Clinical trial NCT04459598
Conditions: Healthy Subjects Drug-drug Interaction Pharmacokinetics Quizartinib
Keywords: Healthy Subjects Drug-drug Interaction Pharmacokinetics Quizartinib CYP3A Inducer
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2020-08-19; Completion date: 2020-10-14
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This drug-drug interaction (DDI) study has been designed to investigate the effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of quizartinib and its major circulating active metabolite AC886.

Detailed description:
In vitro, quizartinib is metabolized primarily by CYP3A. Therefore, co-administration of quizartinib with CYP3A inducers may decrease quizartinib exposure. This study will assess the effect of a moderate CYP3A inducer efavirenz on the single dose (60 mg) quizartinib pharmacokinetics in healthy participants.

Arms: arm 1: Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz. arm 2: Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Interventions: intervention 1: Efavirenz intervention 2: Quizartinib
Intervention descriptions: intervention 1: Single oral dose, 600-mg tablet intervention 2: Single oral dose, 60 mg (2 x 30 mg) tablets

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
An Open-label, Randomized, Parallel-group, Drug 
Interaction Study to Evaluate the Effect of a CYP3A 
Moderate Inducer Efavirenz on the Pharmacokinetics 
of Quizartinib in Healthy Subjects 
 
Effect of a Moderate CYP3A Inducer Efavirenz on Quizartinib 
Pharmacokinetics 
 
 
PROTOCOL NUMBER: AC220-A-U106 
 
IND NUMBER: 074552 
 
 
VERSION 1.0, 04 Aug 2020 
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 
04 Aug 2020 
 




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TABLE OF CONTENTS 
DOCUMENT HISTORY .................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
List of Tables ...................................................................................................................................7 
List of Figures ..................................................................................................................................8 
1. 
PROTOCOL SUMMARY ................................................................................................9 
1.1. 
Protocol Synopsis ..............................................................................................................9 
1.2. 
Study Schema ..................................................................................................................12 
1.3. 
Schedule of Events ..........................................................................................................13 
2. 
INTRODUCTION ...........................................................................................................17 
2.1. 
Background ......................................................................................................................17 
2.2. 
Study Rationale ...............................................................................................................17 
2.3. 
Benefit and Risk Assessment ..........................................................................................18 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ....................................19 
3.1. 
Primary Objective/Endpoint ............................................................................................19 
3.2. 
Secondary Objective /Endpoint .......................................................................................19 
3.3. 
Rationale for Selection of Primary and Key Secondary Endpoints ................................19 
4. 
STUDY DESIGN ............................................................................................................20 
4.1. 
Overall Design .................................................................................................................20 
4.2. 
Rationale for Study Design .............................................................................................21 
4.3. 
Justification for Dose .......................................................................................................22 
5. 
STUDY POPULATION ..................................................................................................23 
5.1. 
Inclusion Criteria .............................................................................................................23 
5.2. 
Exclusion Criteria ............................................................................................................24 
5.3. 
Contraception Requirements ...........................................................................................26 
5.4. 
Screening Failures, Rescreening, and Subject Replacement ...........................................27 
6. 
STUDY TREATMENT(S) ..............................................................................................28 
6.1. 
Study Drug(s) Description ...............................................................................................28 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) ..........................28 
6.3. 
Measure to Minimize Bias: Randomization and Blinding ..............................................29 
6.4. 
Treatment Compliance ....................................................................................................29 


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6.5. 
Guidelines for Dose Modification ...................................................................................29 
6.6. 
Prior and Concomitant Medications ................................................................................30 
6.7. 
Prohibited Therapies/Products .........................................................................................30 
6.8. 
Permitted Therapies/Products ..........................................................................................30 
7. 
WITHDRAWAL/DISCONTINUATION FROM THE STUDY ....................................31 
7.1. 
Subject Withdrawal/Discontinuation from the Study ......................................................31 
7.2. 
Withdrawal Procedures ...................................................................................................31 
7.3. 
Lost to Follow-up ............................................................................................................31 
8. 
STUDY PROCEDURES .................................................................................................32 
8.1. 
Eligibility Assessment .....................................................................................................32 
8.2. 
Informed Consent ............................................................................................................32 
8.3. 
General Medical History and Baseline Conditions .........................................................32 
8.4. 
Demographics ..................................................................................................................32 
8.5. 
Pharmacokinetic/Pharmacodynamic Assessments ..........................................................32 
8.6. 
Safety Assessments .........................................................................................................33 
8.7. 
Pharmacogenomic (Inherited Genetic) Analysis .............................................................38 
9. 
STATISTICAL CONSIDERATIONS ............................................................................39 
9.1. 
Statistical Hypothesis ......................................................................................................39 
9.2. 
Sample Size Determination .............................................................................................39 
9.3. 
Exposure and Compliance ...............................................................................................39 
9.4. 
Population for Analysis Sets ...........................................................................................39 
9.5. 
Statistical Analysis ..........................................................................................................39 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ......................................................................................................43 
10.1. 
Appendix 1 Regulatory and Ethical Considerations .......................................................43 
10.2. 
Appendix 2: Central and/or Local Laboratory ................................................................49 
10.3. 
Appendix 3: Reference Standards ...................................................................................50 
10.4. 
Appendix 4: General Information - Adverse Events .......................................................54 
10.5. 
Appendix 5: Pharmacokinetic Blood Samples Collection, Processing, Storage, 
and Shipment ...................................................................................................................58 
10.6. 
Appendix 6: Pharmacogenomic Blood Samples Collection, Processing, Storage, 
and Shipment ...................................................................................................................60 
10.7. 
Appendix 7: Allowable Time Windows for Pharmacokinetic Blood Samples, 
and Vital Sign and Electrocardiogram Assessments .......................................................62 


