Clinical trial NCT04473664
Conditions: Hepatic Impairment Moderate Impaired Hepatic Function
Keywords: Hepatic Impairment Healthy Subjects Drug-drug Interaction Pharmacokinetics Quizartinib
Sponsor: Daiichi Sankyo
Start date: 2020-09-22; Completion date: 2021-07-22
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Quizartinib is a novel oral Class III receptor tyrosine kinase (RTK) inhibitor exhibiting highly potent and selective but reversible inhibition of Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3). Quizartinib is currently being studied alone or in combination with other agents as a treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in adult and pediatric populations.

Detailed description:
The primary objective of this study is to determine the plasma pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 after a single oral dose of 30 mg in participants with moderate hepatic impairment (HI) (as defined by National Cancer Institute-Organ Dysfunction Working Group \[NCI-ODWG\] criteria) compared to the healthy control participants with normal hepatic function.

Arms: arm 1: Participants with moderate hepatic impairment as defined by NCI-ODWG criteria who received a single, oral dose of quizartinib 30 mg on Day 1. arm 2: Healthy participants with normal hepatic function matched as a group by sex, age (±10 years), and weight (±20%) who received a single, oral dose of quizartinib 30 mg on Day 1.
Interventions: intervention 1: Quizartinib
Intervention descriptions: intervention 1: Single oral dose, 30 mg tablet

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
An Open-label, Single-dose Study to Assess the 
Pharmacokinetics, Safety and Tolerability of 
Quizartinib in Subjects with Moderate Impaired 
Hepatic Function as Defined by National Cancer 
Institute-Organ Dysfunction Working Group 
(NCI-ODWG Criteria) 
 
(Quizartinib PK in subjects with moderate hepatic 
impairment) 
 
PROTOCOL NUMBER: AC220-A-U105 
 
IND NUMBER: 074552 
 
VERSION 2.0, 17 May 2021 
 
DAIICHI SANKYO, INC  
211 Mount Airy Road 
Basking Ridge, New Jersey 07920 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or any 
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo, Inc. 


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DOCUMENT HISTORY 
Version Number 
Version Date 
1.0 
19 Aug 2020 
2.0 
17 May 2021 


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INVESTIGATOR AGREEMENT 
An Open-label, Single-dose Study to Assess the Pharmacokinetics, Safety and 
Tolerability of Quizartinib in Subjects with Moderate Impaired Hepatic Function as 
Defined by National Cancer Institute-organ Dysfunction Working Group (NCI-
ODWG Criteria) 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by then Daiichi Sankyo, Inc. 
representative listed below. 
 
 
Print Name 
Signature 
 Quantitative Clinical 
Pharmacology 
 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and should 
not be disclosed, other than to those directly involved in the execution or the ethical review of the 
study, without written authorization from the Sponsor.  It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in accordance 
with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Guideline for Good Clinical Practice (ICH E6[R2]), which has its foundations 
in the Declaration of Helsinki, and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records in order to verify the data that I have entered into the case 
report forms.  I am aware of my responsibilities as a Principal Investigator as provided by the 
Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate my 
intention immediately in writing to the Sponsor. 
 
Print Name 
Signature 
Principal Investigator 
 
Title 
Date (DD MMM YYYY) 
PPD
PPD


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TABLE OF CONTENTS 
DOCUMENT HISTORY.................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Protocol Synopsis .......................................................................................................11 
1.2. 
Study Schema .............................................................................................................15 
1.3. 
Schedule of Events .....................................................................................................16 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Background .................................................................................................................18 
2.2. 
Study Rationale ...........................................................................................................18 
2.3. 
Benefit and Risk Assessment ......................................................................................19 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ...............................21 
3.1. 
Primary Objective/Endpoint .......................................................................................21 
3.2. 
Secondary Objectives/Endpoints ................................................................................21 
3.3. 
Rationale for Selection of Primary and Key Secondary Endpoints ............................21 
4. 
STUDY DESIGN .......................................................................................................22 
4.1. 
Overall Design ............................................................................................................22 
4.1.1. 
Design Overview ........................................................................................................22 
4.1.2. 
End-of-Study ...............................................................................................................22 
4.1.3. 
Duration ......................................................................................................................22 
4.1.4. 
Dose Regimen .............................................................................................................22 
4.2. 
Justification for Dose ..................................................................................................23 
5. 
STUDY POPULATION .............................................................................................24 
5.1. 
Inclusion Criteria ........................................................................................................24 
5.2. 
Exclusion Criteria .......................................................................................................25 
5.3. 
Contraception Requirements ......................................................................................27 
5.4. 
Screening Failures, Rescreening, and Subject Replacement ......................................28 
6. 
STUDY TREATMENT(S) .........................................................................................29 
6.1. 
Study Drug(s) Description ..........................................................................................29 


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6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) .....................29 
6.2.1. 
Preparation, Handling, and Disposal ..........................................................................29 
6.2.2. 
Administration ............................................................................................................29 
6.2.3. 
Storage ........................................................................................................................29 
6.2.4. 
Drug Accountability ...................................................................................................30 
6.3. 
Measure to Minimize Bias: Randomization and Blinding .........................................30 
6.3.1. 
Method of Treatment Allocation ................................................................................30 
6.3.2. 
Blinding ......................................................................................................................30 
6.4. 
Treatment Compliance ................................................................................................30 
6.5. 
Guidelines for Dose Modification ..............................................................................30 
6.6. 
Prior and Concomitant Medications ...........................................................................31 
6.7. 
Prohibited Medications, Dietary Supplements, and Foods .........................................31 
6.8. 
Permitted Therapies/Products .....................................................................................31 
7. 
WITHDRAWAL/DISCONTINUATION FROM THE STUDY ...............................32 
7.1. 
Subject Withdrawal/Discontinuation from the Study .................................................32 
7.2. 
Withdrawal Procedures ...............................................................................................32 
7.3. 
Lost to Follow-up .......................................................................................................32 
8. 
STUDY PROCEDURES ............................................................................................33 
8.1. 
Eligibility Assessment ................................................................................................33 
8.2. 
Informed Consent .......................................................................................................33 
8.3. 
General Medical History and Baseline Conditions ....................................................33 
8.4. 
Demographics .............................................................................................................33 
8.5. 
Pharmacokinetic/Pharmacodynamic Assessments .....................................................33 
8.5.1. 
Pharmacokinetic Assessment(s) .................................................................................33 
8.5.2. 
Pharmacodynamic Assessment(s) ..............................................................................33 
8.6. 
Safety Assessments .....................................................................................................34 
8.6.1. 
Reporting of Exposure to COVID-19 (SARS-CoV-2) ...............................................34 
8.6.2. 
Adverse Events ...........................................................................................................34 
8.6.2.1. 
Method to Detect Adverse Events ..............................................................................34 
8.6.2.2. 
Time Period for Collecting Adverse Events, including AESIs and Serious 
Adverse Events ...........................................................................................................35 
8.6.2.3. 
Reporting Procedure for Investigators ........................................................................35 
8.6.2.4. 
Serious Adverse Events Reporting .............................................................................35 


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8.6.2.5. 
Reporting Requirement to Sites and Regulatory Authorities .....................................36 
8.6.2.6. 
Follow-up for AEs and SAEs .....................................................................................36 
8.6.2.7. 
Adverse Events of Special Interest .............................................................................36 
8.6.2.8. 
Overdose .....................................................................................................................37 
8.6.2.9. 
Pregnancy ...................................................................................................................37 
8.6.2.10. 
Pregnancy Testing ......................................................................................................38 
8.6.3. 
Clinical Laboratory Evaluations .................................................................................38 
8.6.4. 
Physical Examinations ................................................................................................38 
8.6.5. 
Vital Signs ..................................................................................................................39 
8.6.6. 
Electrocardiograms .....................................................................................................39 
8.7. 
Pharmacogenomic (Inherited Genetic) Analysis ........................................................39 
8.7.1. 
Banking of Specimens for Inherited Genetic Analysis...............................................39 
8.7.2. 
Storage and Disposal of Specimens ............................................................................40 
8.7.3. 
Disclosure of the Results of Future Pharmacogenetic Analysis .................................40 
9. 
STATISTICAL CONSIDERATIONS .......................................................................41 
9.1. 
Statistical Hypothesis ..................................................................................................41 
9.2. 
Sample Size Determination ........................................................................................41 
9.3. 
Exposure and Compliance ..........................................................................................41 
9.4. 
Population for Analysis Sets .......................................................................................41 
9.4.1. 
Pharmacokinetic Population .......................................................................................41 
9.4.2. 
Safety Population ........................................................................................................41 
9.5. 
Statistical Analysis ......................................................................................................41 
9.5.1. 
Safety Analyses ..........................................................................................................41 
9.5.1.1. 
Adverse Events ...........................................................................................................41 
9.5.1.2. 
Clinical Laboratory Evaluation ...................................................................................42 
9.5.1.3. 
Electrocardiograms .....................................................................................................42 
9.5.1.4. 
Vital Signs ..................................................................................................................42 
9.5.1.5. 
Other ...........................................................................................................................42 
9.5.2. 
Pharmacokinetic Analysis ..........................................................................................43 
9.5.2.1. 
Pharmacokinetic Parameters .......................................................................................43 
9.5.2.2. 
Statistical Analysis of Pharmacokinetic Endpoints ....................................................43 
9.6. 
Interim Analyses .........................................................................................................44 


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10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS .....................................................................45 
10.1. 
Appendix 1 Regulatory and Ethical Considerations ...................................................45 
10.1.1. 
Regulatory Compliance ..............................................................................................45 
10.1.2. 
Compliance Statement, Ethics, and Regulatory Compliance .....................................45 
10.1.3. 
Supply of New Information Affecting the Conduct of the Study ...............................45 
10.1.4. 
Informed Consent .......................................................................................................46 
10.1.5. 
Subject Confidentiality ...............................................................................................46 
10.1.6. 
Data Integrity and Quality Assurance.........................................................................47 
10.1.6.1. 
Monitoring and Inspections ........................................................................................47 
10.1.6.2. 
Data Collection ...........................................................................................................47 
10.1.6.3. 
Data Management .......................................................................................................48 
10.1.6.4. 
Study Documentation and Storage .............................................................................48 
10.1.6.5. 
Record Keeping ..........................................................................................................49 
10.1.7. 
Finances ......................................................................................................................49 
10.1.8. 
Reimbursement, Indemnity, and Insurance ................................................................50 
10.1.9. 
Publication and Public Disclosure Policy ...................................................................50 
10.1.10. 
Protocol Deviations ....................................................................................................50 
10.1.11. 
Study and Site Closure................................................................................................50 
10.1.12. 
Product Complaints ....................................................................................................51 
10.2. 
Appendix 2: Central and/or Local Laboratory ............................................................51 
10.3. 
Appendix 3: Reference Standards ..............................................................................52 
10.3.1. 
Cockcroft-Gault Equation ...........................................................................................52 
10.3.2. 
CYP3A4 Inhibitors and Inducers ................................................................................52 
10.4. 
Appendix 4: General Information - Adverse Events ..................................................54 
10.4.1. 
Definition of Adverse Event .......................................................................................54 
10.4.2. 
Serious Adverse Event ................................................................................................55 
10.4.3. 
Grade Assessment .......................................................................................................56 
10.4.4. 
Difference between Severity and Seriousness ............................................................56 
10.4.5. 
Causality Assessment .................................................................................................57 
10.4.6. 
Action Taken Regarding Study Drug(s) .....................................................................57 
10.4.7. 
Other Action Taken for Event ....................................................................................57 
10.4.8. 
Adverse Event Outcome .............................................................................................57 


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10.5. 
Appendix 5: Pharmacokinetic Blood Samples Collection, Processing, 
Storage, and Shipment ................................................................................................59 
10.6. 
Appendix 6: Pharmacogenomic Blood Samples Collection, Processing, 
Storage, and Shipment ................................................................................................62 
10.7. 
Appendix 7: Allowable Time Windows for Pharmacokinetic Blood Samples, 
Safety Laboratory Collection, and Vital Sign and Electrocardiogram 
Assessments ................................................................................................................64 
10.8. 
Appendix 8: Classification of Hepatic Impairment by the National Cancer 
Institute Organ Dysfunction Working Group and Child-Pugh Scoring .....................65 
11. 
REFERENCES ...........................................................................................................67 
12. 
LIST OF ABBREVIATIONS.....................................................................................68 


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LIST OF TABLES 
Table 1.1: Schedule of Events .....................................................................................................16 
Table 6.1: Study Drug Dosing Information .................................................................................29 
Table 10.1: Clinical Laboratory Tests ...........................................................................................51 
Table 10.2: CYP3A4 Inhibitors .....................................................................................................53 
Table 10.3: CYP3A4 Inducers .......................................................................................................54 
Table 10.4: Acceptable Time Windows .........................................................................................64 
 


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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................15 
 
 






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scan, liver biopsy, or magnetic resonance imaging or history of chronic (>6 months) hepatitis B 
virus or hepatitis C virus infection.  
- 
Moderate HI as assessed by NCI-ODWG classification1:  total bilirubin (TBil) >1.5 to 3 × upper 
limit of normal (ULN) (not due to Gilbert’s syndrome). 
- 
Physical examination findings that are normal or not clinically significant and clinical laboratory 
evaluations with normal limits or not clinically significant deviations, with exception of findings 
that in the opinion of the investigator are consistent with the subject’s HI. 
 
