Clinical trial NCT04796831
Conditions: Healthy Subjects
Keywords: Quizartinib Healthy Subjects Pharmacokinetics Oral Bioavailability Microtracer
Sponsor: Daiichi Sankyo
Start date: 2021-04-26; Completion date: 2021-06-11
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Quizartinib, a selective FLT3 inhibitor, is being developed as a treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The absolute oral bioavailability of quizartinib has not yet been studied. This study is designed to estimate quizartinib bioavailability of quizartinib following oral and intravenous (IV) administration.

Detailed description:
Quizartinib bioavailability based on the dose-adjusted exposure of quizartinib following oral and IV administration will be assessed in healthy male subjects. The primary objective of this study is to determine the absolute oral bioavailability of quizartinib. Secondary objectives will include characterizing the plasma PK of quizartinib, radiolabeled quizartinib, and the major circulating metabolite after a single oral dose and IV administration. Safety and tolerability of quizartinib will also be assessed.

Arms: arm 1: Participants who will receive a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing.
Interventions: intervention 1: Quizartinib dihydrochloride intervention 2: 14C-Quizartinib solution for infusion
Intervention descriptions: intervention 1: Single oral dose of 60 mg quizartinib (2 x 30 mg tablets) intervention 2: 50 μg solution for infusion containing NMT 22.84 kBq 14C in 5 mL; administered once as a 15-minute infusion

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
An Open Label Study to Determine the Absolute Oral 
Bioavailability of Quizartinib Using a Radiolabeled 
Microtracer in Healthy Subjects 
 
Absolute Bioavailability of Quizartinib 
 
PROTOCOL NUMBER: AC220-A-U107 (QSC203118) 
 
EUDRACT NUMBER: 2021-000198-10 
NCT NUMBER: NCT04796831 
IND NUMBER: 074552 
 
 
VERSION 2.0, 23 Mar 2021 
DAIICHI SANKYO, INC 
211 Mount Airy Road 
Basking Ridge, New Jersey 07920 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc. The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement. Do not give this document or any 
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo, Inc.  
 


Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
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DOCUMENT HISTORY 
 
Version Number 
Version Date 
1.0 
08 Feb 2021 
2.0 
23 Mar 2021 
 


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Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 4 
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 ...........................................................................................................18 
2.1. 
Background ......................................................................................................................18 
2.2. 
Study Rationale ...............................................................................................................19 
2.3. 
Benefit and Risk Assessment ..........................................................................................19 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ....................................24 
3.1. 
Primary Objective/Endpoints ..........................................................................................24 
3.2. 
Secondary Objectives/Endpoints .....................................................................................24 
3.3. 
Exploratory Objectives/Endpoints ...................................................................................24 
4. 
STUDY DESIGN ............................................................................................................26 
4.1. 
Overall Design .................................................................................................................26 
4.2. 
Rationale for Study Design .............................................................................................27 
4.3. 
Justification for Dose .......................................................................................................28 
5. 
STUDY POPULATION ..................................................................................................30 
5.1. 
Inclusion Criteria .............................................................................................................30 
5.2. 
Exclusion Criteria ............................................................................................................31 
5.3. 
Contraception Requirements ...........................................................................................34 
5.4. 
Screening Failures, Re-screening, and Subject Replacement .........................................35 
6. 
STUDY TREATMENT(S) ..............................................................................................36 
6.1. 
Study Drug(s) Description ...............................................................................................36 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) ..........................36 
6.3. 
Measure to Minimize Bias: Randomization and Blinding ..............................................38 
6.4. 
Treatment Compliance ....................................................................................................39 


Protocol AC220-A-U107 (QSC203118) 
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6.5. 
Guidelines for Dose Modification ...................................................................................39 
6.6. 
Prior and Concomitant Medications ................................................................................39 
6.7. 
Prohibited Therapies/Products .........................................................................................39 
6.8. 
Permitted Therapies/Products ..........................................................................................40 
7. 
WITHDRAWAL/DISCONTINUATION FROM THE STUDY ....................................41 
7.1. 
Subject Withdrawal/Discontinuation from the Study Drugs ...........................................41 
7.2. 
Withdrawal Procedures ...................................................................................................42 
7.3. 
Lost to Follow-up ............................................................................................................42 
8. 
STUDY PROCEDURES .................................................................................................43 
8.1. 
Eligibility Assessment .....................................................................................................43 
8.2. 
Informed Consent ............................................................................................................43 
8.3. 
General Medical History and Baseline Conditions .........................................................44 
8.4. 
Demographics ..................................................................................................................44 
8.5. 
Pharmacokinetic/Pharmacodynamic Assessments ..........................................................44 
8.6. 
Safety Assessments .........................................................................................................44 
8.7. 
Pharmacogenomic (Inherited Genetic) Analysis .............................................................50 
9. 
STATISTICAL CONSIDERATIONS ............................................................................52 
9.1. 
Statistical Hypothesis ......................................................................................................52 
9.2. 
Sample Size Determination .............................................................................................52 
9.3. 
Exposure and Compliance ...............................................................................................52 
9.4. 
Population for Analysis Sets ...........................................................................................52 
9.5. 
Statistical Analysis ..........................................................................................................52 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ......................................................................................................57 
10.1. 
Appendix 1 Regulatory and Ethical Considerations .......................................................57 
10.2. 
Appendix 2: Central and/or Local Laboratory ................................................................65 
10.3. 
Appendix 3: Reference Standards ...................................................................................66 
10.4. 
Appendix 4: General Information - Adverse Events .......................................................70 
10.5. 
Appendix 5: Pharmacokinetic Blood, Urine and Fecal Samples Collection, 
Processing, Storage, and Shipment .................................................................................74 
10.6. 
Appendix 6: Pharmacogenomic Blood Samples Collection, Processing, Storage, 
and Shipment ...................................................................................................................75 


Protocol AC220-A-U107 (QSC203118) 
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10.7. 
Appendix 7: Allowable Time Windows for Pharmacokinetic Blood, Urine and 
Fecal Samples, Clinical Laboratory Safety Samples, and Vital Sign, and 
Electrocardiogram Assessments ......................................................................................76 
11. 
REFERENCES ................................................................................................................78 
12. 
LIST OF ABBREVIATIONS .........................................................................................79 
 


Protocol AC220-A-U107 (QSC203118) 
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Proprietary and Confidential 
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LIST OF TABLES 
Table 1.1: Schedule of Events .....................................................................................................13 
Table 6.1: Study Drug Dosing Information .................................................................................36 
Table 10.1: Clinical Laboratory Tests ...........................................................................................65 
Table 10.2 CYP3A4 Inhibitors .....................................................................................................67 
Table 10.3 CYP3A4 Inducers .......................................................................................................69 
Table 10.4: Acceptable Time Windows .........................................................................................76 
 


Protocol AC220-A-U107 (QSC203118) 
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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................12 
 
 










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1.3. 
Schedule of Events 
Table 1.1: 
Schedule of Events 
Study Period 
Screening 
Pre-
Admission 
(if required) 
Residency In Clinic 
Admission 
1 
2 
3 
4 
5 
Study Day 
-21 to -2 
-2 
-1 
Time Point Relative to Oral Dosing 
(hours)a 
 
 
 
Pre-
dose 0 
1 
2 
4 4.25 4.5 4.75 5 
6 
8 
12 
24 
48 
72 
96 
Time Point Relative to Start of IV 
Infusion (hours) 
 
 
 
 
-4 
-3 
-2 
0 0.25 0.5 0.75 1 
2 
4 
8 
20 
44 
68 
92 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
Xb 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted (symptom driven) Physical 
Examinationd 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight, Height and BMIe 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antibodyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antigenf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drugs of Abuse, Cotinine 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI: body mass index, COVID-19: coronavirus disease 2019, IV: intravenous, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 
 
a All assessments will be timed and performed relative to the start of oral dosing. 
b Eligibility will be re-assessed at admission/pre-dose. 
c Update only. 
d Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the Investigator’s judgement. 
e Height to be measured and BMI to be calculated at screening only. 
f Testing for SARS-CoV-2 will be performed based on current infection rates and availability of tests. If required, testing will comprise an antibody blood test 
performed at screening, and an antigen polymerase chain reaction (PCR) test or other antigen test performed at screening, the day before admission (i.e., Day -2), 
and discharge (i.e., Day 22). The decision on COVID-19 testing and the definition of the testing time points will be agreed by the study team and documented in 
the Investigator Site File (ISF) via the Clinical Kick-Off Meeting minutes. 