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11. 
REFERENCES ................................................................................................................63 
12. 
LIST OF ABBREVIATIONS .........................................................................................64 
 


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LIST OF TABLES 
Table 1.1: Treatment Group A .....................................................................................................13 
Table 1.2: Treatment Group B .....................................................................................................15 
Table 6.1: Study Drug Dosing Information .................................................................................28 
Table 10.1: Clinical Laboratory Tests ...........................................................................................49 
Table 10.2 CYP3A4 Inhibitors .....................................................................................................51 
Table 10.3 CYP3A4 Inducers .......................................................................................................53 
Table 10.4: Acceptable Time Windows .........................................................................................62 
 


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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................12 
 
 








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1.2. 
Study Schema 
Figure 1.1: 
Study Level Flow Diagram 
 
PK = pharmacokinetic 


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1.3. 
Schedule of Events 
Table 1.1: 
Treatment Group A  
Study Period 
Screeninga Check-in 
Treatment Period 
EOS/ETb 
Study Day 
Day -21  
to Day -1 
Day -1 
Days 1 - 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Days 20 - 35 
Day 36 
PK Samples Postdose (hours) 
 
 
 
Predose 
<24 
24 
48 
72 
96 
144 - 432 
504 
Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications 
<-------------------------------------------------------------------------continuous--------------------------------------------------------------> 
Complete Physical 
Examinationsc 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Body Weight and BMId 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drugs of Abuse and 
Alcohol Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Virology 
(HBsAg/HIV/HAV/HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(WOCBP)e 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
FSHf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistryg 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
 
X 
Coagulation (PT, INR) 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECGsh 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
Vital Signs (BP, pulse, 
respiratory rate, oral 
temperature)i 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
Efavirenz Administrationj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Quizartinib Administrationk 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK Blood Samplesl 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGx Sample 
 
 
 
X 
 
 
 
 
 
 
 
 
 


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Study Period 
Screeninga Check-in 
Treatment Period 
EOS/ETb 
Study Day 
Day -21  
to Day -1 
Day -1 
Days 1 - 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Days 20 - 35 
Day 36 
PK Samples Postdose (hours) 
 
 
 
Predose 
<24 
24 
48 
72 
96 
144 - 432 
504 
Procedures 
AE Monitoring 
X 
X 
<---------------------------------------continuous--------------------------------------------------------------------> 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
<----------------------------------------------------continuous-------------------------------------------------------------------> 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE = adverse event; BMI = body mass index; ECG = electrocardiogram; EOS = end-of-study; 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; 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 EOS. 
c 
A full physical examination that includes an evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems will be performed at Screening, and on Day -1, Day 14, and EOS.  
d 
BMI at Screening only 
e 
Female subjects (WOCBP only) 
f 
Naturally postmenopausal female subjects only 
g 
Blood samples for hematology and serum chemistry will be collected after a 10-hour fast at Screening, and on Day -1, Day 7, predose (quizartinib) on 
Day 15, and on Day 19, Day 27, and EOS. 
h 
Triplicate ECG (approximately 2 minutes apart) and after at least 5 minutes of quiet rest in the supine position. When a blood collection is scheduled 
concomitantly with an ECG, the ECG should be taken at least 5 minutes prior to the blood collection and at predose, 2, 4, and 8 hours after quizartinib 
administration.  
i 
Vital signs will be taken after at least a 5-minute supine rest; vital signs should be taken at all ECG timepoints. 
j 
Efavirenz will be dosed as 600 mg once daily from Day 1 through Day 35. Efavirenz will be taken before bedtime on an empty stomach (no food for at least 
2 hours before and after dosing). 
k 
A single dose of 60-mg quizartinib (2 × 30 mg) will be administered following an overnight fast of 10 h on Day 15. 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 hours 
postdose.  
l 
Day 15 through 36 (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. 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. 
 
 


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Table 1.2: 
Treatment Group B 
Study Periods 
Screeninga Check-in 
Treatment Period 
EOS/ETb 
Study Day 
Day -21  
to Day -1 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Days 6 - 21 
Day 22 
PK Sampling Postdose (hours) 
 
 
Pre-dose 
<24 
24 
48 
72 
96 
144 - 432 
504 
Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications <------------------------------------------------------------------continuous-------------------------------------------------------------------> 
Complete Physical 
Examinationsc 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Body Weight and BMId 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Drugs of Abuse and 
Alcohol Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Virology 
(HBsAg/HIV/HAV/HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(WOCBP)e 
X 
X 
 
 
 
 
 
 
 
 
 
 
FSHf 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistryg 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
Coagulation (PT, INR) 
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECGsh 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
Vital Signs (BP, pulse, 
respiratory rate, oral 
temperature)i 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
Quizartinib Administrationj 
 
 
X 
 
 
 
 
 
 
 
 
 
PK Blood Samplesk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGx Sample 
 
 
X 
 
 
 
 
 
 
 
 
 
AE Monitoring 
X 
X 
<-------------------------------------------continuous-----------------------------------------------------------> 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 


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Study Periods 
Screeninga Check-in 
Treatment Period 
EOS/ETb 
Study Day 
Day -21  
to Day -1 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Days 6 - 21 
Day 22 
PK Sampling Postdose (hours) 
 
 
Pre-dose 
<24 
24 
48 
72 
96 
144 - 432 
504 
Procedures 
Confinement 
 
<---------------------------------------------------------continuous------------------------------------------------------------> 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
X 
AE = adverse event; BMI = body mass index; ECG = electrocardiogram; EOS = end-of-study; 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; 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 EOS  
c 
A full physical examination that includes an evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems will be performed at Screening, and on Day -1, Day 14, and EOS.  
d 
BMI at Screening only 
e 
Female subjects (WOCBP only) 
f 
Naturally postmenopausal female subjects only 
g 
Blood samples for hematology and serum chemistry will be collected after a 10-hour fast at Screening, and on Day -1, Day 5, Day 13, and EOS. 
h 
Triplicate ECG (approximately 2 minutes apart) and after at least 5 minutes of quiet rest in the supine position. When a blood collection is scheduled 
concomitantly with an ECG, the ECG should be taken at least 5 minutes prior to the blood collection and at predose, 2, 4, and 8 hours after quizartinib 
administration.  
i 
Vital signs will be taken after at least a 5-minute supine rest; vital signs should be taken at all ECG timepoints. 
j 
A single dose of 60-mg quizartinib (2 × 30 mg) will be administered following an overnight fast of 10 h on Day 1. 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 hours 
postdose.  
k 
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. 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. 
 