Estimated creatinine clearance ≥60 mL/min by Cockcroft-Gault equation at Screening and Check-in.  
 
Subjects with known hypertension provided that: 
- 
They did not have paracentesis in the last 2 months before the start of quizartinib in the study. 
- 
Are not anticipated to need paracentesis during the period of the study (as assessed by the 
investigator).  Subjects who previously had a shunting procedure or are planned for one are 
excluded from the study. 
Key Exclusion Criteria: 
Subjects meeting any exclusion criteria for this study will be excluded from this study.  Below is a list limited to 
the key exclusion criteria: 
 
In the opinion of the investigator, history of a clinically significant illness within 4 weeks prior to 
administration of quizartinib. 
 
Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome).  
 
Women who are pregnant or breastfeeding 
 
Laboratory results (serum chemistry, hematology, and urinalysis) outside the normal range, if considered 
clinically significant by the investigator. 
 
History, or presence in the average of triplicate ECGs at Screening and Day -2, of any of the following 
cardiac conduction abnormalities:  
- 
For healthy subjects: QTcF >450 milliseconds (ms) 
- 
For hepatically impaired subjects: QTcF >470 ms; patient with QTcF 450-470 ms may be 
enrolled provided their electrolytes values (potassium, calcium, and magnesium) are within normal 
limits. 
- 
Evidence of second- or third-degree atrioventricular block 
- 
Evidence of complete left or right bundle branch block 
- 
QRS or T wave morphology that could, in the Investigator’s opinion, render QT interval 
assessment unreliable (confirmed with triplicate ECG) 
 
Use of drugs with a risk of QT interval prolongation or Torsades de Pointes within 14 days of Day -2 (or 
5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days).  
Additional Exclusion Criteria for Matched Healthy Subjects: 
 
Any clinically relevant abnormality identified on the physical examination, ECG, vital signs, or laboratory 
tests at Screening. 
 
Liver function (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase of liver origin, 
gamma-glutamyl transaminase, and TBil) test results above the upper limit of normal at Screening and 
during Enrollment on Day -2 are exclusionary.  If transaminase levels are above ULN at Screening the 
subject will be excluded and cannot be rescreened. 
Additional Exclusion Criteria for Subjects with HI: 
 
Subjects with active stage 3 or stage 4 encephalopathy. 
 
Fluctuating or rapidly deteriorating hepatic function as indicated by recent history or worsening of clinical 
and/or laboratory signs of HI as judged by the investigator. 




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1.2. 
Study Schema 
The study schema is presented in Figure 1.1. 
 
Figure 1.1: 
Study Level Flow Diagram 
Subjects with moderate HI (as defined by NCI-ODWG) = 8 
Healthy control subjects = 8 
 
HI = hepatic impairment, PK = pharmacokinetic 
Screening
Day -21 to Day -1
Quizartinib (30 mg)
Single dose
PK sample: Day 1 - 22
22 day
Check-out


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1.3. 
Schedule of Events 
The schedule of study activities is in Table 1.1. 
Table 1.1: 
Schedule of Events 
Study Period → 
Screeninga 
Check-
in 
In-Clinic Period 
Study Day→ 
-22 to -2 
-2 
-1 
1 
2 
3 
4 
5 
6 - 21 
22 
 
 
 
 
Hour PostDose 
Study Event ↓ 
Study Hour → 
 
 
 
Pre-
dose 
<24 
24 
48 
72 
96 
144 - 480 
ET/Check-outb 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
NCI-ODWG assessment 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Child-Pugh assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Body Weight and BMId 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drugs of Abuse, Cotinine, Alcohol 
Screene 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Virology (HBsAg/HIV/HAV/HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (WOCBP)f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
FSHg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistry, 
Urinalysish 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Coagulation (PT, INR) 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
12-lead ECGsi 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
Vital Signs (BP, pulse, respiratory rate, 
oral temperature)j 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
Study Drug Administrationk 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK Blood Samples 
 
 
 
X 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
Protein Binding Sample 
 
 
 
X 
Xm 
 
 
 
 
 
 
 
 
PGx Sample 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Record eGFR 
X 
X 
 


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Study Period → 
Screeninga 
Check-
in 
In-Clinic Period 
Study Day→ 
-22 to -2 
-2 
-1 
1 
2 
3 
4 
5 
6 - 21 
22 
 
 
 
 
Hour PostDose 
Study Event ↓ 
Study Hour → 
 
 
 
Pre-
dose 
<24 
24 
48 
72 
96 
144 - 480 
ET/Check-outb 
AE Monitoring 
X 
X 
------------------------------------- continuous -------------------------------→ 
Prior/Concomitant Medications 
-------------------------------------------------------------- continuous ---------------------------------→ 
Clinic Confinement 
 
---------------------------------------- continuous --------------------------------------→ 
BP = blood pressure; BMI = body mass index; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; FSH = follicle-
stimulating hormone; HAV = hepatitis A virus; HBsAg = hepatitis B virus surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
NCI-ODWG = National Cancer Institute Organ Dysfunction Working Group; INR = international normalized ratio; PGx = pharmacogenomic; 
PK = pharmacokinetic; PT = prothrombin time; WOCBP = women of childbearing potential 
a. 
To be conducted within 21 days prior to dosing 
b. Following final blood collections; same procedures to be performed at ET as at Check-out  
c. 
If a subject’s laboratory results need to be repeated because their NCI-ODWG classification has changed from screening, then the subject will be 
assigned to the HI group after confirmation of laboratory results on 2 out of 3 occasions.  In such cases, HI classification must also be confirmed with 
the Sponsor before dosing the subject. 
d. BMI at Screening only. 
e. 
A breath test is also acceptable for alcohol screening  
f. 
Female subjects (WOCBP) only. 
g. Naturally postmenopausal female subjects only. 
h. Samples for serum chemistry will be collected after a 10-hour fast.  
i. 
Triplicate ECG (at least 2 minutes apart) in the supine position.  When a blood collection is scheduled concomitantly with an ECG, the ECG should be 
taken within 5 to 10 minutes prior to the blood collection at predose, 2, 4, 8 and 24 hours after quizartinib administration.  
j. 
Vital signs will be taken in the supine position and should be taken at all ECG time points 
k. Quizartinib 30 mg will be administered following an overnight fast of 10 hours.  Water consumption will be restricted from 1 hour predose to 2 hours 
postdose, except for the 240 mL of water that is to be administered with quizartinib.  Subjects will continue to fast for 4 hour postdose.  
l. 
Day 1 through 22 (relative to quizartinib) PK samples for quizartinib will be collected at predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 
432, and 504 hours post-quizartinib dose 
m. Protein binding samples will be collected at predose and at 4 hours postdose 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Quizartinib is a novel oral Class III receptor tyrosine kinase (RTK) inhibitor exhibiting highly 
potent and selective but reversible inhibition of Feline McDonough sarcoma (FMS)-like tyrosine 
kinase 3 (FLT3).  At clinically relevant concentrations, quizartinib also binds to KIT proto 
oncogene receptor tyrosine kinase (KIT) (another RTK), but with lower affinity than to FLT3, 
and has little or no affinity for other RTKs.  Quizartinib has been approved in Japan for the 
treatment of adult patients with relapsed/refractory FTL3-ITD-positive acute myeloid leukemia 
(AML).  Currently quizartinib is being studied alone or in combination with other agents as a 
treatment for AML and myelodysplastic syndrome (MDS) in adult and pediatric populations.  
Following oral administration, the peak exposure of quizartinib and its major circulating active 
metabolite, (AC886), occurs at a median of approximately 4 hours (range: 2 hours to 8 hours) 
and 5 hours (range: 4 hours to 120 hours) postdose, respectively.  The plasma exposure of 
quizartinib and AC886 increased proportional with the dose of quizartinib over a dose range of 
20 mg to 90 mg.  At steady state, AC886 exposure was approximately 60% of the parent steady 
state exposure.  In vitro reaction phenotyping using human liver microsomes and recombinant 
human cytochrome P450 (CYP) enzymes showed that quizartinib and AC886 are primarily 
metabolized by CYP3A and have estimated effective half- lives (t1/2) of 73 hours and 119 hours, 
respectively.  Additionally, AC886 is also formed from quizartinib by CYP3A.  
In a previously conducted dedicated hepatic impairment (HI) study (AC220-016 Clinical Study 
Report [CSR]) in subjects with mild and moderate HI as defined by Child-Pugh score, 
quizartinib exposure increased approximately 30% and 15% increase in AUCinf, respectively.  
The total active exposure (AUC) of quizartinib plus AC886 increased in subjects with mild HI 
by 17%, which was not considered clinically meaningful.  Quizartinib can be administered with 
pH-modifying drugs such as proton pump inhibitors, H2 antagonists, or antacids, and without 
regard to food.  Strong CYP3A inhibitor (ketoconazole) and moderate CYP3A inhibitor 
(fluconazole) increased quizartinib AUC by 94% and 20%, respectively.  Strong CYP3A inducer 
rifampin decreased quizartinib AUC by approximately 70%; however, due to bioanalytical issue, 
the results were not quantitatively conclusive.   
This is a Phase 1, open-label, multicenter, single dose study to evaluate the PK of a 30 mg dose 
of quizartinib in subjects with normal hepatic function and subjects with moderate HI (as defined 
by National Cancer Institute-Organ Dysfunction Working Group (NCI-ODWG criteria; See 
Section 10.7).  
2.2. 
Study Rationale 
Study AC220-016 assessed the effects of mild and moderate HI (based on Child-Pugh criteria) 
on the pharmacokinetics (PK) of quizartinib and AC886, the active metabolite.  The study was 
designed and conducted in accordance the FDA Guidance for Hepatic Impairment Studies using 
the Child-Pugh classification for HI (observed Child-Pugh score ranged from 5 to 9).  However, 
FDA requires assessment of effect of HI on PK using NCI-ODWG criteria as an alternative to 
Child-Pugh criteria for oncology drugs.  A post hoc analysis was conducted per FDA request by 


