers: 
In the biomarker analysis set, the measured values of the 
plasma inhibitory activity of quizartinib on phosphorylated 
FLT3 and c-Kit proteins will be summarized at each time point. 
 


 
 
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Table of Contents 
1. INTRODUCTION ...................................................................................................... 21 
1.1 Background of This Study ......................................................................................... 21 
1.2 Study Rationale .......................................................................................................... 22 
1.2.1 Summary of the Investigational Drug .................................................................... 22 
1.2.1.1 
Nonclinical Study Data ...................................................................................... 22 
1.2.1.2 
Clinical Study Data ............................................................................................ 25 
1.2.1.3 
Known and Expected Risks and Benefits .......................................................... 29 
1.2.2 Study Rationale ...................................................................................................... 30 
2. STUDY OBJECTIVES AND HYPOTHESIS ......................................................... 31 
2.1 Study Objectives ........................................................................................................ 31 
2.1.1 Primary Objective .................................................................................................. 31 
2.1.2 Secondary Objectives ............................................................................................. 31 
2.2 Study Hypotheses ....................................................................................................... 31 
3. STUDY DESIGN ........................................................................................................ 32 
3.1 Overall Design ........................................................................................................... 32 
3.2 Discussion of Study Design ....................................................................................... 33 
3.2.1 Rationale for the Dose and Dosage of the Study Drug ......................................... 33 
3.2.2 Rationale for the Method of Dose Increase of the Study Drug ............................. 34 
3.2.3 Rationale for Sample Size ...................................................................................... 35 
4. STUDY POPULATION ............................................................................................. 35 
4.1 Inclusion Criteria ........................................................................................................ 36 
4.2 Exclusion Criteria ...................................................................................................... 38 
5. STUDY TREATMENT .............................................................................................. 40 
5.1 Assigning Patients to Treatments and Blinding......................................................... 40 
5.1.1 Treatment Groups ................................................................................................... 40 
5.1.2 Method of Treatment Allocation ............................................................................ 40 
5.1.3 Blinding .................................................................................................................. 42 
5.1.4 Emergency Unblinding Procedure ......................................................................... 42 
5.2 Study Drug ................................................................................................................. 42 
5.2.1 Description ............................................................................................................. 42 
5.2.2 Labeling and Packaging ......................................................................................... 43 
5.2.3 Preparation ............................................................................................................. 43 
5.2.4 Administration ........................................................................................................ 43 
5.2.4.1 
Dose of the Study Drug ...................................................................................... 43 


 
 
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5.2.4.2 
Regimen.............................................................................................................. 44 
5.2.4.3 
Criteria for Dose Increase of the Study Drug .................................................... 44 
5.2.5 Storage .................................................................................................................... 46 
5.2.6 Drug Accountability ............................................................................................... 46 
5.3 Control Treatment ...................................................................................................... 46 
5.4 Dose Interruptions and Reductions ............................................................................ 46 
5.4.1 QTcF Prolongation ................................................................................................. 47 
5.4.2 Non-hematological Toxicity .................................................................................. 48 
5.4.3 Bone Marrow Depression ...................................................................................... 48 
5.4.4 If Concomitant Use of Strong CYP3A4 Inhibitors Is Started during the Study 
Period...................................................................................................................... 48 
5.4.5 Dose Increase after Dose Reduction ...................................................................... 48 
5.5 Method of Assessing Treatment Compliance ............................................................ 49 
5.6 Concomitant Medications .......................................................................................... 49 
5.6.1 Investigation Items ................................................................................................. 49 
5.6.2 Prohibited Concomitant Drugs, Restricted Concomitant Drugs, and Drugs to Be 
Coadministered with Care ...................................................................................... 49 
5.6.2.1 
Prohibited Concomitant Drugs .......................................................................... 49 
5.6.2.2 
Drugs to Be Coadministered with Care ............................................................. 50 
5.7 Subject Withdrawal/Discontinuation ......................................................................... 51 
5.7.1 Discontinuation Criteria for Treatment with the Study Drug ................................ 51 
5.7.2 Reasons for Discontinuation during the Post-treatment Observation Period and the 
Follow-up Period .................................................................................................... 51 
5.7.3 Withdrawal Procedures .......................................................................................... 52 
6. STUDY PROCEDURES ............................................................................................ 52 
6.1 Procedures to Be Performed before Patient Registration .......................................... 55 
6.2 Procedures during the Study Conduct Phase ............................................................. 58 
6.3 Procedures When Treatment with the Study Drug Is Discontinued .......................... 61 
6.4 Procedures during the Post-treatment Observation Period ....................................... 62 
6.5 Post Treatment ............................................................................................................ 62 
6.6 Follow-up ................................................................................................................... 62 
6.7 Definition of the Study Period ................................................................................... 63 
6.8 Pharmacokinetics ....................................................................................................... 63 
6.9 FLT3-ITD Mutation Test ............................................................................................ 64 
6.10 Biomarker Study ........................................................................................................ 64 


 
 
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6.10.1 Plasma Inhibitory Activity of Quizartinib on Phosphorylated FLT3 and c-Kit 
Proteins ................................................................................................................... 64 
7. EFFICACY ASSESSMENTS .................................................................................... 65 
7.1 Definition of Efficacy Endpoints ............................................................................... 65 
7.2 Best Response ............................................................................................................ 66 
7.3 Primary Efficacy Endpoint ........................................................................................ 66 
7.4 Secondary Efficacy Endpoints ................................................................................... 67 
7.5 Appropriateness of Selected Efficacy Endpoints ...................................................... 67 
8. PHARMACOKINETIC/BIOMARKER ASSESSMENTS .................................... 67 
8.1 Pharmacokinetic Endpoints ....................................................................................... 67 
8.1.1 Amount and Time Points of Blood Collection ...................................................... 68 
8.2 Biomarker Endpoints ................................................................................................. 68 
8.3 Anonymization, Storage, and Disposal of Specimens for Biomarker Testing .......... 68 
8.3.1 Anonymization of Specimens ................................................................................ 68 
8.3.2 Storage of Specimens ............................................................................................. 68 
8.3.3 Disposal of Specimens ........................................................................................... 68 
9. SAFETY EVALUATION AND REPORTING ........................................................ 69 
9.1 Adverse Event Collection and Reporting .................................................................. 69 
9.2 Safety Endpoints ........................................................................................................ 70 
9.2.1 Combined Elevations of Aminotransferases and Bilirubin ................................... 71 
9.3 Adverse Events........................................................................................................... 71 
9.3.1 Definition of Adverse Events ................................................................................. 71 
9.3.2 Serious Adverse Events .......................................................................................... 72 
9.3.3 Severity Assessment ............................................................................................... 72 
9.3.4 Causality Assessment ............................................................................................. 73 
9.3.5 Action Taken Regarding the Study Drug ............................................................... 73 
9.3.6 Other Action Taken for Event ................................................................................ 74 
9.3.7 Adverse Event Outcome ........................................................................................ 74 
9.4 Serious Adverse Events Reporting Procedure for Investigators .............................. 74 
9.5 Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ............................................................................................ 75 
9.6 Exposure In Utero during Clinical Studies ................................................................ 76 
9.7 Clinical Laboratory Evaluations ................................................................................ 76 
9.8 ECOG PS .................................................................................................................... 77 
9.9 Vital Signs .................................................................................................................. 77 


 
 
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9.10 Electrocardiograms .................................................................................................... 77 
9.10.1 Measurement Method ............................................................................................ 77 
9.10.2 Measures Taken in Case of QTcF Prolongation .................................................... 78 
9.10.3 Chest X-ray Examination ....................................................................................... 79 
9.10.4 MUGA Scan or Echocardiography ........................................................................ 79 
10. OTHER ASSESSMENTS .......................................................................................... 79 
11. STATISTICAL METHODS ...................................................................................... 79 
11.1 General Statistical Considerations ............................................................................. 79 
11.2 Analysis Sets .............................................................................................................. 80 
11.3 Statistical Analyses .................................................................................................... 80 
11.3.1 Efficacy Analyses ................................................................................................... 80 
11.3.1.1 Primary Efficacy Analyses ................................................................................. 81 
11.3.1.2 Secondary Efficacy Analyses ............................................................................. 81 
11.3.1.3 Exploratory Efficacy Analyses .......................................................................... 81 
11.3.2 Pharmacokinetic/Pharmacodynamic Analyses ...................................................... 81 
11.3.2.1 Pharmacokinetic Analyses ................................................................................. 81 
11.3.2.2 Pharmacodynamic Analyses .............................................................................. 81 
11.3.2.3 Biomarker Analyses ........................................................................................... 81 
11.3.2.4 Pharmacogenomic Analyses .............................................................................. 82 
11.3.3 Safety Analyses ...................................................................................................... 82 
11.3.3.1 Adverse Event Analyses ..................................................................................... 82 
11.3.3.2 Clinical Laboratory Evaluation Analyses .......................................................... 82 
11.3.3.3 Vital Sign Analyses ............................................................................................ 83 
11.3.3.4 Electrocardiogram Analyses .............................................................................. 83 
11.3.3.5 Analyses of Physical Findings ........................................................................... 83 
11.3.3.6 Exploratory Safety Analyses .............................................................................. 83 
11.3.4 Other Analyses ....................................................................................................... 83 
11.3.5 Blinded Review ...................................................................................................... 84 
11.4 Interim Analysis ......................................................................................................... 84 
11.4.1 Purposes of the Interim Analysis ........................................................................... 84 
11.4.2 Possible Options to Be Taken at Interim Analysis ................................................ 84 
11.4.3 Criteria .................................................................................................................... 85 
11.4.4 Data Monitoring Committee .................................................................................. 85 
11.5 Determination of Sample Size ................................................................................... 86 
11.6 Statistical Analysis Process ........................................................................................ 87 


 
 
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12. DATA INTEGRITY AND QUALITY ASSURANCE ............................................. 87 
12.1 Monitoring and Inspections ....................................................................................... 88 
12.2 Data Collection........................................................................................................... 88 
12.2.1 Completion of the Case Report Forms .................................................................. 88 
12.2.2 Precautions for Entering Data in the Case Report Form ....................................... 89 
12.3 Data Management ...................................................................................................... 90 
12.4 Study Documentation and Storage ............................................................................. 90 
12.5 Record Keeping .......................................................................................................... 91 
13. Payment and Insurance ............................................................................................. 92 
13.1 Payment ...................................................................................................................... 92 
13.2 Payment, Compensation for Study-related Injury, and Insurance ............................. 92 
14. PUBLICATION POLICY ......................................................................................... 93 
15. ETHICS AND STUDY ADMINISTRATIVE INFORMATION ........................... 93 
15.1 Compliance Statement, Ethics, and Regulatory Compliance .................................... 93 
15.2 Subject Confidentiality .............................................................................................. 94 
15.3 Informed Consent ....................................................................................................... 94 
15.4 Regulatory Compliance ............................................................................................. 95 
15.5 Protocol Deviations .................................................................................................... 96 
15.6 Provision of New Information Affecting the Conduct of the Study ......................... 96 
15.7 Protocol Amendment .................................................................................................. 97 
15.8 Discontinuation of the Study ..................................................................................... 97 
16. Others .......................................................................................................................... 98 
16.1 Payment for Participation, Compensation for Study-related Injuries, and Insurance .... 98 
16.1.1 Payment for Participation ...................................................................................... 98 
16.1.2 Compensation for Study-related Injuries ............................................................... 98 
16.1.3 Insurance ................................................................................................................ 98 
16.1.4 Notifying Any Other Physicians Treating Patients of Their Study Participation .... 99 
16.1.5 Quality Control and Quality Assurance ................................................................. 99 
17. Data and Safety Monitoring Board ........................................................................ 100 
18. Address List .............................................................................................................. 100 
18.1 Sponsor’s Responsible Medical Officer .................................................................. 100 
18.2 Sponsor’s Clinical Study Leader ............................................................................. 100 
18.3 Sponsor’s Safety Contacts ....................................................................................... 100 
18.4 Medical Monitor....................................................................................................... 100 
18.5 Contract Research Organization .............................................................................. 100 


 
 
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18.6 EDC Vendor ............................................................................................................. 100 
18.7 IXRS Vendor ............................................................................................................ 101 
18.8 Central Laboratory ................................................................................................... 101 
18.8.1 Measurement of Drug Concentrations ................................................................. 101 
18.8.2 Investigation of Mutations of the FLT3-ITD Gene ............................................. 101 
18.8.3 Agency for Collection etc. of Specimens for Drug Concentration Measurement 
and Investigation of Mutations of the FLT3-ITD Gene ...................................... 101 
18.8.4 12-lead Electrocardiogram Measurement and Assessment ................................. 101 
18.9 Sponsor’s Biostatistician .......................................................................................... 101 
18.10 Data Safety Monitoring Board ............................................................................. 102 
18.11 Emergency Contact Information .......................................................................... 102 
19. REFERENCES ......................................................................................................... 103 
20. APPENDICES/ATTACHMENTS .......................................................................... 105 
 


 
 
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List of Tables 
Table 1.2-1  Maximum Values of QT Corrected for Heart Rate Using Fridericia’s 
Method (QTcF) and Maximum Changes from Baseline in QTcF in Two Phase 
2 Studies ........................................................................................................... 27 
Table 1.2-2  Composite Complete Remission and Partial Response Rates in Two Phase 2 
Studies .............................................................................................................. 27 
Table 5.2-1  Information Displayed on the Study Drug Label ........................................ 43 
Table 5.2-2  Method of Dose Increase of Quizartinib ..................................................... 45 
Table 5.4-1  Method of Dose Reduction of Quizartinib .................................................. 47 
Table 5.4-2  Criteria for Dose Interruption and Reduction When QTcF Prolongation 
Occurs during Treatment with Quizartinib at 30 mg/day or 60 mg/day ......... 47 
Table 5.4-3  Criteria for Dose Interruption and Reduction When QTcF Prolongation 
Occurs during Treatment with Quizartinib at 20 mg/day ................................ 47 
Table 6-1  Schedule of Study Procedures ........................................................................ 53 
Table 6.8-1  Blood Collection Points for Pharmacokinetic Assessment ......................... 64 
Table 6.10-1  Blood Collection Points for Plasma Inhibitory Activity ........................... 65 
Table 7.1-1  Definition of Efficacy Endpoints ................................................................ 66 
Table 9.3-1  Evaluation of Severity of Adverse Events................................................... 73 
Table 11.5-1  Number of Patients Evaluated at Each Stage and Assessment Criteria .... 87 
Table 12.2-1  EDC System ............................................................................................... 90 
 


 
 
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List of Figures 
Figure 5-1  Patient Registration Procedure ...................................................................... 42 
 


 
 
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List of Abbreviations 
Abbreviation 
Full Expression 
ALP 
alkaline phosphatase 
ALT 
L alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
L aspartate aminotransferase 
CDISC 
Clinical Data Interchange Standards Consortium 
CR 
complete remission 
CRc 
composite CR 
CRi 
CR with incomplete hematological recovery 
CRO 
Contract Research Organization 
CRp 
CR with incomplete platelet recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electric case report form 
EDC 
electronic data capturing 
eGFR 
estimated glomerular filtration rate 
FLT3 
FMS like tyrosine kinase 3 
GCP 
Good Clinical Practice 
γ GT 
γ glutamyl transferase 
GVHD 
graft versus host disease 
hERG 
human ether à go go related gene 
HIV 
human immunodeficiency virus 
HSCT 
hematopoietic stem cell transplant 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IKr 
potassium current carried by channel formed from hERG subunits 
IKs 
potassium current carried by channel formed from KVLQT1 (KCNQ1) subunits 
and minK (KCNE1) b subunits 
IRB 
institutional review board 
ITD 
internal tandem duplication 
LVEF 
left ventricular ejection fraction 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 
NR 
no response 
OS 
overall survival 
PIA 
plasma inhibitory activity 
PK 
pharmacokinetics 
PR 
partial remission 


 
 
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Abbreviation 
Full Expression 
PS 
performance status 
QT 
interval between the start of the Q wave and the end of the T wave 
QTc 
corrected QT interval 
QTcF 
QT corrected for heart rate using Fridericia’s method 
RET 
ret proto oncogene 
RTK 
receptor tyrosine kinase 
SAP 
statistical analysis plan 
SAVER 
Serious Adverse Event Report 
STAT5 
signal transducer and activator of transcription 5 
TdP 
torsades de pointes 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
WT 
wild type 
 
List of Pharmacokinetic Parameters 
Abbreviation 
Full Expression 
AUC 
area under the plasma concentration time curve 
AUCinf 
area under the plasma concentration time curve up to infinity 
AUCtau 
area under the plasma concentration time curve during dosing interval 
AUCtau, ss 
area under the plasma concentration time curve during dosing interval at steady state 
Cmax 
maximum plasma concentration 
Cmax, ss 
maximum plasma concentration at steady state 
Ctrough 
trough plasma concentration 
Tmax 
time to reach maximum plasma concentration 
Tmax, ss 
time to reach maximum plasma concentration at steady state 
 
List of Terms 
Term 
Definition 
AC220 
Development code of quizartinib 
AC886 
Active metabolite of quizartinib 
 


 
 
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1. 
INTRODUCTION 
1.1 
Background of This Study 
Acute myeloid leukemia (AML) is a hematological malignant tumor characterized by 
autonomous growth of myeloid blast cells (myeloblasts) that are unable to differentiate or 
further develop into mature white blood cells, and its clinical presentation is diverse.1)  
According to “Cancer Registration and Statistics” of the Cancer Information Service, 
National Cancer Center, the crude prevalence rate of leukemia is 9.6 (11.4 for males and 
7.9 for females) per 100 000 people in 2011 and it is increasing each year.2)  The 
prevalence rate of AML by itself is unknown; however, acute leukemia accounts for 
about 80% of all leukemias, and AML accounts for approximately 80% of adult acute 
leukemia cases and 20% of pediatric acute leukemia cases.  While AML has become a 
disease that is considered curable in recent years, the long-term survival rate after 
complete remission (CR) with chemotherapy in AML patients remains low at about 
40%.3)  This is attributable to frequent relapse after remission.  How to prevent relapse 
is a major problem of chemotherapy.  To solve this problem, many research studies have 
identified poor prognostic factors in attempts to stratify AML.  In patients with poor 
prognostic factors, intensified treatment does not necessarily improve the prognosis.  
Therefore, it is necessary to develop molecular targeting drugs in line with the molecular 
platform that plays a key role in AML.4),5),6) 
FMS-like tyrosine kinase 3 (FLT3) mutations, which are found in approximately 30% of 
AML patients, represent an important poor prognostic factor and are listed as gene 
abnormalities that can be searched in the World Health Organization (WHO) 
classification version 4.5),6)  FLT3 is a Class III receptor tyrosine kinase (RTK), like 
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), colony 
stimulating factor 1 receptor (CSF1R), and platelet-derived growth factor receptor 
(PDGFR), and contains an intracellular tyrosine kinase domain split in two by the 
juxtamembrane domain.  FLT3 is primarily expressed on hematopoietic progenitor cells 
and is dimerized and activated by ligand binding, and then involved in hematocyte 
differentiation and proliferation as well as self-replication of hematopoietic stem cells.7)  
FLT3 molecules are expressed on the leukemia cell surface in most cases of AML and 
acute lymphocytic leukemia, and play a role in the survival and proliferation of leukemia 
cells.  There are two main types of FLT3 mutations: FLT3-internal tandem duplication 
(FLT3-ITD), which involves repetition of part of the juxtamembrane domain, and kinase 
domain mutation (KDM), which involves point mutation or deletion of the aspartic acid 
residue at position 835 (D835) in the tyrosine kinase domain or surrounding residues.7)  


 
 
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These gene mutations cause FLT3 ligand-independent, constant activation of FLT3 
molecules and contribute to the promotion of leukemia cell proliferation via activation of 
downstream signaling pathways, including signal transducer and activator of 
transcription 5 (STAT5), mitogen-activated protein kinase (MAPK), and 
phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT).  Therefore, mutated 
FLT3 molecules are recognized as promising target molecules for the treatment of 
AML.6) 
 
1.2 
Study Rationale 
1.2.1 
Summary of the Investigational Drug 
Quizartinib (development code: AC220), synthesized by Ambit Biosciences Corporation, 
is a Class III RTK inhibitor that has potent and selective FLT3 inhibitory activity.  
Quizartinib for the treatment of AML is currently under clinical development overseas 
and in Japan.  Shown below is a brief summary of data from the major nonclinical and 
clinical studies that have been conducted overseas and in Japan. 
 
1.2.1.1 
Nonclinical Study Data 
1.2.1.1.1 
Pharmacology 
In a biochemical binding assay using a panel of 441 kinases, quizartinib and its 
metabolite, AC886, exhibited the highest binding affinity for FLT3.  The binding 
affinity of quizartinib for other Class III RTKs (eg, KIT, CSF1R/FMS, PDGFRβ, RET) 
was within 10-fold lower than that for FLT3, and quizartinib had little or no affinity for 
other kinases, or for other enzymes, receptors, or channels than kinases. 
In human MV4-11 leukemia cell line with FLT3-ITD mutations treated with quizartinib 
and AC886, these compounds inhibited FLT3-ITD autophosphorylation, as well as 
FLT3-dependent cell proliferation.  Following 28-day (once daily) repeated oral dosing 
of quizartinib in mice with flank solid tumors established by subcutaneously implanted 
MV4-11 cells, quizartinib inhibited tumor growth at 1 mg/kg and induced tumor 
regression at 3 mg/kg and 10 mg/kg.  At 10 mg/kg, tumors did not regrow throughout 
the entire 32-day follow-up period after quizartinib dosing.  Quizartinib administered in 
combination with chemotherapy (cytarabine and daunorubicin) was also confirmed to 
have superior antitumor activity and be well tolerated in the above-mentioned mouse 
model. 
 