 


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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 active metabolite, 
(AC886) occurs at a median of approximately 4 h (range: 2 h to 8 h) and 5 h (range: 4 h to 120 h) 
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 CYP enzymes showed that 
both quizartinib and AC886 are primarily metabolized by CYP3A and have estimated effective 
half- lives (t1/2) of 73 h and 119 h, respectively. Additionally, AC886 is also formed from 
quizartinib by CYP3A. 
In a previously conducted dedicated hepatic impairment (HI) study 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. Therefore, this study aims to evaluate the effect of a moderate CYP3A inducer, 
efavirenz, on quizartinib PK.   
This is an open-label, randomized, parallel-group, drug interaction study to evaluate the effect of 
a moderate CYP3A moderate inducer efavirenz on the PK of quizartinib in healthy male and 
female subjects. 
2.2. 
Study Rationale 
In vitro reaction phenotyping using human liver microsomes and recombinant human CYP 
enzymes showed that quizartinib is metabolized primarily by CYP3A. Concomitant 
administration of strong (ketoconazole) and moderate (fluconazole) CYP3A inhibitors increased 
quizartinib area under the plasma concentration-time curve (AUC) by 94% and 20%, 
respectively. In a previously conducted drug-drug (DDI) interaction study, coadministration of 
multiple doses of the strong CYP3A inducer rifampin with a single quizartinib dose of 60 mg 


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resulted in approximately 70% decrease in quizartinib AUC. However, due to bioanalytical 
issues, the results were not quantitatively conclusive. Therefore, the current DDI study has been 
designed to investigate the effect of a moderate CYP3A inducer efavirenz on the PK of 
quizartinib and its major circulating metabolite AC886. 
2.3. 
Benefit and Risk Assessment 
This is a Phase 1 study being conducted in healthy subjects, and, as such, no benefit to the 
subjects from either efavirenz or 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 a single dose of quizartinib. 
Toxicities observed for quizartinib in healthy subjects (n = 307) following single dose 
administration were headache (21 [6.8%] subjects), upper respiratory tract infection (8 [2.6%] 
subjects), and diarrhea (6 [2.0%] subjects). QT prolongation and combined elevations of 
ALT >3 × ULN and TBil >2 × ULN are the two adverse events of special interest following 
quizartinib dosing. In approximately 3% of patients with AML in a Phase 3 clinical study with 
repeated daily dosing, the QTc interval was prolonged to 500 milliseconds 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 QTcF 
interval greater than 500 ms, and 12.4% had an increase from baseline QTcF greater than 60 ms 
based on central review of 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 
AEs observed with quizartinib treatment could be managed by monitoring, dose 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 current version of the prescribing information for the risks associated 
with efavirenz and the most recent version of the Investigator’s Brochure 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 the effect of efavirenz on the plasma PK of quizartinib and AC886 in 
healthy subjects. 
The primary endpoints of this study are: 
• Plasma PK parameters (Cmax AUClast, AUCinf) for quizartinib and its active 
metabolite (AC886); additionally Tmax, t1/2, metabolite-to-parent ratio (MPR) 
AUClast, and MPR AUCinf for quizartinib and its active metabolite (AC886), and 
CL/F and Vz/F for quizartinib only. 
3.2. 
Secondary Objective /Endpoint 
The secondary objective of this study is: 
• To assess the safety and tolerability of quizartinib in healthy subjects when 
administered alone and when co-administered with efavirenz. 
The secondary endpoints of this study are: 
• Treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms 
(ECG), clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis), 
and physical examinations.  
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 
determination of DDI studies.  


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label, randomized, parallel-group, Phase 1 study in 32 healthy subjects to assess 
the effect of the moderate CYP3A inducer efavirenz on the PK of quizartinib and its major 
circulating metabolite AC886. After a 21-day Screening Period, eligible subjects will be enrolled 
and will check-in to the clinical research unit (CRU) on Day -1. Subjects will be randomized in a 
1:1 ratio on Day 1 to either Treatment Group A to receive a 600-mg efavirenz tablet once daily 
for 35 days and a single dose of 60-mg quizartinib (2 × 30 mg) on Day 15 or to Treatment 
Group B to receive a single dose of quizartinib on Day 1. Collection of blood samples for PK 
determinations and safety assessments will be collected predose and at selected timepoints 
postdose in both treatment groups.  
4.1.1. 
Design Overview 
In this study, 32 eligible subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups; 
16 subjects in Treatment Group A and 16 subjects in Treatment Group B. 
At the beginning of the Screening Period, subjects will sign the informed consent form (ICF). 
During the 21-day Screening Period, subjects’ eligibility will be confirmed. They will undergo 
medical history evaluation, physical examination, vital sign determination, ECGs, and clinical 
laboratory assessments. 
During the Treatment Period, subjects will receive study drug in the assigned treatment group. 
Treatment Group A: On Day 1, subjects will begin a regimen of 600-mg efavirenz tablet once 
daily and will continue the regimen through Day 35. Efavirenz will be taken before bedtime on 
an empty stomach (no food for at least 2 hours before and after dosing). On Day 15, subjects will 
receive a single dose of 60-mg quizartinib (2 × 30 mg), which will be administered with 240 mL 
of water after at least 10 hours of fasting. Quizartinib will be taken in the morning. Subjects will 
continue to fast for 4 hours postdose. Pharmacokinetic blood samples will be collected from Day 
15 through Day 36. Subjects will be discharged from the CRU and from the study at end-of-
study (EOS) on Day 36 after study procedures are completed. Safety assessments will be 
conducted from Day 1 through Day 36. 
Treatment Group B: On Day 1, subjects will be given a single dose of 60-mg quizartinib 
(2 × 30 mg) with 240 mL of water after 10 hours of fasting. Quizartinib will be taken in the 
morning followed by an additional 4 hours of fasting. Pharmacokinetic blood samples will be 
collected from Day 1 through Day 22. Subjects will be discharged from the CRU and from the 
study at EOS on Day 22 after study procedures are completed. Safety assessments will be 
conducted from Day 1 through Day 22. 
After study treatment is discontinued, subjects will be followed for 30 days for safety.  
The subject population is described in Section 5. A flow diagram of study activities is presented 
in Figure 1.1. 