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recategorizing the subjects using NCI-ODWG criteria.  Based on the reanalysis, mild HI (as 
defined by NCI-ODWG criteria) was not expected to have clinical meaningful effect on 
quizartinib or AC886 PK and no dose adjustment was recommended.  No conclusion could be 
made about the effect of moderate HI (as defined by NCI-ODWG criteria) on quizartinib and 
AC886 PK since only one subject qualified as moderate based on NCI-ODWG criteria.  
Therefore, the current study aims to investigate the effect of moderate HI (as defined by 
NCI-ODWG criteria) on the PK of quizartinib and AC886 following single dose of 30 mg 
quizartinib. 
2.3. 
Benefit and Risk Assessment 
This is a Phase 1 study being conducted in subjects with normal hepatic function and subjects 
with moderate HI (defined by NCI-ODWG criteria), and, as such, no benefit to the subjects from 
quizartinib is intended or expected.  
In the clinical program, a total of 1,881 subjects had received quizartinib in 23 studies: 
1,396 subjects with AML, 13 subjects with solid tumors, and 472 healthy subjects.  In addition, 
777 subjects have been treated in 6 Investigator-initiated studies.  The dose of quizartinib 
administered in these studies ranged from 12 mg to 450 mg with treatment duration up to 
169 weeks.  Out of 472 healthy subjects, 307 subjects received single dose of quizartinib.  
Toxicities observed for quizartinib in healthy subjects (n = 307) following single dose 
administration were headache ([6.8% subjects), upper respiratory tract infection (2.6% subjects), 
and diarrhea (2.0% subjects).  QT prolongation and combined elevations of alanine 
aminotransferase (ALT) >3 × upper limit of normal (ULN) and total bilirubin (TBil) >2 × ULN 
are the two adverse events of special interest (AESIs) following quizartinib dosing.  In 
approximately 3% of patients with AML in a Phase 3 clinical study with repeated daily dosing, 
the corrected QT interval (QTc) interval was prolonged to 500 milliseconds (ms) or more.  
Of the 241 subjects treated with quizartinib monotherapy in the completed Phase 3 clinical study 
in adults with relapsed/refractory AML (Study AC220-007), 3.3% were found to have a QT 
interval corrected with Fridericia’s formula (QTcF) interval greater than 500 ms, and 12.4% had 
an increase from baseline QTcF greater than 60 ms based on central review of electrocardiogram 
(ECG) data; there were no cases of Torsades de Pointes (TdP), cardiac arrest, or sudden death 
reported.  One reported case of ventricular tachycardia was not associated with QTc prolongation 
and did not require cardiac intervention.  In the remaining completed monotherapy studies in the 
treatment of relapsed or refractory AML, there was 1 subject in a Phase 2 clinical study who 
developed non-fatal TdP while receiving a dose of 90 mg, and the event resolved following 
discontinuation of quizartinib; and one event of fatal cardiac arrest in which a potential 
arrhythmia event cannot be excluded.  
In clinical studies to date, the most common serious adverse reactions are myelosuppressive in 
nature and include infections, febrile neutropenia, and bleeding.  Overall, the most common 
adverse reactions also included nausea, asthenic conditions, pyrexia, vomiting, and diarrhea.  
Further, there is a clear association between quizartinib and QT prolongation which occurs in a 
dose dependent manner.  Risk management for QT prolongation in the multiple dose studies 
includes ECG (QTcF)-based dose modifications (including dose escalation, dose interruption, 
dose reduction, and dose discontinuation) as well as correction of electrolytes.  In summary, the 
adverse events (AEs) observed with quizartinib treatment could be managed by monitoring, dose 


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modifications, and/or standard supportive therapies.  Overall, quizartinib treatment was well 
tolerated at the proposed dose and dose regimen in adults with relapsed/refractory AML with 
FLT3-ITD.  Furthermore, based on the results of the transgenic rat mutation assay (TGR) 
quizartinib is not mutagenic and can be dosed in healthy subjects (report ongoing).  
Please refer to the most updated version of the Investigator’s Brochure (IB) for the risks 
associated with quizartinib.  


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3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS 
3.1. 
Primary Objective/Endpoint 
The primary objective of this study is 
 To determine plasma PK of quizartinib in subjects with moderate HI (as defined by 
NCI-ODWG criteria) compared to subjects with normal hepatic function 
The primary endpoints of this study are: 
 Plasma PK parameters, Cmax, AUClast, AUCinf for quizartinib will be estimated 
 Additionally, Tmax, CL/F, Vz/F, and t1/2 for quizartinib will be estimated  
3.2. 
Secondary Objectives/Endpoints 
The secondary objectives of this study are: 
 To determine the plasma PK of AC886 in subjects with moderate HI (as defined by 
NCI-ODWG criteria) compared to subjects with normal hepatic function  
 To determine the impact of moderate HI (as defined by NCI-ODWG criteria) on plasma 
protein binding of quizartinib and AC886  
 To assess the safety and tolerability of quizartinib in subjects with moderate HI (as 
defined by NCI-ODWG criteria) and in subjects with normal hepatic function 
The secondary endpoints of this study are: 
 Plasma PK parameters, Cmax, Tmax, AUClast, AUCinf, and t1/2 for AC886 will be 
estimated. Additionally, metabolite-to-parent ratio (MPR) based on AUClast and AUCinf 
for AC886 will be calculated 
 Plasma unbound fraction and unbound PK parameters of quizartinib and AC886 
 Treatment-emergent adverse events (TEAEs), vital signs, 12-lead ECG, and clinical lab 
tests (chemistry, hematology) 
3.3. 
Rationale for Selection of Primary and Key Secondary Endpoints 
The objectives and endpoints selected for this study are consistent with those used for similar 
studies. 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1, open-label, multicenter, single-dose PK study of 30 mg of quizartinib in 
subjects with normal hepatic function and subjects with moderate HI (as defined by NCI-ODWG 
criteria).  The severity of HI will be assessed by the NCI-ODWG classification.  This study is 
planned to be conducted at up to 4 sites in the United States (US).  The subject population is 
described in Section 5.  A flow diagram of study activities is presented in Figure 1.1.  
4.1.1. 
Design Overview 
In this study, a total of 16 subjects will be assigned to 2 cohorts.  Eight subjects will have 
moderate HI (as per NCI-ODWG criteria) and 8 subjects will be healthy subjects with normal 
hepatic function.  The healthy subjects will be matched to the HI group for group 
mean/proportion by gender, age (±10 years), and weight (±20%).  The sample sizes are not based 
on statistical considerations.  
This study includes a Screening Period up to 22 days prior to the enrolment and a 22-day 
In-Clinic Period, including screening, each enrolled subject will be in the study for 
approximately 43 days.  The total duration of study conduct will be approximately 10 months.  
4.1.2. 
End-of-Study 
At the defined end of study (EOS)/Day 22 (early termination [ET]/Check-out), subjects will have 
a final PK blood sample taken and safety assessments of AEs, laboratory tests, vital signs, ECGs, 
and physical examination conducted.   
4.1.3. 
Duration 
The Screening Period will occur from 22 days prior to Day 1 of the In-Clinic Period.  The study 
start date is the date when the first subject has signed informed consent.  A subject is eligible to 
be enrolled into the interventional phase of the study when the Investigator or designee has 
obtained written consent, has confirmed all eligibility criteria have been met by the subject, and 
all screening procedures have been completed.   
4.1.4. 
Dose Regimen 
The In-Clinic Period will consist of 22 days.  Subjects will be admitted to the clinical site on 
Day –2 and a single 30 mg dose of quizartinib will be administered orally with 240 mL of water 
after at least 10 hours of fasting on Day 1.  The subjects should continue fasting for 4 hours after 
dosing.  The subjects will be confined at the site until the Day 22 PK samples are collected and 
will be discharged at the EOS (Day 22 [ET/Check-out]), upon completion of all procedures and 
assessments.   
Key procedures include safety assessments (monitoring of AEs and concomitant medications, 
clinical laboratory tests, vital sign measurements, ECG, and physical examinations), and 
collection of blood samples for PK parameters that occur at scheduled time points during the 
study. 


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4.2. 
Justification for Dose 
Although the highest approved dose for relapse/refractory AML in Japan and highest therapeutic 
dose in the ongoing first-line AML study (QUANTUM-First study) is 60 mg once daily, 
quizartinib dose of 30 mg will be investigated in this study.  Subjects with HI can have reduced 
hepatic metabolism which may lead to higher drug exposures.  In the completed AC220-016 
study, the AUC of quizartinib (30 mg single dose) was increased by approximately 30% and 
15% in the mild and moderate HI subjects (Child-Pugh classification), respectively.  
Additionally, liver function based on the NCI-ODWG scale tends to be on the more severe 
categories compared to the Child-Pugh scale.  As mentioned above, of the 8 subjects with the 
moderate HI based on Child-Pugh criteria in AC220-016, only one was classified as moderate by 
NCI-ODWG criteria.  Additionally, out of those 8 subjects, 3 subjects were categorized as 
normal and 4 subjects as mild by NCI-ODWG criteria.  To be prudent, a single oral dose of 
30 mg will be used in the current study, the same as in AC220-016.  Finally, investigation of the 
effect of HI at the same dose in both the studies will allow a pooled, comprehensive analysis of 
the effect of HI (based on NCI-ODWG criteria) on quizartinib PK using data from both the 
studies (AC220-106 and the current study).  


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5. 
STUDY POPULATION 
This Phase 1 study is being conducted in subjects with moderate HI (as defined by NCI-ODWG 
criteria) and matched healthy subjects.  
5.1. 
Inclusion Criteria 
Subjects eligible for inclusion in this study have to meet all inclusion criteria for this study: 
1. Voluntarily consents to participate in this study and provides written informed consent 
before the start of any study-specific procedures. 
2. Male and female subjects 18 to 75 years of age (inclusive), with a body mass index 
(BMI) of 18 kg/m2 to 37 kg/m2 (inclusive).  
3. In females: 
- 
Documented surgical sterilization, postmenopausal status for at least 1 year (follicle 
stimulating hormone [FSH] >40 mIU/mL serum at Screening), or agreement to have 
sterile male partner, or agreement to use 1 of the protocol-approved means of 
contraception from Screening until 6 months after the dose of quizartinib.  See 
Section 5.3 Contraception Requirements. 
- 
Must not retrieve eggs/ova via assisted reproductive technology (ART) either for their 
own use or donation while on study or for 6 months after the last dose of quizartinib, 
whichever is later. 
4. In males:  
- 
Documented surgical sterilization, or sexual abstinence, or agreement to use 1 of the 
protocol-approved means of contraception from Screening until 6 months after the 
dose of quizartinib.  See Section 5.3 Contraception Requirements. 
- 
Agreement to avoid sperm donation for 6 months after the dose of quizartinib. 
5. Subjects must agree to refrain from donation of blood from 56 days prior to Screening, 
plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening. 
6. Must be willing to refrain from consuming grapefruit/grapefruit juice, Seville oranges, 
and pomegranates/pomegranate juice 10 days before the dose of the study drug is given 
on Day 1 until ET/Check-out. 
7. Subjects with HI are required to have:  
a. Documented history of chronic liver disease diagnosed by ultrasonography, 
computed tomography (CT) scan, liver biopsy, or magnetic resonance imaging or 
history of chronic (>6 months) hepatitis B virus (HBV) or hepatitis c virus (HCV) 
infection.  
b. Moderate HI as assessed by NCI-ODWG classification1: TBil >1.5 to 3 × ULN 
(not due to Gilbert’s syndrome). 
c. Physical examination findings that are normal or not clinically significant and 
clinical laboratory evaluations with normal limits or not clinically significant 