 
 
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1.2.1.1.2 
Safety Pharmacology Studies 
In a telemetry study in cynomolgus monkeys, quizartinib dose-dependently prolonged the 
corrected QT interval (QTc) and transiently increased systemic blood pressure at 
10 mg/kg or more; however, no hemodynamic or electrocardiographic (ECG) changes 
were seen at 3 mg/kg.  In the assessment of potential effects of quizartinib and AC886 
on potassium current carried by the channel formed from human ether-à-go-go related 
gene (hERG) subunits (IKr) channel-coded by hERG using a patch clamp approach in 
HEK293 cells overexpressing hERG, quizartinib did not inhibit the IKr channel, whereas 
AC886 inhibited the IKr channel concentration-independently (maximum inhibition: 
30% to 40%).  In the assessment of potential effects of quizartinib and AC886 on 
sodium current (INa), potassium current carried by the channel formed from KVLQT1 
(KCNQ1) subunits and minK (KCNE1) b-subunits (IKs), and long-lasting calcium 
current (ICa-L), quizartinib inhibited IKs, and AC886 inhibited INa, IKs, and ICa-L.  In 
ex vivo studies using rabbit heart preparations, quizartinib and AC886 caused increases 
in QTc interval at concentrations of more than 3 μM.  It was thus suggested that the 
effects of the two compounds on potassium currents (IKs + IKr) would play a role in QTc 
prolongation. 
 
1.2.1.1.3 
Pharmacokinetics and Drug Metabolism 
Plasma exposure of quizartinib was approximately dose proportional in mice, rats, dogs, 
and monkeys.  In all examined species, quizartinib was converted to the active 
metabolite, AC886.  Bioavailability of quizartinib across species ranged from 16% in 
monkeys to 40% in dogs.  The low bioavailability of quizartinib in monkeys was 
considered to be related to the high metabolic clearance of quizartinib to the active 
metabolite AC886.  The presence of food was suggested to enhance the fraction of 
administered quizartinib dose absorbed in rats.  In rats given repeated doses, there was 
evidence of accumulated quizartinib, but no evidence of self-induced metabolism.  
Quizartinib and AC886 were shown to be highly bound to plasma proteins (> 99% in all 
species tested), and quizartinib was shown to poorly penetrate the brain in rats.  
Quizartinib was confirmed to be neither an inhibitor (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 
and 3A4) nor an inducer (3A4 and 1A) of major human cytochrome P450 (CYP) 
isoenzymes.  AC886 showed weak inhibitory activity against CYP2C8, but had no 
inhibitory activity against the other isoenzymes, which suggests that AC886 is unlikely to 
show inhibitory activity against CYPs at physiologic concentrations.  Quizartinib and 
AC886 are substrates for CYP3A4, and quizartinib is metabolized by CYP3A4 to AC886.  


 
 
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On the other hand, CYP2B6, 2C8, 2C9, 2C19, 2D6, and 1A2 are found to be barely 
involved in the metabolism of quizartinib. 
 
1.2.1.1.4 
Toxicology 
Quizartinib was tested in single-dose toxicity studies (rats, dogs, and monkeys) and 
repeated-dose toxicity studies (28-day and 90-day studies in rats, dogs, and monkeys), 
genetic toxicity studies (in vitro and in vivo), reproductive and developmental toxicity 
studies (rats), and in vitro neutral red uptake phototoxicity assay using a murine 
fibroblast line (3T3). 
In repeated-dose toxicity studies, the principal organs affected were the lymphoid and 
hematopoietic organs in all species tested.  In addition, toxicologic effects were 
observed in the kidneys, liver, and genital organs (ovary, vagina, and testis).  
Target-organ toxicity appeared to be quizartinib dose- and time-dependent, and most 
toxicologic findings were reversible following a 28- or 30-day recovery period; however, 
slight decreases in red blood cell and white blood cell parameters, minimal bone marrow 
hypocellularity, and liver crystal deposition (only in dogs) persisted after the end of the 
recovery period.  In 90-day studies, toxicologic findings were evident in high-dose rats 
and dogs at 10 mg/kg and 15 mg/kg, respectively, and included decreases in hematology 
parameters, increased liver enzymes, and histopathological changes in bone marrow and 
lymphoid organs.  In 90-day studies in monkeys, the mortality and toxic signs were 
reported at 10 mg/kg/day, resulting in a dose reduction to 6 mg/kg/day during the dosing 
period; these toxicologic findings observed in monkeys were consistent with those seen 
in rats and/or dogs.  The no adverse effect level (NOAEL) from 90-day repeated oral 
doses was established at 3 mg/kg/day in rats and monkeys and 5 mg/kg/day in dogs.  
The Cmax and AUC of quizartinib at the NOAEL were 0.82 μg/mL and 12.1 μg·h/mL in 
rats, 0.11 μg/mL and 0.727 μg·h/mL in monkeys, and 0.42 μg/mL and 3.93 μg·h/mL in 
dogs, respectively. 
Quizartinib was evaluated for genotoxic potential; quizartinib was positive in bacterial 
reverse mutation assay, but was not genotoxic in chromosomal aberration assay in human 
lymphocytes, mammalian cell mutagenicity assay, or micronucleus assay in rats.  In the 
mammalian cell mutagenicity assay, it was evaluated whether the positive result obtained 
from the bacterial reverse mutation assay could be reproduced or not.  In mouse 
lymphoma L5178Y TK+/  cells incubated with quizartinib, no substantial increases in 
mutation frequency were observed at doses up to the cytotoxicity limit, and quizartinib 
did not induce genetic mutations.  Consequently, quizartinib is considered to have a low 


 
 
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genotoxic risk. 
In embryo-fetal toxicity studies in rats, systemic edema was found in fetuses at the 
maximum dose of 6 mg/kg/day, in addition to decreased fetal weight and delayed skeletal 
ossification.  The NOAEL for embryo-fetal development was considered to be 
2 mg/kg/day. 
In the neutral red uptake phototoxicity assay, quizartinib had a photo irritation factor of 
3.13 and a mean photo effect of 0.122.  These results suggested that the compound 
would have a “phototoxic potential” according to the guidelines at the time of the 
assay.8),9),10)  However, a review of the assay data in accordance with the guidance on 
photosafety evaluation of pharmaceuticals issued on 21 May 201411) resulted in the 
conclusion that quizartinib is not phototoxic. 
 
1.2.1.2 
Clinical Study Data 
1.2.1.2.1 
Overseas Phase 1 Study (Study CP0001) 
Quizartinib was tested in 76 AML patients with treatment cycles of intermittent dosing 
(14 days on the drug followed by 14 days of rest) at doses of 12 mg/day to 450 mg/day, 
and 28-day continuous dosing at 200 and 300 mg/day. 
Dose-limiting toxicities (DLTs) were pyrexia in 1 of 5 patients on intermittent dosing at 
135 mg/day, Grade 3 QTc prolongation in 1 of 17 patients on continuous dosing at 
200 mg/day, and Grade 3 QTc prolongation in 3 of 8 patients on continuous dosing at 
300 mg/day.  The maximum tolerated dose (MTD) was determined to be 200 mg/day 
continuous dosing. 
The overall response rate (CR + partial remission [PR]) was 53% in FLT3-ITD positive 
patients and 14% in FLT3-ITD negative patients. 
In this study, plasma specimens were collected from quizartinib-treated patients and were 
tested in an ex vivo assay of plasma inhibitory activity of quizartinib on FLT3 
phosphorylation.  Plasma from the patients suppressed FLT3-ITD and wild-type FLT3 
(FLT3-WT) autophosphorylation activity.  In cells expressing FLT3-WT, higher doses 
and longer exposures of quizartinib were necessary to eliminate detectable 
phosphorylated FLT3 as compared with FLT3-ITD-expressing cells. 
Moreover, a subset of 20 AML patients in the study were evaluated for the effect of 
quizartinib on phosphorylated STAT5 (pSTAT5), using a whole blood-based assay.  
Quizartinib treatment decreased pSTAT5 levels in 10 of 11 FLT3-ITD positive patients 
and 7 of 9 FLT3-ITD negative patients.  There was an enhanced effect on pSTAT5 
inhibition in FLT3-ITD positive patients.  These data suggest that quizartinib inhibits 


 
 
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pSTAT5 production regardless of FLT3-ITD mutation status in AML patients. 
 
1.2.1.2.2 
Overseas Phase 2 Studies (Studies AC220-002 and 2689-CL-2004) 
In Study AC220-002 conducted in 333 patients with relapsed or refractory AML, 12 
patients received 28-day continuous dosing at 200 mg/day, which is the MTD determined 
in Study CP0001, and Grade 3 QTc prolongation was reported at this dose in 42% of 
patients in Study AC220-002.  The study demonstrated that the incidence of QTc 
prolongation tended to be higher in females than in males.  To address this issue, the 
dose of quizartinib was reduced to 135 mg/day for males and 90 mg/day for females 
during the course of Study AC220-002.  After dose reduction, 1 female patient on 
continuous dosing at 90 mg/day, concomitantly with a strong CYP3A4 inhibitor, 
experienced Grade 4 QTc prolongation (torsades de pointes [TdP]). 
In Study AC220-002, patients were divided into 2 cohorts according to age and previous 
treatment status.  Specifically, AML patients aged 60 years or older with relapsed or 
refractory AML after one first-line chemotherapy regimen, were enrolled in Cohort 1, 
while AML patients aged 18 years or older with relapsed or refractory AML after salvage 
regimen, or relapsed AML after hematopoietic stem cell transplant (HSCT) were enrolled 
in Cohort 2.  In Cohort 1, the composite CR (CRc) rate was 57% in a subset of 
FLT3-ITD positive patients, with a median overall survival of 25.3 weeks.  In Cohort 2, 
the CRc rate was 46% in a subset of FLT3-ITD positive patients, with a median overall 
survival of 24.0 weeks.  In Cohort 2, 35% of FLT3-ITD positive patients proceeded to 
HSCT, and almost all (94%) of those proceeding to HSCT achieved CRc or PR with 
quizartinib treatment, with a 1-year survival rate of 39%. 
Study 2689-CL-2004 was conducted in 76 FLT3-ITD positive patients with relapsed or 
refractory AML, who were assigned to 28-day cycles of 30 or 60 mg/day continuous 
dosing of quizartinib (for both males and females) to evaluate the efficacy and safety of 
quizartinib at lower doses than those tested in Study AC220-002.  In the study, the 
incidence of QTc prolongation was much lower than that observed in Study AC220-002, 
indicating that the risk of QTc prolongation was dose-dependent (Table 1.2-1).  The 
study also demonstrated that the CRc rates were comparable to those observed in Study 
AC220-002 (Table 1.2-2).  In Study 2689-CL-2004 as well, 34% of patients proceeded 
to HSCT, and the patients who underwent HSCT tended to have a longer survival than 
those who did not. 
Common adverse events (AEs) reported in Studies AC220-002 and 2689-CL-2004 were 
nausea, diarrhea, vomiting, pyrexia, fatigue, edema peripheral, febrile neutropenia, 


 
 
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anemia, and electrocardiogram QT prolonged.  Although the hematologic toxicities 
appear to be associated with the underlying disease, AML, data suggest delayed recovery 
or continued suppression of absolute neutrophil count (ANC) and platelets as a 
consequence of continued treatment with quizartinib. 
 
Table 1.2-1  Maximum Values of QT Corrected for Heart Rate Using Fridericia’s 
Method (QTcF) and Maximum Changes from Baseline in QTcF in Two Phase 2 Studies 
 
Study AC220 002 (Cohort 2) 
Study 2689 CL 2004 
Daily dose of quizartinib 
90 mg/day 
(N  57) 
† Female 
135 mg/day 
(N  67) 
† Male 
200 mg/day 
(N  12) 
30 mg/day 
(N  38) 
60 mg/day 
(N  36)* 
Maximum QTcF (ms) 
> 480, ≤ 500 (Grade 2) 
21% 
13% 
33% 
5% 
14% 
> 500 (Grade 3) † Asymptomatic 
21% 
15% 
42% 
5% 
3% 
Maximum change in QTcF from baseline (ms) 
≤ 30 
9% 
9% 
0% 
47% 
39% 
> 30, ≤ 60 
46% 
51% 
8% 
47% 
42% 
> 60 
46% 
39% 
92% 
5% 
19% 
* Two patients in the 60 mg/day group were randomized but never treated with quizartinib. 
 
Table 1.2-2  Composite Complete Remission and Partial Response Rates in Two Phase 2 
Studies 
 
Study AC220 002 (Cohort 2) 
Study 2689 CL 2004 
Daily dose of quizartinib 
90 mg/day 
(N  57) 
† Female 
135 mg/day 
(N  67) 
† Male 
200 mg/day 
(N  12) 
30 mg/day 
(N  38) 
60 mg/day 
(N  38) 
CRc rate 
47% 
45% 
42% 
47% 
47% 
PR rate 
25% 
28% 
50% 
13% 
24% 
 
1.2.1.2.3 
Overseas Phase 3 Study (Study AC220-007: QuANTUM-R) 
Study AC220-007 is a multicenter, randomized, open-label, two-arm, Phase 3 study to 
compare the effect of quizartinib monotherapy versus salvage chemotherapy on overall 
survival in patients with FLT3-ITD positive AML that is refractory or has relapsed within 
6 months after first-line therapy with or without consolidating HSCT.  Treatment with 
quizartinib is started at a dose of 30 mg/day and the dose may be increased to 60 mg/day 
based on the safety and efficacy requirements.  If a strong CYP3A4 inhibitor is 
concomitantly used, treatment with quizartinib is started at a dose of 20 mg/day and the 
dose may be increased to 30 mg/day.  This study is ongoing and the updated status as of 
22 Jan 2016 is shown below. 
Of 326 target subjects, 160 subjects were enrolled in the study; male subjects accounted 
for 46% and most subjects were white (134 of 160 subjects, 84%) and aged 18 to 60 


 
 
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years (96 of 160 subjects, 60%, median: 55 years).  The majority of the subjects did not 
have prior HSCT (125 of 160 subjects, 78%).  A total of 99 subjects (62%) discontinued 
the study treatment.  Major reasons for discontinuation of treatment were a lack of 
response/disease progression (39 of 99 subjects, 39%) and relapse (22 of 99 subjects, 
22%).  There were 19 deaths due to AEs.  The AEs resulting in death included 
infections and infestations in 10 subjects, blood and lymphatic system disorders, cardiac 
arrest/failure, graft-versus-host disease (GVHD) in gastrointestinal tract, and respiratory 
distress/failure in 2 subjects each, and acute kidney injury in 1 subject.  Of these AEs, 
GVHD in gastrointestinal tract, infections and infestations (bronchopulmonary 
aspergillosis and necrotising fasciitis), cardiac failure acute, and blood and lymphatic 
system disorders (thrombocytopenia) were assessed to be related to quizartinib.  A total 
of 161 SAEs were reported, and the most common SAE was febrile neutropenia (29 of 
160 subjects, 18%).  The profile of reported AEs is consistent with safety data from 
clinical studies that have previously been conducted, and no new safety concerns have 
been identified.  The Safety Data Monitoring Committee assessed this study as, “there 
are no concerns about the continued conduct of the study” at the meeting held in Jun 
2016, and a total of 255 subjects were randomized as of 06 Sep 2016. 
 
1.2.1.2.4 
Japanese Phase 1 Studies (Studies AC220-A-J101 and AC220-A-J102) 
Study AC220-A-J101 is a multicenter, open-label, Phase 1 study to evaluate the safety 
and pharmacokinetics of quizartinib monotherapy that assesses the recommended dose 
for subsequent phase clinical studies in Japanese AML patients.  Since this was the first 
clinical study in Japanese AML patients, treatment with quizartinib was started at a dose 
of 20 mg/day, which was lower than the dose used in Study AC220-007, taking safety 
into consideration.  Based on the results of DLT assessment etc. at each dose cohort, the 
dose was increased up to 60 mg/day.  The dose of 60 mg/day was the maximum dose 
used in Studies 2689-CL-2004 and AC220-007. 
There were no reports of protocol-specified DLTs, including Grade 3 or more severe 
QTcF prolongation, based on the results of DLT assessment in each cohort of 20 mg/day, 
30 mg/day, and 60 mg/day (3 subjects, 3 subjects, and 3 subjects, respectively) (end date 
of DLT assessment in the 60 mg/day cohort: 17 Nov 2016). 
Study AC220-A-J102 is a multicenter, open-label, Phase 1 study to evaluate the safety 
and pharmacokinetics of quizartinib in combination with standard remission induction 
and consolidation therapy that assesses the dose for subsequent phase clinical studies in 
Japanese patients with newly diagnosed AML.  Chemotherapy in this study consisted of 


 
 
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remission induction therapy and consolidation therapy given for up to 2 and 4 cycles, 
respectively, each of which was 28 days long.  Since this was the first clinical study of 
quizartinib in Japanese patients with newly diagnosed AML, treatment with quizartinib 
was started at a dose of 20 mg, which had been the initial dose used in Study 
AC220-A-J101, and was administered in combination with standard therapy, taking the 
subjects’ safety into consideration. 
 
1.2.1.2.5 
Pharmacokinetics 
Pharmacokinetic data of quizartinib and its active metabolite AC886 from clinical studies 
in AML patients and healthy volunteers have been evaluated.  After administration of 
quizartinib, the plasma concentrations of quizartinib and AC886 increased rapidly (Tmax 
of quizartinib, 2 to 8 hours post quizartinib dosing during the first day of dosing).  
Quizartinib and AC886 had terminal elimination half-lives of approximately 3 days, 
resulting in approximately 4-fold accumulation from the first day of dosing for exposure 
at the steady state after daily dosing.  Plasma exposure to both quizartinib and AC886 
was generally proportional with the dose in the tested dose range of 30 mg to 90 mg.  
Overall, Cmax and AUC showed moderate to high variability.  Plasma concentrations of 
AC886 at the steady state paralleled quizartinib levels with a plasma concentration ratio 
of AC886 to quizartinib (AC886/quizartinib) of 0.5.  AC886 is the only major 
metabolite of quizartinib in the circulation.  Quizartinib was mainly eliminated by 
non-renal clearance.  The presence of concomitant ketoconazole, a strong CYP3A4 
inhibitor, increased the observed AUCinf of quizartinib approximately 2-fold.  The 
presence of concomitant fluconazole, a moderate CYP3A4 inhibitor, increased the 
observed AUCinf of quizartinib approximately 1.2-fold. 
 
1.2.1.3 
Known and Expected Risks and Benefits 
AEs that were particularly frequently reported in previous clinical studies were body as a 
whole general disorders (eg, pyrexia and fatigue) and gastrointestinal disorders (eg, 
nausea, diarrhea, and vomiting).  In addition, blood disorders (eg, anemia, neutropenia, 
and thrombocytopenia), neutrophilic dermatosis/pyoderma gangrenosum, effects of 
cytopenia (eg, increased risk of infection and hemorrhage), and QTc prolongation have 
also been reported. 
Although the hematotoxicities may be associated with AML, safety reports of Study 
AC220-002 indicate delayed recovery of neutrophil and platelet counts as a consequence 
of continued treatment with quizartinib in many patients. 


 
 
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SAEs related to bone marrow depression (eg, neutropenia, bone marrow hypocellularity, 
lymphopenia, anemia, hemorrhage, thrombocytopenia, and pancytopenia), and/or 
infections (particularly, but not exclusively, fungal and other opportunistic infections, 
Gram negative bacterial infections, and bacteremia/sepsis) have been reported in 
quizartinib clinical studies.  Reports of infections have often been in the context of 
neutropenia, pyrexia, or both.  Investigators should recognize that AML may raise the 
risk of infection.  Attention should also be paid to infections from diverse pathogens in 
different organ systems (including sepsis and bacteremia). 
There are also reports of SAEs related to hemorrhage (eg, epistaxis, hemoptysis, melena, 
gastrointestinal hemorrhage, and intracranial hemorrhage). 
QTc prolongation is as stated in “1.2.1.2.2 Overseas Phase 2 Studies (Studies AC220-002 
and 2689-CL-2004).”  Treatment with quizartinib may induce TdP depending on the 
concomitant administration of QTc prolonging drugs, a history of TdP, preexisting QTc 
prolongation, congenital long QT syndrome, or other clinical states of physiologic stress 
(eg, pneumonia and other infections), administration of potassium-wasting diuretics, or 
other conditions that result in hypokalemia or hypomagnesemia. 
The efficacy of quizartinib at various doses was assessed in three overseas clinical 
studies in patients with relapsed or refractory AML (Studies CP0001, AC220-002, and 
2689-CL-2004).  Based on combined data from FLT3-ITD positive and negative 
patients, the CRc rate was 13% to 63%.  The median duration of remission was 10.4 to 
13.3 weeks.  The median overall survival (OS) was 8.6 to 24.6 weeks.  Quizartinib was 
more effective in FLT3-ITD positive patients, with a CRc rate of 24% to 52%.  Based 
on these findings, it was considered that quizartinib would provide clinically significant 
sustained effects in patients with relapsed or refractory AML. 
 
1.2.2 
Study Rationale 
An international guideline for the treatment of AML (NCCN Clinical Practice Guideline 
in Oncology: Acute Myeloid Leukemia) has been established, and overseas and Japanese 
treatment strategies are generally the same.  Patients with relapsed or refractory AML 
are treated with monotherapy or combination therapy with cytarabine, mitoxantrone, 
etoposide, fludarabine, aclarubicin, gemtuzumab ozogamicin, and others.  None of these 
therapies, however, provide an adequate therapeutic effect.  No standard treatment has 
been established for these patients.12)  There are also no molecular targeting drugs that 
can be used for newly diagnosed AML patients, in whom a high relapse rate is still a 
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As mentioned above, it has been confirmed that quizartinib is highly effective and safe at 
30 mg and 60 mg doses in patients with FLT3-ITD positive relapsed or refractory AML 
in the overseas Study 2689-CL-2004, while Study AC220-007 is currently underway in 
patients with relapsed or refractory AML, mainly in the US and Europe. 
In Japan, Study AC220-A-J101 in patients with relapsed or refractory AML and a Phase 
1b clinical study of quizartinib in combination with standard therapy in Japanese patients 
with newly diagnosed AML (Study AC220-A-J102) are currently underway.  As 
mentioned above, DLT assessment at all doses up to 60 mg/day has been completed in 
Study AC220-A-J101.  The present study will be conducted primarily to confirm the 
efficacy of the regimen that was used in the quizartinib group in the preceding Study 
AC220-007, in Japanese patients.  Treatment with the study drug in patients in the 
present study will start after DLT assessment in Study AC220-A-J101 has been 
completed and quizartinib has been confirmed to be safe at doses of up to 60 mg/day. 
 