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Proprietary and Confidential 
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Table 1.1 Continued: 
Schedule of Events 
Study Period 
Screening 
Pre-
Admission 
(if required) 
Residency In Clinic 
Admission 
1 
2 
3 
4 
5 
Study Day 
-21 to -2 
-2 
-1 
Time Point Relative to Oral Dosing 
(hours)a 
 
 
 
Pre-
dose 0 
1 
2 
4 4.25 4.5 4.75 5 
6 
8 
12 
24 
48 
72 
96 
Time Point Relative to Start of IV 
Infusion (hours) 
 
 
 
 
-4 
-3 
-2 
0 0.25 0.5 0.75 1 
2 
4 
8 
20 
44 
68 
92 
Virology (HBsAg/HIV/HAV/HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistryg 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Estimated creatinine clearance (CrCl)h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECGsi 
X 
 
X 
X 
 
 
X 
Xj 
 
 
 
 
 
 
 
X 
 
X 
 
Vital Signsk 
X 
 
X 
X 
 
 
X 
Xj 
 
 
 
 
 
 
 
X 
 
X 
 
IMP Administrationl 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK samples for quizartinib 
and AC886 
 
 
 
X 
 
X 
X 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
14C: carbon-14, aPTT: activated partial thromboplastin time, ECG: electrocardiogram, HAV: hepatitis A virus, HBsAg: hepatitis B surface antigen, HCV: hepatitis 
C virus, HIV: human immunodeficiency virus, IMP: investigational medicinal product, INR: international normalized ratio, IV: intravenous, PK: pharmacokinetic, 
PT: prothrombin time 
 
 
a All assessments will be timed and performed relative to the start of oral dosing. 
g Samples for serum chemistry will be collected after a 8 hour fast. 
h The estimated creatinine clearance (CrCl; mL/min) will be calculated at screening from serum creatinine using the Cockcroft-Gault equation. 
i 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 prior to the blood collection. 
j Assessment to be performed prior to the start of the IV infusion. 
k Blood pressure, heart rate, respiratory rate and oral temperature will be measured at all time points after at least a 5 minutes supine rest. 
l A single, oral dose of 60 mg quizartinib will be administered following an overnight fast of a minimum of 8 hours on Day 1 and a single, IV administration of 
50 µg 14C-quizartinib containing NMT 22.84 kBq 14C will be administered as an infusion over 15 minutes beginning at 4 hours post-oral dosing (also in the 
fasted state). This infusion will be in the opposite arm being used for PK sampling. 
m Sample to be taken prior to the start of the IV infusion. 


Protocol AC220-A-U107 (QSC203118) 
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Proprietary and Confidential 
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Table 1.1 Continued: 
Schedule of Events 
Study Period 
Screening 
Pre-
Admission 
(if required) 
Residency In Clinic 
Admission 
1 
2 
3 
4 
5 
Study Day 
-21 to -2 
-2 
-1 
Time Point Relative to Oral Dosing 
(hours)a 
 
 
 
Pre-
dose 0 
1 
2 
4 4.25 4.5 4.75 5 
6 
8 
12 
24 
48 
72 
96 
Time Point Relative to Start of IV 
Infusion (hours) 
 
 
 
 
-4 
-3 
-2 
0 0.25 0.5 0.75 1 
2 
4 
8 
20 
44 
68 
92 
Plasma PK samples for total 
radioactivity, 14C-quizartinib and 
14C-AC886 
 
 
 
 
 
 
 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood PK samples for 
quizartinib and AC886 
 
 
 
X 
 
X 
X 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Samples for total radioactivity, 
quizartinib and AC886o 
 
 
-------------------------------------------------------X------------------------------------------------------→ 
Fecal Samples for total radioactivity, 
quizartinib and AC886p 
 
 
-------------------------------------------------------X------------------------------------------------------→ 
Pharmacogenomic Blood Sample 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Monitoring 
-----------------------------------------------------------------------X----------------------------------------------------------------------→ 
Prior/Concomitant Medications 
-----------------------------------------------------------------------X----------------------------------------------------------------------→ 
Clinic Confinement 
 
 
-------------------------------------------------------X------------------------------------------------------→ 
14C: carbon-14, IV: intravenous, PK: pharmacokinetic 
 
 
a All assessments will be timed and performed relative to the start of oral dosing. 
m Sample to be taken prior to the start of the IV infusion. 
n Pre-dose sample for total radioactivity, 14C-quizartinib and 14C-AC886. Sample to be taken prior to the start of the IV infusion. 
o The pre-dose urine sample will be taken any time between admission and pre-dose. Post-dose urine samples will be taken at the following collection periods: 
0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours post-oral dose and then daily (24 hour intervals) until discharge at 504 hours post-oral dose (Day 22). 
p The pre-dose fecal sample can be collected any time between admission and pre-dose. Post-dose fecal samples will be collected at 24 hour intervals post-oral 
dosing. 


Protocol AC220-A-U107 (QSC203118) 
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Proprietary and Confidential 
Page 16 
Table 1.1 Continued: 
Schedule of Events 
Study Period 
Residency In Clinic 
Study Day 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
(ET/ 
Discharge)q 
Time Point Relative to Oral 
Dosing (hours)a 
120 
144 
168 
192 
216 
240 
264 
288 
312 
336 
360 
384 
408 
432 
456 
480 
504 
Time Point Relative to Start of 
IV Infusion (hours) 
116 
140 
164 
188 
212 
236 
260 
284 
308 
332 
356 
380 
404 
428 
452 
476 
500 
Targeted (symptom driven) 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body Weight, Height and BMIe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SARS-CoV-2 Antigenf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology, Serum Chemistryg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECGsi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signsk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Plasma PK samples for 
quizartinib and AC886 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
aPTT: activated partial thromboplastin time, BMI: body mass index, COVID-19: coronavirus disease 2019, ECG: electrocardiogram, ET: early termination, 
INR: international normalized ratio, IV: intravenous, PK: pharmacokinetic, PT: prothrombin time, SARS-CoV-2: severe acute respiratory syndrome 
coronavirus 2 
 
a All assessments will be timed and performed relative to the start of oral dosing. 
d Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the Investigator’s judgement. 
e Height to be measured and BMI to be calculated at screening only. 
f Testing for SARS-CoV-2 will be performed based on current infection rates and availability of tests. If required, testing will comprise an antibody blood test 
performed at screening, and an antigen polymerase chain reaction (PCR) test or other antigen test performed at screening, the day before admission (i.e., Day -2), 
and discharge (i.e., Day 22). The decision on COVID-19 testing and the definition of the testing time points will be agreed by the study team and documented in 
the ISF via the Clinical Kick-Off Meeting minutes. 
g Samples for serum chemistry will be collected after an 8 hour fast. 
i 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 prior to the blood collection. 
k Blood pressure, heart rate, respiratory rate and oral temperature will be measured at all time points after at least a 5 minutes supine rest. 
q Discharge from the clinical unit will follow final blood sample collections; the same procedures are to be performed at early termination/withdrawal as at 
discharge. 


Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 17 
Table 1.1 Continued: 
Schedule of Events 
Study Period 
Residency In Clinic 
Study Day 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
(ET/ 
Discharge)q 
Time Point Relative to Oral 
Dosing (hours)a 
120 
144 
168 
192 
216 
240 
264 
288 
312 
336 
360 
384 
408 
432 
456 
480 
504 
Time Point Relative to Start of 
IV Infusion (hours) 
116 
140 
164 
188 
212 
236 
260 
284 
308 
332 
356 
380 
404 
428 
452 
476 
500 
Plasma PK samples for total 
radioactivity, 14C-quizartinib 
and 14C-AC886 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Whole blood PK samples for 
quizartinib and AC886 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine Samples for total 
radioactivity, quizartinib and 
AC886o 
-----------------------------------------------------------------------X------------------------------------------------------------------------→ 
Fecal Samples for total 
radioactivity, quizartinib and 
AC886p 
-----------------------------------------------------------------------X------------------------------------------------------------------------→ 
Adverse Event Monitoring 
-----------------------------------------------------------------------X------------------------------------------------------------------------→ 
Prior/Concomitant Medications 
-----------------------------------------------------------------------X------------------------------------------------------------------------→ 
Clinic Confinement 
-----------------------------------------------------------------------X------------------------------------------------------------------------→ 
14C: carbon-14, IV: intravenous, PK: pharmacokinetic 
 
a All assessments will be timed and performed relative to the start of oral dosing. 
o The pre-dose urine sample will be taken any time between admission and pre-dose. Post-dose urine samples will be taken at the following collection periods: 
0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours post-oral dose and then daily (24 hour intervals) until discharge at 504 hours post-oral dose (Day 22). 
p The pre-dose fecal sample can be collected any time between admission and pre-dose. Post-dose fecal samples will be collected at 24 hour intervals post-oral 
dosing. 
q Discharge from the clinical unit will follow final blood sample collections; the same procedures are to be performed at early termination/withdrawal as at 
discharge. 
 


Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
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Page 18 
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 FLT3-internal tandem duplication 
(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 in healthy subjects under fasting conditions, the peak exposure of 
quizartinib and its major circulating active metabolite (AC886) occurs at a median of 
approximately 4 hours (range: 2 hours to 8 hours) and 5 hours (range: 4 hours to 120 hours) 
post-dose, 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 area 
under the curve (AUC) exposure was approximately 60% of the parent steady state exposure. In 
vitro reaction phenotyping using human liver microsomes and recombinant human cytochrome 
P450 (CYP) enzymes showed that both quizartinib and AC886 are primarily metabolized by 
CYP3A and have estimated effective half-lives (t1/2) of 73 hours and 119 hours, respectively. 
Additionally, AC886 is also formed from quizartinib by CYP3A. 
In a clinical absorption, distribution, metabolism, and elimination (ADME) study (AC220-006), 
a single oral dose of 60 mg carbon-14 (14C)-quizartinib containing approximately 100 μCi 
(3.7 MBq) 14C was administered to healthy male subjects. Approximately 76% of the radioactive 
dose was recovered in feces, and 1.6% of the dose was recovered in urine at study completion at 
14 days post-dose. Since <2% of the total dose was excreted in urine, quizartinib is eliminated 
primarily by hepatobiliary pathways. The major circulating components were the unchanged 
parent (quizartinib) and the oxidative metabolite (AC886), which represented more than 10% of 
the total radioactivity exposure in plasma.  
In a hepatic impairment (HI) study (AC220-016) in subjects with mild and moderate HI as 
defined by Child Pugh score, quizartinib overall exposure (AUC from the time of dosing 
extrapolated to infinity [AUCinf]) increased approximately 30% and 15%, 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. Use of a strong CYP3A inhibitor (ketoconazole) and a moderate CYP3A inhibitor 
(fluconazole) increased quizartinib AUC by 96% and 20%, respectively. Strong CYP3A inducer 
rifampin decreased quizartinib AUC by approximately 70%; however, due to bioanalytical issue, 
the results were not quantitatively conclusive.  
As of 28 Oct 2020, a total of 2,215 subjects had received quizartinib in 26 clinical studies: 
1673 subjects with AML, 13 subjects with solid tumors, 21 subjects with mild/moderate hepatic 


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impairment, and 508 healthy volunteers. In addition, 798 subjects have been treated in 
10 investigator-initiated studies. 
In 11 studies in healthy volunteers or subjects with HI, quizartinib was generally well tolerated 
as single doses ranging from 20 mg to 90 mg, with most adverse events (AEs) of mild severity. 
Four subjects experienced severe AEs. In Study AC220-014, there were 2 Grade 3 AEs 
experienced in 2 subjects. One treatment-emergent adverse event (TEAE) of increased alanine 
aminotransferase (ALT) resolved without treatment. The second Grade 3 AE was a serious 
adverse event (SAE) of limb abscess. The subject required hospitalization and was withdrawn 
from the study due to this event. Neither AE was considered related to study drug. In Study 
AC220-019, 1 subject experienced a Grade 3 elevation of blood creatine phosphokinase. The 
event was considered not related to study drug. In Study AC220-015, 1 subject had a Grade 3 AE 
of musculoskeletal stiffness of the neck. The AE was considered not related to any of the study 
drugs (quizartinib, ketoconazole, or rifampin) and resolved in 15 days. 
2.2. 
Study Rationale 
Quizartinib, a selective FLT3 inhibitor, is being developed as a treatment for AML and MDS. 
The absolute oral bioavailability of quizartinib has not yet been studied. Therefore, this study is 
designed to estimate quizartinib bioavailability based on the dose-adjusted exposure of 
quizartinib following oral and intravenous (IV) administration. 
Knowing the absolute bioavailability of an oral drug product is a regulatory requirement in some 
regions. In addition, understanding the bioavailability of a drug and the factors that influence 
absorption, may guide the formulation development strategy and risk assessment for drug-drug 
interactions.  
As this is a Phase 1 study assessing the absolute bioavailability, pharmacokinetic (PK) and safety 
of quizartinib, the most relevant population is healthy volunteers, as recommended by the United 
States (US) Food and Drug Administration (FDA) (1) and the European Medicines Agency 
(EMA) (2). Subjects who are non-smokers without a history of alcohol or drug abuse or regular 
co-medication are proposed to avoid interaction on drug metabolism and to avoid 
non-compliance.  
There are no human data on the effect of quizartinib on fertility. Based on findings in animals, 
female and male fertility may be impaired with treatment with quizartinib. Fetotoxicity and 
teratogenicity in rats has also been observed. Therefore, female subjects will not be enrolled in 
this study. In addition, subjects with pregnant or lactating partners will be excluded from the 
study. 
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 quizartinib is intended or expected.  
2.3.1. 
Risks Associated with the Oral Quizartinib Dose 
In the clinical program, as of 28 Oct 2020, a total of 2,215 subjects had received quizartinib in 
26 clinical studies: 1673 subjects with AML, 13 subjects with solid tumors, 21 subjects with 
mild/moderate hepatic impairment, and 508 healthy volunteers. In addition, 798 subjects have 