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deviations, with exception of findings that in the opinion of the investigator are 
consistent with the subject’s HI.  
8. Estimated creatinine clearance (CrCl) ≥60 mL/min by Cockcroft-Gault equation at 
Screening and Check-in.  
9. Subjects with known hypertension provided that: 
a. They did not have paracentesis in the last 2 months before the start of quizartinib in 
the study. 
b. Are not anticipated to need paracentesis during the period of the study (as assessed by 
the investigator).  Subjects who previously had a shunting procedure or are planned 
for one are excluded from the study. 
5.2. 
Exclusion Criteria 
Subjects meeting any exclusion criteria for this study will be excluded from this study. 
Medical History  
1. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions 
(including lab abnormality except HI) that could interfere with participant’s safety, 
obtaining informed consent or compliance to the study procedures.  
2. Subjects with primary biliary cirrhosis or primary sclerosing cholangitis. 
3. Subjects with history of Gilbert’s syndrome. 
4. Presence or history of clinically severe adverse reaction to any drug. 
5. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (with the exception of 
appendectomy, hernia repair, and/or cholecystectomy). 
6. History of any cancer, except non-melanoma skin cancer, or resected non-metastatic 
cancer with no evidence of disease accepted by the Investigator and Sponsor medical 
monitor.  
7. Bradycardia of less than 45 beats per minute. 
8. History of moderate to heavy alcohol use defined as consumption of more than 28 units 
of alcohol per week for males or 14 units of alcohol per week for females, where 1 unit of 
alcohol equals one-half pint of beer, 4 ounces (oz) of wine, or 1 oz of spirits, or 
significant history of alcoholism or drug/chemical abuse within the last 2 years.  
9. Diagnosis of or suspicion of long QT syndrome (including family history of long QT 
syndrome). 
10. In the opinion of the investigator, history of a clinically significant illness within 4 weeks 
prior to administration of quizartinib. 
Medication Use and Lifestyle 
11. Concomitant medication (inhibitor or inducer of CYP3A4 [eg, itraconazole, rifampin]) 
within 2 weeks before dosing and throughout study.  


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12. Receipt of any prescribed or over-the-counter (OTC) systemic, herbal (including St 
John’s wort), or topical medication within 14 days of quizartinib administration, or any 
expectation of requiring use of such medication while participating in the study is 
prohibited.  
13. Concomitant use of medications known to affect the elimination of serum creatinine (eg, 
trimethoprim or cimetidine) and inhibitors of renal tubular secretion (eg, probenecid) 
within 14 days or 5 half-lives, if known, of the drugs, whichever is greater, prior to 
quizartinib administration.  
14. Use of drugs with a risk of QT interval prolongation or TdP within 14 days of Day -2 (or 
5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days). 
15. Start of any new medication or any changes to a current dosage within 14 days prior to 
IMP administration excluding approved oral contraceptives.  
16. Consumption of alcohol, xanthine-containing beverages, or foods including regular 
coffee, regular tea, caffeine-containing soft drinks and energy drinks, and chocolate 
within 72 hours before Day -2 and throughout the study. 
Laboratory Tests 
17. History, or presence in the average of triplicate ECGs at Screening and Day -2, of any of 
the following cardiac conduction abnormalities: 
- 
For healthy subjects: QTcF >450 ms 
- 
For hepatically impaired subjects: QTcF >470 ms; patient with QTcF 450-470 ms 
may be enrolled provided their electrolytes values (potassium, calcium, and 
magnesium) are within normal limits. 
- 
Evidence of second- or third-degree atrioventricular block 
- 
Evidence of complete left or right bundle branch block 
- 
QRS or T wave morphology that could, in the investigator’s opinion, render QT 
interval assessment unreliable (confirmed with triplicate ECG) 
18. Laboratory results (serum chemistry, hematology, and urinalysis) outside the normal 
range, if considered clinically significant by the investigator.  
19. Women who are pregnant or breastfeeding.  
20. A positive drugs of abuse screen including urine ethanol test (unless the drug is medically 
prescribed by a licensed health care provider) or alcohol breath test at Screening or at 
Check-in on Day -2 or a subject who will not agree to smoke ≤10 cigarettes or equivalent 
per day from Screening up to Enrollment, and is unable to be restricted to ≤5 cigarettes 
per day and for 6 hours postdose during their period of residence in the clinical unit. 
21. Positive serology for hepatitis B surface antigen and anti-HCV (healthy subjects), 
hepatitis A virus immunoglobulin M, or anti-human immunodeficiency virus Type 1 and 
Type 2 (all subjects).  
22. Loss of more than 450 mL blood during the 3 months before the trial (eg, as a blood 
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23. Current enrollment in or have not yet completed at least 30 days or 5 elimination 
half-lives, whichever is longer, since receiving an investigational device or product, or 
receipt of other investigational agents within 30 days of quizartinib.  
Additional Exclusion Criteria for Matched Healthy Subjects:  
24. Any clinically relevant abnormality identified on the physical examination, ECG, vital 
signs, or laboratory tests at Screening.  
25. Liver function (aspartate aminotransferase [AST], ALT, and alkaline phosphatase of liver 
origin, gamma-glutamyl transaminase, and TBil) test results above the upper limit of 
normal at Screening and during Enrollment on Day -2 are exclusionary.  If transaminase 
levels are above ULN at Screening the subject will be excluded and cannot be rescreened.  
Additional Exclusion Criteria for Subjects with HI:  
26. Subjects with active stage 3 or stage 4 encephalopathy.  
27. Fluctuating or rapidly deteriorating hepatic function as indicated by recent history or 
worsening of clinical and/or laboratory signs of HI as judged by the Investigator.  
5.3. 
Contraception Requirements 
Female Subjects 
Females of childbearing potential must use contraception while enrolled in this study.  
From Screening until 6 months after the dose of quizartinib:  
 Sterile male partner  
 Any of the following with spermicide:  
○ Non-hormonal intrauterine device (IUD) 
○ Female or male condom 
○ Contraceptive sponge 
○ Diaphragm 
○ Cervical cap 
Any of the following (hormonal contraceptives may be started only after Day 22.  However, one 
of the non--hormonal methods listed above must be used in conjunction with the hormonal 
contraceptive for 2 weeks until the hormonal contraceptive becomes effective and then the 
hormonal contraceptive must be continued until 6 months after the dose of quizartinib): 
 Hormonal IUD 
 Intravaginal system 
 Oral, implantable, transdermal, or injectable contraceptive 
Male Subjects 
Males of reproductive potential must use contraception while enrolled in this study.  
From Screening until 6 months after the dose of quizartinib: 
 Sterile or postmenopausal female partner 


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 Male condom with spermicide 
 Use of any of the following with spermicide by female partner: 
○ Non-hormonal IUD 
○ Female condom 
○ Contraceptive sponge 
○ Diaphragm 
○ Cervical cap 
 Use of any of the following by female partner: 
○ Hormonal IUD 
○ Intravaginal system 
○ Oral, implantable, transdermal, or injectable contraceptive 
5.4. 
Screening Failures, Rescreening, and Subject Replacement 
Subjects who withdraw or are withdrawn from the study will not be replaced unless approved by 
the Sponsor.  Subjects with HI may be replaced with approval from the Sponsor.  
If transaminase levels are above ULN at Screening the subject will be excluded and cannot be 
rescreened.  
If a subject’s TBil need to be repeated because their NCI-ODWG classification prior to dosing 
has been changed from screening, then the subject will be assigned to the HI group (as defined 
by NCI-ODWG criteria) after confirmation of laboratory results on 2 out of 3 occasions before 
subject can be dosed.  In such cases, HI classification (as defined by NCI-ODWG criteria) must 
also be confirmed with the Sponsor before dosing the subject.  


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6. 
STUDY TREATMENT(S) 
6.1. 
Study Drug(s) Description 
Quizartinib is a white to off-white crystalline powder, dichloride salt, administered orally as a 
30 mg tablet (26.5 mg free base).   
Table 6.1 describes the formulation, dose, regimen, duration, packaging, and labeling of the 
study drug.  
Table 6.1: 
Study Drug Dosing Information 
Study Drug Name 
Quizartinib 
Dosage Formulation 
Tablets 
Dosage Level(s) 
30 mg 
Route of Administration 
Oral 
Dosing Regimen 
30 mg tablet to be administered on Day 1 
Duration 
Single dose on Day 1 
Packaging 
Packaging will clearly display the name of product, storage 
condition, and other required information as applicable in accordance 
with local regulations 
Labeling 
Bottles will be labeled as required per local regulatory requirement 
Quizartinib will be supplied by the Sponsor. 
6.2. 
Preparation, Handling, Storage, and Accountability for Study 
Drug(s) 
6.2.1. 
Preparation, Handling, and Disposal 
The quizartinib will be supplied as tablets.  
Procedures for proper handling and disposal should be followed in compliance with the standard 
operating procedures (SOP) of the site. 
6.2.2. 
Administration 
A single 30 mg tablet of quizartinib will be administered with 240 mL of water after at least 
10 hours of fasting. 
6.2.3. 
Storage 
Quizartinib tablets should be stored at controlled room temperature, 20°C to 25°C (68°F to 77°F) 
with allowed excursions between 15°C and 30°C (59°F and 86°F) and protected from light.  The 
storage condition of quizartinib drug bottles must be logged daily.  If the storage room/cabinet 
does not have an automated continuous temperature recording system to record the daily 
temperature data, daily temperature must be monitored and recorded on a temperature log. 


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6.2.4. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug against the shipping documentation.  
The Receipt of Shipment Form should be faxed as instructed on the form.  The original will be 
retained at the study site.   
The investigational pharmacy will maintain a record of study drug inventory.  
The investigator or designee will maintain subject ID, lot number and date dispensed on a subject 
study drug dispensing and accountability log.  
6.3. 
Measure to Minimize Bias: Randomization and Blinding 
6.3.1. 
Method of Treatment Allocation 
There is no randomization in this study.  All subjects will be assigned to receive quizartinib on 
Day 1. 
6.3.2. 
Blinding 
This is an open-label study.  No blinding will be required. 
6.4. 
Treatment Compliance 
To ensure treatment compliance, the single dose will be administered under the supervision of 
clinical study personnel.  A mouth and hand check must be carried out for all the subjects to 
ensure that the study medication has been swallowed. 
The exact times of investigational medicinal product (IMP) dosing and the number of units 
administered will be recorded in the electronic case report form (eCRF). 
6.5. 
Guidelines for Dose Modification 
Not applicable.  No dose modification will be allowed. 


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6.6. 
Prior and Concomitant Medications 
All therapies received by subjects within 22 days prior to enrollment will be recorded as prior 
therapies.  
All therapies used from the time the subject signs the informed consent form (ICF) for study 
participation to the ET/Check-out will be recorded as concomitant therapies.  Concomitant 
therapies include all prescription, OTC, and herbal remedies. 
Any concomitant medications received from screening through the final study visit (ET or EOS) 
will be recorded in the eCRF.  Concomitant medications and other prescription medications, 
OTC and herbal products, and dietary supplements, are not permitted unless discussed and 
allowed by the Sponsor and Medical Monitor. 
6.7. 
Prohibited Medications, Dietary Supplements, and Foods 
The following (except medications approved by the Sponsor on a case-by-case basis) are 
prohibited within 14 days (or 5 drug half-lives, if 5 drug half-lives were expected to exceed 
14 days) before Day -2 and throughout the study:  
 Hormonal contraceptives and all other prescription medications including CYP3A 
inducers (Table 10.3) and inhibitors (Table 10.2).  
 Medical marijuana 
 Melatonin and all other OTC products 
 Echinacea, gingko biloba, ginseng, kava kava, St. John’s wort, and all other herbal 
products 
 Vitamins and minerals generally consistent with daily requirements are permitted 
during the 14 days before Day -2.  However, all dietary supplements are prohibited 
starting on Day -2 and throughout the study.   
 Blood oranges, grapefruit, grapefruit juice, pomegranates, pomegranate juice, Seville 
(bitter) oranges, and star fruit are prohibited for 10 days before the dose of the study 
drug is given on Day 1 until ET/Check-out.. 
 Alcohol, xanthine-containing beverages, or foods including regular coffee, regular 
tea, caffeine-containing soft drinks and energy drinks, and chocolate are prohibited 
for 72 hours before Day -2 and throughout the study. 
6.8. 
Permitted Therapies/Products 
The use of acetaminophen of less than 2 grams/day and 1% topical hydrocortisone for contact 
dermatitis are acceptable concomitant therapies at any time during the study.  Prune juice and 
stool softeners for constipation may not be given from 2 days prior to quizartinib dosing through 
the day of quizartinib dosing, but may be given at any time 24 hours after the dose of quizartinib. 