2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
To evaluate the CRc rate (defined as the proportion of patients whose best response is CR, 
CR with incomplete platelet recovery [CRp], or CR with incomplete hematological 
recovery [CRi]) after treatment with quizartinib as multiple-dose monotherapy in 
Japanese patients with FLT3-ITD positive relapsed or refractory AML. 
 
2.1.2 
Secondary Objectives 
• 
To evaluate the overall survival with quizartinib 
• 
To evaluate the event-free survival with quizartinib 
• 
To evaluate the leukemia-free survival with quizartinib 
• 
To evaluate the safety of quizartinib 
• 
To evaluate the pharmacokinetics of quizartinib 
• 
To evaluate quizartinib-related biomarkers 
 
2.2 
Study Hypotheses 
To confirm that the CRc rate with quizartinib monotherapy is at least 23.5% in Japanese 
patients with FLT3-ITD positive relapsed or refractory AML. 
 




 
 
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will be assessed as follows: Concerning the 41 patients included in the efficacy analysis 
set, if CRc is achieved in 15 or more patients, the treatment is determined to be effective 
(rejection of the null hypothesis).  The details of interim analyses are shown in “11.4 
Interim Analysis.” 
Registration of patients will be continued during the course of the interim analysis.  If it 
is decided to terminate the study early, the registration of patients will be discontinued; 
however, treatment with the study drug in patients who continue receiving the study drug 
will be continued until “5.7.1 Discontinuation Criteria for Treatment with the Study 
Drug” are met. 
 
3.2 
Discussion of Study Design 
3.2.1 
Rationale for the Dose and Dosage of the Study Drug 
In the overseas Phase 1 study (Study CP0001), quizartinib was administered 
intermittently at doses of 12 mg/day to 450 mg/day (14 days on treatment, followed by 
14 days of rest) and at doses of 200 mg/day and 300 mg/day for 28 consecutive days in 
76 AML patients, and the maximum tolerated dose of quizartinib was 200 mg/day that 
was administered for 28 consecutive days.  In the overseas Phase 2 study (Study 
AC220-002), quizartinib was administered at a dose of 200 mg/day for 28 consecutive 
days in 333 AML patients, and Grade 3 QTc prolongation was reported in 42% of the 
patients.  The incidence of QTc prolongation tended to be higher in female than male 
patients, and the dose of quizartinib was reduced to 135 mg/day in male patients and 
90 mg/day in female patients during the course of Study AC220-002.  TdP associated 
with Grade 4 QTc prolongation occurred in one female patient receiving consecutive-day 
treatment with quizartinib at a dose of 90 mg/day concomitantly with a strong CYP3A4 
inhibitor.  Therefore, in the overseas Phase 2b study (Study 2689-CL-2004), quizartinib 
was administered at 30 mg/day or 60 mg/day for 28 consecutive days to assess the safety 
and efficacy of quizartinib at lower doses.  As a result, the incidence of QTc 
prolongation significantly decreased in the 30 mg and 60 mg groups compared with the 
higher dose groups (90 mg to 200 mg) established in Study AC220-002, which indicated 
that the potential risk of QTc prolongation was dose-dependent.  The incidence of 
increased QTc interval to longer than 500 ms was 5% and 3% in the 30 mg and 60 mg 
groups, respectively, while the incidence of change in QTc interval of longer than 60 ms 
from baseline was 3% and 19%, respectively (Table 1.2-1).  It was also clarified that the 
CRc rate in the 30 mg and 60 mg groups was equivalent to that in the high dose groups 
(90 mg to 200 mg) in Study AC220-002 (Table 1.2-2). 


 
 
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Increased QT/QTc interval to longer than 500 ms and an increase of longer than 60 ms in 
QT/QTc interval from baseline are important changes to decide whether to conduct a 
clinical study or not.13)  According to the results of Study 2689-CL-2004, the incidence 
of increased QTc interval to longer than 500 ms was as low as 5% or less in the 30 mg 
and 60 mg groups, and the incidence of a longer than 60 ms increase in QTc interval from 
baseline was lower in the 30 mg and 60 mg groups than in the 90 mg or higher dose 
groups.  Based on these data, it was considered that quizartinib is tolerated at doses of 
30 mg and 60 mg, and the initial dose of 30 mg was chosen in this study.  The rationale 
for setting 20 mg/day as the initial dose of quizartinib for patients concomitantly using 
strong CYP inhibitors is shown below. 
In a drug-drug interaction study in healthy adult subjects, ketoconazole (strong CYP3A4 
inhibitor) or fluconazole (moderate CYP3A4 inhibitor) was administered as multiple 
doses, followed by quizartinib as a single dose; concomitant treatment with ketoconazole 
or fluconazole resulted in 1.17-fold or 1.11-fold Cmax, respectively, and 1.94-fold or 
1.20-fold AUCinf, respectively, compared with quizartinib monotherapy.  Based on this 
result, it was estimated that the steady-state plasma quizartinib concentration following 
administration of multiple-dose quizartinib concomitantly with ketoconazole or 
fluconazole would increase by 1.86-fold or 1.21-fold, respectively, for Cmax and by 
1.96-fold or 1.21-fold, respectively, for AUC0 24, compared with quizartinib monotherapy.  
This result indicates that exposure to quizartinib nearly doubles when quizartinib is 
concomitantly used with strong CYP3A4 inhibitors, and it was therefore considered 
appropriate to administer quizartinib at a dose of 20 mg/day, which is about half the dose, 
in the presence of strong CYP inhibitors.  Meanwhile, exposure to quizartinib 
concomitantly used with moderate CYP3A4 inhibitors is limited, and it was therefore 
considered unnecessary to reduce the dose of quizartinib in the presence of moderate 
CYP3A4 inhibitors.  The initial dose of quizartinib in Study AC220-007 was set at 
30 mg/day (20 mg/day in the presence of strong CYP3A4 inhibitors) for the same reason. 
 
3.2.2 
Rationale for the Method of Dose Increase of the Study Drug 
In Study 2689-CL-2004, the CRc rate at the final analysis was 47% in both the 30 mg 
and 60 mg groups; however, CRc was not achieved in 63% (24/38 patients) of the 
patients in the 30 mg group after the end of Cycle 1, and the dose was increased to 60 mg 
accordingly.  Meanwhile, the proportion of patients in the 60 mg group who did not 
achieve CRc after the end of Cycle 1 and for whom the dose was increased to 90 mg was 
19% (7/36 patients).  Although these data are limited, a higher tendency for efficacy 


 
 
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was observed in the 60 mg group than the 30 mg group when it was measured by other 
endpoints such as the transplantation rate, PR rate, duration of CRc, and median OS, and 
the 60-mg dose is thus likely to be superior to the 30-mg dose in terms of efficacy.  
When the relationship between exposure to AC220 and its active metabolite AC886 and 
the efficacy on Day 15 of Cycle 1 was compared between the two dose groups, no 
significant correlation between the 30 mg and 60 mg groups was observed in the CRc 
rate after the end of Cycle 1, or AUC0 24h of AC220, AUC0 24h of AC886, or the sum of 
AUC0 24h of AC220 and AC886 on Day 15 of Cycle 1, which suggests that there is no 
difference in exposure between these dose groups at the end of Cycle 1.  Accordingly, it 
is considered that there is no great difference in efficacy when quizartinib is administered 
at an initial dose of 30 mg and increased to 60 mg on Day 16 of Cycle 1 and when 
quizartinib is administered at an initial dose of 60 mg. 
In addition, when the relationship between drug concentrations and QTc interval was 
evaluated using the data from Study 2689-CL-2004, a linear relationship between 
prolongation of QTc interval and plasma AC220 concentrations was found.  The 
half-life of AC220 was approximately 3 days, and quizartinib exposure reached a steady 
state on Day 15 of Cycle 1 in both the 30 mg and 60 mg groups.  Therefore, 
prolongation of QTc interval caused by AC220 was estimated to reach a peak on Day 15 
of Cycle 1.  Data from Study 2689-CL-2004 did not show any significant correlation 
between plasma AC886 concentrations and prolongation of QTc interval. 
In view of these data, it was considered possible to increase the dose of quizartinib from 
30 mg to 60 mg on Day 16 of Cycle 1 or later based on the assessment on Day 15 of 
Cycle 1, when the plasma quizartinib concentration reaches a steady state, in accordance 
with “5.2.4.3 Criteria for Dose Increase of the Study Drug.” 
 
3.2.3 
Rationale for Sample Size 
Refer to Section “11.5 Determination of Sample Size.” 
 
4. 
STUDY POPULATION 
Prior to assessment of eligibility for enrollment in the study, patients must sign the 
informed consent form (ICF) provided by the study center, and date it. 
patients who meet all of the following inclusion criteria and do not fit any of the 
exclusion criteria and who provide written informed consent of their free will are eligible 
for the study. 
 


 
 
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4.1 
Inclusion Criteria 
Patients must satisfy all of the following criteria to be included in the study: 
1) Provision of written informed consent for participation in the study. 
2) Patients aged 20 years or older when consent is obtained. 
3) Primary AML patients or AML patients with a history of myelodysplastic syndrome 
(MDS). 
4) AML patients who have first relapsed within 6 months after achieving remission 
with initial remission induction therapy or those who are refractory to all therapies 
given prior to the start of the study and failed to achieve remission.  The initial 
remission induction therapy must be a regimen containing at least 1 cycle of 
standard-dose treatment with anthracyclines or mitoxantrone.  It is not taken into 
consideration whether they have HSCT or not. 
• 
Definition of refractory to treatment 
• 
Patients who have less than 50% reduction in bone marrow blasts and have 
failed to achieve CR, CRp, or CRi after 1 cycle of treatment. 
• 
Patients who have failed to achieve CR, CRp, or CRi after 2 cycles of 
treatment. 
• 
Definition of first relapse (within 6 months after achieving remission) 
• 
Patients who have achieved CR, CRp, or CRi after initial remission 
induction therapy and have relapsed within 6 months.  It is not taken into 
consideration whether they have received consolidation therapy, 
maintenance therapy, or HSCT or not. 
• 
The duration of remission is defined as the day of the bone marrow test 
when CR, CRp, or CRi was confirmed or the day of HSCT to the day of the 
bone marrow test when relapse was confirmed or the day of reappearance of 
leukemic blasts in the peripheral blood. 
5) Patients with mutations of the FLT3-ITD gene in bone marrow or peripheral blood. 
* A specimen for the FLT3-ITD mutation test will be submitted to Navigate 
BioPharma Services, Inc. (Navigate BioPharma), the central laboratory, to test 
mutations in the FLT3-ITD gene.  However, patients who have been confirmed to 
be FLT3-ITD positive in the FLT3-ITD testing previously performed at another 
testing company or the central laboratory, SRL Inc. (SRL), may be assessed for 
eligibility for the study without waiting for the result of measurement at Navigate 
BioPharma. 
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(refer to “Appendix 2”). 
7) Patients in whom the intervals listed below can be achieved between the last dose or 
application of prior therapy and the first dose of the study drug in the study: 
• 
Cytotoxic drugs (excluding hydroxycarbamide used for the purpose of 
controlling the increase in white blood cells): 2 weeks 
• 
Non-cytotoxic drugs: at least 5 × the half-life of the drug 
8) Laboratory test results obtained within 14 days before registration meet all of the 
following requirements: 
Laboratory Parameter 
Requirement 
AST 
≤ 2.5 times the upper limit of the institutional reference range 
ALT 
≤ 2.5 times the upper limit of the institutional reference range 
Total bilirubin 
≤ 1.5 times the upper limit of the institutional reference range 
Serum creatinine 
≤ 1.5 times the upper limit of the institutional reference range  
(or estimated glomerular filtration rate [eGFR]* 
≥ 25 mL/min/1.73 m2) 
Serum K 
Within the institutional reference range** 
Serum Mg 
Within the institutional reference range** 
Serum Ca (corrected for albumin) 
Within the institutional reference range** 
* eGFR (mL/min/1.73 m2)  194 × serum creatinine 1.094 × age 0.287 (× 0.739 for females) 
** Patients with electrolytes outside the institutional reference range will be eligible if these values are 
corrected upon retesting following any necessary supplementation. 
 
9) Patients who can receive quizartinib orally. 
 
Rationale 
1), 9) 
To ensure the eligibility as a study patient and for ethical considerations. 
2) Twenty is considered the minimum age for patients to be able to provide appropriate 
informed consent based on their own decision. 
3) to 6) To appropriately evaluate the efficacy of quizartinib in Japanese patients with 
FLT3-ITD positive relapsed or refractory AML. 
7) To ensure that patients are in a stable physiological condition at the time of 
registration based on the “Guidelines for the Clinical Evaluation of Anticancer 
Drugs.14)” 
8) To ensure that organ functions allowing the appropriate evaluation of patient safety 
have been maintained based on the “Guidelines for the Clinical Evaluation of 
Anticancer Drugs.14)” 
 


 
 
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4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be disqualified from entering the 
study: 
1) Diagnosis of acute promyelocytic leukemia. 
2) Patients who developed AML in association with prior chemotherapy or radiotherapy 
given to treat another malignant tumor than AML (patients with treatment-related 
AML).  However, this shall not apply to patients with a history of MDS. 
3) History of malignant tumor within 5 years before registration.  However, 
participation of the following patients in the study is allowed. 
• 
Curatively treated skin cancer other than malignant melanoma, carcinoma in situ, 
or cervical carcinoma in situ (The time to onset of AML is not considered when 
the standard therapy has been completed.) 
• 
Prostate cancer without local recurrence or progression (any of the cases in 
which hormonal therapy has been initiated, the tumor has been surgically 
removed, or the lesion has disappeared with radiotherapy) 
4) Persistent, symptomatic Grade 2 or more severe non-hematological toxicity 
(excluding alopecia) from prior therapy. 
5) GVHD that is clinically significant or requiring treatment, those who need to start 
treatment for GVHD, those requiring intensified treatment for GVHD within 21 days 
before registration, or those with Grade 2 or more severe clinically significant or 
irreversible non-hematological toxicity related to HSCT. 
6) History of or current symptomatic central nervous system involvement with clinical 
symptoms. 
7) Disseminated intravascular coagulation, or other clinically significant coagulation 
abnormalities. 
8) Prior treatment with quizartinib or prior participation in any clinical study of 
quizartinib. 
9) Prior treatment with other FLT3 inhibitors (sorafenib or other FLT3 inhibitors under 
development) (This does not include midostaurin.) 
10) Extensive surgery within 28 days before registration. 
11) Radiation therapy within 28 days before registration. 
12) History of or current cardiovascular disease as specified below: 
• 
QTcF interval of 450 ms or longer, determined as the average of three central 
ECG measurements taken within 14 days before registration 
• 
Heart rate of 50 beats/min or lower, determined as the average of three central 


 
 
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ECG measurements taken within 14 days before registration (excluding patients 
with a cardiac pacemaker) 
• 
Previous, current, or suspected long QT syndrome, or a family history of 
congenital long QT syndrome 
• 
History of life-threatening ventricular arrhythmia, such as ventricular 
tachycardia, ventricular fibrillation, or TdP 
• 
Second or third degree heart block 
(This shall not apply to patients who have second or third degree heart block, but 
who have a cardiac pacemaker and have never experienced syncope or 
arrhythmia before.) 
• 
History of myocardial infarction within 6 months before registration 
• 
History of uncontrolled angina pectoris within 6 months before registration 
• 
Class III or more severe congestive heart failure according to “Appendix 3 New 
York Heart Association (NYHA) Functional Classification” 
• 
Left ventricular ejection fraction (LVEF) below 45% or the lower limit of the 
institutional reference range 
• 
Uncontrolled hypertension 
• 
Complete left or right bundle branch block 
13) Active infection that is not well controlled with antibacterial, antifungal, or antiviral 
therapy. 
14) Active liver disease (hepatitis B, hepatitis C, etc.) 
15) Tested positive for human immunodeficiency virus (HIV) antibody within 120 days 
before registration. 
16) Women of childbearing potential, or their male partners who are unable or unwilling 
to practice appropriate contraception using effective contraceptive methods (eg, 
barrier contraceptives combined with spermicides, intrauterine device) for the entire 
study period and 3 months after the last dose of the study drug. 
Women of non-childbearing potential (postmenopausal women with no menses for at 
least 2 years and women who have undergone hysterectomy etc. at least 1 month 
before registration) may be registered in the study. 
Male patients may not donate their sperm during the period from 14 days before 
registration to 105 days after the last dose of the study drug.  Female patients may 
not donate their eggs during the period from 14 days before registration to 12 weeks 
after the last dose of the study drug. 
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registration. 
18) Women who may need to breastfeed during the study period and for 25 days after the 
last dose of the study drug. 
19) Patients who are otherwise considered ineligible for the study in the opinion of the 
investigators. 
 
Rationale 
1) to 18) 
Established to appropriately evaluate the efficacy of quizartinib, taking the 
safety of the use of quizartinib into consideration. 
16) to 18) Established because effects of quizartinib on the fetus and nursing babies 
cannot be ruled out.  Breastfeeding women, independent of whether they interrupt 
breastfeeding or not, are not eligible for participation in the study. 
19) Established so that the investigators can determine the eligibility for participation in 
the study from a comprehensive standpoint with careful consideration for patient 
safety. 
 
5. 
STUDY TREATMENT 
5.1 
Assigning Patients to Treatments and Blinding 
5.1.1 
Treatment Groups 
This is a single-arm study. 
 
5.1.2 
Method of Treatment Allocation 
This is a single-arm study and randomization will therefore not be performed.  
Registration of patients will be performed via fax.  The procedure for patient 
registration is shown in Figure 5-1. 
After obtaining written informed consent from each patient, the investigators will assign 
a subject identification code to the patient.  If the above-stated patient is assessed to be 
eligible for the study, the investigators will enter the necessary information on the patient 
in the subject registration form and send it to the sponsor by fax. 
The sponsor will check the eligibility of the patient in the light of the inclusion and 
exclusion criteria for the study based on the entries in the received subject registration 
form.  If there are any questions about the entries in the registration form, the sponsor 
should immediately contact the investigators to make inquiries.  When the sponsor 
determines that the patient is eligible for the study, the sponsor will register the patient 
and assign the subject number. 


 
 
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The sponsor will immediately fax the registration confirmation form together with the 
result of the eligibility assessment to the investigator; the confirmation form should 
include the date of registration, subject number, and dose of the study drug for patients 
assessed to be eligible, and the fact that the patient is not eligible and the reason for it for 
patients assessed to be ineligible.  The investigators will explain the reason for 
ineligibility to patients assessed to be ineligible by the sponsor. 
 
Address for sending the subject registration form  
(the sponsor’s address) 
Working hours: Monday to Friday, 9:00 to 17:30 
(closed on Saturdays, Sundays, and public holidays) 
FAX: 
 
TEL: 
 
The investigators may not dispense the study drug to a patient until the patient is 
registered. 
If any patient provides informed consent but is not registered, the investigators will 
describe the reason why the patient is not registered in the medical record.  The patient 
will not be included in the number of patients enrolled in the study. 
Even if a patient is considered ineligible by the investigators at the time of eligibility 
check after providing informed consent, and the subject registration form of the patient is 
not faxed to the sponsor, if the investigators later confirms that the patient meets the 
eligibility criteria, the investigators may again obtain consent for participation in the 
study from the patient and fax the subject registration form to the sponsor. 
 




 
 
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4) Lot number: 
Lot numbers are listed in the “Study Drug 
Management Procedures.” 
 
5.2.2 
Labeling and Packaging 
The packaging form and information displayed on the label of the study drug will be 
provided in the “Study Drug Management Procedures.” 
Thirty study drug tablets are packaged in a plastic bottle (for 1 patient). 
The information displayed on the label is shown in “Table 5.2-1 Information Displayed 
on the Study Drug Label.” 
 
Table 5.2-1  Information Displayed on the Study Drug Label 
Statement, “For clinical study” 
Name of the study drug 
Protocol number 
Lot number of the study drug 
Storage conditions 
Statement, “Do not discard but store any unused study drug tablets; they will be collected later.” 
Name of the sponsor 
Address of the sponsor 
 
5.2.3 
Preparation 
All study drugs will be supplied as tablets that need no further preparation at the study 
centers. 
 
5.2.4 
Administration 
5.2.4.1 
Dose of the Study Drug 
Quizartinib will be administered at an initial dose of 30 mg/day.  For patients receiving 
strong CYP3A4 inhibitors, an initial dose of 20 mg/day will be used.  Subsequently, 
whether or not to increase the initial dose of 30 mg/day to 60 mg/day or 20 mg/day to 
30 mg/day will be determined on Day 16 of Cycle 1 and Day 1 of Cycle 2 (or thereafter) 
in accordance with “5.2.4.3 Criteria for Dose Increase of the Study Drug.”  If patients 
who achieve CR, CRp, or CRi after the start of treatment with the study drug and then 
subsequently relapse meet “5.2.4.3 Criteria for Dose Increase of the Study Drug,” the 
dose of quizartinib may be increased in the same manner. 
The dose of the study drug will be reduced in accordance with each of the criteria for 
dose reduction given in “5.4 Dose Interruptions and Reductions.”  If the dose is reduced 
due to QTcF prolongation, treatment for QTcF prolongation will be given in accordance 


 
 
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with “9.10.2 Measures Taken in Case of QTcF Prolongation.” 
In principle, central ECG assessment results will be used to make a decision on dose 
increase or reduction of the study drug.  If it is necessary to urgently confirm the central 
assessment results on Day 15 of Cycle 1 or Day 1 of Cycle 2, etc., the study center 
should contact the Central ECG Reading Center and request immediate assessment 
(within 24 hours). 
 