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been treated in 10 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. Toxicities 
observed for quizartinib in healthy subjects following single dose administration included those 
in the system organ classes of Gastrointestinal Disorders (e.g., constipation, diarrhea, and 
gastroesophageal reflux disease), Infections and Infestations, Musculoskeletal and Connective 
Tissue Disorders, and Nervous System Disorders (e.g., headache and dysgeusia). Most AEs were 
mild in severity. 
Quizartinib is associated with QT prolongation in a dose dependent manner. The incidence of 
QT prolongation (corrected QT interval using Fridericia's formula ([QTcF]) >500 ms was 3% to 
5% among subjects with AML receiving 30 mg to 60 mg quizartinib daily, 15% to 17% among 
subjects receiving 90 mg to 135 mg quizartinib daily, and 35% among 17 subjects receiving 
200 mg quizartinib daily. The concentration-corrected QT interval (C QTc) analysis 
demonstrated that quizartinib, not AC886, is the primary contributor to QT prolongation. 
Corrected QT interval (QTc) interval prolongation is a risk factor for the development of cardiac 
arrythmias, including Torsade de Pointes (TdP). 
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 electrocardiogram (ECG) data; there were no cases of 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. 
Other adverse reactions to quizartinib, observed in patients with AML include cytopenias 
(leukopenia, anemia, thrombocytopenia, neutropenia, febrile neutropenia, pancytopenia, 
lymphopenia) and associated disorders of infection and bleeding, gastrointestinal (GI) disorders 
(abdominal pain, nausea, vomiting, diarrhea, dyspepsia, dysgeusia, stomatitis, and decreased 
appetite), general disorders (pyrexia, fatigue, asthenia, malaise, weight decreased, and edema 
peripheral), skin rash, petechiae, acute febrile neutrophilic dermatosis, electrolyte abnormalities 
(hypokalemia and hypomagnesemia), liver function test abnormalities (ALT increased, increased 
aspartate aminotransferase [AST], increased blood alkaline phosphatase, increased blood 
bilirubin). In addition, embryo-fetal toxicity and impaired fertility are considered potential risks 
for quizartinib. 
The nonclinical safety program for quizartinib, which includes its active metabolite AC886, has 
been conducted using both in vitro and in vivo systems (mice, rats, rabbits, guinea pigs, dogs, 
and monkeys) in pharmacological, PK, and toxicological studies (including single-dose toxicity, 
repeated-dose toxicity, genotoxicity, reproductive and developmental toxicity, juvenile toxicity, 
antigenicity, and photo safety studies). Notably, quizartinib was not phototoxic in the in vitro 
neutral red uptake (NRU) phototoxicity test with Balb/c 3T3 mouse fibroblasts and therefore 
restrictions relating to phototoxicity will not be required in this study. However, studies in rats 
and monkeys suggested quizartinib may cause male and female fertility impairment, fetotoxicity 


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and teratogenicity; therefore, females and male subjects with pregnant or lactating partners will 
not be enrolled in this study. 
Please refer to the most recent version of the Investigator’s Brochure (IB) for the risks associated 
with quizartinib (3). 
2.3.2. 
Risks Associated with the Intravenous 14C-Quizartinib Microdose 
The IV (infused) microdose to be administered is 1200-fold lower than the oral dose and the 
exposure to quizartinib originating from the infused microdose is therefore considered negligible 
and no AEs are expected to occur. 
Although subjects in this study are exposed to ionizing radiation, the amount is negligible. The 
radiation dose from a dose of not more than (NMT) 22.84 kBq will result in an effective dose of 
12.79 microsievert (µSv), falling into International Commission on Radiological Protection 
(ICRP) Category I. The United Kingdom (UK) average radiation exposure for an individual is 
about 2.7 mSv (= 2,700 µSv; data obtained from Public Health England [PHE] Ionising 
Radiation Exposure of the UK Population: 2010 Review) per year and as such the radiation risk 
to subjects in this study is considered negligible. 
2.3.3. 
COVID-19 Related Risks and Risk Mitigation Measures 
The following risks and risk mitigating measures apply to the time in which the study is 
conducted during the coronavirus disease 2019 (COVID-19) pandemic. 
Against the background of the COVID-19 pandemic, the potential risk of a subject developing 
COVID-19 has been considered in terms of the risk-benefit evaluation.  
As described in the IB, AEs associated with immune systems disorders have been reported 
following administration of quizartinib (3). Therefore, the study includes several features to 
mitigate any potential risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection: 
• The study entry criteria that exclude subjects with current infections or exaggerated risk of 
infection (see Section 5.2). 
• Subjects must be otherwise healthy and aged ≤55 years; persons in this demographic are 
intrinsically less vulnerable to symptomatic infection by SARS-CoV-2 and its clinical 
sequelae (4, 5, 6). 
• The clinical research unit (CRU) has implemented standard operating procedures (SOPs) for 
risk mitigation as outlined in Section 2.3.3.1. 
• The protocol excludes subjects with any evidence of current SARS-CoV-2 infection (see 
Sections 5.2 and 7.1) in order to prevent subjects who are shedding the virus from entering 
into the CRU, and from being dosed with quizartinib. 
• Subjects will be resident in the clinic until 21 days post-oral dose. This allows sufficient time 
for the compound to be cleared from the body before subjects leave the CRU and are exposed 
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2.3.3.1. 
General COVID-19 Related Risk Mitigation Measures 
General risk mitigation against COVID-19 will be implemented in accordance with the contract 
research organization (CRO)’s (i.e., Quotient Sciences [hereafter referred to as Quotient]s’) 
monitoring and prevention control measures. 
COVID-19 testing will be performed based on current infection rates and availability of tests. 
Testing will comprise an antibody blood test performed at screening, and an antigen polymerase 
chain reaction (PCR) test or other antigen test performed at screening, the day before admission, 
and discharge or the day before discharge. Testing time points may be changed and additional 
time points may be added throughout the study as required. The decision on the processes for 
COVID-19 testing and the definition of the testing time points will be agreed by the study team 
and documented in the Investigator Site File (ISF) via the Clinical Kick Off Meeting minutes. 
The risk mitigation measures, where applicable, will be amended based on emerging government 
guidance.   
2.3.3.2. 
COVID-19 Vaccine-Related Risk  
Following the granting of the conditional (temporary) marketing authorization of the COVID-19 
vaccines by the UK Medicines and Healthcare products Regulatory Agency (MHRA), e.g., 
Pfizer and BioNTech’s vaccine, Oxford-AstraZeneca vaccine, these vaccines may be permitted 
according to the Investigator’s discretion and per local guidance. In this study, a washout period 
of 72 hours prior to investigational medicinal product (IMP; i.e., quizartinib – an RTK inhibitor) 
administration has been recommended to minimize the possibility of any drug-drug interactions 
between the IMP and the vaccine.   
Based on the mechanism of action of the IMP (quizartinib), as a RTK inhibitor, there is no 
perceived impact on the safety of the study subjects or on the study objectives for subjects who 
may receive these vaccines (either first or second doses). It is also unlikely that administration of 
the IMP would interfere with COVID-19 vaccination response; however, no specific preclinical 
or clinical investigations have been conducted at this point with quizartinib. 
The emerging safety and efficacy data from millions of vaccinated people, many of whom are 
elderly and with underlying health conditions and taking multiple concomitant medications, 
indicate that these vaccines have a good safety and efficacy record. In the broader interests of 
society and to limit the extent of the global pandemic, it is important that subjects should receive 
a vaccine when it is offered to them. 
2.3.4. 
General Risks  
Collecting a blood sample from a vein may cause pain, swelling, bruising, light headedness, 
fainting, and very rarely, clot formation, nerve damage and/or infection at the site of the needle 
stick. Usually these changes are mild, transient and resolve within a few days to weeks without 
any intervention. 
During cannulation, more than one attempt may be needed to insert the cannula in a vein of a 
subject and it is possible that bruising and/or inflammation may be experienced at the site of 
cannulation.  


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Electrocardiogram (ECG) stickers on the subjects' chests and limbs may cause some local 
irritation and may be uncomfortable to remove but subjects will be closely monitored to ensure 
any local irritation does not persist. 