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7. 
WITHDRAWAL/DISCONTINUATION FROM THE STUDY 
7.1. 
Subject Withdrawal/Discontinuation from the Study  
Subjects may discontinue from the study for any of the following reasons:  
 AE 
 Withdrawal by subject 
 Investigator decision 
 Pregnancy 
 Protocol deviation 
 Study termination by Sponsor 
7.2. 
Withdrawal Procedures 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has the 
right to withdraw from the study at any time and for any reason without prejudice to his or her 
future medical care by the study physician or at the study site.  
If a subject withdraws from the study, s/he will be required to have ET study procedures 
performed (refer to Section 4.1.2).  
If a subject is withdrawn from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal, including the date of last 
treatment and the reason for withdrawal.  
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the AE has 
resolved or stabilized.  
All subjects who are withdrawn from the study should complete protocol-specified withdrawal 
procedures.  
See Table 1.1 for data to be collected at the time of study discontinuation and for any further 
evaluations that need to be completed.  
7.3. 
Lost to Follow-up 
Subjects will be considered lost to follow-up if he/she leaves the clinical research unit prior to 
the ET/Check-out and is unable to be contacted by the study site staff.  Before a subject is 
deemed lost to follow-up, the Investigator or designee will make every effort to regain contact 
with the subject (by telephone call, texts, emails).  These contact attempts should be documented. 


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8. 
STUDY PROCEDURES 
See Schedule of Events (SoE) (Table 1.1) for the procedures conducted at specific time points 
during Screening, Check-in, In-Clinic Period, and ET/Check-out.  
8.1. 
Eligibility Assessment 
Review the subject's demographics, medical history, vital signs (blood pressure, heart rate, 
respiratory rate, and temperature), and results of tests (eg, physical examination, ECG, and 
laboratory assessments) and compare against the eligibility criteria (Section 5.1 and Section 5.2). 
8.2. 
Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive responses 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.  See Section 10.1.4 for additional details. 
8.3. 
General Medical History and Baseline Conditions 
Subject’s medical history will be obtained by the Investigator or a qualified designee.  
An untoward medical occurrence (including clinically relevant laboratory values/vital signs that 
are out-of-range) that is noted prior to the first dose of study medication will be recorded on 
General Medical History and Baseline Conditions eCRF, not the adverse event eCRF.   
8.4. 
Demographics 
Review the subject’s demographics against the eligibility criteria.  
8.5. 
Pharmacokinetic/Pharmacodynamic Assessments 
8.5.1. 
Pharmacokinetic Assessment(s) 
PK blood samples will be collected, processed, and shipped as detailed in the SoE and in the 
Laboratory Processing Specification document as detailed in Section 10.5. 
Allowable time windows for PK blood samples are provided in Section 10.7. 
Quizartinib and AC886 showed temperature- and concentration-dependent partitioning into 
blood cells; therefore, blood samples must be processed at room temperature for determination of 
plasma quizartinib and AC886 concentrations. 
8.5.2. 
Pharmacodynamic Assessment(s) 
No pharmacodynamic (PD) assessments are planned for this study. 


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8.6. 
Safety Assessments 
8.6.1. 
Reporting of Exposure to COVID-19 (SARS-CoV-2) 
All confirmed or suspected coronavirus disease 2019 (COVID-19) events must be recorded in 
the eCRF. 
 Subjects who test positive for COVID-19 should be reported as “Confirmed COVID-19”, 
either as an AE or serious adverse event (SAE). 
 Subjects whose medical history and clinical manifestations, signs, and possible exposure 
are consistent with COVID-19 but for whom no polymerase chain reaction or antibody 
test for COVID-19 is available should be reported as “Suspected COVID-19”, either as 
an AE or SAE.  
The usual protocol mandated SAE reporting requirements should be followed for confirmed or 
suspected COVID-19 (or SARS-CoV-2) as done for any other AE, ie, the investigator should 
assess whether any seriousness criteria are met per protocol, and appropriate protocol reporting 
requirements should be followed. 
In the event that the Investigator assesses that a COVID-19 case does not meet any seriousness 
criteria as outlined in the protocol, it should be reported as a non-serious AE in the case report 
form (CRF).  
When assessing the severity of the COVID-19 AE, please use the severity grading criteria as 
defined in Section 10.4.3 will be used.  
All study drug interruption or dose reduction or discontinuation due to the COVID-19 event must 
be recorded on the AE and drug administration eCRFs. 
For both serious and non-serious COVID-related AEs, the following information should be 
provided as a minimum: 
 Date and laboratory results confirming the COVID-19 diagnosis (including viral antigen 
test and/or antiviral antibody serological test) in the lab eCRF, if available. 
 Clinical course of the case including presenting signs, symptoms, exposure, actions taken 
with the investigational products, medications used for treatment or prophylaxis of 
COVID-19, and outcome in relevant eCRF (eg, concomitant medication, AE). 
 Findings from diagnostic imaging (including CT scan or other chest imaging). 
8.6.2. 
Adverse Events 
8.6.2.1. 
Method to Detect Adverse Events 
The definitions of an AE or SAE can be found in Section 10.4.  AEs may be directly observed, 
reported spontaneously by the subject or by questioning the subject (or, when appropriate, by a 
caregiver, surrogate, or the subject's legally authorized representative) at each study visit.  
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptoms.  The Investigator must assess all AEs to determine seriousness, severity, and 
causality.  The Investigator and any qualified designees are responsible for detecting, 


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documenting, and recording events that meet the definition of an AE or SAE and remain 
responsible for following AEs that are serious, considered related to the study drug or study 
procedures, or that caused the subject to discontinue the study drug.  
All clinical laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study drug discontinuation, lead to dose reduction, require 
corrective treatment, or constitute an AE in the Investigator’s clinical judgment.   
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 medical 
history.  
8.6.2.2. 
Time Period for Collecting Adverse Events, including AESIs and Serious 
Adverse Events 
All AEs occurring after the subject signs the ICF and up to 30 days after the last dose of study 
medication whether observed by the Investigator or reported by the subject, will be recorded.  
All SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the 
subject is lost to follow-up.  
8.6.2.3. 
Reporting Procedure for Investigators 
All AEs (including AESIs and SAEs) will be reported.  All AEs (serious and non-serious) must 
be reported with the Investigator’s assessment of seriousness, severity, and causality to the study 
drugs.  
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.  
8.6.2.4. 
Serious Adverse Events Reporting 
The following types of events must be reported by the Investigator within 24 hours of awareness:  
 SAEs (Section 10.4.2) 
 Hepatic events (both serious and non-serious) meeting the laboratory criteria of a 
potential Hy’s Law criteria (as defined in Section 8.6.2.7.1). 
 QTcF prolongation, TdP, and other ventricular arrhythmias (as defined in 
Section 8.6.2.7.2) 
Details summarizing the course of the SAE, including its evaluation, treatment, and outcome 
should be provided and updated, as needed.  Specific or estimated dates of AE onset, treatment, 
and resolution should be included.  Medical history, concomitant medications, and laboratory 
data that are relevant to the event should also be summarized in the SAE report.  For fatal events, 
the SAE report should state whether an autopsy was or will be performed and should include the 


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results if available.  Source documents (including medical reports) will be retained at the study 
site and should not be submitted to the Sponsor for SAE reporting purposes.  
Call the local SAE Hotline or your study monitor for any questions on SAE reporting.  
See Section 8.6.2.2 for details on the time period for collecting SAEs.  
8.6.2.5. 
Reporting Requirement to Sites and Regulatory Authorities 
The investigator must report all SAEs to the Sponsor and may need to report any suspected 
unexpected serious adverse reactions occurring in study sites or other studies of quizartinib to the 
Institutional Review Board (IRB).  
The Sponsor will comply with any additional local safety reporting requirements.  The Sponsor 
will assess if an AE is to be considered “unexpected” based on the “Reference Safety 
Information” section in the current IB.3  
8.6.2.6. 
Follow-up for AEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations. 
Urgent safety queries must be followed up and addressed promptly.  The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of receipt of the information.  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 report. 
8.6.2.7. 
Adverse Events of Special Interest 
Hepatic events which meet the potential Hy’s law criteria defined as the combined elevations of 
ALT >3 × ULN and TBil >2 × ULN, and QT prolongation are the two AESIs following 
quizartinib dosing.  
8.6.2.7.1. Hepatic Events 
Hepatic events (both serious and non-serious) which meet the criteria below should be reported 
as AESI:  
 For healthy subjects: an elevated (ALT and/or AST) ≥3 × ULN and an elevated TBil 
>2 × ULN,  
 For hepatically impaired subjects: Taking into consideration the NCI-ODWG 
criteria for moderate HI (which requires any elevation of ALT or AST and TBil 
>1.5-3 × ULN), worsening of baseline hepatobiliary parameters should be considered.  
Worsening of baseline values defined as an increase of 3 × the baseline ALT and/or 
AST value AND increase of TBil from baseline, with increased TBil values being at 
least >2 × ULN. 
These events must be reported with the Investigator’s assessment of seriousness, severity, 
causality, and a detailed narrative.  These events should be reported within 24 hours of 


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Investigator’s awareness of the event regardless of seriousness.  A targeted questionnaire will be 
available as an eCRF to collect relevant additional information for these potential cases.  Please 
refer to Section 10.7 for NCI-ODWG criteria table.  
If the subject discontinues study drug due to liver enzyme abnormalities, the subject will have 
additional clinical and laboratory evaluations as described in Section 10.2 in order to determine 
the nature and severity of the potential liver injury.  
8.6.2.7.2. QTcF Prolongation, Torsades de Pointes, and Other Ventricular Arrhythmias 
Subjects who experience >480 ms QTcF prolongation must be monitored closely with ECGs, 
performed twice weekly for the first week of the QTcF prolongation and then weekly thereafter 
until the QTcF prolongation is resolved.  QTcF prolongation ≥Grade 3, either serious or 
non-serious and whether or not causally related, must be recorded as an AE or SAE in the eCRF 
within 24 hours of the assessment, with the Investigator’s assessment of seriousness, causality, 
and a detailed narrative. 
Monitoring in subjects with QTcF prolongation will include the following: 
 Electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range. 
 Concomitant medications should be reviewed to identify and, if appropriate, 
discontinue any medication with known QT prolonging effects. 
8.6.2.8. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.  All occurrences of overdose must be 
reported to the Sponsor within 24 hours of awareness and recorded via SAVER/overdose form or 
eCRF.  
An “excessive and medically important” overdose includes any overdose in which either an 
SAE, a non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject.  Occupational exposures must be 
reported via the SAVER form.  
8.6.2.9. 
Pregnancy 
It is the responsibility of the Investigator or designee to notify the Sponsor of any pregnancy 
while receiving or within 6 months of the dose of quizartinib in a female subject or a male 
subject’s female partner using the Exposure In Utero (EIU) Reporting Form. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  If a pregnancy is reported, the Investigator should inform the Sponsor 
within 24 hours of learning of the pregnancy as this information is important for drug safety and 
public health concerns. 
The Investigator should make every effort to follow the female subject or partner of a male 
subject (upon obtaining written consent from partner) until completion of the pregnancy and 
record the complete pregnancy outcome information, including normal delivery or induced 