5.2.4.2 
Regimen 
Quizartinib will be orally administered once daily every morning.  Treatment with 
quizartinib will be administered in 28-day cycles and continued until “5.7.1 
Discontinuation Criteria for Treatment with the Study Drug” are met.  The first dose of 
the study drug will be started, in principle, within 7 days of registration.  If treatment 
with the study drug is started more than 7 days after registration, it should be confirmed 
again that the patient meets the eligibility criteria before the start of the first dose of the 
study drug. 
If a patient vomits after taking a dose of the study drug, a replacement dose may not be 
given on the same day. 
A patient who did not take the study drug at the usual hour of dosing (eg, forgot to take 
the dose) will be allowed to take the missed dose within 10 hours after the usual hour of 
dosing (for example, if the patient usually takes the drug at 7:00 or 8:00, he/she may take 
it by 18:00).  In this case, the next dose of the study drug on the following day should be 
taken at least 12 hours after the time when the last dose was taken.  If the patient does 
not take the missed dose by 10 hours after the usual hour of dosing, he/she should not 
take the study drug on that day and resume taking the drug on the following day.  The 
patient may not take two doses at once on the day when the drug is resumed. 
 
5.2.4.3 
Criteria for Dose Increase of the Study Drug 
If the patient’s condition satisfies the following criteria on Day 16 of Cycle 1 or Day 1 of 
Cycle 2 (or thereafter), the dose of quizartinib will be increased according to Table 5.2-2.  
A 12-lead ECG will be measured at least once weekly for the first 2 weeks after a dose 
increase to confirm the presence or absence of QTcF prolongation after the dose increase.  
When doing this, triplicate ECG recordings will be obtained.  The dose of quizartinib 
should not exceed 60 mg/day throughout the study period (30 mg/day for patients 
concomitantly using strong CYP3A4 inhibitors). 
 


 
 
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Table 5.2-2  Method of Dose Increase of Quizartinib 
Dose 
One level Increased Dose 
20 mg/day 
30 mg/day 
30 mg/day 
60 mg/day 
60 mg/day 
No dose increase 
 
Assessment criteria for dose increase on Day 16 of Cycle 1 
Patients not concomitantly using strong CYP3A4 inhibitors: 
The dose of quizartinib will be increased to 60 mg/day if all QTcF data (determined as 
the average of three measurements) taken by Day 15 of Cycle 1 are 450 ms or shorter. 
 
Patients concomitantly using strong CYP3A4 inhibitors: 
The dose of quizartinib will be increased to 30 mg/day if all QTcF data (determined as 
the average of three measurements) taken by Day 15 of Cycle 1 are 450 ms or shorter.  
A list of CYP3A4 inhibitors is provided in Appendix 4. 
 
If treatment with quizartinib is interrupted by Day 16 of Cycle 1, whether to increase the 
dose or not will be determined in accordance with the following criteria. 
• 
Interruption of treatment for 2 days or shorter: The dose may be increased on Day 16 
of Cycle 1. 
• 
Interruption of treatment for 3 to 6 days: Consult with the sponsor’s medical monitor 
etc. and assess whether to increase the dose or not on Day 16 of Cycle 1. 
• 
Interruption of treatment for 7 days or longer: The dose will not be increased on Day 
16 of Cycle 1.  Decide whether to increase the dose or not on Day 1 of Cycle 2 or 
later. 
 
Assessment criteria for dose increase on Day 1 of Cycle 2 or later 
For patients who have not achieved CR, CRp, or CRi after at least 1 cycle of treatment 
with quizartinib* and whose condition before the decision on dose increase satisfies the 
following requirements, the dose of quizartinib will be increased. 
• 
Absence of Grade 3 or more severe treatment-related non-hematological toxicity 
• 
60 ms or shorter increase in QTcF interval from baseline 
• 
Absence of hypoplastic bone marrow upon the decision of a dose increase 
* At least 1 cycle of treatment with quizartinib: Treatment with quizartinib is given for at 
least 13 consecutive days 
 


 
 
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For patients who have relapsed after achieving CR, CRp, CRi, or PR, and satisfy the 
assessment criteria for dose increase on Day 1 of Cycle 2 or later, the dose of quizartinib 
may be increased.  The dose will be increased to 60 mg/day if strong CYP3A4 
inhibitors are not concomitantly used, and to 30 mg/day if strong CYP3A4 inhibitors are 
concomitantly used. 
 
5.2.5 
Storage 
The study drug manager will store and manage the study drug at 25°C or lower without 
freezing. 
 
5.2.6 
Drug Accountability 
After receiving the delivered study drug, the study drug manager or designee will check 
the quantity and condition of the study drug and confirm the appropriateness of the 
labeling as well as the expiry date of the study drugs etc.  In addition, the investigator or 
designee shall contact the sponsor as soon as possible if there is a problem with the study 
drug. 
The study drug will be managed using the Drug Accountability Record.  The 
Accountability Record must be updated, and should contain such information as the date 
of receipt of the study drug, the quantity of the received study drug, patients supplied 
with the study drug (identification number, or if applicable, supply number), date of 
supply of the study drug, quantity supplied and residual quantity, and the signed initials 
and seal of the person who supplied the study drug.  At the end of the study, the 
investigator or designee must prepare the final version of the study drug 
management-related record, and submit it to the sponsor. 
Other procedures related to study drug management and collection will be performed in 
accordance with the “Study Drug Management Procedures.” 
 
5.3 
Control Treatment 
Not applicable 
 
5.4 
Dose Interruptions and Reductions 
If any of the criteria in Section 5.4.1 to Section 5.4.4 apply, treatment with quizartinib 
will be interrupted or the dose of quizartinib will be reduced.  The dose of quizartinib 
will be reduced by one level at a time according to Table 5.4-1.  If quizartinib is 
administered at a dose of 20 mg/day, a further dose reduction is not allowed. 


 
 
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Table 5.4-1  Method of Dose Reduction of Quizartinib 
Dose 
One level Reduced Dose 
60 mg/day 
30 mg/day 
30 mg/day 
20 mg/day 
20 mg/day 
No dose reduction 
 
5.4.1 
QTcF Prolongation 
In case of QTcF prolongation, the dose will be reduced in the following manner. 
 
Table 5.4-2  Criteria for Dose Interruption and Reduction When QTcF Prolongation 
Occurs during Treatment with Quizartinib at 30 mg/day or 60 mg/day 
CTCAE Grade 
Method of Dose Reduction 
Grade 2 
• 
Reduce the dose by one level.  It is not necessary to interrupt treatment. 
• 
The dose may be increased to the dose before dose reduction if QTcF 
prolongation recovers to Grade 1 or less severe after treatment at the 
reduced dose for at least 28 days. 
Grade 3 
• 
Interrupt quizartinib treatment for a maximum of 14 days. 
• 
Resume quizartinib treatment at a one level reduced dose, relative to the 
dose immediately before the interruption, if the increase in QTcF interval 
from baseline is 30 ms or shorter or the QTcF interval recovers to 450 ms 
or shorter within 14 days after the onset. 
• 
Do not increase the dose after resumption of quizartinib treatment. 
Grade 4 
Discontinue quizartinib treatment. 
For the treatment of QTcF prolongation, “9.10.2 Measures Taken in Case of QTcF Prolongation” should be 
followed. 
 
Table 5.4-3  Criteria for Dose Interruption and Reduction When QTcF Prolongation 
Occurs during Treatment with Quizartinib at 20 mg/day 
CTCAE Grade 
Method of Dose Reduction 
Grade 2 
• 
Interrupt quizartinib treatment for a maximum of 14 days. 
• 
Resume quizartinib treatment at a dose of 20 mg/day if QTcF prolongation 
recovers to Grade 1 or less severe. 
Grade 3 
[If strong CYP3A4 inhibitors are concomitantly used] 
• 
Interrupt quizartinib treatment for a maximum of 14 days. 
• 
Resume quizartinib treatment at a dose of 20 mg/day if the increase in 
QTcF interval from baseline is 30 ms or shorter or the QTcF interval 
recovers to 450 ms or shorter within 14 days after the onset, and the 
concomitant use of strong CYP3A4 inhibitors is discontinued. 
• 
Do not increase the dose after resumption of quizartinib treatment. 
 
[If strong CYP3A4 inhibitors are not concomitantly used] 
• 
Discontinue quizartinib treatment. 
Grade 4 
Discontinue quizartinib treatment. 
For the treatment of QTcF prolongation, “9.10.2 Measures Taken in Case of QTcF Prolongation” should be 
followed. 
 


 
 
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5.4.2 
Non-hematological Toxicity 
If a quizartinib-related Grade 3 or more severe non-hematological toxicity does not 
improve to Grade 2 or less severe, and it persists for at least 48 hours, treatment with 
quizartinib should be interrupted for a maximum of 14 days when quizartinib has been 
administered at a dose of 30 mg/day or 60 mg/day.  If the toxicity recovers to Grade 1 or 
less severe within 14 days after the onset, treatment with quizartinib may be resumed at a 
reduced dose.  When quizartinib is administered at a dose of 20 mg/day, treatment with 
quizartinib should be discontinued. 
 
5.4.3 
Bone Marrow Depression 
If all of the following criteria apply in patients achieving CRp or CRi, dose reduction 
should be considered in the opinion of the investigators.  If an improvement in bone 
marrow depression is not observed even after dose reduction, interruption of treatment 
for a maximum of 14 days should be considered (also when quizartinib is administered at 
a dose of 20 mg/day in patients meeting all of the following criteria, interruption of 
treatment should be considered). 
• 
Completion of 1 or more cycles of treatment with quizartinib 
• 
Platelet count of less than 100 000/mm3 and neutrophil count of 1000/mm3 or less 
• 
Less than 5% blasts in the bone marrow 
• 
Absence of extramedullary lesions 
If an improvement in bone marrow depression is observed within 14 days after 
interruption of treatment, treatment with quizartinib may be resumed at the dose before 
interruption of treatment.  If the dose before interruption of treatment is 20 mg/day, the 
treatment may be resumed at 20 mg/day. 
 
5.4.4 
If Concomitant Use of Strong CYP3A4 Inhibitors Is Started during the 
Study Period 
If concomitant use of strong CYP3A4 inhibitors is started during the study period, the 
dose of quizartinib will be reduced by one level.  If concomitant use of strong CYP3A4 
inhibitors is discontinued, quizartinib may be administered at the dose used before dose 
reduction after a 7-day washout. 
 
5.4.5 
Dose Increase after Dose Reduction 
The dose of quizartinib will be increased by one level at a time in patients whose dose 
has once been reduced.  However, if the dose of quizartinib is reduced associated with 


 
 
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Grade 3 QTcF prolongation, the dose may not be increased.  If the dose of quizartinib is 
reduced associated with Grade 2 QTcF prolongation, the dose may be increased to the 
dose before dose reduction if QTcF prolongation recovers to Grade 1 or less severe after 
treatment at a reduced dose for at least 28 days. 
If the dose of quizartinib is reduced due to AEs, the dose must not be increased unless the 
concerned AE recovers to Grade 1 or less severe.  If the dose of quizartinib is reduced 
because concomitant use of a strong CYP3A4 inhibitor is started during the study, 
quizartinib may be administered at the dose before dose reduction after a 7-day washout 
when the concomitant use of the strong CYP3A4 inhibitor is discontinued. 
 
5.5 
Method of Assessing Treatment Compliance 
The investigators will evaluate the patient’s treatment compliance with the study drug 
based on the information in the dosing diary filled out by the patients and the number of 
tablets returned.  Administration of the study drug will be recorded in the case report 
form (CRF)/Drug Accountability Record.  If there are no returned tablets, the 
investigators should ask the patient whether any tablets were disposed of, rather than 
taken orally. 
As the information on administration of the study drug, the dose of the study drug, date 
and time of administration, start date of treatment, date of discontinuation of treatment, 
date of interruption of treatment, date of resumption of treatment, reason for interruption 
of treatment, etc. will be clearly documented in the CRF. 
 
5.6 
Concomitant Medications 
5.6.1 
Investigation Items 
All concomitant drugs and other therapies than the study drug that are used and 
transfusions introduced during the period from the day of the first dose of the study drug 
to the day of post-treatment observation will be recorded in the CRF.  For concomitant 
drugs or therapies, or transfusion that is newly started after the day following the last 
dose of the study drug, those used only for the treatment of AEs will be recorded in the 
CRF.  Concerning the details of the items to be entered, refer to Section 6.2. 
 
5.6.2 
Prohibited Concomitant Drugs, Restricted Concomitant Drugs, and Drugs 
to Be Coadministered with Care 
5.6.2.1 
Prohibited Concomitant Drugs 
The drugs listed below should not be used concomitantly with the study drug from the 


 
 
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day of informed consent to the study through the day of post-treatment observation.  It 
is, however, allowed to concomitantly use hydroxycarbamide at doses of up to 2 g/day 
only during the period from 14 days before the first dose of quizartinib to 4 days after the 
start of treatment with quizartinib.  If hydroxycarbamide has been used at least 15 days 
before the start of the first dose of quizartinib, the first dose of quizartinib may be started 
with a 1-day washout. 
1) Antiarrhythmic drugs, antibacterial, antifungal, psychotropic, and other drugs that 
may potentially prolong the QT/QTc interval (excluding medically unavoidable cases 
in the opinion of the investigators) 
2) Strong or moderate CYP3A4 inducers 
3) Crude drugs and food products with CYP3A4-inhibiting or -inducing properties (eg, 
foods and beverages containing St. John’s wort or grapefruit) 
4) Anticancer treatments other than quizartinib (Concomitant use of hydroxycarbamide 
during the aforementioned period is allowed.) 
5) Investigational drugs other than quizartinib, and investigational devices 
 
5.6.2.2 
Drugs to Be Coadministered with Care 
The following points should be noted during the period from the day of informed consent 
to the day of post-treatment observation. 
• 
During treatment with quizartinib, use of substrates of P-glycoprotein should be 
avoided as far as possible. 
• 
Concomitant use of strong CYP3A4 inhibitors is not prohibited, but should be 
avoided because it is required to start treatment with quizartinib at a reduced dose.  
Moderate or weak CYP3A4 inhibitors (fluconazole etc.) may be used concomitantly 
without reducing the dose of quizartinib. 
 
<Rationale> 
These specifications are provided for proper safety evaluation of quizartinib. 
Quizartinib and AC886 are mainly metabolized by CYP3A4.  If the need arises to use 
drugs that may potentially prolong the QT/QTc interval or strong or moderate CYP3A4 
inducers by necessity for the prevention or treatment of infection during the study, 
concomitant use of these drugs with quizartinib should be avoided. 
In addition, in vitro data indicate that quizartinib inhibits P-glycoprotein.  For this 
reason, concomitant use of quizartinib with substrates of P-glycoprotein should be 
avoided as far as possible.  Concomitant use of quizartinib with P-glycoprotein 


 
 
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substrates may increase the blood concentrations of the P-glycoprotein substrates. 
 
5.7 
Subject Withdrawal/Discontinuation 
5.7.1 
Discontinuation Criteria for Treatment with the Study Drug 
If any of the following criteria apply, the investigators should immediately discontinue 
treatment with the study drug and proceed to the post-treatment observation period. 
1) Overt disease progression is observed. 
2) Grade 4 QTcF prolongation is observed. 
3) The investigators decide that continued treatment with the study drug is no longer 
beneficial to the patient based on AEs and the results of laboratory test values. 
4) LVEF is less than 45%. 
5) The investigators decide to introduce HSCT. 
6) Treatment with quizartinib is interrupted for longer than 14 days. 
7) The patient is found to deviate from the inclusion criteria or fit the exclusion criteria 
after registration. 
8) Pregnancy is found after registration. 
9) The sponsor decides to discontinue the study. 
10) The patient requests for withdrawal from treatment with the study drug. 
11) Other circumstances why the study cannot be continued in the opinion of the 
investigators 
 
If treatment with the study drug is discontinued, the investigators should take appropriate 
actions for the patients, and then perform tests/assessments specified in “6.3 Procedures 
When Treatment with the Study Drug Is Discontinued,” and record the obtained 
information in the CRF.  The date of discontinuation of treatment with the study drug 
and the reason for discontinuation will also be recorded in the CRF.  The date of 
discontinuation of treatment with the study drug is not the date when the AE leading to 
discontinuation occurs, but the date when the investigators determine discontinuation of 
the treatment. 
 
5.7.2 
Reasons for Discontinuation during the Post-treatment Observation Period 
and the Follow-up Period 
If the study is discontinued during the patient’s post-treatment observation period or the 
follow-up period for the following reasons, the date of discontinuation and the reason for 
discontinuation will be recorded in the CRF. 


 
 
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1) The patient died. 
2) The patient requests for withdrawal from the study during the post-treatment 
observation period or the follow-up period. 
3) The patient is lost to follow-up. 
4) The sponsor decides to discontinue the study. 
5) Other 
 
5.7.3 
Withdrawal Procedures 
If a patient is withdrawn from the study, the investigators will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of 
last administration and the reason for withdrawal. 
If the patient is withdrawn due to an AE, the investigators will follow the patient as far as 
possible until the AE has resolved or stabilized. 
All patients who are withdrawn from the study should complete protocol-specified 
withdrawal procedures. 
 
6. 
STUDY PROCEDURES 
Study procedures specified in the protocol are shown in “Table 6-1 Schedule of Study 
Procedures.” 
In the study, the period from the day of informed consent through the last day of the 
follow-up period is defined as the “study period” for each patient.  However, if a patient 
has difficulty to attend the follow-up at the study center for reasons including transfer to 
another hospital or he/she refuses to visit the study center after the final dosing of 
quizartinib, then the study period for the patient will be terminated on the relevant day. 
 


 
 
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Table 6-1  Schedule of Study Procedures 
 
Screening  
(≤ 14 Days 
before 
Registration) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
Thereafter 
At 
Withdrawal 
Post  
treatment 
Observation Follow  
up 
Day 1 Day 2 and 
8 
Day 15 
Day 16 
Day 1 Day 15 
Day 1 
Day 1 
30 Days 
after the 
Last Dose 
Acceptable limit (unit: days) 
 
 
Day 2: 
Scheduled 
Day 
Day 8: ±1 
±1 
(Must Be 
the Day 
Following 
Day 15) 
±3 
±1 
±3 
±3 
3 to +7 
+15 
Every 3 
Months 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
FLT3 ITD test 
●*1 
 
 
 
 
 
 
 
 
 
 
 
Administration of quizartinib (at the 
study center) 
 
●*2 
●*2 
●*2 
●*2 
●*2 
●*2 
●*2 
●*2 
 
 
 
Medical history/complications 
● 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurement 
● 
● 
● 
● 
 
● 
● 
● 
● 
● 
● 
 
ECOG PS/body weight 
● 
● 
 
 
 
● 
 
● 
● 
● 
● 
 
Height 
● 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests (hematology, blood 
chemistry, urinalysis) 
● 
●*3 
●*3 
●*3 
 
●*3 
●*3 
●*3 
●*3 
● 
● 
 
Pregnancy test 
● 
 
 
 
 
 
 
 
 
 
 
 
HIV antibody 
●*4 
 
 
 
 
 
 
 
 
 
 
 
12 lead ECG 
●*5 
●*5 
●*5 
●*5 
 
●*5 
 
●*5 
●*5 
●*5 
 
 
X ray examination 
● 
○ (as needed) 
MUGA scan or echocardiography 
●*6 
○ (as needed) 
Assessment of bone marrow findings 
(tumor assessment) 
●*7 
 
 
 
 
●*7 
 
●*7 
●*7 
●*7 
 
 
Measurement of drug concentrations 
 
●*8 
●*8 
●*8 
●*8 
●*8 
 
●*8 
 
 
 
 
Inhibitory activity on phosphorylated 
FLT3 and c Kit proteins 
 
●*9 
●*9 
●*9 
 
●*9 
 
 
 
 
 
 
AEs 
●*10 
 
Assessment of concomitant drugs and 
therapies 
 
● 
 
Investigation of survival status 
Other leukemia treatment etc. 
 
 
 
 
 
 
 
 
 
 
● 
● 
1) 
FLT3 ITD levels will be measured using a bone marrow specimen or peripheral blood.  The collected bone marrow specimen or peripheral blood will immediately be 
submitted to the specimen collection agency. 
2) 
Quizartinib will be administered on Days 1, 2, 8, 15, and 16 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3, and Day 1 of Cycle 4 and subsequent cycles at the 
study center.  Quizartinib may be administered at home on the other days. 