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4.1.2. 
End-of-Study 
At the defined EOS in both treatment groups (Day 36 for Treatment Group A and Day 22 for 
Treatment Group B), 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. 
Dose Regimen 
In Treatment Group A, subjects will be on a 35-day regimen of 600-mg efavirenz tablet once 
daily and will receive a single dose of 60-mg quizartinib (2 × 30 mg) on Day 15 of the efavirenz 
regimen. Efavirenz will be taken before bedtime on an empty stomach (no food for at least 
2 hours before and after dosing). Quizartinib is to be administered with 240 mL of water in the 
morning after at least 10 hours of fasting. Subjects will continue to fast for 4 hours postdose. 
In Treatment Group B, subjects will receive a single dose of 60-mg quizartinib (2 × 30 mg) on 
Day 1. Quizartinib is to be administered with 240 mL of water in the morning after at least 
10 hours of fasting. Subjects will continue to fast for 4 hours postdose. 
4.1.4. 
Duration 
The duration of the study for each subject in Treatment Group A is up to 58 days and for each 
subject in Treatment Group B is up to 44 days. 
The anticipated total duration of the study is approximately 2 months. 
The study overall will be completed when the last datapoints for primary and secondary 
endpoints are collected and recorded. 
4.2. 
Rationale for Study Design 
In vitro reaction phenotyping using human liver microsomes and recombinant human CYP 
enzymes showed that quizartinib is metabolized primarily by CYP3A. Therefore, 
coadministration of quizartinib with CYP3A inducers may decrease its exposures. This DDI 
study has been designed to investigate the effect of a moderate CYP3A inducer efavirenz on the 
PK of quizartinib and AC886. 
To assess the effect of efavirenz on quizartinib PK, the subjects in Treatment Group A will be 
given efavirenz at a clinical dose of 600 mg once daily for 35 days. On Day 15 of the efavirenz 
regimen, a single dose of 60-mg quizartinib (2 × 30 mg) will administered. Pharmacokinetic 
blood sampling will begin predose on Day 15 and will continue through Day 36 of the study. 
Efavirenz will be continued throughout the PK sample collection period of quizartinib. The 
lead-in 14 days of dosing with efavirenz 600 mg daily is necessary to maximize the induction of 
CYP3A while limiting the length of the study based on a survey of reported efavirenz DDI 
studies in the University of Washington DDI database and model-based analysis of efavirenz 
CYP3A induction time course.1 A reference group, Treatment Group B, will be given a single 
dose of 60-mg quizartinib (2 × 30 mg) with PK sampling taken predose and through 22 days 
postdose. Safety assessments will be conducted on the basis of the known effects of efavirenz 
and quizartinib. 


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4.3. 
Justification for Dose 
The quizartinib dose of 60 mg is the approved dose for relapse/refractory acute myeloid 
leukemia (AML) in Japan and the maximum maintenance therapeutic dose currently being 
investigated for AML first-line therapy in the QuANTUM-First study NCT02668653.2 
Therefore, the quizartinib dose of 60 mg was selected to assess the effect of efavirenz on 
quizartinib PK.  
The efavirenz dose of 600 mg is the dose approved for use in the United States for the treatment 
of HIV, as well as in the published literature on DDI studies involving efavirenz. 


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5. 
STUDY POPULATION 
This Phase 1 study is being conducted in 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 55 years of age (inclusive), with a body mass index (BMI) of 
18 kg/m2 to 32 kg/m2 (inclusive) at Screening.  
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. 
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. 
5. In females, 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.  
6. In males, agreement to avoid sperm donation for 6 months after the dose of quizartinib. 
7. Has vital signs (measured after subject has been supine for at least 5 minutes) at Screening 
within the following ranges: heart rate: 50–100 bpm; systolic blood pressure (BP): 
90-145 mmHg; diastolic BP: 50-95 mmHg. Out-of-range vital signs may be repeated once. 
8. Has liver function test results (ALT, AST, and total bilirubin) equal to or below the upper 
limit of normal. Hemoglobin levels must be at least11.5 g/dL for female subjects and at least 
12.5 g/dL for male subjects.  
9. 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. 
10. Must be willing to refrain from consuming blood oranges, grapefruit, grapefruit juice, 
pomegranates, pomegranate juice, Seville (bitter) oranges, and star fruit from 10 days before 
Day -1 until EOS. 
11. Is willing and able to remain in the study unit for the entire duration of the confinement 
period. 