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abortion.  Any adverse pregnancy outcome, either serious or non-serious, should be reported in 
accordance with study procedures.  If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (ie, post-partum complications, spontaneous or induced 
abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
Investigator should follow the procedures for reporting SAEs.  For reports of pregnancy in the 
female partner of a male subject, the EIU Reporting Form (or SAE form if associated with an 
adverse outcome) should be completed with the subject’s ID number, initials, and date of birth, 
and details regarding the female partner should be entered in the narrative section.  
For women of childbearing potential, document the results of a negative serum pregnancy test.  
For eligibility, a serum pregnancy test must be performed with the results available prior to 
enrollment.  
Toxicities will be graded according to the National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), version 5.0.  If multiple toxicities are encountered, 
then DLT assessment will be based on the most severe toxicity experienced.  
8.6.2.10. Pregnancy Testing 
Women of childbearing potential will have a serum pregnancy test conducted at Screening and 
the results documented.  For eligibility (as defined in Section 5.1), a serum pregnancy test must 
be performed with the results available prior to enrollment. 
Women who are postmenopausal will have an FSH test conducted at Screening. 
8.6.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed as detailed in the SoE in Section 1.3. 
The clinical laboratory tests will include hematology, coagulation, blood chemistry, and 
urinalysis.  Refer to Section 10.2 for the complete list of laboratory parameters.  
Allowable time windows for safety laboratory collections are provided in Section 10.7. 
Abnormal laboratory values occurring during the clinical study will be followed until repeat test 
results return to normal (or baseline), stabilize, or are no longer clinically relevant.  New or 
worsened clinically relevant laboratory abnormalities should be recorded as AEs.  
Urine drugs of abuse, cotinine, alcohol screen will be tested during the Screening and Check-in.  
A breath test is also acceptable for alcohol screening   
8.6.4. 
Physical Examinations 
Physical examination will be performed as detailed in the SoE in Section 1.3.  
A complete physical examination should include a height (at Screening only), weight, and 
calculation of BMI, and an evaluation of the head, eyes, ears, nose, and throat and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems.  Any abnormality identified at baseline should be recorded.  At subsequent visits (or as 
clinically indicated), limited, symptom-directed physical examinations can be performed at the 
discretion of the investigator.  Changes from baseline abnormalities should be collected in the 


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subject’s study record.  New or worsened clinically relevant abnormalities should be recorded as 
AEs.  
8.6.5. 
Vital Signs 
Vital signs will be collected from each subject as detailed in the SoE in Section 1.3.  
Allowable time windows for vital sign assessments are provided in Section 10.7. 
Vital signs will include the measurements of respiratory rate, heart rate, systolic and diastolic 
blood pressures, and temperature.  Blood pressure and pulse rate will be measured after the 
subject has rested in a supine position for at least 5 minutes or more and prior to laboratory 
draws.  Vital signs will be taken in the supine position and should be taken at all ECG time 
points.  
8.6.6. 
Electrocardiograms 
ECGs will be performed as detailed in the SoE in Section 1.3.  
Allowable time windows for vital sign assessments are provided in Section 10.7. 
Triplicate ECG will be performed (at least 2 minutes apart) in the supine position.  When a blood 
collection is scheduled concomitantly with an ECG, the ECG should be taken within 5 to 
10 minutes prior to the blood collection at predose, 2, 4, 8 and 24 hours after quizartinib 
administration. Abnormal, clinically relevant findings occurring post-baseline will be reported as 
AEs.  Whether or not the measurement is performed, the date the ECG is to be performed and 
results will be recorded.  
8.7. 
Pharmacogenomic (Inherited Genetic) Analysis 
A single blood sample for pharmacogenomic (PGx) analysis will be collected pre-dose on the 
morning of Day 1.  Detailed instructions for the collection, handling, and shipping of samples are 
outlined in the Laboratory Specifications Document as detailed in Section 10.6.  
Genetic analyses will not be performed on blood samples collected for PK or safety assessments.  
Subject confidentiality will be maintained.  
Deoxyribonucleic acid (DNA) samples will be stored, as outlined in Section 8.7.2 for performing 
possible PGx analysis in the future; otherwise all remaining DNA samples will be destroyed.  
8.7.1. 
Banking of Specimens for Inherited Genetic Analysis 
Procedures for the long-term preservation (banking) of blood and/or DNA specimens extracted 
from subjects' blood samples for each subject that consented are described in Section 10.6.  
The banked samples may be analyzed for genes involved in absorption, distribution, metabolism, 
elimination, safety, and efficacy of quizartinib.  Additionally, samples may be analyzed for genes 
involved in quizartinib related signaling pathways, or to examine diseases or physiologic 
processes related to quizartinib.  DNA samples will not be immortalized or sold to anyone.  This 
information may be useful in increasing the knowledge of differences among individuals in the 
way they respond to the study drug, as well as helping in the development of new drugs or 
improvement of existing drugs.  


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8.7.2. 
Storage and Disposal of Specimens 
Banked DNA samples will be stored for a maximum of 15 years after the finalization of the 
clinical study report for this protocol.  These specimens will be kept for PGx analysis in case 
new genomic or genetic information is obtained in the future regarding the response (PK) to 
quizartinib, or in case serious adverse drug reactions are noted in a clinical study and PGx 
analysis is to be conducted for investigation into the cause.  
During the storage period, the samples will be coded with labels having no personal information 
and will not be immortalized or sold to anyone.  Subjects will have the right to withdraw consent 
and have their sample destroyed at any time.  However, the data will not be discarded if analysis 
has been completed before the subject withdraws consent.  
8.7.3. 
Disclosure of the Results of Future Pharmacogenetic Analysis 
Because the nature and value of future PGx analysis cannot be known at this time, any results 
obtained from research involving PGx samples will not be disclosed to the subject or 
Investigators now or in the future.  


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9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical Hypothesis 
This is not a hypothesis testing study.  
9.2. 
Sample Size Determination 
Sixteen subjects will be enrolled.  Eight subjects will be with moderate HI (as defined by 
NCI-ODWG criteria) and 8 subjects will be healthy subjects with normal hepatic function.  The 
healthy subjects will be matched to the HI group for group mean/proportion by gender, age 
(±10 years), and weight (±20%).  The sample sizes are not based on statistical considerations.  
The number of subjects is considered sufficient to achieve the study objectives (see FDA 
Guidance 20032).  Subjects who discontinue after receiving study drug will not be replaced 
unless approved by the Sponsor. 
9.3. 
Exposure and Compliance 
As the dose administration is under the control of the study sites, compliance to study medication 
will not be an issue.  Study drug administration will be summarized by subject, treatment, and 
time of dosing. 
9.4. 
Population for Analysis Sets 
9.4.1. 
Pharmacokinetic Population 
The PK analysis will be performed using the PK Population defined as all evaluable subjects 
who received 1 dose of study drug and has a measurable concentration.  
9.4.2. 
Safety Population 
The safety analysis will be performed using the Safety Population defined as all subjects who 
received 1 dose of study drug.  
9.5. 
Statistical Analysis 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the subject populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints.  
9.5.1. 
Safety Analyses 
9.5.1.1. 
Adverse Events 
TEAEs are defined as new AEs that occur after the first dose of study drug or as AEs that were 
present prior to first dose of study drug but which worsened in severity after the start of study 
drug.  AEs collected 30 days after the last dose of study drug will not be considered TEAEs 
unless they are treatment-related.  AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  An AE will be assigned to the study day in which it started, 


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even if it resolved on a subsequent day.  The incidence of TEAEs will be summarized by 
treatment group.  The number and percentage of subjects reporting TEAEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group.  
TEAEs will be further summarized by CTCAE grade and relationship to study drug.  Similarly, 
the number and percentage of subjects reporting treatment-emergent SAEs and related treatment-
emergent SAEs will be tabulated, treatment-emergent AESIs, and TEAEs leading to 
discontinuation of study drug.  
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to study drug 
will be provided.  Deaths, SAEs, AESIs, and AEs associated with study drug discontinuation, 
will be listed.  
9.5.1.2. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation and by treatment group, as well as for the change from baseline.  The baseline value is 
defined as the last non-missing value before the initial administration of study drug.  In addition, 
mean change from baseline will be presented by treatment group for the maximum and minimum 
post-treatment values and the values at the ET/Check-out.  
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
by treatment group the two-way frequency tabulation for baseline and the worst post-treatment 
value according to the CTCAE grade, will be provided for clinical laboratory tests.  A listing of 
abnormal clinical laboratory test results deemed of clinical significance or of Grade 3 or 4 will be 
generated.  
9.5.1.3. 
Electrocardiograms 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation and by treatment group, as well as for the change from baseline.  The baseline value is 
defined as the last non-missing value before the initial administration of study drug.  In addition, 
the number and percentage of subjects with ECG interval values meeting the criteria will be 
tabulated (eg, QTc ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms).  
A listing of ECG data will be generated.  
9.5.1.4. 
Vital Signs 
Descriptive statistics will be provided for the vital sign measurements by scheduled time of 
evaluation and by treatment group, as well as for the change from baseline.  The baseline value is 
defined as the last non-missing value before the initial administration of study treatment.  A 
listing of vital sign data will be generated.  
9.5.1.5. 
Other 
Listings of all other safety endpoints (eg, physical examination findings) will be generated.  


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9.5.2. 
Pharmacokinetic Analysis 
PK analysis and statistical analysis of PK endpoints will be conducted in accordance with the 
protocol, SAP, and the Daiichi Sankyo, Inc. Non-Compartmental Analysis Guidelines.  
Descriptive statistics will be presented for plasma concentrations and protein binding at each 
evaluation time point and for all PK parameters for quizartinib and AC886 by hepatic function 
group (normal and moderate HI as defined by NCI-ODWG criteria).   
9.5.2.1. 
Pharmacokinetic Parameters 
PK and statistical analysis will be performed using appropriate software; eg, Phoenix™ 
WinNonlin® (Version 8.1 or higher, Certara, L.P.) and/or SAS® (Version 9.4 or higher, SAS 
Institute Inc.).   
The following PK parameters will be calculated for quizartinib and AC886, as applicable:  
Cmax 
Maximum concentration, determined directly from individual concentration-time 
data 
Tmax 
Time to reach maximum concentration 
t1/2 
The observed terminal half-life 
AUClast  
Area under the concentration-time curve from time-zero to the time of the last 
quantifiable concentration; calculated using the linear trapezoidal rule 
AUCinf 
Area under the concentration-time curve from time-zero extrapolated to infinity 
AUCextr (%) 
The percentage of AUCinf based on extrapolation 
Note: If AUCextr is greater than 20%, AUCinf and related parameters (CL/F and 
Vz/F) for the specific treatment will be summarized with and without subjects for 
whom AUCextr >20%. 
CL/F 
Clearance after extravascular administration (for quizartinib only) 
Vz/F 
Volume of distribution in the terminal phase (for quizartinib only) 
MPR AUClast 
Metabolite-to-parent ratio for AUClast, AUClast(AC886)/AUClast 
MPR AUCinf 
Metabolite-to-parent ratio for AUCinf, AUCinf (AC886)/AUCinf  
9.5.2.2. 
Statistical Analysis of Pharmacokinetic Endpoints 
Plasma concentration-time data will be analyzed using noncompartmental methods and 
summarized with descriptive statistics. 
In the primary analysis, Cmax, AUClast, and AUCinf will be compared for subjects in the 
moderate HI group (as defined by NCI-ODWG criteria) to those of normal hepatic function.  
Note that when percent extrapolated AUC (%AUCextr) is greater than 20%, AUCinf and related 
parameters will be summarized with and without those individuals having >20% AUCextr.  
These comparisons between the moderate HI group (as defined by NCI-ODWG criteria) with the 
healthy control group will be made using an analysis of variance model on 
logarithm-transformed Cmax, AUClast, and AUCinf.  The resulting point estimates 
(least-squares means) differences (HI/normal hepatic function), and 90% confidence intervals 


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(CIs) for the difference will be exponentiated to get the ratio and corresponding 90% CI of the 
ratio on the untransformed scale and will be presented for each HI cohort (normal and moderate 
HI as defined by NCI-ODWG criteria).   
Each comparison will also be made by performing an analysis of covariance (ANCOVA) on the 
logarithm-transformed Cmax, AUClast, and AUCinf including the hepatic function, sex, age, and 
weight as factors.  Within the framework of ANCOVA, the estimate and 90% CI will be 
provided for the ratio of central values between the HI group and normal hepatic function group.  
9.6. 
Interim Analyses 
PK and safety analyses may be conducted as ongoing basis.  