 
 
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3) 
To be measured before administration of the study drug. 
4) 
To be performed within 120 days before registration. 
5) 
ECG will be measured three times (triplicate ECGs) at each of the following time points.  Triplicate ECGs will be obtained at least once weekly for the first 2 weeks 
after increasing the dose of quizartinib to carefully confirm the QTcF interval. 
Screening, Day 1 of Cycle 1 (before administration of the study drug and at 2, 4, and 6 hours after the end of administration of the study drug), Day 2 and Day 8 of 
Cycle 1 (before administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), Day 15 of Cycle 1 (before administration of the 
study drug and at 2, 4, and 6 hours after the end of administration of the study drug), Day 1 of Cycle 2 ([if the dose of quizartinib is increased on Day 16 of Cycle 1]: 
before administration of the study drug and at 2, 4, and 6 hours after the end of administration of the study drug, [if the dose of quizartinib is not increased on Day 16 of 
Cycle 1]: before administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), Day 1 of Cycle 3 (before administration of the 
study drug and at 2 to 4 hours after the end of administration of the study drug), and Cycle 4 thereafter (before administration of the study drug on Day 1 of each cycle) 
6) 
A multiple gated acquisition (MUGA) scan or echocardiography must be performed at screening except in case LVEF is 45% or more within 1 month before 
registration. 
7) 
It is desirable to assess bone marrow findings with specimens obtained by both bone marrow aspiration and biopsy; however, bone marrow biopsy may be skipped if the 
antitumor effect can be evaluated adequately only by bone marrow aspiration in the opinion of the investigators.  Assessment of bone marrow findings will be 
performed at screening (it is desirable to obtain the specimen within 14 days before registration; however, the specimen collected before the time may be used with the 
consent of the medical monitor etc.), on Day 1 of Cycle 2 and subsequent cycles, at the time of discontinuation of the study, and other time points if assessment is 
considered necessary by the investigators.  For patients achieving CR, CRp, or CRi, bone marrow findings will be assessed every 3 cycles. 
8) 
A plasma specimen for pharmacokinetic measurement will be collected at the following specified time points.  If ECG and blood collection for pharmacokinetics (PK) 
are scheduled at the same time, blood collection for PK will be performed immediately after the end of ECG. 
Day 1 of Cycle 1 (before administration of the study drug and at 1, 2, 4, 6, and 24 hours after the end of administration of the study drug), Day 8 of Cycle 1 (before 
administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), Day 15 of Cycle 1 (before administration of the study drug and at 
1, 2, 4, 6, and 24 hours after the end of administration of the study drug), Day 1 of Cycle 2 ([if the dose of quizartinib is increased on Day 16 of Cycle 1]: before 
administration of the study drug and at 1, 2, 4, 6, and 24 hours after the end of administration of the study drug, [if the dose of quizartinib is not increased on Day 16 of 
Cycle 1]: before administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), and Day 1 of Cycle 3 (before administration of the 
study drug and at 2 to 4 hours after the end of administration of the study drug). 
9) 
A specimen for measurement of inhibitory activity on phosphorylated FLT3 and c Kit proteins will be collected at the following specified time points. 
Day 1 of Cycle 1 (before administration of the study drug and at 2, 4, and 6 hours after the end of administration of the study drug), Day 8 of Cycle 1 (before 
administration of the study drug), Day 15 of Cycle 1 (before administration of the study drug), and Day 1 of Cycle 2 (before administration of the study drug). 
10) Only information on SAEs will be collected during the period from the day of informed consent to before the first dose of the study drug. 
 
 


 
 
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6.1 
Procedures to Be Performed before Patient Registration 
The procedures listed below will be performed, and the results will be recorded in the 
CRF. 
For each assessment item, data obtained before informed consent within the allowable 
time limits for each item may also be used. 
If the study drug is started on Day 7 or later if the day of registration is defined as Day 0, 
the patient’s eligibility should be assessed again on the preceding day or the start day 
(before dosing) of treatment with the study drug. 
If 12-lead ECG measurement, vital sign measurement, and blood collection for 
laboratory tests etc. are scheduled on the same day, blood collection will be performed 
after 12-lead ECG and vital sign measurements. 
 
1) Items to be collected or assessed after informed consent is obtained but before the 
start of the patient registration procedure 
• 
If informed consent for tests for mutations of the FLT3-ITD gene is obtained 
before obtaining informed consent for participation in the study, the date of 
informed consent 
• 
Date of informed consent for participation in the study 
• 
Presence or absence of mutations of the FLT3-ITD gene and FLT3-ITD 
assessment result 
• 
Mutations of the FLT3-ITD gene will be tested at Navigate BioPharma using 
peripheral blood or bone marrow liquid after informed consent.  Patients 
who have not previously undergone mutation tests of the FLT3-ITD gene at 
any testing company may be tested for mutations of the FLT3-ITD gene at 
SRL, if necessary, and their eligibility for the study may be assessed without 
having to wait for the result of the test at Navigate BioPharma. 
• 
If the test result of Navigate BioPharma is found to be different from the test 
result of the hospital or SRL after registration based on the result of the 
previous FLT3-ITD mutation test performed at the testing company or SRL, 
the investigators will decide whether to continue treatment with the study 
drug or not for the concerned patient.  In other words, even if the test result 
of Navigate BioPharma is negative, if continued treatment with the study 
drug may be beneficial to the patient in the opinion of the investigators, 
treatment with the study drug may be continued. 
• 
Subject identification code 


 
 
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• 
Date of birth 
• 
Sex 
• 
Race 
• 
Height 
• 
Eligibility 
• 
Medical history and complications 
Assess the presence or absence of medical history and complications, presence 
or absence of symptoms on the day of the first dose of the study drug (if any 
symptoms are present, it should be handled as a complication), findings, and the 
diagnosis. 
Only the medical history that needs to be reported in the opinion of the 
investigators, will be listed. 
• 
Information on the underlying disease (AML) 
Collect data on the date of the first diagnosis, the WHO classification, and the 
date of relapse. 
• 
Prior therapy: 
Collect data on the following items: 
• 
Medications for AML: Presence or absence, drug name, stop date, best 
response, number of courses 
• 
Radiation therapy for AML: Presence or absence, purpose, location, stop 
date, best response 
• 
HSCT: Presence or absence, details, date of transplantation 
• 
Others: Presence or absence, details, stop date 
• 
Confirmation of serious adverse events (SAEs) 
Information on SAEs that occur during the period from informed consent to 
before the first dose of the study drug will be collected.  Collection of 
information on nonserious AEs is not required. 
 
2) Items to be collected or assessed between Day 14 and Day 0 (  day of registration) 
(collected or assessed on a day as close as possible to the day of registration) 
• 
Vital sign measurement 
Axillary body temperature, pulse rate, and systolic and diastolic blood pressure 
will be measured in the supine position after a 5-minute rest. 
• 
Body weight 
• 
ECOG PS assessment 


 
 
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The patient’s PS will be assessed according to the criteria provided in Appendix 
2. 
• 
12-lead ECG (including QTcF assessment) 
A 12-lead ECG will be performed in triplicate in the supine position after a 
10-minute rest.  The measurements will be performed at approximately 3- to 
5-minute intervals. 
• 
Laboratory tests 
 
Laboratory Parameter 
Hematology test 
Red blood cell count, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), 
hemoglobin, hematocrit, white blood cell count, white blood cell differential count 
(neutrophils, basophils, eosinophils, lymphocytes, monocytes), platelet count, and 
PT INR 
Blood chemistry 
test 
Total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ GT, 
LDH, lipase, BUN, serum creatinine, creatine kinase, uric acid, glucose, 
electrolytes (K, Na, Cl, Ca, P, Mg), CRP, total cholesterol,* LDL,* HDL,* and 
triglyceride* 
Urinalysis 
Specific gravity, pH, occult blood, glucose, protein, bilirubin, and ketone bodies 
* These parameters will be measured only at screening and at the time of discontinuation (no dietary 
restrictions). 
 
• 
Assessment of bone marrow findings 
Assessment will be made based on the bone marrow findings and peripheral 
blood results (neutrophil count, platelet count, and presence or absence of blasts) 
in accordance with “7.1 Definition of Efficacy Endpoints.”  Even if a bone 
marrow test is not performed within 14 days (Day 14) before registration (day 
of registration is regarded as Day 0), if consent of the medical monitor etc. is 
obtained, the concerned data may be used for assessment of bone marrow 
findings. 
• 
Chest X-ray (Posterior or lateral radiographs will be taken, as necessary.) 
• 
Pregnancy test 
A urine or serum pregnancy test will be performed in female patients. 
A pregnancy test is not necessary in women who have been amenorrheic for at 
least 2 years after the last menstruation and who are considered to have no 
childbearing potential, or women who are not of childbearing potential after 
permanent surgical sterilization, etc.  In this case, the information and reason 
will be recorded in the CRF. 
A pregnancy test must be performed in women who have been amenorrheic for 
at least 2 years for medical reasons other than surgical sterilization (eg, 
medication) because they are considered to have childbearing potential. 
• 
A MUGA scan or echocardiography (however, excluding cases of LVEF of 45% 


 
 
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or more based on the result of the test performed within 1 month after the 
screening test) 
 
3) Items to be collected or assessed between Day 120 and Day 0 (  day of 
registration) 
• 
HIV antibody 
 
6.2 
Procedures during the Study Conduct Phase 
The procedures listed below will be performed, and the results will be recorded in the 
CRF. 
The details of the procedures are the same as those described in “6.1 Procedures to Be 
Performed before Patient Registration.” 
If 12-lead ECG measurement, vital sign measurement, and blood collection for 
laboratory tests etc. are scheduled on the same day, blood collection will be performed 
after 12-lead ECG and vital sign measurements. 
 
1) Confirmation of the status of administration of the study drug 
• 
Presence or absence of administration 
• 
Dates of doses administered 
• 
Timing of dosing 
• 
Amount of dose administered (mg/day) 
• 
Presence or absence of interruption and dose reduction (if present, the details 
and reason for it) 
 
2) Vital sign measurement 
Cycle 1 
Day 1 
* Day of the first dose 
of the study drug 
Pre dose 
Day 2 
Pre dose 
Day 8 (±1 day) 
Pre dose 
Day 15 (±1 day) 
Pre dose 
Cycle 2 
Day 1 (±3 days) 
Pre dose 
Day 15 (±1 day) 
Pre dose 
Cycle 3 and thereafter 
Day 1 (±3 days) 
Pre dose 
 
3) Body weight 
Cycle 1 
Day 1 
* Day of the first dose 
of the study drug 
Pre dose 
Cycle 2 and thereafter 
Day 1 (±3 days) 
Pre dose 


 
 
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4) ECOG PS assessment 
Cycle 1 
Day 1 
* Day of the first dose 
of the study drug 
Pre dose 
Cycle 2 and thereafter 
Day 1 (±3 days) 
Pre dose 
 
5) 12-lead ECG 
A 12-lead ECG will be performed in triplicate (triplicate ECG) in the supine position 
after a 10-minute rest.  The measurements will be performed at approximately 3- to 
5-minute intervals.  For the details, refer to “9.10.1 Measurement Method.” 
It should be noted that the measurement time points are different if the dose of 
quizartinib is increased or not increased on Day 16 of Cycle 1, as shown below. 
 
Cycle 1 
Day 1 
* Day of the first dose 
of the study drug 
Pre dose 
2 hours (±10 minutes) post dose 
4 hours (±10 minutes) post dose 
6 hours (±10 minutes) post dose 
 
Day 2 
Pre dose (24 hours post dose on Day 1) 
2 to 4 hours post dose 
 
Day 8 (±1 day) 
Pre dose 
2 to 4 hours post dose 
 
Day 15 (±1 day) 
Pre dose 
2 hours (±10 minutes) post dose 
4 hours (±10 minutes) post dose 
6 hours (±10 minutes) post dose 
Cycle 2 
Day 1 (±3 days) 
 
 
If the dose of 
quizartinib is increased 
on Day 16 of Cycle 1 
Pre dose 
2 hours (±10 minutes) post dose 
4 hours (±10 minutes) post dose 
6 hours (±10 minutes) post dose 
 
If the dose of 
quizartinib is not 
increased on Day 16 of 
Cycle 1 
Pre dose 
2 to 4 hours post dose 
Cycle 3 
Day 1 (±3 days) 
Pre dose 
2 to 4 hours post dose 
Cycle 4 and thereafter 
Day 1 (±3 days) 
Pre dose 
A 12 lead ECG will be performed at least once weekly for 2 weeks after increasing the dose of quizartinib to 
carefully confirm the QTcF interval. 
 
6) Laboratory tests 
Cycle 1 
Day 1 
* Day of the first dose 
of the study drug 
Pre dose 
 
Day 2 
Pre dose 
 
Day 8 (±1 day) 
Pre dose 
 
Day 15 (±1 day) 
Pre dose 
Cycle 2 
Day 1 (±3 days) 
Pre dose 
 
Day 15 (±1 day) 
Pre dose 
Cycle 3 and thereafter 
Day 1 (±3 days) 
Pre dose 


 
 
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7) Assessment of bone marrow findings 
Assessment will be made based on the bone marrow findings and peripheral blood 
results (neutrophil count, platelet count, and presence or absence of blasts) in 
accordance with “7.1 Definition of Efficacy Endpoints.” 
It is desirable to obtain bone marrow specimens by bone marrow aspiration and 
biopsy.  If the investigator or subinvestigator considers that the antitumor effect of 
quizartinib can be assessed adequately using specimens obtained by bone marrow 
aspiration alone, bone marrow biopsy may be omitted. 
 
Cycle 2 
Day 1 
On the specified day (±3 days) 
Cycle 3 
Day 1 
On the specified day (±3 days) 
Cycle 4 and thereafter 
Day 1 
On the specified day (±3 days) 
After achievement of CR, CRi, or CRp, the antitumor effect will be assessed every 3 cycles until the 
appearance of leukemic blasts in the peripheral blood.  Assessment will be performed at other time points if 
necessary. 
 
8) Confirmation of concomitant drugs and therapies, and transfusion 
• 
Concomitant drugs and therapies 
The following information on concomitant drugs and therapies other than the 
study drug, which are used during the period from the day of the first dose of the 
study drug to the day of post-treatment observation will be confirmed.  As for 
concomitant drugs or therapies that are newly started after the day following the 
last dose of the study drug, those used only for the treatment of AEs will be 
confirmed. 
• 
Name of drug (therapy), dose, unit, mode of administration, frequency 
• 
Start and stop dates of drug (therapy) 
• 
Reason for use (application) 
The following items do not have to be recorded in the CRF unless a relationship 
of them with the AEs occurring during study participation cannot be ruled out: 
• 
Antiseptic solutions 
• 
Heparin for heparin lock flush 
• 
Test or procedural agents used for tests including bone marrow aspiration or 
biopsy 
 
• 
Transfusion 
The following information on transfusion that is introduced during the period 
from the day of the first dose of the study drug to the day of post-treatment 


 
 
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observation will be confirmed.  As for transfusion that is newly started after the 
day following the last dose of the study drug, the one used only for the treatment 
of AEs will be confirmed. 
• 
Type of blood products (whole blood, red blood cells, plasma, platelets, 
others) 
• 
Start date, end date, amount of use (unit) 
• 
Reason for use 
 
9) Monitoring of AEs 
10) Collection of specimens for pharmacokinetic assessment and the biomarker study 
Refer to “6.8 Pharmacokinetics,” “6.9 FLT3-ITD Mutation Test,” and “6.10 
Biomarker Study.” 
 
6.3 
Procedures When Treatment with the Study Drug Is Discontinued 
The procedures listed below will be performed on the day when the investigators decide 
discontinuation of treatment with the study drug (within 3 to +7 days). 
The details of the procedures are the same as those described in “6.1 Procedures to Be 
Performed before Patient Registration” and “6.2 Procedures during the Study Conduct 
Phase.” 
• 
Date of discontinuation of treatment with the study drug and reason for 
discontinuation 
• 
Vital sign measurement 
• 
Body weight 
• 
ECOG PS assessment 
• 
12-lead ECG 
• 
Laboratory tests 
• 
Assessment of bone marrow findings (It is desirable to obtain bone marrow 
specimens by bone marrow aspiration and biopsy.  If the investigator or 
subinvestigator considers that the antitumor effect of quizartinib can be assessed 
adequately using specimens obtained by bone marrow aspiration alone, bone 
marrow biopsy may be omitted.) 
• 
Confirmation of concomitant drugs and therapies, and transfusion 
• 
Monitoring of AEs 
• 
Confirmation of the status of administration of quizartinib 
 


 
 
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6.4 
Procedures during the Post-treatment Observation Period 
The procedures listed below will be performed at day 30 (+15 days) when the day of the 
last dose of the study drug is set day 0.  The post-treatment observation will be 
performed before the start of post treatment, if it is initiated. 
The day when all the procedures have been completed is defined as the day of completion 
of the post-treatment observation period. 
If any AEs have not resolved by the day of completion of the post-treatment observation 
period, follow-up should be continued as far as possible until the AE is resolved or 
reduced. 
The details of the procedures are the same as those described in “6.1 Procedures to Be 
Performed before Patient Registration” and “6.2 Procedures during the Study Conduct 
Phase.” 
• 
Vital sign measurement 
• 
Body weight 
• 
ECOG PS assessment 
• 
Laboratory tests 
• 
Confirmation of survival (the last date of confirming survival) or death (the date 
of death) 
• 
Confirmation of concomitant drugs and therapies, and transfusion 
• 
Monitoring of AEs 
• 
Post treatment for AML after discontinuation of treatment with quizartinib 
• 
Presence or absence of relapsed AML, and if present, the date of relapse 
 
6.5 
Post Treatment 
Treatment used for AML after the day of the last dose of the study drug (eg, HSCT, 
chemotherapy, immunotherapy, radiation therapy, and others) is defined as “post 
treatment.” 
Post treatment should not be started before the day of completion of the post-treatment 
observation period as far as possible.  If post treatment is started by necessity before 
completion of the post-treatment observation period, the name and start date of the post 
treatment will be recorded in the CRF. 
 
6.6 
Follow-up 
The following information will be confirmed every 3 months after assessment during the 
post-treatment observation period (confirmation by phone is allowed). 


 
 
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• 
Investigation of survival status 
• 
Post treatment for AML after discontinuation of treatment with quizartinib 
• 
Presence or absence of relapsed AML, and if present, the date of relapse 
 
6.7 
Definition of the Study Period 
The study period for each patient is from the time of informed consent to the end of the 
follow-up assessment. 
 
6.8 
Pharmacokinetics 
A total of 2 mL of blood will be drawn, well mixed by inverting the tube, and centrifuged 
(≥ 15°C, 1500 g, 10 minutes) within 20 minutes after blood collection.  The obtained 
plasma will be stored frozen between 90°C and 70°C.  The specimens in a frozen 
state will be submitted to the agency contracted by the sponsor to collect the specimens.  
Details including the handling of specimens will be specified in separate procedures.  
The date and time of blood collection will be recorded in the CRF. 
If 12-lead ECG measurement, vital sign measurement, and blood collection are scheduled 
at the same time, blood collection will be performed after 12-lead ECG and vital sign 
measurements. 
 


 
 
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Table 6.8-1  Blood Collection Points for Pharmacokinetic Assessment 
Treatment Cycle 
Treatment Day 
Blood Collection Point (Acceptable Limit) 
Cycle 1 
Day 1 
Pre dose ( 60 minutes) 
1 hour (±30 minutes) post dose 
2 hours (±30 minutes) post dose 
4 hours (±30 minutes) post dose 
6 hours (±30 minutes) post dose 
24 hours post dose (within 3 hours pre dose on Day 2 of 
Cycle 1) 
 
Day 8 (±1 day) 
Pre dose ( 60 minutes) 
2 to 4 hours post dose 
 
Day 15 (±1 day) 
Pre dose ( 60 minutes) 
1 hour (±30 minutes) post dose 
2 hours (±30 minutes) post dose 
4 hours (±30 minutes) post dose 
6 hours (±30 minutes) post dose 
24 hours post dose (within 3 hours pre dose on Day 16 of 
Cycle 1) 
Cycle 2 
Day 1 (±3 days) 
 
 
If the dose of quizartinib 
is increased on Day 16 of 
Cycle 1 
Pre dose ( 60 minutes) 
1 hour (±30 minutes) post dose 
2 hours (±30 minutes) post dose 
4 hours (±30 minutes) post dose 
6 hours (±30 minutes) post dose 
24 hours post dose (within 3 hours pre dose on Day 2 of 
Cycle 2) 
 
If the dose of quizartinib 
is not increased on Day 
16 of Cycle 1 
Pre dose ( 60 minutes) 
2 to 4 hours post dose 
Cycle 3 
Day 1 (±3 days) 
Pre dose ( 60 minutes) 
2 to 4 hours post dose 
 
6.9 
FLT3-ITD Mutation Test 
To investigate the presence or absence of mutations of the FLT3-ITD gene, 2 mL of bone 
marrow liquid or 4 mL of peripheral blood (1 mL of bone marrow liquid or 2 mL of 
peripheral blood if the measurement is not performed at SRL) will be collected after 
obtainment of informed consent, but before registration, and the specimen will 
immediately be submitted to the specimen collection agency contracted by the sponsor 
under the designated temperature conditions. 
 
6.10 Biomarker Study 
6.10.1 Plasma Inhibitory Activity of Quizartinib on Phosphorylated FLT3 and 
c-Kit Proteins 
A total of 2 mL of blood will be drawn, well mixed by inverting the tube, and centrifuged 
(≥ 15°C, 1500 g, 10 minutes) within 20 minutes after blood collection.  The obtained 
plasma will be stored frozen between 90°C and 70°C.  The specimens in a frozen 
state will be submitted to the agency contracted by the sponsor to collect the specimens.  
Details including the handling of specimens will be specified in separate procedures.  


 
 
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The date and time of blood collection will be recorded in the CRF. 
If 12-lead ECG measurement, vital sign measurement, and blood collection are scheduled 
at the same time, blood collection will be performed after 12-lead ECG and vital sign 
measurements. 
 
Table 6.10-1  Blood Collection Points for Plasma Inhibitory Activity 
Treatment Cycle 
Treatment Day 
Blood Collection Point (Acceptable Limit) 
Cycle 1 
Day 1 
Pre dose ( 60 minutes) 
2 hours (±30 minutes) post dose 
4 hours (±30 minutes) post dose 
6 hours (±30 minutes) post dose 
 
Day 8 (±1 day) 
Pre dose ( 60 minutes) 
 
Day 15 (±1 day) 
Pre dose ( 60 minutes) 
Cycle 2 
Day 1 (±3 days) 
Pre dose ( 60 minutes) 
 
7. 
EFFICACY ASSESSMENTS 
The antitumor effect of quizartinib will be assessed based on bone marrow findings and 
neutrophil and platelet counts in the peripheral blood, as specified in “7.1 Definition of 
Efficacy Endpoints.” 
 