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3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS 
3.1. 
Primary Objective/Endpoints 
The primary objective of this study is: 
• To determine the absolute oral bioavailability of quizartinib. 
The primary endpoints of this study are: 
• Absolute bioavailability assessment based on the PK parameters AUClast and AUCinf for 
quizartinib following IV and oral administrations. 
3.2. 
Secondary Objectives/Endpoints 
The secondary objectives of this study are: 
• To characterize the plasma PK of quizartinib and 14C-quizartinib following a single, oral dose 
of 60 mg quizartinib and a single, IV administration of 50 µg 14C-quizartinib. 
• To characterize the plasma PK of the major circulating metabolite, AC886, and 14C-AC886 
following a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 µg 
14C-quizartinib. 
• To characterize the plasma PK of total radioactivity following a single, IV administration of 
50 µg 14C-quizartinib. 
• To assess the safety and tolerability of a single dose of quizartinib in healthy subjects. 
The secondary endpoints of this study are: 
• Plasma PK parameters for quizartinib following the single oral dose: Cmax, Tmax, t1/2, 
AUClast, AUCinf, CL/F and Vz/F. 
• Plasma PK parameters for 14C-quizartinib following the single IV administration: Cmax, 
Tmax, t1/2, AUClast, AUCinf, CL and Vz. 
• Plasma PK parameters for both AC886 and 14C-AC886: Cmax, Tmax, t1/2, AUClast, 
AUCinf, metabolite to parent ratio (MPR) based on AUC. 
• Plasma PK parameters for total radioactivity: AUClast, AUCinf, t1/2. 
• AEs, vital signs, 12-lead ECGs, clinical laboratory tests (serum chemistry, hematology, 
coagulation, urinalysis), physical examinations. 
3.3. 
Exploratory Objectives/Endpoints 
The exploratory objective of this study is: 
• To assess the fecal and urinary recovery of total radioactivity following a single, IV 
administration of 50 µg 14C-quizartinib. 
• To assess the fecal and urinary recovery of quizartinib and AC886 following a single, oral 
dose of 60 mg quizartinib. 


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• To characterize the whole blood PK of quizartinib and AC886 following a single, oral dose 
of 60 mg quizartinib. 
• To determine whole blood-to-plasma concentration ratios (Kbp) of quizartinib and AC886 
following a single, oral dose of 60 mg quizartinib. 
The exploratory endpoints of this study are: 
• Amount of total radioactivity excreted in urine and feces (Ae). 
• Amount of total radioactivity excreted in feces and urine as a fraction of the administered IV 
dose (Fe). 
• Amount of quizartinib and AC886 excreted in urine and feces (Ae). 
• Amount of quizartinib and AC886 excreted in feces and urine as a fraction of the 
administered oral dose (Fe). 
• Whole blood PK parameters for quizartinib: Cmax, Tmax, AUClast, AUCinf, t1/2, CL/F and 
Vz/F. 
• Whole blood PK parameters for AC886: Cmax, Tmax, AUClast, AUCinf and t1/2. 
• Kbp based on whole blood and plasma concentrations of quizartinib and AC886. 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a single center, open-label, Phase 1 study to determine the absolute oral bioavailability in 
healthy male subjects. It is planned to enroll 8 subjects to ensure data in a minimum of 6 subjects 
who are evaluable for PK. An evaluable subject is defined as a subject who has received both the 
oral and IV microtracer IMPs (i.e., a single, oral dose of 60 mg quizartinib dihydrochloride 
tablets [2 x 30 mg tablets] and an IV administration of 50 µg 14C-quizartinib solution for infusion 
10 µg/mL containing NMT 22.84 kBq 14C in 5 mL [NMT 4.6 kBq/mL] over 15 minutes at 
4 hours post-oral dose) and has sufficient samples for evaluation of plasma PK parameters. 
4.1.1. 
Design Overview 
The subject population is described in Section 5. A flow diagram of study activities is presented 
in Figure 1.1. 
Subjects will undergo preliminary screening procedures for the study up to 21 days before IMP 
administration (Day -21 to Day-2). Subjects will be admitted in the morning on the day prior to 
IMP administration (i.e., Day -1), at which time admission procedures will be undertaken to 
confirm eligibility. Subjects will be dosed in the morning of Day 1 following an overnight fast of 
a minimum of 8 hours for the oral dose (a minimum of 12 hours for the IV dose).  
To assess tolerability of the IV administration, dosing will be staggered. The first subject will 
receive the oral dose at least 30 minutes prior to the second subject. All subsequent dosing will 
be staggered by at least 15 minutes. The IV administration will start at 4 hours post-oral dosing 
for all subjects, and will therefore be staggered as well. 
Blood, urine and fecal samples will be collected pre-dose and at regular intervals until Day 22 
for PK analysis. Safety and tolerability will be monitored by clinical and laboratory assessments 
at intervals throughout the study. 
4.1.2. 
End-of-Study 
Subjects will remain resident in the clinical unit until 504 hours post-oral dose (i.e., Day 22) 
when they will be discharged from the clinical unit. Safety discharge assessments will be 
performed at the time of actual discharge from the clinical unit; discharge PK samples will be 
collected at 504 hours post-oral dose or at time of actual discharge if earlier (i.e., due to early 
termination [ET]/withdrawal; see Sections 7.1 and 7.2). 
If a subject reports any AEs between discharge and 7 days post-discharge (i.e., between Day 22 
and Day 29) that represent a cause for concern, they will be required to attend the clinical unit 
for a follow-up assessment as per the discretion of the Investigator or delegate. This will be an 
unscheduled visit. 
The end of the study is defined as the last visit of the last subject (e.g., follow-up assessment). 
Any changes to this definition will be notified as a substantial amendment. 
The MHRA and Ethics Committee (EC) should be notified in writing of the conclusion of the 
study within 90 days of the end of the study, or within 15 days if the study is terminated early, 
clearly explaining the reasons for the termination. 


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The Administration of Radioactive Substances Advisory Committee (ARSAC) and the ARSAC 
Practitioner will also be notified of the end of trial or ET of the trial in writing within an 
appropriate timeframe. 
4.1.3. 
Dose Regimen 
Each subject will receive a single, oral dose of 60 mg quizartinib dihydrochloride tablets 
(administered as 2 x 30 mg tablets) and a single, IV administration of 50 µg 14C-quizartinib 
solution for infusion containing NMT 22.84 kBq 14C in 5 mL (NMT 4.6 kBq/mL), administered 
as an infusion over 15 minutes beginning at 4 hours post-oral dosing. Both IMPs will be 
administered in the fasted state. 
4.1.4. 
Duration 
Subjects will receive a single oral dose of 60 mg quizartinib dihydrochloride tablets and a single 
IV dose of 50 µg 14C-quizartinib solution for infusion at 4 hours post-oral dosing on a single 
occasion during this study. The estimated time from screening until discharge from the study is 
approximately 6 weeks. 
4.2. 
Rationale for Study Design 
The IV microtracer technique is an established methodology for measuring the IV and oral 
kinetics of a drug in the same individuals in a single dosing period. The technique involves 
concurrent administration of a microdose of the drug containing microtracer amounts of 14C with 
a single oral therapeutic dose, which avoids the concerns of dose dependent kinetics when 
extrapolating IV PK from a microdose, as the systemic exposure is at therapeutic concentrations. 
Moreover, for this reason the IV administration is timed to coincide with the expected Tmax of 
the oral dose. This technique also enables a lower dose to be administered intravenously 
compared to the oral dose (which is advantageous from a safety perspective), and allows for dose 
adjustment for the purposes of absolute bioavailability calculation. This design enables 
measurement of 14C labelled drug in plasma following IV dosing via sensitive accelerator mass 
spectrometry (AMS) techniques, and measurement of the unlabeled parent in the plasma by 
standard high-performance liquid chromatography mass spectrometry/mass spectrometry (HPLC 
MS/MS) techniques. Thus, it is possible to obtain the IV PK parameters with the associated 
variability, and calculate the absolute bioavailability. In addition, because the IV dose 
administration involves giving a low volume of a low concentration of parent drug, an advantage 
of this approach is that it is much easier to develop an IV formulation for microdosing, than it 
would be for a higher clinical dose. Moreover, by administering the IV formulation as a 
microdose, this avoids any exposure-related safety concerns that could potentially arise from 
administering a 60 mg dose of quizartinib intravenously. 
The effect of food on the PK of quizartinib has been investigated in previous clinical studies in 
healthy subjects and was suggested to be minimal (based on Cmax, AUClast and AUCinf). 
Administration of quizartinib in the fed state delayed quizartinib absorption compared to the 
fasted state, with an increase in quizartinib Tmax of approximately 2 hours. The t1/2 of 
quizartinib was comparable with or without food. The slight food effect of Tmax increase is not 
considered to be clinically relevant and quizartinib can be administered with or without food. An 
oral dose of quizartinib administered in the fasted state has been chosen in this absolute 