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10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS  
10.1. 
Appendix 1 Regulatory and Ethical Considerations 
10.1.1. 
Regulatory Compliance 
The study protocol, the IB, available safety information, recruitment procedures (eg, 
advertisements), subject information and consent form, any subject written instructions to be 
given to the subject, information about payments and compensation available to the subjects, and 
documentation evidencing the Investigator’s qualifications should be submitted to the 
independent 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.  Written approval of all protocol amendments and changes to any of 
the above listed documents must be obtained from the IRB. 
The Investigator should notify the IRB of deviations from the protocol or SAEs occurring at the 
study site and other AE reports in accordance with local procedures. 
The Sponsor will appoint all Investigators.  Among other possible duties, each Investigator will 
be responsible for reviewing the Final Clinical Study Report and testifying to the accuracy of the 
description of the study conduct.  Because the Investigators should have personal knowledge of 
the conduct of the study, they will normally be chosen from among those investigators who have 
enrolled and treated at least one subject.  However, where any Investigator has special 
knowledge of the field or of the study, the Investigator can be chosen prior to enrollment of the 
first subject.  In all cases, the Investigator must be chosen prior to locking the data base. 
10.1.2. 
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 International Council for Harmonization (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
applicable regulatory requirement(s) including the following: 
 US Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Other applicable local regulations. 
In addition, the Investigator will inform the Sponsor in writing within 24 hours of any urgent 
safety measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator becomes 
aware of. 
10.1.3. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 


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IRBs, and regulatory authorities of such information, and when needed, will amend the protocol 
and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IRB.  The Investigator will 
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. 
10.1.4. 
Informed Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The ICF and any revision(s) should be approved 
by the IRB prior to being provided to potential subjects. 
The subject’s written informed consent 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 institutional policy, and a copy of the signed ICF should 
be provided to the subject.  The date and time (if applicable) that informed consent was given 
must be recorded in the eCRF. 
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 their participation.  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. 
A separate special consent for inherited genetic analysis will be obtained from subjects in 
accordance with health authorities in their particular region/country. 
Suggested model text for the ICF for the study and any applicable subparts (PK, PD, etc) is 
provided in the Sponsor’s ICF template for the Investigator to prepare the documents to be used 
at his or her study site.  Updates to applicable forms will be communicated via letter from the 
Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act. 
10.1.5. 
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. 


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The Investigator must ensure that the subject’s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor, subjects should be identified by a unique subject 
identification (SID) as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor (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 institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
independent 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. 
10.1.6. 
Data Integrity and Quality Assurance 
10.1.6.1. Monitoring and Inspections 
The Sponsor monitor and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (eg, eCRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH 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 
site.  The monitor is responsible for inspecting the eCRFs and ensuring completeness of the 
study essential documents.  The monitor should have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs.  Detailed information is 
provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, 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 site 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. 
10.1.6.2. Data Collection 
An eCRF must be completed for each subject.  Screen failure information will be collected at the 
clinical site in a log.  All data collected during the study will be recorded in the individual, 


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subject-specific eCRF.  Instructions will be provided for the completion of the eCRF and any 
corrections made will be automatically documented via an “audit trail.” 
The eCRF should be kept current to enable the study monitor to review the subject’s status 
throughout the course of the study.  Upon completion of the subject’s eCRF, it will be reviewed 
and signed off by the Investigator via the electronic data capture (EDC) system’s electronic 
signature.  This signature will indicate that the Investigator inspected or reviewed the data in the 
subject-specific eCRF, the data queries, and the site notifications and agrees with the eCRF 
content. 
10.1.6.3. Data Management 
Each subject will be identified in the database by a unique SID. 
To ensure the quality of clinical data across all subjects and study sites, a contract research 
organization (CRO) Clinical and Data Management review will be performed on subject data 
according to specifications developed by the Sponsor.  Data will be vetted both electronically by 
programmed data rules within the application and manually.  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. 
All AEs will be coded using MedDRA.  SAEs in the clinical database will be reconciled with the 
safety database. 
10.1.6.4. 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 obtain informed consent and make 
entries and/or corrections on eCRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date and outcome of the screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential SID code list.  This confidential list of names of all 
subjects allocated to study numbers on enrolling in the study allows the Investigator to reveal the 
identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Electronic CRF entries may be considered source data if the eCRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, the study 
eCRF may be used as source documents. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB 


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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 site (site specific Trial Master 
File).  Source documents include all recordings and observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the 
clinical study.  These records will be retained in a secure file for the period required by local 
laws or regulations or study site policy.  Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to provide further instruction. 
10.1.6.5. Record Keeping 
The Investigators and study staff are responsible for maintaining a comprehensive and 
centralized filing system (site specific Trial Master File) of all study-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting source 
documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the independent IRB and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All essential documentation will be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have lapsed since the 
formal discontinuation of clinical development of the investigational drug.  These documents 
should be retained for a longer period, however, if required by the applicable laws or regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator/Institution as to when these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice.  
No study document should be destroyed without prior written agreement between 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 in writing of the new responsible 
person and/or the new location. 
10.1.7. 
Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical study 
agreement with CRO.  This agreement will include the financial information agreed upon by the 
parties. 


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10.1.8. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.9. 
Publication and Public Disclosure Policy 
10.1.10. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by the 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRBs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. 
The Sponsor must be notified in writing of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, missed study visits) within 24 hours and in accordance 
with the clinical study agreement between the parties. 
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 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB of deviations from the protocol in 
accordance with local procedures. 
10.1.11. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 


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The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further study intervention development 
10.1.12. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product.  Individuals who identify a potential 
product complaint situation should immediately report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative form the Sponsor. 
For product complaints, refer to the Pharmacy Manual for instructions and details. 
10.2. 
Appendix 2: Central and/or Local Laboratory 
The clinical laboratory tests listed in Table 10.1 are to be performed in this study. 
Table 10.1: 
Clinical Laboratory Tests 
Test 
Analytes 
Blood Chemistry 
albumin 
albumin globulin (A/G) ratio 
alanine aminotransferase (ALT) 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
bicarbonate/CO2 
bilirubin (total) 
bilirubin (direct) 
blood urea nitrogen (BUN)/urea 
calcium (Ca) 
chloride (Cl) 
creatinine 
cholesterol (total) 
 
creatine phosphokinase 
gamma-glutamyl transaminase (GGT) 
glucose ([non-fasting/fasting]) 
lactate dehydrogenase 
lipase 
lipoprotein, high density (HDL) 
lipoprotein, low density (LDH) 
magnesium (Mg) 
phosphorus 
potassium (K) 
protein (total) 
sodium (Na) 
triglycerides 
uric acid 
Troponin 
high sensitivity troponin-I 
troponin-T 
 


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Test 
Analytes 
Hematology 
hemoglobin 
hematocrit 
platelet count 
red blood cell (RBC) count 
white blood cell (WBC) count 
mean corpuscular hemoglobin 
mean corpuscular hemoglobin 
concentration 
mean corpuscular volume 
differential WBC count: 
basophils  
eosinophils 
lymphocytes 
monocytes 
neutrophils 
Coagulation 
prothrombin time (PT)/international normalized ratio (INR) 
Urinalysis 
(abbreviated) 
bilirubin 
glucose 
ketone bodies 
occult blood 
pH 
protein 
urobilinogen 
sediments: 
casts  
RBC 
WBC 
10.3. 
Appendix 3: Reference Standards 
10.3.1. 
Cockcroft-Gault Equation 
The estimated CrCl (mL/min) will be calculated using the Cockcroft-Gault equation4 based on 
[actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds):  
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) =  
Female: 
CrCl (mL/min) = 
× 0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) =  
Female: 
 
10.3.2. 
CYP3A4 Inhibitors and Inducers  
Table 10.2 lists the generic names of strong, moderate, and weak CYP3A4 inhibitors.  
[140 - age (in y)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in y)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in y)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 
[140 - age (in y)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 


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Table 10.2: 
CYP3A4 Inhibitors 
Inhibitor Type 
Generic Drug Name 
Allowance 
Strong 
boceprevir 
cobicistat  
danoprevir and ritonavir 
elvitegravir and ritonavir 
grapefruit juice 
indinavir and ritonavir 
itraconazole 
ketoconazole, lopinavir, and ritonavir 
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir) 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
tipranavir and ritonavir 
telithromycin 
troleandomycin 
voriconazole 
Use is prohibited 
Moderate 
aprepitant 
ciprofloxacin 
conivaptan 
crizotinib 
cyclosporine diltiazem 
dronedarone  
erythromycin 
fluconazole 
fluvoxamine imatinib 
tofisopam 
verapamil 
Use is prohibited 
Weak 
chlorzoxazone 
cilostazol 
cimetidine 
clotrimazolefosaprepitant istradefylline 
ivacaftor 
lomitapide 
ranitidine 
ranolazine 
ticagrelor 
Use is prohibited 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table3-2 
 


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Table 10.3 lists the generic names of strong, moderate, and weak CYP3A4 inducers.  
Table 10.3: 
CYP3A4 Inducers 
Inducer Type 
Generic Drug Name 
Allowance 
Strong 
apalutamide 
carbamazepine 
enzalutamide 
mitotane 
phenytoin 
rifampin 
St. John’s wort 
Use is prohibited 
Moderate 
bosentan 
efavirenz 
etravirine 
phenobarbital 
primidone 
Use is prohibited 
Weak 
armodafinil 
modafinil 
rufinamide 
Use is prohibited 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table3-3  
10.4. 
Appendix 4: General Information - Adverse Events 
10.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  
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. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically relevant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 


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 New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
Events NOT Meeting the AE Definition 
 Any clinically relevant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
10.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 


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 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
 Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These events should usually be 
considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
10.4.3. 
Grade Assessment 
The severity of AEs will be graded using the latest NCI-CTCAE (version 5.0).  For each episode, 
the highest severity grade attained should be reported. 
The NCI-CTCAE guidelines do not allow certain grades for certain AEs.  For example, pain can 
be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 
or 5 (ie, can only be life-threatening or fatal).  In addition, alopecia can only be Grade 1 or 2.  
The NCI-CTCAE guidelines should be followed closely. 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe AE 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
10.4.4. 
Difference between Severity and Seriousness 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as "serious," which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 


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10.4.5. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug based on 
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 subject’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 sequence from study drug administration or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications). 
10.4.6. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Unknown: Subject is lost to follow-up 
 Not applicable 
10.4.7. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or OTC medication was required to treat the AE. 
10.4.8. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no sequelae observed. 
 Recovered/Resolved with Sequelae 
 The subject fully recovered from the AE but with sequelae. 
 Recovering/Resolving 