7.1 
Definition of Efficacy Endpoints 
The efficacy endpoints are defined in Table 7.1-1. 
 


 
 
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Table 7.1-1  Definition of Efficacy Endpoints 
Complete remission (CR) 
For patients to be classified as CR, they must achieve a 
morphologic leukemia free state, must have less than 5% blasts 
in the bone marrow (no Auer rods), a neutrophil count of 
1000/mm3 or more, and a platelet count of 100 000/mm3 or more, 
must be independent of red blood cell (RBC) and platelet 
transfusions (defined as 4 weeks without RBC transfusion and 1 
week without platelet transfusion), and may not have 
extramedullary leukemia. 
CR with incomplete hematological recovery 
(CRi) 
For patients to be classified as CRi, they must fulfill all the 
criteria for CR, except for incomplete hematological recovery 
with residual neutropenia of less than 1000/mm3.  Platelet 
recovery status and RBC and platelet transfusion independence 
are not required. 
CR with incomplete platelet recovery (CRp) 
For patients to be classified as CRp, they must fulfill all the 
criteria for CR, except for incomplete platelet recovery 
(< 100 000/mm3). 
Partial remission (PR) 
For patients to be classified as PR, they must have bone marrow 
regenerating normal hematopoietic cells, no or minimal residual 
blast cells in the peripheral blood, a decrease of at least 50% in 
the percentage of blasts in the bone marrow aspirate, and total 
marrow blasts between 5% and 25% inclusive.  Whether the 
neutrophil count or platelet count has recovered or not, or 
whether erythrocyte or platelet transfusion has been performed or 
not, will not be taken into consideration. 
No response (NR) 
NR is defined as a condition not reaching any of CR, CRi, CRp, 
or PR. 
Unknown 
No assessment is made after baseline. 
Composite CR rate (CRc rate) 
Composite CR rate (CRc rate) is defined as the proportion of 
patients whose best response is CR, CRi, or CRp. 
Response rate 
Response rate is defined as the proportion of patients whose best 
response is CR, CRi, CRp, or PR. 
Relapse 
Relapse after CR, CRi, or CRp: 
Defined as the reappearance of leukemic blasts in the 
peripheral blood or an increase in the percentage of blasts in 
the bone marrow aspirate to 5% or more, or the reappearance 
or new appearance of extramedullary leukemia. 
Relapse after PR: 
Defined as the reappearance of significant numbers of blasts 
in the peripheral blood or an increase in the percentage of 
blasts in the bone marrow aspirate to more than 25%, or the 
reappearance or new appearance of extramedullary leukemia. 
 
7.2 
Best Response 
Best response is defined as the best measured response over all response assessments 
(CR, CRp, CRi, PR, NR, or Unknown) at all time points after the first dose of the study 
drug.  The best response is presented as CR, CRp, CRi, PR, NR, or Unknown in 
descending order of efficacy. 
 
7.3 
Primary Efficacy Endpoint 
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the proportion of patients whose best response is CR, CRp, or CRi. 
 
7.4 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are as follows. 
• 
Best response 
• 
Response rate 
• 
Overall survival (time from registration to death) 
• 
Event-free survival (time from registration to progression, relapse, or death, 
whichever occurs first) 
• 
Leukemia-free survival (time from first achievement of CRc to relapse or death, 
whichever occurs first) 
• 
Transplantation rate (proportion of patients who start HSCT immediately after the 
end of treatment with the study drug without receiving other treatment for AML) 
 
7.5 
Appropriateness of Selected Efficacy Endpoints 
This study will be conducted to evaluate the efficacy of quizartinib in Japanese patients 
with FLT3-ITD positive relapsed or refractory AML.  The reasons why the CRc was 
chosen as the primary efficacy endpoint are as follows: Prolonged OS has been reported 
in patients achieving CRc compared with patients failing to achieve CRc in the study in 
patients with relapsed or refractory AML,15) and achievement of CRc in Japanese patients 
with relapsed or refractory AML allows them to undergo HSCT, which is expected to 
provide prolongation of OS. 
 
8. 
PHARMACOKINETIC/BIOMARKER ASSESSMENTS 
The following items will be measured to evaluate the pharmacokinetics of quizartinib and 
quizartinib-related biomarkers. 
 
8.1 
Pharmacokinetic Endpoints 
The pharmacokinetic parameters listed below will be calculated from the plasma 
concentrations of quizartinib and its active metabolite AC886 using a model independent 
approach. 
Day 1 of Cycle 1: Cmax, Tmax, AUCtau 
Day 15 of Cycle 1 and Day 1 of Cycle 2 (if the dose of quizartinib is increased on Day 16 
of Cycle 1): Cmax,ss, Ctrough, Tmax,ss, AUCtau,ss 
The details of the method of calculation of pharmacokinetic parameters are specified in 


 
 
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the Statistical Analysis Plan. 
 
8.1.1 
Amount and Time Points of Blood Collection 
Refer to “6.8 Pharmacokinetics.” 
 
8.2 
Biomarker Endpoints 
• 
The presence or absence of mutations of the FLT3-ITD gene will be investigated 
using 2 mL of bone marrow liquid or 4 mL of peripheral blood collected after 
obtainment of informed consent, but before registration. 
• 
The plasma inhibitory activity of quizartinib on phosphorylated FLT3 and c-Kit 
proteins will be measured using 2 mL of peripheral blood. 
 
8.3 
Anonymization, Storage, and Disposal of Specimens for Biomarker Testing 
8.3.1 
Anonymization of Specimens 
Prior to submission, the specimens will be anonymized with the subject identification 
code so that patient’s personal information cannot be identified.  Since the linking table 
between the subject identification code and their personal information will be strictly 
retained at the study center, not the sponsor, specimen collection agency, or biomarker 
assay facility can identify the patient’s personal information.  The sponsor can interlink 
biomarker study results to the subject identification code and the study data of the 
concerned patient. 
 
8.3.2 
Storage of Specimens 
Considering the possibility that the relationship between the efficacy or safety of the 
study drug and biomarkers may be additionally measured, and the possibility that the 
items given in “6.9 FLT3-ITD Mutation Test” and “6.10 Biomarker Study” may be 
remeasured based on newly obtained knowledge, the submitted specimens will be stored 
at the biomarker assay facility for a maximum of 5 years after the end of the study.  
Biomarkers that may be additionally measured are point mutations and deletions in the 
tyrosine kinase domain of FLT3. 
 
8.3.3 
Disposal of Specimens 
At the time of expiration of the specimen storage period, the biomarker assay facility will 
dispose of all the specimens as instructed by the sponsor. 
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specimens will be disposed of, depending on the location of the specimens at the time, 
according to the following procedure.  If biomarker analysis has been performed at the 
biomarker assay facility before a patient’s withdrawal of consent, the data will not be 
disposed of. 
1) In cases where the specimens are temporarily stored at the study center: 
The investigators will identify the specimens of the patient and dispose of them. 
2) In case the specimens are stored at the specimen collection agency or the assay 
facility: 
The investigators will report the subject identification code of the pertinent patient to the 
sponsor.  The sponsor will instruct the specimen collection agency or the assay facility 
to dispose of the specimens of the patient. 
 
9. 
SAFETY EVALUATION AND REPORTING 
Safety endpoints are defined as AEs, laboratory data, body weight, ECOG PS, vital signs, 
12-lead ECG, MUGA/echocardiography, and X-ray examination. 
 
9.1 
Adverse Event Collection and Reporting 
All clinical AEs (for the definition, see “9.3.1 Definition of Adverse Events”) that occur 
during the period from the day of the first dose of the study drug to the day of 
post-treatment observation will be recorded on the AE page of the CRF.  SAEs that 
occur during the period from the day of informed consent to before the first dose of the 
study drug will also be recorded in the CRF. 
Medical conditions (including laboratory values/vital signs that are out of range) that 
were diagnosed or known to exist prior to informed consent will be recorded as part of 
complications/medical history. 
AEs and SAEs are to be reported according to the procedures in “9.4 Serious Adverse 
Events Reporting Procedure for Investigators.” 
All clinical laboratory results, vital signs, and 12-lead ECG results and findings should be 
appraised by the investigators 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 study drug 
discontinuation, dose reduction, require corrective treatment, or constitute an AE in the 
investigators’ clinical judgment. 
At each visit, the investigators will determine whether any AEs have occurred by 
evaluating the patient.  AEs may be directly observed, reported spontaneously by the 


 
 
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patient or by questioning the patient at each study visit.  Patients should be questioned 
in a general way, without asking about the occurrence of any specific symptoms.  The 
investigators must assess all AEs to determine seriousness, severity, and causality, in 
accordance with the definitions in “9.3 Adverse Events.”  The investigator’s assessment 
must be clearly documented in the site’s source documentation. 
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 
preexisting conditions that do not worsen in severity should not be reported as SAEs 
(refer to Section “9.3.2 Serious Adverse Events” for definitions). 
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 
investigators assesses as related to study drug should also be reported and managed as an 
SAE. 
 
If any AE has occurred, the investigators will take appropriate actions, notify the sponsor 
as required, and continue follow-up until the patient recovers to the pre-event condition 
with resolution or relief of the AE as far as possible (even after the end of the specified 
observation period).  However, even if the AE is not confirmed to have resolved or 
relieved, if it is judged that the patient’s condition remains stable and the safety can be 
assured, the investigators will explain the matter to the patient, and the follow-up of the 
study will be completed (treatment of the relevant symptom will be continued). 
 
9.2 
Safety Endpoints 
Safety endpoints are defined as AEs, laboratory data, body weight, ECOG PS, vital signs, 
12-lead ECG, MUGA/echocardiography, and X-ray examination. 
 


 
 
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9.2.1 
Combined Elevations of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law 
case (ALT or AST ≥ 3 × upper limit of normal [ULN] with simultaneous total bilirubin 
≥ 2 × ULN) should always be reported to the sponsor using a Serious Adverse Event 
Report (SAVER) form, with the investigators’ assessment of seriousness, causality, and a 
detailed narrative.16)  These events should be reported within 24 hours of investigators’ 
awareness of the event. 
If the patient discontinues study drug due to liver enzyme abnormalities, the patient will 
have additional clinical and laboratory evaluations as described in “5.7 Subject 
Withdrawal/Discontinuation” in order to determine the nature and severity of the 
potential liver injury. 
 
9.3 
Adverse Events 
9.3.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient 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 (International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use [ICH] E2A Guideline.  Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
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. 
The progression of the underlying disease (AML) will be handled as described below: 
• 
Tumor progression will not be handled as an AE.  However, tumor progression 
leading to the outcome of death during the AE collection period should be handled as 
an SAE (with the name and outcome of the event recorded as “disease progression” 
and “fatal,” respectively). 
• 
Tumor progression resulting in exacerbated signs or symptoms will be handled as an 
AE. 
 


 
 
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9.3.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• 
results in death, 
• 
is life-threatening, 
• 
requires inpatient hospitalization or prolongation of existing hospitalization for 
treatment, 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly or birth defect, or 
• 
is an important medical event. 
 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient 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 severe (ICH E2A Guideline.  
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994). 
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 patient or may require intervention to prevent one 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 preexisting conditions that do not worsen in severity are not 
SAEs. 
 
9.3.3 
Severity Assessment 
Severity of AEs will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0 Japanese version.  The severity of AEs not included in 
the CTCAE v4.0 Japanese version will be assessed according to the grades specified in 
Table 9.3-1. 
 


 
 
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Table 9.3-1  Evaluation of Severity of Adverse Events 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental activities of daily living (ADL). 
Grade 3 
Severe or medically significant but not immediately life threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 
Severity vs 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. 
 
9.3.4 
Causality Assessment 
The investigators should assess causal relationship between an AE and the study drug on 
the basis of his/her clinical judgment and the following definitions.  The causality 
assessment must be made based on the available information and can be updated as new 
information becomes available. 
• 
Related: 
• 
The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the patient’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
• 
The AE follows a reasonable temporal sequence from study drug 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 does not follow a reasonable temporal sequence from study drug 
administration, or can be reasonably explained by the patient’s clinical state or 
other factors (eg, disease under study, concurrent diseases, and concomitant 
medications). 
 
9.3.5 
Action Taken Regarding the Study Drug 
• 
Dose not changed: No change in study drug dosage was made. 
• 
Drug withdrawn: The study drug was permanently stopped. 


 
 
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• 
Dose reduced: The dosage of the study drug was reduced. 
• 
Drug interrupted: The study drug was temporarily stopped. 
• 
Dose increased: The dosage of the study drug was increased. 
• 
Not applicable: patient died, treatment with the study drug 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. 
• 
Medication required. 
• 
Prescription and/or over-the-counter (OTC) medication was required to treat the 
AE. 
• 
Hospitalization or prolongation of hospitalization required. 
• 
Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
• 
Other. 
 
9.3.7 
Adverse Event Outcome 
• 
Recovered/Resolved 
• 
The patient 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/residual effect(s) present 
• 
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 
Serious Adverse Events Reporting–Procedure for Investigators 
All AEs and SAEs will be reported in the CRF. 
The following types of events should be reported by the investigator to the sponsor by 
telephone or on a SAVER form within 24 hours of awareness.  The SAVER form for 


 
 
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reporting events to the sponsor should be sent via e-mail or fax. 
• 
SAEs (refer to Section “9.3.2 Serious Adverse Events” for definition) 
• 
Hepatic events meeting combination abnormalities (ALT or AST ≥ 3 × ULN with 
simultaneous total bilirubin ≥ 2 × ULN) (potential Hy’s Law case), both serious and 
nonserious. 
 
The investigator should report the details of each SAE in writing to the sponsor and the 
head of the study center.  A written report to the head of the study center will be made in 
accordance with the procedures and format specified by the study center. 
 
All events (serious and nonserious) must be reported with investigators’ assessment of 
the event’s seriousness, severity, and causality to the study drug.  A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome 
should be reported to the sponsor.  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 narrative when available.  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. 
The investigator must sign all completed SAVER forms, and then send them as attached 
documents to the appropriate e-mail address or fax them to the appropriate fax number.  
For the detailed reporting procedure, refer to the separately prepared procedural 
document. 
The contact information for reporting SAEs is provided in “18.3 Sponsor’s Safety 
Contacts” and the separately prepared procedural document.  If there are any questions 
about reporting SAEs, the clinical monitor etc. should be contacted. 
 
9.5 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee 
If a serious adverse drug reaction occurs in other study centers enrolled in this study or 
other ongoing clinical studies of quizartinib, the sponsor should report to the 


 
 
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investigators, the institutional review board/ethics committee (IRB/EC), and the 
regulatory authorities. 
 
9.6 
Exposure In Utero during Clinical Studies 
If it becomes known that a patient or a patient’s partner has become pregnant during 
treatment with the study drug or within 6 months after discontinuation of treatment with 
the study drug, the investigators must notify the sponsor. 
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 investigators to report 
any pregnancy in a female patient or a male patient’s female partner using the form 
provided by the sponsor (Exposure in Utero Reporting Form).  Please contact your 
study monitor to receive the Exposure in Utero Reporting Form upon learning of a 
pregnancy.  The investigators should make every effort to follow the patient until 
completion of the pregnancy and complete the Exposure in Utero Reporting Form with 
complete pregnancy outcome information, including normal delivery and induced 
abortion.  If the outcome of the pregnancy meets the criteria for immediate classification 
as an SAE (ie, post-partum complications, spontaneous or induced abortion, stillbirth, 
neonatal death, or congenital anomaly, including that in an aborted fetus), the 
investigators should follow the procedures for reporting SAEs outlined in Section 9.4. 
 
9.7 
Clinical Laboratory Evaluations 
The following items will be measured.  For clinical laboratory parameters, the reference 
range of the institution that performs the measurements will be used. 
Information will be entered in the CRF on whether measured, date of measurement, and 
measurement results for the following items. 
1) Hematology test 
Red blood cell count, MCV, MCH, MCHC, hemoglobin, hematocrit, white blood cell 
count, white blood cell differential count (neutrophils, basophils, eosinophils, 
lymphocytes, monocytes), platelet count, and PT-INR 
2) Blood chemistry test 
Total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GT, LDH, 
lipase, BUN, serum creatinine, creatine kinase, uric acid, glucose, electrolytes (K, Na, 
Cl, Ca, P, Mg), CRP, total cholesterol, LDL, HDL, and triglyceride 
3) Urinalysis 


 
 
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Specific gravity, pH, occult blood, glucose, protein, bilirubin, and ketone bodies 
 
9.8 
ECOG PS 
The date of measurement and the results of investigators’ assessment will be recorded in 
the CRF. 
 
9.9 
Vital Signs 
Blood pressure and pulse rate will be measured after the patient has rested in a recumbent 
position for 5 minutes or more. 
Information will be entered in the CRF on whether or not measured, date of measurement, 
and measurement results for the following items. 
Systolic blood pressure, diastolic blood pressure, pulse rate, body temperature, height, 
and body weight 
 
9.10 Electrocardiograms 
9.10.1 Measurement Method 
ECG will be performed consecutively three times (triplicate ECGs) at intervals of 3 to 5 
minutes after patients have remained at rest in the supine position for 10 minutes.  The 
QTcF interval will be determined as the average of three measurements and used for 
safety evaluation and for making a decision on quizartinib dose increase on Day 16 of 
Cycle 1 and on Day 1 of Cycle 2 or later.  The ECG results will be transferred to the 
Central ECG Reading Center (eResearch Technology, Inc. [ERT]).  The investigators 
may check the ECGs without waiting for a central assessment if an urgent decision is 
required to assure the patient’s safety at the study center. 
If a foreseeable abnormal ECG finding is observed (eg, QTcF > 480 ms), the study center 
should contact the Central ECG Reading Center to request immediate assessment (within 
24 hours), and determine the action to be taken for the patient (dose increase or reduction 
of the study drug etc.) based on the central assessment results.  In this case, triplicate 
ECGs should be obtained again within 2 hours after the ECG measurement in which the 
above abnormal finding has been detected, and the results should be submitted to the 
Central ECG Reading Center. 
The analysis results of the Central ECG Reading Center will be regarded as the final 
ECG data.  All QT-related events will be decided using QTcF. 
Additional ECG may be performed if the investigators consider it necessary.  In such a 
case, the time of the ECG should be recorded.  Triplicate ECGs should be obtained at all 


 
 
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the measurement time points, and the QTcF determined as the average of the three 
recordings will be used as the representative ECG data. 
Whether to measure the ECG or not, date and time of measurement, and investigators’ 
assessment results will be recorded in the CRF. 
 
9.10.2 Measures Taken in Case of QTcF Prolongation 
To reduce the risk of arrhythmia caused by quizartinib, laboratory monitoring should be 
performed to keep blood electrolytes (K+, Ca++, and Mg++) within the institutional 
reference ranges, and further to ensure K+ levels of 4.0 mEq/L or more as far as possible. 
If Grade 2 or more severe QTcF prolongation occurs, treatment should be given 
according to the following procedure.  In patients for whom treatment with quizartinib 
is interrupted or the dose of quizartinib is reduced in association with Grade 2 or more 
severe QTcF prolongation, 12-lead ECG should be performed at any subsequent 
appropriate timing to carefully confirm whether QTcF prolongation has recovered or not. 
 
Grade 2 (QTcF: 481 ms to 500 ms) 
• 
Measure electrolyte levels (K+, Ca++, and Mg++) and supply the electrolytes to ensure 
recovery to the institutional reference ranges. 
• 
Check concomitant drugs, and discontinue drugs that are known to prolong QTcF, as 
necessary. 
• 
Reduce the dose of quizartinib by one level.  It is not necessary to interrupt 
treatment. 
• 
The dose may be increased to the dose before dose reduction if QTcF prolongation 
recovers to Grade 1 or less severe after treatment at the reduced dose for at least 28 
days.  However, whether prolongation of QT interval occurs or not should be 
confirmed carefully for the first cycle (28 days) after the dose increase. 
 
Grade 3 (QTcF ≥ 501 ms) 
• 
Measure electrolyte levels (K+, Ca++, and Mg++) and supply the electrolytes to ensure 
recovery to the institutional reference ranges. 
• 
Check concomitant drugs, and discontinue drugs that are known to prolong the QT 
interval, as necessary. 
• 
Interrupt treatment with quizartinib for a maximum of 14 days.  Resume treatment 
with quizartinib at a one-level reduced dose, relative to the dose immediately before 
the interruption, if the increase in QTcF interval from baseline is 30 ms or shorter or 


 
 
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the QTcF interval recovers to 450 ms or shorter within 14 days after the onset.  If 
Grade 3 QTcF prolongation occurs, subsequent dose increase is not allowed. 
 
Grade 4 (increased QTcF to 501 ms or longer or a 60 ms or longer change in QTcF from 
baseline associated with any signs or symptoms of TdP, polymorphic ventricular 
tachycardia, or any other serious arrhythmia) 
• 
Measure electrolyte levels (K+, Ca++, and Mg++) and supply the electrolytes to ensure 
recovery to the institutional reference ranges. 
• 
Check concomitant drugs, and discontinue drugs that are known to prolong the QT 
interval, as necessary. 
• 
Discontinue treatment with quizartinib. 
 
9.10.3 Chest X-ray Examination 
The date of measurement and the results of investigators’ assessment will be recorded in 
the CRF. 
 