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5.2. 
Exclusion Criteria 
Subjects meeting any exclusion criteria for this study will be excluded from this study.  
Medical History 
1. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, 
or psychiatric disease or any other condition, including laboratory abnormality, that in the 
opinion of the Investigator, would jeopardize the safety of the subject, obtaining informed 
consent, compliance to the study procedures, or the validity of the study results. 
2. History of a clinically significant illness, in the opinion of the Investigator, within 4 weeks 
prior to administration of quizartinib. 
3. Bradycardia of less than 50 beats per minute. 
4. History, or presence in the average of triplicate ECGs at Screening and Day -1, of any of the 
following cardiac conduction abnormalities:  
• QTcF > 450 milliseconds (ms) 
• 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) 
5. Diagnosis of or suspicion of long QT syndrome (including family history of long QT 
syndrome).  
6. Presence or history of clinically severe adverse reaction to any drug. 
7. 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). 
8. 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. 
9. 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. 
10. Loss of more than 450 mL blood during the 3 months before the trial (e.g., as a blood donor). 
Medication Use and Lifestyle 
11. Use of drugs with a risk of QT interval prolongation or TdP within 14 days of Day -1 (or 
5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days). 
12. Use of any drugs or substances known to be inhibitors or inducers of CYP3A4/5 within 
28 days from the first dose or 5 half-lives, if known, of the drugs or substances, whichever is 
greater, prior to quizartinib administration and during the study. 


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13. Concomitant use of medications known to affect the elimination of serum creatinine (e.g., 
trimethoprim or cimetidine) and inhibitors of renal tubular secretion (e.g., probenecid) within 
14 days or 5 half-lives, if known, of the drugs, whichever is greater, prior to quizartinib 
administration.  
14. Use 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. 
Note: 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. 
15. Start of any new medication or any changes to a current dosage within 14 days prior to 
quizartinib administration excluding approved oral contraceptives. 
16. Consumption of alcohol- and caffeine-containing beverages within 72 hours prior to 
Check-in and during confinement. 
17. Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of 
study medication. 
18. Engagement in strenuous exercise from 48 hours before the first dose of study medication 
until the EOS. 
Laboratory Tests 
19. Is a female with a positive pregnancy test result or is lactating. 
20. Laboratory results (serum chemistry, hematology, and urinalysis) outside the normal range, if 
considered clinically significant by the Investigator. Estimated glomerular filtration rate 
(eGFR) <90 mL/min (calculated using the Cockcroft-Gault Equation equation) at Screening. 
21. Has a positive serology for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), 
hepatitis A virus (HAV) immunoglobulin M (IgM), or human immunodeficiency virus 
(HIV). 
22. Has a positive urine screen for drugs of abuse or for ethanol at Screening or at Check-in on 
Day -1. 
23. Current enrollment in or have not yet completed receiving an investigational device or 
product (at least 30 days or 5 elimination half-lives, whichever is longer) within 30 days of 
the dose of quizartinib. 


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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 IUD 
○ Female or male condom 
○ Contraceptive sponge 
○ Diaphragm 
○ Cervical cap 
Any of the following hormonal contraceptives may be started only after Day 36 for Treatment 
Group A and Day 22 for Treatment Group B. 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 
• Male condom with spermicide 
• Use of any of the following with spermicide by female partner: 
○ Non-hormonal intrauterine device (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 


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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. 


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6. 
STUDY TREATMENT(S) 
6.1. 
Study Drug(s) Description 
Table 6.1: 
Study Drug Dosing Information 
Study Drug Name 
Quizartinib 
Efavirenz 
Dosage Formulation 
30-mg tablet a 
600-mg tablet 
Dosage Level(s) 
60 mg 
600 mg 
Route of Administration 
Oral 
Oral 
Dosing 
Single dose 
Once daily 
Duration 
Once 
Once daily for 35 doses 
Packaging 
High-density polyethylene (HDPE) 
bottles of 30 tablets 
Packaging will clearly display the 
name of product, storage condition, 
and other required information as 
applicable in accordance with local 
regulations 
Bottles of 30 tablets 
Labeling 
Bottles will be labeled as required 
per local and regulatory 
requirements 
Bottles will be labeled as 
required per local and 
regulatory requirements 
a 
Each 30-mg tablet contains 30-mg quizartinib dihydrochloride (26.5 mg free base). 
Quizartinib will be supplied by the Sponsor, and efavirenz will be supplied by Worldwide 
Clinical Trials (Worldwide). 
6.2. 
Preparation, Handling, Storage, and Accountability for Study 
Drug(s) 
6.2.1. 
Preparation, Handling, and Disposal 
Procedures for proper handling and disposal should be followed in compliance with the standard 
operating procedures (SOP) of the site. 
6.2.2. 
Administration 
Quizartinib tablets, 30 mg: Quizartinib will be taken as a single dose of 60 mg (2 × 30 mg) (in 
Treatment Group A and Treatment Group B) to be administered after at least 10 hours of fasting 
with approximately 240 mL of water. Quizartinib will be taken in the morning. Subjects will 
continue to fast for 4 hours postdose. 
Efavirenz tablet, 600 mg: Efavirenz will be taken once daily for 35 days (in Treatment Group A 
only). Efavirenz will be taken before bedtime on an empty stomach (no food for at least 2 hours 
before and after dosing). 


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6.2.3. 
Storage 
Quizartinib tablets must be stored according to the directions on the label (store up to 25°C 
[77°F]; do not freeze).  
Efavirenz tablets should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F). 
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.  
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment. 
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (i.e., Receipt of Shipment Form, dispensation/return record, and certificate of 
destruction/return receipt). 
6.3. 
Measure to Minimize Bias: Randomization and Blinding 
6.3.1. 
Method of Treatment Allocation 
Subjects will be randomized in a 1:1 ratio to either Treatment Group A or Treatment Group B. 
6.3.2. 
Blinding 
This is an open-label study. 
6.4. 
Treatment Compliance 
Each dose of the study drugs will be administered by qualified study site staff. Hand and mouth 
checks will be performed after each dose. 
6.5. 
Guidelines for Dose Modification 
Not applicable. 