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bioavailability study, as fasted oral dosing is the standard study design for absolute 
bioavailability studies. (This is also the route of administration for ongoing clinical studies and 
the approved route of administration in Japan.) 
The primary objective of this study is to determine the absolute oral bioavailability of 
quizartinib, based on the dose-adjusted exposure of quizartinib following oral and IV 
administration. Furthermore, characterization of the PK of total radioactivity will be performed 
to provide additional information on the metabolism of quizartinib, by demonstrating the amount 
of circulating radioactivity that is not accounted for by the presence of 14C-quizartinib and 
14C-AC886. To achieve these objectives, the PK sampling schedule has been selected on the 
basis of data from previous studies in which single oral doses of quizartinib have been 
administered to healthy volunteers. The frequent sampling schedule that follows the single doses 
of quizartinib and 14C-quizartinib is designed to capture data at a sufficient number of time 
points to provide a detailed profile of the PK of quizartinib and its main metabolite. A 504-hour 
sample collection period is planned based on the projected total radioactivity recovery of close to 
85% based on the previous clinical ADME study AC220-006. Moreover, both quizartinib and 
AC886 have long terminal elimination half- lives (t1/2) of approximately 73 hours and 
119 hours, respectively, and therefore PK sampling until 504 hours post-dose is planned in order 
to ensure the terminal eliminations phases of both analytes are captured. 
The first exploratory objective of this study is to assess the fecal and urinary recovery of total 
radioactivity following a single, IV administration of 50 µg 14C-quizartinib. In the clinical 
ADME study AC220-006, the total radioactivity dose recovery observed after 14 days post-dose 
was <80% and was considered inadequate. Therefore, it is planned to collect urine and fecal 
samples for up to 504 hours post-dose, as this will enable assessment of the recovery of total 
radioactivity following an IV dose of 14C-quizartinib over a longer collection period to that 
previously performed. The fecal and urinary recovery of quizartinib and AC886 following a 
single, oral dose of 60 mg quizartinib will also be assessed. 
Additionally, the whole blood PK of quizartinib and AC886 will be characterized, including the 
whole blood-to-plasma concentration ratios of both analytes. This is being performed in order to 
assess clinical blood-to-plasma partitioning, as there is evidence of concentration-dependent 
blood-to-plasma partitioning occurring in vitro. 
An open-label study design is felt to be suitable because quizartinib and 14C-quizartinib 
concentrations, on which the primary endpoints are based, are objective measures.  
4.3. 
Justification for Dose 
The quizartinib dose of 60 mg is the approved dose for relapse/refractory AML in Japan and the 
maximum maintenance therapeutic dose currently being investigated for AML first-line therapy 
in the QuANTUM-First study NCT02668653 (7).  
This an absolute bioavailability study where an IV microdose of quizartinib containing 
microtracer amounts of 14C is administered following administration of an oral dose of 
quizartinib to determine the bioavailability of the oral dose compared with the IV dose. 
According to the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) M3 guidance, a microdose is a dose that is <1/100th of 
the pharmacologically active dose up to a maximum of 100 µg. In addition, to ensure that the IV 


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microdose does not contribute significantly to the exposure following oral dosing, the IV dose is 
reduced further and in this study will be 1/1200th of the oral dose. 
The IV microtracer dose has been selected to contain NMT 22.84 kBq. This has been selected as 
it is below the standard radioactive dose used in this type of study, and will be sufficient to meet 
the objectives, but contains a low enough amount of radioactivity so as not to cause a significant 
risk to the subjects.  
Therefore the IV dose for this study will be 50 µg 14C-quizartinib containing NMT 22.84 kBq. 
This IV dose is 1/1200th of the oral dose administered in this study and <1/100th of the likely 
therapeutic dose, and hence is an appropriate ‘IV microtracer dose’. 
To ensure that the [14C] drug product does not exceed the limit for radioactive dose approved by 
ARSAC, the target specific activity of the drug substance will be set at 90% of 90% of the 
threshold radioactive dosing limit. This will allow for tolerances in the manufacturing processes 
for both drug substance and drug product thereby providing continued assurance for compliance 
with the ARSAC-approved limit for drug product radioactivity dose. 


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5. 
STUDY POPULATION 
This Phase 1 study is being conducted in healthy male subjects. 
Subjects will be recruited from the Quotient panel or by direct advertising to the public.  
Before subjects are admitted to the clinical unit, The Over Volunteering Prevention System 
(TOPS) will be checked to ensure that each subject has not been dosed in a study within 90 days 
of the planned dosing date of this study. 
5.1. 
Inclusion Criteria 
Subjects eligible for inclusion in this study have to meet all inclusion criteria for this study.  
1. Healthy males. 
2. Aged 18 years to 55 years of age (inclusive) at the time of signing informed consent. 
3. Body mass index (BMI) of 18.0 kg/m2 to 32.0 kg/m2 (inclusive) at screening.  
4. Must be willing and able to communicate and participate in the whole study. 
5. Must provide written informed consent. 
6. Subjects must agree to use one of the means of contraception specified in Section 5.3 from 
screening until 115 days after the dose of quizartinib. 
7. Subjects must agree to avoid sperm donation for the duration of the study until 115 days after 
the dose of quizartinib.  
8. Subjects must refrain from donation of blood or plasma within the previous 3 months, and 
platelets within 6 weeks, and must not have loss of greater than 400 mL of blood, throughout 
the study duration, and for at least 90 days following last dose of study medication. 
9. Liver function test results must be below the upper limit of normal (ULN) and hemoglobin 
levels must be ≥ 12.5 g/dL (125 g/L) at screening and admission (Day -1). 
10. Must have regular bowel movements (ie average stool production of ≥1 and ≤3 stools per 
day) 
11. All subjects must be willing to refrain from consuming grapefruit/grapefruit juice, 
cranberries/cranberry juice, Seville oranges, and pomegranates/pomegranate juice from 
10 days before the dose of the study drug is given on Day 1 until discharge from the clinical 
unit. 
12. All subjects must be willing to refrain from consuming anything likely to disturb GI transit 
(eg spicy or high-fat meals, such as curry or fish and chips, or foods of a high-fiber content 
such as All Bran) for 24 hours prior to admission (Day -1) until discharge from the clinical 
unit. 
13. All subjects must be willing to refrain from consuming food containing poppy seeds for 
48 hours prior to screening and for 48 hours prior to admission (Day -1) until discharge from 
the clinical unit. 
14. All subjects must be willing to refrain from showering for 24 hours post-oral dose (to ensure 
the collection of all samples). 
Inclusion criteria 9, 11, 12, 13, and 14 from the list above will be re-assessed at 
admission/pre-dose. 