9.10.4 MUGA Scan or Echocardiography 
The date of measurement and LVEF (%) will be recorded in the CRF. 
 
10. OTHER ASSESSMENTS 
Not applicable 
 
11. STATISTICAL METHODS 
11.1 General Statistical Considerations 
The primary objective (hypothesis) of this study is to confirm that the CRc rate with 
quizartinib monotherapy is at least 23.5% in Japanese patients with FLT3-ITD positive 
relapsed or refractory AML. 
Efficacy analyses will be performed using the efficacy analysis set.  Safety, 
pharmacokinetic, and biomarker analyses will be performed using the safety analysis set, 
the pharmacokinetic analysis set, and the biomarker analysis set, respectively. 
The analyses, excluding pharmacokinetic and biomarker analyses, in this study will be 
performed in all patients included in each analysis set regarded as one dose group, 
whether the dose is increased or reduced. 
Unless otherwise noted, continuous variables will be summarized by the number of 
patients analyzed, arithmetic mean, standard deviation, minimum, median, and maximum, 


 
 
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whereas categorical variables will be summarized by frequency and proportion.  
Baseline values of each patient, unless otherwise specified, will be the last observed 
values that are available before the first dose of the study drug.  Analyses of changes 
from baseline (eg, absolute change, shift table) will be performed on patients with 
baseline values and at least one post-treatment value available. 
This study will be conducted using a two-stage design, and interim analysis is planned to 
be performed once.  The details of interim analysis are shown in Section 11.4. 
 
11.2 Analysis Sets 
The sponsor will finalize the population flag of individual patients for each analysis set 
after CRF lock.  Patients with major Good Clinical Practice (GCP) violations (eg, a 
violation of the informed consent procedure, a major violation of study procedures) will 
be excluded from all analysis sets. 
• 
All enrolled patients will include all patients who have signed the ICF. 
• 
All registered patients will include all patients who have signed the ICF and are 
assessed as eligible for the study. 
• 
The safety analysis set will include all patients who have signed the ICF and received 
at least one dose of the study drug. 
• 
The efficacy analysis set will include patients who have signed the ICF (including 
consent for measurement of FLT3-ITD mutations), have a positive result of the 
FLT3-ITD mutation test performed at Navigate BioPharma, and have received at 
least one dose of the study drug. 
• 
The pharmacokinetic analysis set will include patients who have signed the ICF and 
received at least one dose of the study drug, and whose plasma drug concentration 
data obtained are available for at least one time point after the start of treatment with 
the study drug. 
• 
The biomarker analysis set will include patients who have signed the ICF and 
received at least one dose of the study drug, and whose biomarker data shown in 
Section 6.10 are available for at least one time point after the start of treatment with 
the study drug. 
 
11.3 Statistical Analyses 
11.3.1 Efficacy Analyses 
Efficacy analyses will be performed in the efficacy analysis set. 
 


 
 
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11.3.1.1 
Primary Efficacy Analyses 
For the CRc rate, frequency tables will be prepared, and the 90% and 95% confidence 
intervals (CIs) will be calculated. 
 
11.3.1.2 
Secondary Efficacy Analyses 
For the best response and the response rate, frequency tables will be prepared, and the 
95% CI will be calculated. 
For OS, event-free survival, and leukemia-free survival, Kaplan-Meier curves will be 
prepared, and medial survival and the 95% CI will be calculated using the method of 
Brookmeyer and Crowley. 
For the transplantation rate, frequency tables will be prepared, and the 95% CI will be 
calculated. 
 
11.3.1.3 
Exploratory Efficacy Analyses 
Not applicable 
 
11.3.2 Pharmacokinetic/Pharmacodynamic Analyses 
11.3.2.1 
Pharmacokinetic Analyses 
In the pharmacokinetic analysis set, summary statistics of the plasma concentrations of 
quizartinib and AC886 will be calculated by dose at each time point, and plasma 
concentration-time profiles will be prepared.  Summary statistics of pharmacokinetic 
parameters will be calculated by dose at each time point. 
A population pharmacokinetic analysis of quizartinib and quizartinib exposure-response 
analysis will be performed to evaluate the relationship between the dose and exposure as 
well as between exposure and the efficacy or safety endpoints.  If population 
pharmacokinetic and exposure-response analyses are performed, the reports should be 
prepared separately. 
 
11.3.2.2 
Pharmacodynamic Analyses 
Not applicable 
 
11.3.2.3 
Biomarker Analyses 
In the biomarker analysis set, measured values of plasma inhibitory activity of quizartinib 
on phosphorylated FLT3 and c-Kit proteins will be summarized at each time point. 
 


 
 
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11.3.2.4 
Pharmacogenomic Analyses 
Not applicable 
 
11.3.3 Safety Analyses 
Safety analyses will be performed in the safety analysis set. 
AEs that occur or worsen relative to the pre-treatment state after the first dose of the 
study drug (treatment emergent AEs [TEAEs]) will be tabulated.  AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) terminology 
developed by the ICH, and be tabulated by body organ group using the MedDRA system 
organ class (SOC) and by AE term using preferred terms (PTs). 
 
11.3.3.1 
Adverse Event Analyses 
For TEAEs and TEAEs assessed as “related” to the study drug, frequency tables will be 
prepared as classified below.  The grade of each AE will be assessed according to the 
CTCAE v4.0 Japanese version.  In the tabulation by grade, only the highest-grade event 
in each patient will be included. 
• 
TEAEs (by grade; including classification into Grade 3 or more severe events) 
• 
Serious TEAEs 
• 
Patients who have interrupted treatment with the study drug due to TEAEs 
• 
Patients with treatment discontinuation because of TEAE 
 
For TEAEs and TEAEs assessed as “related” to the study drug, frequency tables will be 
prepared by event as classified below.  The grade of each AE will be assessed according 
to the CTCAE v4.0 Japanese version.  If a patient reports the same event several times, 
only the highest-grade event will be counted for tabulation. 
• 
TEAEs 
• 
TEAEs by grade (including classification into Grade 2 or less severe events and 
Grade 3 or more severe events) 
• 
Serious TEAEs 
• 
TEAEs leading to interruption of treatment with the study drug 
• 
TEAEs causing treatment discontinuation 
 
11.3.3.2 
Clinical Laboratory Evaluation Analyses 
For hematology and blood chemistry tests, summary statistics of measured values and 
changes from baseline will be calculated at each time point.  For urinalysis (except 


 
 
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specific gravity), shift tables of measured values at baseline and those at each time point 
will be prepared.  For specific gravity, summary statistics will be calculated at each time 
point. 
The number and proportion of patients who meet the criteria specified in the Food and 
Drug Administration (FDA) Guidance for Industry Drug-induced Liver Injury (DILI)16) 
in terms of ALT, AST, total bilirubin, and ALP will be calculated, and evaluation of 
drug-induced serious hepatotoxicity (eDISH) plots will be prepared. 
 
11.3.3.3 
Vital Sign Analyses 
For blood pressure (systolic and diastolic), pulse rate, body temperature, and body weight, 
summary statistics of measured values and changes from baseline will be calculated at 
each time point. 
 
11.3.3.4 
Electrocardiogram Analyses 
For 12-lead ECG findings, shift tables of normal-abnormal assessments at baseline and 
each time point will be prepared.  For PR, QRS, RR, QT, QTcB, and QTcF intervals and 
heart rate, summary statistics of measured values and changes from baseline will be 
calculated at each time point.  For QTcF, frequency tables will also be prepared 
according to the following categories. 
Absolute QTcF: 
• 
QTcF > 450 ms 
• 
QTcF > 480 ms 
• 
QTcF > 500 ms 
Changes in QTcF from baseline: 
• 
Increase in QTcF from baseline > 30 ms 
• 
Increase in QTcF from baseline > 60 ms 
 
11.3.3.5 
Analyses of Physical Findings 
Not applicable 
 
11.3.3.6 
Exploratory Safety Analyses 
Not applicable 
 
11.3.4 Other Analyses 
Not applicable 


 
 
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11.3.5 Blinded Review 
Not applicable 
 
11.4 Interim Analysis 
This study is planned with a two-stage design; in Stage 1, interim analysis will be 
performed when 25 patients are included in the efficacy analysis set.  If it is decided to 
continue the study based on the interim analysis (for the assessment criteria, see “11.4.3 
Criteria”), registration of patients will be continued until 41 patients are included in the 
efficacy analysis set (16 patients in Stage 2).  Registration of patients will be continued 
during the course of the interim analysis. 
 
11.4.1 Purposes of the Interim Analysis 
In this study, interim analysis that includes early termination of the study due to efficacy 
and futility is planned for the following reasons.  In the interim analysis, the secondary 
efficacy endpoints, safety, pharmacokinetics, and biomarkers will be evaluated in 
addition to the primary endpoint, CRc rate. 
Since the sample size of this study is calculated based on the alternative hypothesis that 
the CRc rate is 42%, which is the lower limit of the CRc rate of 42% to 47% obtained in 
overseas Phase 2 studies of AC220 monotherapy in patients with FLT3-ITD positive 
relapsed or refractory AML (Studies AC220-002 and 2689-CL-2004) (see Section 11.5), 
the true CRc rate with quizartinib in this study may be higher than 42%.  In such a case, 
to allow early completion of this study, interim analysis including early termination due 
to efficacy is planned.  In addition, since the results of overall Phase 2 studies are highly 
uncertain due to a limited number of patients, taking the possibility that the true CRc rate 
with quizartinib may be about 23.5%, which is set as the threshold level into 
consideration, early termination due to futility is also included in the requirements for 
interim analysis. 
 
11.4.2 Possible Options to Be Taken at Interim Analysis 
The following decisions will be made at the interim analysis.  If it is decided to 
terminate the study early, the registration of patients will be discontinued; however, 
treatment with the study drug in patients who continue receiving the study drug will be 
continued until “5.7.1 Discontinuation Criteria for Treatment with the Study Drug” are 
met. 


 
 
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• 
Continuation of the study 
• 
Early termination of the study due to efficacy 
• 
Early termination of the study due to futility 
 
11.4.3 Criteria 
The assessment criteria in Stage 1 (25 patients will be chosen from the efficacy analysis 
set in the order of registration) and at the end of Stage 2 (41 patients will be chosen from 
the efficacy analysis set in the order of registration) are shown below.  Concerning 
patients for whom the study is continued as of the data cut-off date (see below) of the 
interim analysis, the best response will be calculated from the data collected up to the 
data cut-off date, and whether CRc is achieved or not will be assessed. 
<Stage 1> 
• 
The study will be continued if CRc is achieved in 4 to 10 patients. 
• 
The study will be early terminated due to efficacy if CRc is achieved in 11 or more 
patients. 
• 
The study will be early terminated due to futility if CRc is achieved in 3 or fewer 
patients. 
<Stage 2> 
• 
Treatment will be determined to be effective (rejection of the null hypothesis) if CRc 
is achieved in 15 or more patients. 
 
Data cut-off date: 
The day when the best response is assessed as CR, CRp, or CRi, the day when treatment 
with the study drug is discontinued, or Day 1 of Cycle 4, whichever comes first, will be 
calculated for each patient.  The latest day in the 25 patients included in the interim 
analysis is regarded as the data cut-off date.  The above procedure will also apply to 
analysis at the end of Stage 2. 
 
11.4.4 Data Monitoring Committee 
An in-house Data Monitoring Committee, which consists of medical monitors, persons in 
charge of clinical procedures, biostatisticians, persons in charge of pharmacokinetic 
analysis, and persons in charge of modeling & simulation, will be established and will 
have responsibility to review the interim analysis results.  In principle, the Data 
Monitoring Committee is supposed to make a decision on early termination of the study 
in accordance with “11.4.3 Criteria.”  However, continuation of the study may be 


 
 
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decided depending on the results of safety assessment of the interim analysis.  In the 
review process, the Data Monitoring Committee might consult with external hematology 
oncology specialists as necessary.  The review content and final decision on interim 
analysis will be recorded in the meeting minutes. 
 
11.5 Determination of Sample Size 
The remission induction rate is remarkably low in patients with relapsed or refractory 
AML, compared with anticancer therapy introduced in patients with newly diagnosed 
AML, and it is as low as 12.8% (76/596) according to the report by Giles et al.15)  The 
results of FLT3-ITD-positive AML patients have also been reported by Ravandi17) and 
Levis18) as follows: The rate of remission induction with salvage therapy was 23.5% 
(8/34) in patients with first relapsed AML, and the rate of remission induction was 11.3% 
(6/53) in the subgroup of patients who had a poor prognosis defined as initial remission 
sustained for 6 months or shorter after the initial treatment.  In this way, considering that 
the remission induction rate in patients with relapsed or refractory AML varies among the 
reports and that the data of CRi, which is one of the elements comprising CRc, are not 
available in some reports, the threshold of the CRc rate in this study was set at 23.5% as 
the most conservative value among the values that are available for reference.  
Meanwhile, in preceding overseas Phase 2 studies of quizartinib monotherapy in patients 
with FLT3-ITD-positive relapsed or refractory AML (Studies AC220-002 and 
2689-CL-2004), the CRc rate has been reported to be 42% to 47% at several doses of 
quizartinib including 30 mg and 60 mg.  The expected CRc rate with quizartinib in this 
study was therefore assumed to be 42%. 
The design shown in Table 11.5-1 was established to satisfy the following conditions, 
with a one-sided 5% significance level and 80% power, in reference to the optimal 
two-stage design under the alternative hypothesis proposed by Mander and Thompson.19) 
• 
The number of patients evaluated in Stage 1 is approximately 25 (to assure a certain 
amount of safety information even if the study is early terminated in Stage 1). 
• 
If the study is early terminated due to futility, the observed CRc rate is 12% or less 
(less than the lower limit of the remission induction rate reported). 
• 
The probability of early termination due to efficacy under the condition of the 
expected CRc rate (42%) is approximately 50%. 
 


 
 
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Table 11.5-1  Number of Patients Evaluated at Each Stage and Assessment Criteria 
 
This Study 
Mander*1 
No. of patients assessed in Stage 1 
25 
19 
Criteria for discontinuation due to futility in Stage 1 
≤ 3 
≤ 4 
Criteria for discontinuation due to efficacy in Stage 1 
≥ 11 
≥ 9 
No. of patients assessed at the end of Stage 2 
41 
41 
Assessment criteria for efficacy at the end of Stage 2 
≥ 15 
≥ 15 
Expected No. of patients under the alternative hypothesis 
33.0 
31.1 
*1 Optimal two stage design under the alternative hypothesis proposed by Mander and Thompson 
 
Based on the above, registration of patients will be continued until 25 patients assessable 
for efficacy are enrolled in Stage 1 and 16 patients assessable for efficacy are enrolled in 
Stage 2. 
Shown below are the operating characteristics when the two-stage design applies to this 
study. 
 
CRc Rate 
(True Value) 
Probability of 
Discontinuation Due 
to Futility 
(Stage 1) 
Probability of 
Discontinuation Due 
to Efficacy 
(Stage 1) 
Probability of 
Assessment as 
Futility (Entire Study) 
Probability of 
Assessment as 
Efficacy 
(Entire Study) 
23.5% 
0.128 
0.019 
0.952 
0.048 
42.0% 
0.001 
0.496 
0.186 
0.814 
 
11.6 Statistical Analysis Process 
In this study, statistical analyses will be performed by a contract research organization 
(CRO) using SAS® Version 9.2 or a later version (SAS Institute Inc.) and WinNonliln 
(Version 6.0 or a later version).  The detailed methods of statistical analyses will be 
specified in the separately prepared statistical analysis plan (SAP).  To maintain the 
integrity of conclusions drawn from the statistical analyses and the study, the SAP should 
be fixed before database lock.  If modifications to the SAP lead to a change in major 
contents of the protocol, the protocol will be amended.  In the event of any deviation 
from the protocol-specified statistical analyses, the details will be described in the SAP. 
 
12. DATA INTEGRITY AND QUALITY ASSURANCE 
The head of the study center and the investigator will provide direct access to all 
study-related documents, including source documents, at the implementation of 
monitoring and auditing by the sponsor as well as inspections by the regulatory 
authorities and the IRB.  The sponsor will have direct access to all study-related 
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and auditing to ensure appropriate implementation of the study and the reliability of the 
data.  The sponsor will confer with the investigator in advance regarding the procedures 
for source document verification. 
 
12.1 Monitoring and Inspections 
The sponsor, monitor of Mediscience Planning Inc. (MPI), 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, 
CRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of 
the data; and adherence to ICH 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 CRFs 
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 CRFs.  Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, 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 
12.2.1 Completion of the Case Report Forms 
The investigator, subinvestigator, or study staff will enter the data in the CRF in 
accordance with the CRF Completion Guideline that are provided by the sponsor. 


 
 
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CRF completion should be kept current to enable the monitor to review the subject’s 
status throughout the course of the study.  The CRF will be completed, reviewed, and 
signed off or e-signed by the investigator. 
If the study employs paper CRFs, the investigator will sign and date the indicated places 
on the CRF.  These signatures will indicate that the investigator inspected or reviewed 
the data on the CRF and the data queries, and agrees with the content. 
If the study employs electronic data capturing (EDC), the investigator e-signs according 
to the study data flow. 
Any clinical data entered in the CRF will be subjected to these data management 
procedures and will be included in the final study datasets according to Clinical Data 
Interchange Standards Consortium (CDISC) standards. 
 
Daiichi Sankyo or MPI will supply electric case report forms (eCRFs).  Daiichi Sankyo 
or MPI must complete eCRFs for each of subjects who have signed the ICF for the 
FLT3-ITD test as well as subjects who have signed the ICF for participation in the study 
and have undergone the screening test.  If a subject is not treated, the reason must be 
recorded on the eCRF.  All data collected during the study will be recorded in this 
individual, subject-specific eCRF.  Instructions will be provided for the completion of 
the eCRF and any corrections made will be automatically documented via the EDC 
software’s audit trail. 
 
12.2.2 Precautions for Entering Data in the Case Report Form 
In the study, the CRF will be prepared by the investigator, and the measurement reports 
of 12-lead ECG, pharmacokinetics, and biomarkers will be prepared by each central 
laboratory.  In this study, an electronic CRF will be entered using the EDC system 
(Table 12.2-1), which is designed to prepare electronic CRFs.  The CRF (including an 
audit trail) will be prepared for each subject and the one that was signed by the 
investigator will be handled as the original.  A validated EDC system will be used in the 
study. 
 


 
 
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Table 12.2-1  EDC System 
EDC system name 
 
EDC system development 
corporation 
Medidata Solutions, Inc. 
How to enter data 
Data entry via the web interface 
Terminal for data entry 
PC at the study center 
OS prohibited 
None 
Browser 
 supports any browser that conforms to HTML 5, and CSS2.  
JavaScript needs to be enabled in the browser. 
Recommended screen resolution 
1024 × 764 resolution or higher 
Recommended connection speed 
128 kbps or higher 
Others 
Adobe Flash Player: ver. 10 or higher 
 
A CRF will be prepared for subjects who have provided informed consent for 
participation in the study and for the FLT3-ITD mutation test performed before the start 
of the study although they have not received the study drug due to a negative-result of the 
FLT3-ITD mutation test. 
 
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 the sponsor.  Data will be vetted both electronically and manually for CRFs 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 within the EDC 
application.  During this review, subject data will be checked for consistency, 
completeness and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the 
clinical database in accordance with the data management plan. 
SAEs in the clinical database will be reconciled to the safety database. 
All AEs and complications/medical history will be coded using MedDRA.  Prior and 
concomitant medications will be coded using the World Health Organization Drug 
Reference (WHODRUG). 
 
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 CRFs will be included on the Signature List. 


 
 
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The investigator will maintain a confidential screening log of all potential study 
candidates that includes limited information of the subjects, date and outcome of 
screening process. 
The investigator will be expected to maintain an Enrollment Log of all subjects enrolled 
in the study indicating their assigned study number. 
The investigator 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 
CRF data are obtained.  These include but are not limited to hospital records, medical 
record, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence. 
 
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of the study drug, 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, observations, and 
notations of clinical activities and all 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 institution or study center 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 head of the study center or the person responsible for record keeping 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 CRFs (copy), ICFs, and supporting copies of source 
documentation (if kept). 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 


 
 
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and all correspondence to and from the IRB/EC and the sponsor. 
• 
Study drug-related records containing record of confirmation of receipt by the study 
center, Drug Accountability Record, study drug return form, study drug 
storage/management record (copy), and other correspondence 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
 
All study related essential documentation will be retained by the head of the study center 
or the person responsible for record keeping until at least 3 years after the last approval 
of a marketing application and until there are no pending or contemplated marketing 
applications or at least 3 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, study center, or 
private practice. 
No study document should be destroyed without prior written agreement between the 
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 the sponsor of the 
new responsible person and/or the new location. 
 
13. Payment and Insurance 
13.1 Payment 
Prior to the start of the study, the investigator or the study center will conclude a study 
contract with the sponsor and/or the CRO.  This contract contains the information on 
payment agreed upon by the concerned parties. 
 
13.2 Payment, Compensation for Study-related Injury, and Insurance 
The sponsor will purchase an insurance policy so that subjects who may suffer any 
study-related injury can receive compensation. 
Payment, compensation for study-related injury, and insurance are covered by a separate 
contract on the conditions agreed upon by the parties. 


 
 
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14. PUBLICATION POLICY 
No information obtained from the study may be published partially or entirely without 
prior consultation with the sponsor.  The methods of publication will be determined by 
the sponsor.  Utmost caution should be exercised to protect the privacy of subjects when 
information is published.  The sponsor will use information obtained from the study for 
the purpose of application for manufacturing/marketing approval of the investigational 
drug.  If the investigational drug is approved, information about the study may be 
partially disclosed in accordance with the “Act on Access to Information Held by 
Administrative Organs (Act No. 42, dated 14 May 1999),” “Act on Access to Information 
Held by Independent Administrative Agencies (Act No. 140, dated 05 Dec 2001),” and 
“Notification concerning publication of information on new drug approvals (PFSB/ELD 
Notification No. 0422001, dated 22 Apr 2005).”  Utmost caution should be exercised to 
protect the privacy of subjects when disclosing information. 
 