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6.6. 
Prior and Concomitant Medications 
All therapies received by subjects within 28 days prior to enrollment will be recorded as prior 
therapies.  
All therapies used from the time the subject signs the ICF for study participation to the EOS will 
be recorded as concomitant therapies. Concomitant therapies include all prescription, 
over-the-counter, and herbal remedies. 
All prior and concomitant therapies will be recorded on the electronic case report form (eCRF). 
6.7. 
Prohibited Therapies/Products 
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 -1 and throughout the study: 
• Hormonal contraceptives and all other prescription medications, including CYP3A 
inhibitors and inducers (see Section 10.3.2) or unless included in Section 6.8 
• Hormonal replacement therapy (can be started at any time after EOS) 
• 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 -1. However, all dietary supplements are prohibited starting on 
Day -1 and throughout the study.  
• Blood oranges, grapefruit, grapefruit juice, pomegranates, pomegranate juice, Seville 
(bitter) oranges, and star fruit are prohibited for 10 days before Day -1 and throughout the 
study. 
• 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 -1 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: 
• Adverse event 
• Withdrawal by subject 
• Investigator decision 
• Pregnancy 
• Protocol deviation 
• Study termination by Sponsor 
• Other 
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 SoEs (Table 1.1 and Table 1.2) 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 they leave the CRU prior to the EOS and are 
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 the SoEs, Table 1.1 and Table 1.2, for the procedures conducted at specific timepoints 
during Screening, the Treatment Period, and EOS. 
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 (e.g., physical examination, 
electrocardiogram [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. 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. 
8.4. 
Demographics 
Review the subject’s demographics against the eligibility criteria. 
8.5. 
Pharmacokinetic/Pharmacodynamic Assessments 
8.5.1. 
Pharmacokinetic (PK) Assessment(s) 
Pharmacokinetic blood samples will be collected, processed, and shipped as detailed in the SoEs 
and in the Laboratory Processing Specifications 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 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 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 SAE. 
• Subjects whose medical history and clinical manifestations, signs, and possible 
exposure are consistent with COVID-19 but for whom no polymerase chain reaction 
(PCR) 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, i.e., 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, 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 laboratory 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 (e.g., concomitant medication, AE). 
• Findings from diagnostic imaging (including computed tomography [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. Adverse events 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 


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detecting, 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. 
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 (i.e., 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 
For all randomized subjects, all AEs occurring after the subject signs the ICF and that are 
followed to resolution up to 30 days after the EOS, whether observed by the Investigator or 
reported by the subject, will be recorded as detailed in Section 10.1.6.2. 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 and recorded. 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 should 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). 
• QTcF prolongation, TdP, and other ventricular arrhythmias (as defined in 
Section 8.6.2.7) 
Details summarizing the course of the SAE, including its evaluation, treatment, and outcome 
should be provided. 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 results if available. Source 


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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 CRO will inform the Sponsor of any suspected unexpected serious adverse reactions 
(SUSARs) occurring in study sites or other studies of efavirenz and quizartinib, as appropriate 
per institutional and/or local reporting requirements. 
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.  
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 or consultation with other health care professionals. 
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  
8.6.2.7.1. Hepatic Events 
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law criteria defined 
as an elevated (ALT and/or AST) ≥3 × ULN and an elevated total bilirubin >2 × ULN, that may 
occur at different time points during the study conduct, should always be reported to the 
Sponsor. 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 
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. 
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 Pointe, and Other Ventricular Arrhythmias 
Subjects who experience >480 msec 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 


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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 the SAVER/Overdose 
Form and 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, i.e., 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 in a 
female subject or in a male subject’s female partner that occurs while the subject is receiving or 
within 6 months of having received the dose of quizartinib. 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 
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 (i.e., 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 a female subject or a 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 randomization number, initials, and date of birth, and details regarding the female 
partner should be entered in the narrative section. 
8.6.2.10. Pregnancy Testing 
Women of childbearing potential will have a serum pregnancy test conducted at Screening and at 
Check-in 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. 