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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, GI, 
endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease, as 
judged by the Investigator. 
• 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 stomach or intestinal surgery or resection that would potentially alter absorption 
and/or excretion of orally administered drugs (with the exception of appendectomy, and/or 
hernia repair, unless it was performed within the previous 12 months). 
3. Acute diarrhea or constipation in the 7 days before the predicted Day 1. If screening occurs 
>7 days before the Day 1, this criterion will be determined at admission/pre-dose. Diarrhea 
will be defined as the passage of liquid feces and/or a stool frequency of greater than 3 times 
per day. Constipation will be defined as a failure to open the bowels more frequently than 
every other day. 
4. History of a clinically significant illness, in the opinion of the Investigator, within 4 weeks 
prior to administration of quizartinib. 
5. Evidence of current SARS-CoV-2 infection. 
6. Clinically significant history or presence of acute or chronic bacterial, fungal, or viral 
infection (eg, pneumonia, septicemia) within the 3 months or 90 days prior to screening or 
admission (Day -1). 
7. Any subject with clinically significant symptoms of COVID-19 in the last 4 weeks, including 
but not limited to fever, new and persistent cough, breathlessness or loss of taste or smell, as 
per the judgement of the Investigator. 
8. Known or suspected malignancy, autoimmune disorder, or any history of known or suspected 
congenital or acquired immunodeficiency state or condition that would compromise the 
participant’s immune status or any factor that would predispose participants to develop 
infection (eg, open skin lesions, recurrent issues related to poor dentition, perianal fissures, 
history of splenectomy, primary immunodeficiency). 
9. Presence or history of clinically significant allergy requiring treatment, as judged by the 
Investigator. Hay fever is allowed unless it is active 
10. Bradycardia of less than 50 beats per minute. 
11. History, or presence in the average of triplicate ECGs at screening and admission (Day -1), 
of any of the following cardiac conduction abnormalities:  
• QTcF > 450 ms. 
• Evidence of second- or third-degree atrioventricular block. 


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• 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). 
12. Diagnosis or suspicion of long QT syndrome (including family history of long QT 
syndrome).  
13. Presence or history of clinically severe adverse reaction to any drug. 
14. 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. 
15. History of moderate to heavy alcohol use defined as consumption of more than 21 units of 
alcohol per week for males, where 1 unit of alcohol equals ½ pint of beer or a 25 mL shot of 
40% spirit, and 1.5 to 2 units equal 125 mL glass of wine, depending on type, or significant 
history of alcoholism or drug/chemical abuse within the last 2 years. 
16. A confirmed positive alcohol breath test at screening or admission (Day -1). 
17. Loss of more than 400 mL blood during the 3 months before the trial (e.g., as a blood donor). 
Physical Examination 
18. Subjects who do not have suitable veins for multiple venipunctures/cannulation as assessed 
by the Investigator or delegate at screening. 
Medication Use and Lifestyle 
19. Current smokers and those who have smoked within the last 12 months. A confirmed 
positive urine cotinine test at screening or admission (Day -1). 
20. Current users of e-cigarettes and nicotine replacement products and those who have used 
these products within the last 12 months. 
21. Use of drugs with a risk of QT interval prolongation or TdP within 14 days of admission 
(Day -1) (or 5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days). 
22. 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 admission (Day -1) and during the study. 
23. 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 admission 
(Day -1).  
24. Use of any prescribed or over-the-counter (OTC) systemic, herbal (including St John’s wort), 
or topical medication within 14 days of admission (Day -1), or any expectation of requiring 
use of such medication while participating in the study is prohibited. 
Note: COVID-19 vaccines are accepted concomitant medications. The use of acetaminophen 
(i.e., paracetamol) of up to 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 


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the day of quizartinib dosing, but may be given at any time 24 hours after the dose of 
quizartinib. 
25. Start of any new medication or any changes to a current dosage within 14 days prior to 
quizartinib administration. 
26. Consumption of alcohol- and caffeine-containing beverages within 72 hours prior to 
admission (Day -1) and during confinement. 
27. Engagement in strenuous exercise from the 72 hours before the screening visit and then from 
72 hours prior to admission (Day -1) until the discharge from the clinical unit. 
Laboratory Tests 
28. Laboratory results (serum chemistry, hematology, coagulation, and urinalysis) outside the 
normal range, if considered clinically significant by the Investigator at screening or 
admission (Day -1).  
29. Estimated creatinine clearance (CrCl) <90 mL/min (calculated using the Cockcroft-Gault 
Equation equation) at screening. 
30. Has a positive serology for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), 
hepatitis A virus (HAV), or human immunodeficiency virus (HIV) at screening. 
31. Has a positive urine screen for drugs of abuse at screening or at admission on Day -1. 
32. Subjects who have received any IMP in a clinical research study within the 90 days prior to 
Day 1. 
33. Subjects who report to have previously received quizartinib. 
34. Radiation exposure, including that from the present study, excluding background radiation 
but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 
12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the 
Ionising Radiation Regulations 2017 (8), shall participate in the study. 
35. Subjects who have been administered IMP in an ADME study in the last 12 months. 
Other (Miscellaneous) Exclusions 
36. Male subjects with pregnant or lactating partners. 
37. Subjects who are, or are immediate family members of, a study site or Sponsor employee. 
38. Failure to satisfy the Investigator of fitness to participate for any other reason. 
Exclusion criteria 3, 4, 5, 6, 7, 10, 11, 12, 16, 17, 19, 21, 22, 23, 24, 25, 26, 27, 28, 31, 36, and 
38 from the list above will be re-assessed at admission/pre-dose. 


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5.3. 
Contraception Requirements 
Male Subjects 
Males must use a condom plus an approved method of highly effective contraception while 
enrolled in this study, from the time of informed consent until 115 days after last IMP 
administration. This has been calculated based on 90 days (one cycle of spermatogenesis) plus 
5-half-lives of the metabolite AC886. Five half-lives has been calculated as 25 days. 
The following methods are acceptable: 
• Vasectomized 
• A female partner who is not of childbearing potential 
• Female partner’s use of combined (estrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation:  
o oral  
o intravaginal  
o transdermal  
• Female partner’s use of progestogen-only hormonal contraception associated with inhibition 
of ovulation:  
o oral  
o injectable/implantable 
o intrauterine hormone-releasing system  
• Female partner’s use of intrauterine device  
• Female partner’s bilateral tubal occlusion 
These contraception requirements are considered to be more conservative than the guidance 
issued by the Heads of Medicines Agency: Clinical Trials Facilitation Group (9). 
There is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomized males) that might be harmful to sexual partners. Therefore, even if a male is 
sexually active with a partner of non-childbearing potential they will be required to use a 
condom from first administration of IMP until 25 days post-final dose. A woman is considered of 
childbearing potential unless post-menopausal or permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-
menopausal state is defined as no menses for 12 months without an alternative medical cause and 
confirmed by a follicle stimulating hormone result of ≥40 IU/L. 
Alternatively, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject. 


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5.4. 
Screening Failures, Re-screening, and Subject Replacement 
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (ie subject has not been treated); the reason for failure must be temporary 
and expected to resolve. If re-screened, the subject must be re consented. 
Subjects who withdraw or are withdrawn from the study will not be replaced. 