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) including the 
following: 
• 
“Ordinance on Good Clinical Practice” (MHW Ordinance No. 28, dated 27 Mar 
1997) 
• 
Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics 
(effective as of 25 Nov 2014) 
 
Human genome/gene analysis and banking of clinical specimens for genome/gene 
analysis, and research using the specimens, which are planned in the study, will be 
performed in adherence to the “Ethical Guidelines for Human Genome/Gene Analysis 
Research” and “Ethical Guidelines for Clinical Studies,” in addition to the above 
regulations (only at the study centers that are granted approval for the conduct of 
genome/gene analysis or banking of clinical specimens for genomic/genetic analysis). 
 


 
 
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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 CRFs 
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 
The investigator should provide subjects with sufficient explanations about the details of 
the study including the objectives, methods, expected benefits, and foreseeable risks prior 
to the FLT3-ITD mutation test and/or their participation in the study.  It is the 
investigator’s responsibility to obtain subjects’ written informed consent of their free will 
at the protocol-specified timing or before the start of treatment with the study drug. 
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 ICF 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 consent form and 
any revision(s) should be approved by the EC or IRB prior to being provided to potential 
subjects. 
The subject’s signed ICF should be documented in the subject’s medical records.  The 
ICF 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 ICF should be retained in accordance with study center’s policy, and a 
copy of the signed consent form should be provided to the subject.  The date and time 


 
 
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(if applicable) that informed consent was given should be recorded on the CRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an 
impartial witness should be present during the entire informed consent discussion.  This 
witness should sign the ICF after the subject has consented to the subject’s participation 
and, if possible, signed the ICF.  By signing the ICF, the witness attests that the 
information in the ICF and any other written information was adequately explained to 
and apparently understood by the subject and that informed consent was freely given by 
the subject. 
The sponsor shall provide a draft ICF template for the study and/or FLT3-ITD mutation 
test so that the investigator can prepare the documents used at his/her own study center.  
The investigator will be notified in writing by the sponsor if these forms are amended in 
any way. 
Data collection using the EDC system will be implemented in accordance with the “Use 
of Electromagnetic Records and Electronic Signatures in Applications, etc. for Approval 
of, or License for Pharmaceuticals, etc.” (PFSB Notification No. 0401022). 
 
15.4 Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator’s Brochure, 
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 the sponsor must submit and, where necessary, obtain approval 
from the EC or IRB for all subsequent protocol amendments and changes to the ICF.  
The investigator should notify the EC 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. 
In accordance with the regulatory requirements of the home country, the sponsor’s 
regulatory affairs group or designee should confirm that all legal aspects have been 
covered and that approval of the applicable regulatory authorities has been obtained prior 
to the start of the study, and ensure that changes to the original protocol and other related 


 
 
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study documents are made only after they have been approved by the applicable 
regulatory authorities. 
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 noncompliance that the investigator 
becomes aware of. 
 
15.5 Protocol Deviations 
The investigator should conduct the study in compliance with the protocol agreed to by 
the sponsor and, if required, by the regulatory authorities, and which was given approval 
by the IRBs/ECs. 
A deviation to any protocol procedure or waiver of any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject.  
The 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 study treatment, and had at 
least one dose of the study drug, data should be collected for safety purposes. 
If applicable, the investigator should notify the IRB of deviations from the protocol. 
 
15.6 Provision 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, IRBs/ECs, 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. 


 
 
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If the subject information is revised, it must be re-approved by the IRB/EC.  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 ICF. 
 
15.7 Protocol Amendment 
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.  
Changes made by such amendments will be documented in a “Summary of Changes” 
document.  If the protocol is updated, the sponsor will newly obtain written agreement 
of the investigator and implement the procedures specified by the study center. 
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 Discontinuation of the Study 
If any of the following occurs and the sponsor judges that continuation of the study is 
difficult, the sponsor will temporarily discontinue the study partially or entirely.  The 
sponsor will then determine whether to permanently discontinue the study partially or 
entirely, and document the decision. 
1) If any new safety information regarding the study drug, or information regarding 
SAEs is obtained 
2) If any major GCP violation or significant protocol deviation is committed by the 
sponsor, the study center, or the investigator 
3) If any other new information of such relevance is obtained during the study 
Upon the decision of partial or entire discontinuation of study in consultation with the 
medical expert etc., the sponsor will promptly notify the head of the study center in 
writing of the fact with the reason.  The head of the study center will promptly notify 
the investigator and the IRB in writing of the fact with the reason. 
If the study is discontinued permanently or temporarily for any reason, the investigator 
will promptly notify the subjects participating in the study of the fact, and take 
appropriate actions and perform the necessary tests to verify the safety of subjects. 
 


 
 
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16. Others 
16.1 Payment for Participation, Compensation for Study-related Injuries, and 
Insurance 
16.1.1 Payment for Participation 
As payments for reducing the subject’s burden, the study center will pay subjects from 
the funds paid by the sponsor to the study center according to the separately specified 
regulations of the study center. 
 
16.1.2 Compensation for Study-related Injuries 
If a subject experiences any study-related injury resulting from participation in the study, 
the investigator or subinvestigator will take the necessary actions, including treatment.  
If the subject makes a claim for study-related injury, the sponsor will be promptly 
notified.  The sponsor will specify the procedures for compensation for study-related 
injury resulting from participation in the study and take actions such as purchase of an 
insurance policy.  The sponsor will bear the expenses that are paid by the subject for 
treatment of the injury, excluding the amount covered by health insurance, etc.  The 
sponsor shall also pay medical allowance for study-related injuries requiring 
hospitalization for treatment, based on the amount specified under the Relief System for 
Sufferers from Adverse Drug Reactions.  However, the sponsor will not agree to 
indemnify the subject for study-related injuries arising under the following 
circumstances: 
1) If there is clear evidence of any other cause of study-related injury. 
2) If there is no reasonable temporal relationship between administration of the study 
drug and the occurrence of the study-related injury. 
3) If a perpetrator has been identified (for instance, traffic accident). 
4) If there were no therapeutic benefits because of lack of efficacy. 
5) If a subject or a subject’s partner is found to be pregnant during the study. 
6) If there is any protocol violation without due reason. 
 
If a study-related injury is caused by an intentional act or gross negligence on the part of 
the study center or the subject, compensation may not be paid or may be reduced. 
 
16.1.3 Insurance 
In case of compensation for study-related injury, the sponsor will purchase an insurance 
policy as required.  In case of study-related injury due to medical malpractice, the study 


 
 
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center will purchase an insurance policy and take other measures as required. 
 
16.1.4 Notifying Any Other Physicians Treating Patients of Their Study 
Participation 
If a registered patient has to receive treatment by another physician, the investigator or 
subinvestigator must inform the physician of the patient’s participation in the study with 
the patient’s approval. 
The investigator or subinvestigator will ask patients who have provided informed consent 
whether they are being treated by another physician (eg, a physician in another 
department of the study center or at another medical institution) or not.  If the patient is 
receiving treatment by another physician, the investigator or subinvestigator will inform 
the physician of the patient’s participation in the study with the patient’s approval and 
record the provision of this information in the medical record, etc. 
 
16.1.5 Quality Control and Quality Assurance 
The sponsor will implement the quality assurance and quality control system in 
accordance with the standard operating procedures specified by the sponsor to ensure that 
the implementation of the study and the generation, recording, and reporting of data are 
in compliance with the following: 
1) The clinical study protocol 
2) Standards stipulated in Article 14, Paragraph 3 and Article 80-2 of the Act on 
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics 
(hereinafter, the PMD Act) 
3) GCP ordinance 
In addition, the sponsor will perform quality control at each stage of data handling to 
ensure the reliability and proper processing of all study-related data.  The methods for 
quality control will be prepared in advance in accordance with the standard operating 
procedure specified by the sponsor, and the implementation will be recorded. 
The sponsor’s responsible auditor will perform GCP auditing as part of quality assurance 
operations to determine whether the study is conducted in compliance with GCP, the 
clinical study protocol, and the written procedures independently and separately from the 
regular monitoring and study quality control operations. 
 


 
 
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17. Data and Safety Monitoring Board 
Not applicable 
 
18. Address List 
18.1 Sponsor’s Responsible Medical Officer 
 
 
, Japan 
TEL:
  FAX: 
 
 
18.2 Sponsor’s Clinical Study Leader 
 
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan 
TEL:
  FAX: 
 
18.3 Sponsor’s Safety Contacts 
 
3-5-1 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan 
TEL:
  FAX: 
 
18.4 Medical Monitor 
 
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan 
TEL:
 
 
18.5 Contract Research Organization 
Mediscience Planning Inc. 
, Japan 
TEL
  FAX: 
 
18.6 EDC Vendor 
Medidata Solutions, Inc. 
 
, USA 
TEL: 
 FAX: 
 


 
 
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18.7 IXRS Vendor 
Not applicable 
 
18.8 Central Laboratory 
18.8.1 Measurement of Drug Concentrations 
BASi corporate 
 USA 
TEL: 
  FAX: 
 
18.8.2 Investigation of Mutations of the FLT3-ITD Gene 
Navigate BioPharma Services, Inc. 
, USA 
TEL: 
  FAX: 
 
SRL, Inc. 
 Japan 
TEL:
  FAX: 
 
18.8.3 Agency for Collection etc. of Specimens for Drug Concentration 
Measurement and Investigation of Mutations of the FLT3-ITD Gene 
SRL Medisearch Inc. 
 Japan 
TEL:
  FAX: 
 
18.8.4 12-lead Electrocardiogram Measurement and Assessment 
eResearch Technology, Inc. 
, USA 
TEL: 
  FAX: 
 
18.9 Sponsor’s Biostatistician 
 
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan 
TEL:
  FAX: 
 


 
 
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18.10 Data Safety Monitoring Board 
Not applicable 
 
18.11 Emergency Contact Information 
1) Night hours (18:00 to 9:00) and Saturdays, Sundays, and holidays (all day): 
Daiichi Sankyo Emergency Center 
TEL:
 
 
2) Daytime (9:00 to 18:00) from Monday through Friday (except holidays): 
 
Oncology Clinical Development Department, R&D Division, Daiichi Sankyo Co., 
Ltd. 
TEL:
  FAX:
 


 
 
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19. REFERENCES 
1) 
Japanese Society of Hematology. Guideline on Hematopoietic Malignant Tumors 
(2013 Edition). Kanehara & Co., Ltd. (11 Oct 2013). 
http://www.jshem.or.jp/gui-hemali/1_1.html#cq6 
2) 
Matsuda A, Matsuda T, Shibata A, et al. Cancer Incidence and Incidence Rates in 
Japan in 2008: A Study of 25 Population-based Cancer Registries for the 
Monitoring of Cancer Incidence in Japan (MCIJ) Project. Jpn J Clin Oncol. 
2013;44(4):388-96. 
3) 
Ohtake S, Miyawaki S, Kiyoi H, et al. Randomized trial of response-oriented 
individualized versus fixed-schedule induction chemotherapy with idarubicin and 
cytarabine in adult acute myeloid leukemia: the JALSG AML95 study. Int J 
Hematol. 2010;91(2):276-83. 
4) 
Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 
2015;373(12):1136-52. 
5) 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: 
rationale and important changes. Blood. 2009;114(5):937-51. 
6) 
Kiyoi H. Feasibility of FLT3-targeting treatment for leukemia. The Japanese 
Journal of Clinical Hematology. 2005;46(3):187-97. 
7) 
Kiyoi H. FLT3 inhibitors and anti-FLT3 antibodies. Journal of Clinical and 
Experimental Medicine. 2007;220(9):759-64. 
8) 
Center for Drug Evaluation and Research (CDER). Guidance for Industry: 
photosafety testing. (May 2003). 
9) 
Organisation for Economic Co-operation and Development (OECD). OECD 
guideline for testing of chemicals. In vitro 3T3 NRU phototoxicity test, No. 432 
section 4 Health Effects (Pink pages). (adopted 13 Apr 2004). 
10) Committee for Proprietary Medicinal Products (CPMP). Note for guidance on 
photosafety testing. CPMP/SWP/398/01. (27 Jun 2002). 
11) Guidance on Photosafety Evaluation of Pharmaceuticals. PFSB/ELD Notification 
No. 0521-1 (21 May 2014). 
12) Ohtake S, Miyawaki S. Treatment protocol for acute myeloid leukemia (AML). 
Miyawaki S, Nakao S, editors. Therapeutic manual of leukemia. 3rd rev. ed. 
Nankodo. 2009;27-41. 
13) The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs, PFSB/ELD Notification No. 1023-1 (23 


 
 
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Oct 2009) 
14) Revision of the Guidelines for the Clinical Evaluation of Anticancer Drugs. 
PFSB/ELD Notification No. 1101001 (01 Nov 2005). 
15) Giles F, O’Brien S, Cortes J, et al. Outcome of patients with acute myelogenous 
leukemia after second salvage therapy. Cancer. 2005;104(3):547-54. 
16) Food and Drug Administration. Guidance for industry: drug-induced liver injury: 
premarketing clinical evaluation. (Jul 2009). available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM072278.pdf. 
17) Ravandi F, Kantarjian H, Faderl S, et al. Outcome of patients with FLT3-mutated 
acute myeloidleukemia in first relapse. Leuk Res. 2010;34(6):752-6. 
18) Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage 
chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first 
relapse. Blood. 2011;117:3294-301. 
19) Mander AP, Thompson SG. Two-stage designs optimal under the alternative 
hypothesis for phase II cancer clinical trials. Contemp Clin Trials. 2010;31:572-8. 
 


 
 
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20. APPENDICES/ATTACHMENTS 
Appendix 1 
Study Schedule 
Appendix 2 
ECOG Performance Status (PS) 
Appendix 3 
New York Heart Association (NYHA) Functional Classification 
Appendix 4 
List of CYP3A4 Inhibitors 
 
Attachment 1 
List of Study Centers 
Attachment 2 
Study Administrative Structure 
 
 


 
 
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Appendix 1  Study Schedule 
 
Screening  
(≤ 14 days 
before 
Registration) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
Thereafter 
At 
Withdrawal 
Post  
treatment 
Observation Follow  
up 
Day 1 Day 2 and 
8 
Day 15 
Day 16 
Day 1 Day 15 
Day 1 
Day 1 
30 Days 
after the 
Last Dose 
Acceptable limit (unit: days) 
 
 
Day 2: 
Scheduled 
Day 
Day 8: ±1 
±1 
(Must Be 
the Day 
Following 
Day 15) 
±3 
±1 
±3 
±3 
3 to +7 
+15 
Every 3 
Months 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
FLT3 ITD test 
●*1 
 
 
 
 
 
 
 
 
 
 
 
Administration of quizartinib (at the 
study center) 
 
●*2 
●*2 
●*2 
●*2 
●*2 
●*2 
●*2 
●*2 
 
 
 
Medical history/complications 
● 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurement 
● 
● 
● 
● 
 
● 
● 
● 
● 
● 
● 
 
ECOG PS/body weight 
● 
● 
 
 
 
● 
 
● 
● 
● 
● 
 
Height 
● 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests (hematology, blood 
chemistry, urinalysis) 
● 
●*3 
●*3 
●*3 
 
●*3 
●*3 
●*3 
●*3 
● 
● 
 
Pregnancy test 
● 
 
 
 
 
 
 
 
 
 
 
 
HIV antibody 
●*4 
 
 
 
 
 
 
 
 
 
 
 
12 lead ECG 
●*5 
●*5 
●*5 
●*5 
 
●*5 
 
●*5 
●*5 
●*5 
 
 
X ray examination 
● 
○ (as needed) 
MUGA scan or echocardiography 
●*6 
○ (as needed) 
Assessment of bone marrow findings 
(tumor assessment) 
●*7 
 
 
 
 
●*7 
 
●*7 
●*7 
●*7 
 
 
Measurement of drug concentrations 
 
●*8 
●*8 
●*8 
●*8 
●*8 
 
●*8 
 
 
 
 
Inhibitory activity on phosphorylated 
FLT3 and c Kit proteins 
 
●*9 
●*9 
●*9 
 
●*9 
 
 
 
 
 
 
AEs 
●*10 
 
Assessment of concomitant drugs and 
therapies 
 
● 
 
Investigation of survival status 
Other leukemia treatment etc. 
 
 
 
 
 
 
 
 
 
 
● 
● 
1) 
FLT3 ITD levels will be measured using a bone marrow specimen or peripheral blood.  The collected bone marrow specimen or peripheral blood will immediately be 
submitted to the specimen collection agency. 
2) 
Quizartinib will be administered on Days 1, 2, 8, 15, and 16 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3, and Day 1 of Cycle 4 and subsequent cycles at the 
study center.  Quizartinib may be administered at home on the other days. 


 
 
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3) 
To be measured before administration of the study drug. 
4) 
To be performed within 120 days before registration. 
5) 
ECG will be measured three times (triplicate ECGs) at each of the following time points.  Triplicate ECGs will be obtained at least once weekly for the first 2 weeks 
after increasing the dose of quizartinib to carefully confirm the QTcF interval. 
Screening, Day 1 of Cycle 1 (before administration of the study drug and at 2, 4, and 6 hours after the end of administration of the study drug), Day 2 and Day 8 of 
Cycle 1 (before administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), Day 15 of Cycle 1 (before administration of the 
study drug and at 2, 4, and 6 hours after the end of administration of the study drug), Day 1 of Cycle 2 ([if the dose of quizartinib is increased on Day 16 of Cycle 1]: 
before administration of the study drug and at 2, 4, and 6 hours after the end of administration of the study drug, [if the dose of quizartinib is not increased on Day 16 of 
Cycle 1]: before administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), Day 1 of Cycle 3 (before administration of the 
study drug and at 2 to 4 hours after the end of administration of the study drug), and Cycle 4 thereafter (before administration of the study drug on Day 1 of each cycle) 
6) 
A multiple gated acquisition (MUGA) scan or echocardiography must be performed at screening except in case LVEF is 45% or more within 1 month before 
registration. 
7) 
It is desirable to assess bone marrow findings with specimens obtained by both bone marrow aspiration and biopsy; however, bone marrow biopsy may be skipped if the 
antitumor effect can be evaluated adequately only by bone marrow aspiration in the opinion of the investigators.  Assessment of bone marrow findings will be 
performed at screening (it is desirable to obtain the specimen within 14 days before registration; however, the specimen collected before the time may be used with the 
consent of the medical monitor etc.), on Day 1 of Cycle 2 and subsequent cycles, at the time of discontinuation of the study, and other time points if assessment is 
considered necessary by the investigators.  For patients achieving CR, CRp, or CRi, bone marrow findings will be assessed every 3 cycles. 
8) 
A plasma specimen for pharmacokinetic measurement will be collected at the following specified time points.  If ECG and blood collection for pharmacokinetics (PK) 
are scheduled at the same time, blood collection for PK will be performed immediately after the end of ECG. 
Day 1 of Cycle 1 (before administration of the study drug and at 1, 2, 4, 6, and 24 hours after the end of administration of the study drug), Day 8 of Cycle 1 (before 
administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), Day 15 of Cycle 1 (before administration of the study drug and at 
1, 2, 4, 6, and 24 hours after the end of administration of the study drug), Day 1 of Cycle 2 ([if the dose of quizartinib is increased on Day 16 of Cycle 1]: before 
administration of the study drug and at 1, 2, 4, 6, and 24 hours after the end of administration of the study drug, [if the dose of quizartinib is not increased on Day 16 of 
Cycle 1]: before administration of the study drug and at 2 to 4 hours after the end of administration of the study drug), and Day 1 of Cycle 3 (before administration of the 
study drug and at 2 to 4 hours after the end of administration of the study drug). 
9) 
A specimen for measurement of inhibitory activity on phosphorylated FLT3 and c Kit proteins will be collected at the following specified time points. 
Day 1 of Cycle 1 (before administration of the study drug and at 2, 4, and 6 hours after the end of administration of the study drug), Day 8 of Cycle 1 (before 
administration of the study drug), Day 15 of Cycle 1 (before administration of the study drug), and Day 1 of Cycle 2 (before administration of the study drug). 
10) Only information on SAEs will be collected during the period from the day of informed consent to before the first dose of the study drug. 
 
 


 
 
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Appendix 2 
 
 
ECOG Performance Status (PS) 
 
Score 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light 
housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 


 
 
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Appendix 3 
 
 
New York Heart Association (NYHA) Functional Classification 
 
Class 
Symptoms 
Class 0 
Patients without cardiac disease and with no limitation of physical 
activity. 
Class I 
Patients with cardiac disease but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased. 
 


 
 
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Appendix 4 
 
List of CYP3A4 Inhibitors 
 
Strong Inhibitors 
Moderate Inhibitors 
Weak Inhibitors 
Itraconazole 
Indinavir 
Clarithromycin 
Grapefruit 
Grapefruit juice 
Cobicistat 
Saquinavir 
Telaprevir 
Voriconazole 
Nelfinavir 
Ritonavir 
Lopinavir 
Atazanavir 
Aprepitant 
Amprenavir 
Istradefylline 
Imatinib 
Erythromycin 
Crizotinib 
Ciclosporin 
Ciprofloxacin 
Diltiazem 
Darunavir 
Fluconazole 
Verapamil 
Fosamprenavir 
Miconazole 
Tofisopam 
Atorvastatin 
Amiodarone 
Amlodipine 
Alprazolam 
Ginkgo extract 
Isoniazid 
Chlorzoxazone 
Oral contraceptives 
Goldenseal 
Ciclosporin 
Cimetidine 
Cilostazol 
Tacrolimus 
Nilotinib 
Pazopanib 
Bicalutamide 
Fluvoxamine 
Fosaprepitant 
Ranitidine 
Lapatinib 
 
Drugs in the table are categorized based on the drug-drug interaction database 
(http://www.druginteractioninfo.org/) and its base data, clinical drug-drug interaction 
studies with indicator drugs reported in the academic literature, as well as by checking 
package inserts of the concerned drugs, and then listing them.  Drugs for topical use and 
prescription combination agents are not listed in the table.