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Women who are postmenopausal will have a follicle-stimulating hormone (FSH) test conducted 
at Screening. 
8.6.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed as detailed in the SoEs 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. 
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. 
8.6.4. 
Physical Examinations 
Height, weight, and calculation of BMI and physical examinations will be performed as detailed 
in the SoEs in Section 1.3. 
A full physical examination should include an evaluation of the head, eyes, ears, nose, and throat 
and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems.  
Any abnormality in physical examination identified at baseline and any abnormalities that are 
changes from baseline should be recorded. New or worsened clinically relevant abnormalities 
should be recorded as AEs. 
8.6.5. 
Vital Signs 
Vital signs will be performed as detailed in the SoEs 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. Vital signs will be measured after the subject has rested in a 
supine position for at least 5 minutes, prior to laboratory draws, and at the same timepoints as 
ECGs. 
8.6.6. 
Electrocardiograms 
Electrocardiograms will be performed as detailed in the SoEs in Section 1.3. 
Allowable time windows for ECGs are provided in Section 10.7. 
Triplicate 12-lead ECGs (approximately 2 minutes apart) will be performed at least 5 minutes 
before any blood collection and will be recorded for every subject. The ECG will be measured 
after the subject has rested in a supine position for at least 5 minutes. At any visit during which a 
subject exhibits a heart rate ≤50 bpm or other clinical indications for ECG, the ECG will be 
repeated. Abnormal, clinically relevant findings occurring post-baseline will be reported as AEs. 
Whether or not the measurement is performed, the date the ECG is performed, heart rate, PR 
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8.7. 
Pharmacogenomic (Inherited Genetic) Analysis  
A single blood sample for pharmacogenomic analysis will be collected predose from each 
randomized subject for Treatment Group A and for Treatment Group B. 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. 
DNA samples will be stored, as outlined in Section 8.7.2, for performing possible 
pharmacogenomic 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 longterm preservation (banking) of blood and/or DNA specimens extracted 
from subjects’ blood samples for each subject that consented are described in the 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. 
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 pharmacogenetic analysis 
in case new genomic or genetic information is obtained in the future regarding the response (PK 
or pharmacodynamic) to quizartinib, or in case serious adverse drug reactions are noted in a 
clinical study and pharmacogenetic 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 pharmacogenetic analysis cannot be known at this time, 
any results obtained from research involving pharmacogenetic 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 
The number of subjects planned for this study was not based on statistical power considerations. 
With the assumed intersubject coefficient of variation (CV) of 35%, a target sample size of 30 
(15/treatment) was calculated to provide 90% confidence that the estimated ratios (with and 
without efavirenz) of quizartinib geometric mean Cmax and AUC values would be within 20% 
of true population values. Therefore, 32 subjects (16 subjects in Treatment Group A and 
16 subjects in Treatment Group B) will be enrolled in the study to target at least 30 subjects to 
complete the PK evaluation. 
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 conducted on the PK Population defined as all evaluable subjects who 
are dosed and who have sufficient data to calculate at least 1 of the planned PK parameters. 
9.4.2. 
Safety Population 
The safety analysis will be conducted on the Safety Population defined as all subjects who 
receive at least 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. 
Efficacy Analysis 
No efficacy measures or analysis are planned for this study. 
9.5.2. 
Safety Analysis 
9.5.2.1. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as new AEs that occur after the first 
dose of study drug. AEs collected 30 days after the last dose of study drug will not be considered 


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TEAEs unless they are treatment-related. AEs will be coded using the MedDRA dictionary. An 
AE will be assigned to the study day in which it started, 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. 
Treatment-emergent adverse events will be further summarized by CTCAE grade and 
relationship to study drug or AEs that were present prior to the first dose but which worsened in 
severity after the first dose of 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. 
9.5.2.2. 
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 EOS. 
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. 
9.5.2.3. 
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 (e.g., QTc ≤450 ms, >450 to ≤480 ms, >480 ms to ≤ 500 ms, and >500 ms). 
A listing of ECG data will be generated. 
9.5.2.4. 
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. 


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9.5.2.5. 
Other 
Listings of all other safety endpoints (e.g., physical examination findings) will be generated. 
9.5.3. 
Pharmacokinetics Analysis 
Pharmacokinetic analysis and statistical analysis of PK endpoints will be conducted in 
accordance with the protocol, SAP, and the Daiichi Sankyo Non-Compartmental Analysis 
Guidelines. 
9.5.3.1. 
Pharmacokinetic Parameters 
Pharmacokinetic and statistical analysis will be performed using appropriate software; e.g., 
Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P.) and/or SAS® (Version 9.4 or 
higher, SAS Institute Inc.). Pharmacokinetic analysis will be performed using a 
non-compartmental analysis (NCA) approach. 
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 of the maximum concentration 
Kel 
The observed terminal rate constant; estimated by linear regression through at 
least three data points in the terminal phase of the log concentration-time profile 
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%. 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data 
Tlast 
Time of the last quantifiable concentration 
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  
 
9.5.3.2. 
Statistical Analysis of Pharmacokinetic Endpoints 
Plasma concentrations at each nominal timepoint and the PK parameters of quizartinib and 
AC886 will be summarized by Treatment Group at each nominal timepoint using descriptive 


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statistics: n, mean, standard deviation (SD), minimum (min), median, maximum (max), and 
coefficient of variation (CV%), geometric mean, and geometric CV%, as appropriate.  
Cmax, AUClast, and AUCinf will be compared between Treatment Group A (quizartinib plus 
efavirenz; Test) and Treatment Group B (quizartinib alone; Reference). These comparisons 
between groups will be performed using an ANOVA model and based on logarithm-transformed 
Cmax, AUClast, and AUCinf. The resulting point estimates (least-squares means) differences 
between Treatment Group A and Treatment Group B, and 90% CIs for the difference will be 
exponentiated to get the ratio (Test/Reference) and corresponding 90% CI of the ratio on the 
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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 Investigator Brochure, available safety information, recruitment 
procedures (e.g., 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 a Coordinating Investigator. Among other possible duties, the 
Coordinating 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 Coordinating 
Investigator should have personal knowledge of the conduct of the study, he or she will normally 
be chosen from among those Investigators who have enrolled and treated at least one subject. 
However, where an Investigator has special knowledge of the field or of the study, the 
Coordinating Investigator can be chosen prior to enrollment of the first subject. In all cases, the 
Coordinating Investigator must be chosen prior to locking the database. 
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 (CFR) 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 of which that the Investigator 
becomes aware. 