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 The AE is improving but not recovered 
 Not Recovered/Not Resolved 
 The AE continues without improving. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE 
 Unknown 
 
 


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10.5. 
Appendix 5: Pharmacokinetic Blood Samples Collection, Processing, 
Storage, and Shipment 
Quizartinib PK blood samples for quizartinib and AC886 will be processed as described below.  
Additionally, to determine protein binding, separate 12-mL blood samples will be collected at 
the specified time points.  
Processing Instructions 
1 
PK blood samples will be collected into 4 mL Vacutainer tube containing K2-EDTA.  The 
tube will be filled completely.  The time and date of collection for each sample will be 
recorded.  
2 
Immediately after collection, the 4 mL K2-EDTA tube will be gently invert 8-10 times.  
NOTE: BLOOD SAMPLES SHOULD BE KEPT AT ROOM TEMPERATURE 
UNTIL PLACED IN CENTRIFUGE  
3 
Blood samples will be centrifuged for 10 minutes at approximately 1500-2000G at ROOM 
TEMPERATURE. 
Note: Samples should be centrifuged within 30 minutes of draw.  There should be 
approximately 2 mL of plasma for each blood sample.  If plasma and blood cells have not 
completely separated or the red blood cells suspend in the plasma, re-centrifuge the 
specimen for an additional 5 minutes to achieve complete separation. 
4 
The resulting plasma samples will be carefully aliquoted into two 3.6 mL red cryovials.  
- One disposable pipette should be used for each time point 
- DO NOT pour off plasma 
- Aliquoting should be performed immediately after completion of centrifugation 
- Be sure the plasma supernatant is separated carefully from the red cells without 
contamination 
5 
Cap the two 3.6 mL red cryovials and immediately (within 30 minutes) freeze at -20 
degrees Celsius or colder in an UPRIGHT position. 
6 
Samples will remain frozen until assayed. 
 
Protein Binding Sample Processing Instructions 
1 
Protein binding blood samples will be collected into two 6mL K2-EDTA tubes. The 
tubes will be filled completely.  
The time and date of collection for each sample will be recorded. 
2 
Immediately after collection, the 6 mL K2-EDTA tubes will be gently invert 8-10 
times. 
NOTE: BLOOD SAMPLES SHOULD BE KEPT AT ROOM TEMPERATURE 
UNTIL PLACED IN CENTRIFUGE 
3 
Blood samples will be centrifuged for 10 minutes at approximately 1500-2000G at 
ROOM TEMPERATURE. 


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Note: Samples should be centrifuged within 30 minutes of draw. There should be 
approximately 3 mL of plasma for each blood sample. If plasma and blood cells have 
not completely separated or the red blood cells suspend in the plasma, re-centrifuge 
the specimen for an additional 5 minutes to achieve complete separation. 
4 
The resulting plasma samples will be carefully aliquoted into two 5 mL blue 
cryovials. 
- One disposable pipette should be used for each time point 
- DO NOT pour off plasma 
- Aliquoting should be performed immediately after completion of centrifugation 
- Be sure the plasma supernatant is separated carefully from the red cells without 
contamination 
5 
Cap the two 5 mL blue cryovials and immediately (within 30 minutes) freeze 
at -20 degrees Celsius or colder in an UPRIGHT position. 
6 
Samples will remain frozen until assayed. 
 
A. Labeling of aliquot tubes 
Labels will contain at least the following information: 
a) Study number 
b) SID 
c) Period or dosing phase; sampling time (relative to dosing) 
B. Shipment 
Prior to each study sample shipment, a shipment notification email including a minimum of the 
following information should be provided to the Bioanalytical Principal Investigator and Sample 
Management: 
a) Electronic sample manifest containing all samples in the shipment 
b) Name of courier or transport company 
c) Shipment date and time (if available) 
d) Expected delivery date and time (if available) 
e) Number of samples included in the shipment 
f) Shipment tracking or airway bill number 
g) Email address(es) for shipment receipt acknowledgments 
The bioanalytical laboratory for PK plasma samples will be: 
 
Inotiv 
2701 Kent Avenue 
PPD




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10.6. 
Appendix 6: Pharmacogenomic Blood Samples Collection, 
Processing, Storage, and Shipment 
As part of this study, a genotyping blood sample (1 × 3 mL) will be taken from each subject on 
Study Day 1.  This sample will be stored for possible future PGx and/or PGx analysis.  At 
Screening, all potential subjects should be presented with the standard ICF, which will include 
details of these procedures. 
In the future, the stored sample may be used for genetic and PGx tests related to study drug 
exposure or response and to explore disease pathophysiology if warranted.  Specific candidate 
genes and the entire genome may be examined.  This may provide information on how 
individuals react to the study medication and may facilitate improvements in the understanding 
of differences among individuals with respect to the way the study medication is metabolized.  It 
may also help in the development of new drugs or improvement of existing drugs.  The results of 
the genetic analysis will not be provided to subjects or the Investigator, nor can the results of this 
analysis be requested at a later date.  A subject may not request withdrawal of the PGx blood 
sample after it has been obtained.  Any information obtained from the PGx research will be the 
property of the Sponsor.  The PGx samples will be stored frozen for up to 15 years, at which 
time they will be destroyed.  During this time, the DNA sample will not be immortalized or sold 
to anyone.   
PGx blood samples will be processed as described below. 
Processing Instructions 
1 
PGx blood samples are collected as whole blood in a 3 mL Becton-Dickinson (BD) 
Vacutainer lavender top K2-EDTA tube with Hemogard closure.  
2 
Do not centrifuge 
3 
Transfer whole blood to a 3 mL cryovial that is suitable for longterm storage of whole 
blood at ultra-low temperatures for storage and shipment. 
4 
Freeze immediately. 
5 
Store samples at -80°C or at -20 °C (only in non-cycling freezer) if a -80°C freezer is not 
available.   
A. Labeling of storage tubes 
Labels should be secured to each storage tube.  
Sample label should include:  
a) Designated set number 
b) Subject number 


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c) Study number 
d) Protocol number, if applicable 
e) Barcode, if applicable 
f) Time points 
g) Aliquot number 
B. Shipment 
PGx blood samples will be shipped on dry ice. 
Please copy 
 on shipment notification from the central laboratory to provide 
necessary documents to Fisher Clinical Services in advance of each shipment.   
 
Clinical Sample Management 
Daiichi Sankyo, Inc. 
211 Mt. Airy Road 
Basking Ridge, NJ 07920 
Phone: 
 
Mobile: 
 
 
The bioanalytical laboratory for PGx blood samples will be: 
Thermo Fisher Scientific  
14665 Rothgeb Drive  
Rockville, MD 20850  
The shipping address for PGx blood samples will be: 
 
Client Services, Bioservices  
Thermo Fisher Scientific  
14665 Rothgeb Drive  
Rockville, MD 20850  
Phone: 
 
Mobile: 
  
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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10.7. 
Appendix 7: Allowable Time Windows for Pharmacokinetic Blood 
Samples, Safety Laboratory Collection, and Vital Sign and 
Electrocardiogram Assessments 
Table 10.4: 
Acceptable Time Windows 
Allowable Time Windows (Safety laboratory, PK, Vital Signs, ECGs) 
Procedures  
Allowable Time Window 
Predose 
Postdose 
Safety laboratory 
collection 
± 120 minutes 
≤24 hour ± 1 hour 
 
>1 day ± 1 day 
ECGs  
No more than 90 minutes before 
dose; inclusive of at least 5 minutes 
of quiet rest in the supine position 
Within 20 minutes of nominal time 
point inclusive of supine rest time. 
Approximately 2 minutes between 
triplicate ECGs with 1 additional 
minute allowed between each of the 
triplicate ECGs 
Approximately 2 minutes between 
triplicate ECGs with 1 additional 
minute allowed between each of the 
triplicate ECGs 
Vital signs 
No more than 90 minutes before 
dose; inclusive of at least 5 minutes 
of supine rest 
Within 10 minutes of nominal time 
point, inclusive of supine rest time. 
PK sample collection  
- 60 minutes 
±2 minutes (1 hour postdose) 
 
±10 minutes (2 and 4 hours 
postdose) 
±15 minutes (6, 8, 12 and 24 hours 
postdose) 
±30 minutes (48 through 96 hours 
postdose) 
±60 minutes (144 through 
504 hours postdose) 
ECG = electrocardiogram; PK = pharmacokinetics. 
Note: ECG will be performed prior to PK. 


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10.8. 
Appendix 8: Classification of Hepatic Impairment by the National 
Cancer Institute Organ Dysfunction Working Group and 
Child-Pugh Scoring 
 
 
TBil 
ALT or AST 
Criteria for AESI reporting for hepatic 
Combination AT/TBil 
 
Healthy 
subject 
 
<ULN 
<ULN 
ALT and /or AST ≥3 × ULN and an elevated 
TBil >2 × ULN 
Moderate 
HI 
 
>1.5 to 3 × 
ULN* 
Any* 
Worsening of baseline values; with worsened 
values being ALT and /or AST ≥3 × baseline 
values and an increase of TBil from baseline, 
with increased TBil values being at least 
>2 × ULN. 
*NCI-ODWG criteria for moderate HI 
AESI = adverse event of special interest; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
HI = hepatic impairment; TBil = total bilirubin ULN = upper limit of normal 
 
 
Child-Pugh Scoring System 
 
ASSESSMENT 
DEGREE OF ABNORMALITY 
SCORE 
Encephalopathya 
None 
1 or 2 
3 or 4 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
1 
2 
3 
Serum Bilirubin (mg/dL) 
<2.0 
2.0 – 3.0 
>3.0 
1 
2 
3 
Serum Albumin (g/dL) 
>3.5 
2.8 – 3.5 
<2.8 
1 
2 
3 
Prothrombin Time (seconds > 
control) 
0 – 4.0 
4.0 – 6.0 
>6.0 
1 
2 
3 
a  
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram. 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves. 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves. 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity 
 
 


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Assessment of Severity Based on Child-Pugh Scores 
 
TOTAL SCORE 
GROUP 
SEVERITY 
5-6 
A 
Mild 
7 - 9 
B 
Moderate  
10 -15 
C 
Severe 
 


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11. 
REFERENCES 
1. Krens SD, Lassche G, Jansman FGA, Desar IME, Lankheet NAG, Burger DM, van 
Herpen CML, van Erp NP. Dose recommendations for anticancer drugs in patients with 
renal or hepatic impairment. Lancet Oncol. 2019 Apr; 20(4):e200-e207. doi: 
10.1016/S1470-2045(19)30145-7. Review. PubMed PMID: 30942181. 
2. FDA guidance 2003. https://www.fda.gov/media/71311/download 
3. AC220 Investigator’s Brochure. Most current version. 
4. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16:31-41. 


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12. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
%AUCextr 
percent extrapolated AUC  
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum concentration 
COVID-19 
coronavirus disease 2019 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
ET 
early termination  
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HAV 
hepatitis A virus 
HBsAg 
hepatitis b virus surface antigen 
HCV 
hepatitis c virus 
HI 
hepatic impairment 
HIV 
human immunodeficiency virus 


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Abbreviation 
Definition 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Council of Medical Journal Editors 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPR 
metabolite-to-parent ratio 
NCI-CTCAE 
National Cancer Institute-common terminology criteria for adverse events 
NCI-ODWG 
National Cancer Institute-organ dysfunction working group 
OTC 
over-the-counter 
oz 
ounces 
PD 
pharmacodynamic(s) 
PGx 
pharmacogenomic(s) 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SID 
subject identification 
SoE 
schedule of events 
TBil 
total bilirubin 
TdP 
Torsades de Pointes 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum plasma concentration 
t1/2 
half life 
ULN 
upper limit of normal 
US 
United States