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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, the 
IRB, 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 should 
obtain written informed consent to continue participation with the revised written information 
even if subjects were already informed of the relevant information. The Investigator or other 
responsible personnel who provided explanations and the subject should sign and date the 
revised ICF. 
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. 
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. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA). 
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 as designated by the Sponsor. Documents that are not for submission to the 
Sponsor (e.g., 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 (e.g., 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 the 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 (e.g., 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 randomized subject. Screen failure information will be 
collected at the clinical site in a log. All data collected for randomized subjects during the study 
will be recorded in the individual, subject-specific eCRF. Instructions will be provided for the 


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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 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 subject identifier. 
To ensure the quality of clinical data across all subjects and study sites, a 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. Serious adverse events 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 maintain a confidential subject identification code list. This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Electronic CRF entries may be considered source data if the eCRF is the site of the original 
recording (i.e., 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 (e.g., protocol and amendments, IRB 
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 


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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 Investigator 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, Investigator’s Brochure, 
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 
(e.g., 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 
Study termination may also be requested by (a) competent authority/ies. 
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 
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 


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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 creatinine clearance (CrCl; mL/min) will be calculated using the Cockcroft-Gault 
equation 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: 
CrCl (mL/min) = 
× 0.85 
 
 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 


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10.3.2. 
CYP3A4 Inhibitors and Inducers 
Table 10.2 lists the generic names of strong, moderate, and weak CYP3A4 inhibitors. 
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 
clarithromycin 
idelalisib 
nefazodone 
nelfinavir 
Use is prohibited 
Moderate 
aprepitant 
ciprofloxacin 
conivaptan 
crizotinib 
cyclosporine 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fluvoxamine 
imatinib 
tofisopam 
verapamil 
Use is prohibited 


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Inhibitor Type 
Generic Drug Name 
Allowance 
Weak 
chlorzoxazone 
cilostazol 
cimetidine 
clotrimazole 
fosaprepitant 
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  
 
 


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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. 
10.4.1.1. Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically relevant in the 
medical and scientific judgment of the Investigator (i.e., 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. 
• 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.  
10.4.1.2. 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 (e.g., 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 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 


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• 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. 
− This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., 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 (i.e., cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 


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or 5 (i.e., 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. 
10.4.5. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event 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 
(e.g., 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. 


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• 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 (e.g., 
disease under study, concurrent diseases, and concomitant medications). 
Determinations of causality for Treatment Group A will be categorized as follows: 
• Efavirenz when administered alone 
• Efavirenz and quizartinib when administered in combination 
Determinations of causality for Treatment Group B will be categorized as follows: 
• Quizartinib when administered alone 
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 
10.4.7. 
Other Action Taken for Event 
• None. 
− No treatment was required. 
• Medication required. 
− Prescription and/or over the counter medication was required to treat the adverse 
event. 
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 
− 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. 
Processing Instructions 
1 
Blood samples will be collected into one 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 timepoint 
- 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 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) Subject identification 
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) 


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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 pharmacogenomic 
analysis. At Screening, all potential subjects should be presented with the standard Informed 
Consent Form (ICF), which will include details of these procedures. 
In the future, the stored sample may be used for genetic and pharmacogenomic 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.   
Pharmacogenomic 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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10.7. 
Appendix 7: Allowable Time Windows for Pharmacokinetic Blood 
Samples, and Vital Sign and Electrocardiogram Assessments 
Table 10.4: 
Acceptable Time Windows 
Procedures  
(in order of collection) 
Allowable Time Window 
Predose 
Postdose 
ECG  
(predose, 2, 4, and 8 
hours postdose) 
No more than 30 minutes before dose; 
inclusive of  
at least 5 minutes  
of quiet rest in the supine position  
postdose 
with  
5 additional minutes allowed 
No more than 6 minutes after dose; 
inclusive of  
at least 5 minutes  
of quiet rest in the supine position 
postdose 
with  
1 additional minute allowed 
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 
(predose, 2, 4, and 8 
hours postdose) 
No more than 15 minutes before dose; 
inclusive of 
at least 5 minutes 
of supine rest  
with  
5 additional minutes allowed 
No more than 6 minutes after dose; 
inclusive of  
at least 5 minutes  
of supine rest 
with 
1 additional minute allowed 
PK sample collection 
(predose, 1, 2, 4, 6, 8, 
12, 24, 48, 72, 96, 144, 
216, 288, 360, 432, and 
504 hours 
post-quizartinib dose) 
+ 60 minutes 
±2 minutes 
(1 hour postdose) 
No more than 15 minutes after dose 
inclusive of  
the windows  
for ECGs and vital signs 
(2, 4, and 8 hours postdose) 
±15 minutes  
(6, 12, and 24 hours postdose) 
±30 minutes 
(48 through 96 hours postdose) 
±60 minutes 
(144 through 504 hours postdose) 
 
 


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11. 
REFERENCES 
1. Zhu M et al. Model-based approach to characterize efavirenz autoinduction and concurrent 
enzyme induction with carbamazepine. Antimicrob Agents Chemother. 2009 Jun; 53(6): 
2346–2353. 
2. Altman JK et al. Phase 1 study of quizartinib in combination with induction and 
consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am J 
Hematol. 2018 Feb; 93(2): 213–221. 
3. “Guidance for Industry: Drug Interaction Studies–Study Design, Data Analysis, Implications 
for Dosing, and Labeling Recommendations” Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) February 2012. 
4. Quizartinib (AC220) Investigator’s Brochure. Most current version. 


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12. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CDISC 
clinical data interchange standards consortium 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CrCl 
creatinine clearance 
CRF 
case report form 
CRU 
clinical research unit 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
DSI 
Daiichi-Sankyo, Inc. 
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 
GCP 
good clinical practice 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
health insurance portability and accountability act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 


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Abbreviation 
Definition 
ICMJE 
International Council of Medical Journal Editors 
IMP 
investigational medicinal product 
INN 
international non-proprietary name 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPR 
metabolite-to-parent ratio 
NCI-CTCAE 
National Cancer Institute - common terminology criteria for adverse events 
OATP 
organic anion-transporting polypeptide 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PT 
prothrombin time 
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SID 
subject identifier 
SOC 
standard of care 
SoE 
Schedule of Events 
SUSAR 
suspected unexpected serious adverse reaction 
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