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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 Dihydrochloride 
Tablets 
[14C]-Quizartinib Solution for 
Infusion 10 μg/mL (NMT 
4.6 kBq/mL) 
Dosage Formulation 
30-mg tableta 
50 µg solution for infusion 
containing NMT 22.84 kBq 14C in 
5 mL 
Dosage Level(s)b 
60 mg (2 x 30 mg tablets) 
50 µg (NMT 22.84 kBq 14C) 
Route of Administration 
Oral 
IV 
Dosing 
Single dose 
Single dose 
Duration 
Once 
Once as a 15-minute infusion 
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 
Please refer to the Drug Product  
Investigational Medicinal Product 
Dossier for the details of the 
packaging  
Packaging will clearly display the 
name of product, storage condition, 
and other required information as 
applicable in accordance with local 
regulations 
Labeling 
Bottles will be labeled as required 
per local and regulatory 
requirements 
This will be labeled as required per 
local and regulatory requirements 
a The oral dose will comprise 2 x 30 mg tablets to achieve a single dose of 60 mg quizartinib dihydrochloride. 
b Quizartinib and 14C-quizartinib doses are expressed as the dihydrochloride salt. The free base (active moiety) 
equivalent doses of the 60 mg tablets and 50 µg solution for infusion are 53 mg and 44 µg, respectively. 
Quizartinib will be supplied by the Sponsor. The labeled 14C-quizartinib solution for infusion 
will be manufactured by Quotient Sciences. 
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 SOP of 
the site. 
The quizartinib and 14C-quizartinib are medicinal products that are un-licensed in the UK and are 
for use only in the proposed clinical trial. 
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments will be stored in a secure, 


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environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorized site staff. 
Where Quotient is manufacturing the IMPs, suitability of the manufacturing process will be 
documented in a Pharmaceutical Development and Control Strategy Report. 
The tablets are manufactured, tested and released in accordance with Current Good 
Manufacturing Practice Regulations and Qualified Person (QP) released for clinical use. 
IMPs will be reconciled and destroyed in accordance with the study-specific quality agreement 
and technical addendum. 
6.2.2. 
Administration 
Subjects will be allowed water up to 1 hour before the scheduled oral IMP dosing time and will 
be provided with 240 mL of water at 1 hour post-oral dose. Water will be allowed ad libitum 
after 1 hour post-oral dose. Decaffeinated fluids will be allowed ad libitum from lunch time on 
the day of dosing. 
After the evening meal on Day -1, subjects will be provided with a light snack and then fast from 
all food and drink (except water) for a minimum of 8 hours on the day prior to oral dosing until 
approximately 4 hours post-oral dose (i.e., until administration of the IV dose is complete). 
Lunch will be provided after completion of the IV administration. An evening meal will be 
provided at approximately 10 hours post-oral dose and an evening snack at approximately 
14 hours post-oral dose. On subsequent days, meals will be provided at appropriate times. 
The calorie/fat content of meals are not required to be controlled. Subjects will be provided with 
a standardized menu. 
If, for technical reasons, dosing is delayed for more than 2 hours beyond the expected dosing 
time, subjects will receive 200 mL of an electrolyte drink (eg Lucozade Sport) at the originally 
scheduled dosing time, or earlier if possible. 
If an individual subject has not experienced a bowel movement in any 36 hour period post-dose, 
fluid intake should be increased and administration of a mild laxative (eg prune juice or a mild 
stool softener) should be implemented from 24 hours after the dose of quizartinib (see 
Section 6.8). 
Specific details of IMPs, and doses to be administered are provided in Section 6.1 and 
Section 4.1.3, respectively. Subjects will be dosed on the morning of Day 1. 
The exact time of dosing will be decided based on logistics and will be documented in the 
source. 
The oral dose will be administered with a total of 240 mL of water. If required, additional water 
may be given with the IMP in 50 mL aliquots and will be recorded in the source but will not be 
classed as a protocol deviation.  
4 hours after the oral dose has been administered, the IV dose will be infused over 15 minutes. 
This infusion will be in the opposite arm being used for PK sampling.  
To assess tolerability of the IV administration, dosing will be staggered. The first subject will 
receive the oral dose at least 30 minutes prior to the second subject. All subsequent dosing will 


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be staggered by at least 15 minutes. The IV administration will start at 4 hours post-oral dosing 
for all subjects, and will therefore be staggered as well. 
To allow for potential interruptions and pump variations, up to a 20% difference in duration of 
the IV infusion will not be considered a protocol deviation provided that full planned dosed is 
administered as these minor discrepancies should not have a significant impact on the overall 
study objectives.  
The planned infusion time will be 15 minutes; the actual infusion start and stop time will be 
recorded in the source.  
• 
The infusion will finish within ± 3 minutes of the nominal time point 
6.2.3. 
Storage 
Quizartinib dihydrochloride tablets must be stored according to the directions on the label (store 
up to 25°C [77°F]; do not freeze). The 14C-quizartinib Solution for Infusion must be stored 
according to the directions on the label. 
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 
This is an open-label, non-randomized study; therefore, a randomization schedule will not be 
produced. A treatment allocation will be produced prior to dosing with IMP, which will dictate 
the order in which the treatments should be administered to each subject. The treatment 
allocation will be retained in the ISF. 
Subject numbers will be allocated on the morning of dosing according to the code 10011001 to 
10011008 using the lowest number available (see also Section 10.1.7.3).  
6.3.2. 
Blinding 
This is an open-label study and therefore blinding is not required. 


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6.4. 
Treatment Compliance 
During all clinical phases of the study, subjects will be observed by study staff to assure 
compliance to all study procedures, including dose administration. Each dose of the study drugs 
will be administered by qualified study site staff. 
Mouth and hand checks will be conducted after oral dosing to ensure the tablets have been 
swallowed. 
The IV dose will be administered by trained staff to ensure dosing compliance. 
The date and time that each subject is dosed will be recorded in the subject’s source data. Any 
violation of compliance will require evaluation by the Investigator and Sponsor to determine if 
the subject can continue in the study. 
6.5. 
Guidelines for Dose Modification 
Not applicable. 
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 informed consent form (ICF) for study 
participation to discharge from the clinical unit will be recorded as concomitant therapies. 
Concomitant therapies include all prescription, OTC, and herbal remedies. 
All prior and concomitant therapies will be recorded on the electronic case report form (eCRF). 
6.7. 
Prohibited Therapies/Products 
Subjects will be prohibited from starting any new medication or undergoing any changes to a 
current dosage within 14 days prior to quizartinib administration. 
Any drugs or substances known to be inhibitors or inducers of CYP3A4/5 (see Section 10.3.2) 
are prohibited within 28 days from the first dose or 5 half-lives, if known, of the drugs or 
substances, whichever is greater, prior to admission (Day -1) and during the study. 
Additionally, 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 admission (Day -1) and throughout the study: 
• Drugs with a risk of QT interval prolongation or TdP  
• Medications known to affect the elimination of serum creatinine (e.g., trimethoprim or 
cimetidine) and inhibitors of renal tubular secretion (e.g., probenecid)  
• Any prescribed or OTC systemic, herbal (including St John’s wort), or topical medication, 
with the exception of those specified in Section 6.6. 
• Medical marijuana 
• Melatonin and all other OTC products 


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• 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 admission (Day -1). However, all dietary supplements are prohibited 
starting on admission (Day -1) and throughout the study.  
• Blood oranges, grapefruit, grapefruit juice, cranberries, cranberry juice, pomegranates, 
pomegranate juice, Seville (bitter) oranges, and star fruit are prohibited for 10 days before 
admission (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 admission (Day -1) and throughout the study.  
• Beverages, or foods likely to disturb GI transit (eg spicy or high-fat meals, such as curry or 
fish and chips, or foods of a high-fiber content such as All Bran) are prohibited for 24 
hours prior to admission (Day -1) until discharge from the clinical unit. 
• Foods containing poppy seeds are prohibited for 48 hours prior to screening and for 
48 hours prior to admission (Day -1) until discharge from the clinical unit. 
6.8. 
Permitted Therapies/Products 
The use of acetaminophen (i.e., paracetamol) of up to 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. 
COVID-19 vaccines are accepted concomitant medications. It is preferable for subjects not to 
receive the vaccine within 72 hours prior to study drug dosing, where possible, so that by the 
time of dosing any effects of the vaccine (e.g., pyrexia, fatigue, pain/stiffness at site of injection) 
are likely to have abated; however, subjects would not be excluded on this basis. 


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7. 
WITHDRAWAL/DISCONTINUATION FROM THE STUDY 
7.1. 
Subject Withdrawal/Discontinuation from the Study Drugs 
This is a single dose study, therefore, after an individual subject has received a dose of IMP, 
withdrawal of that subject from further dosing is not possible. Subjects may discontinue from the 
study for any of the following reasons: 
• Adverse event 
• Withdrawal by subject 
• Investigator decision 
• Protocol deviation 
• Study termination by Sponsor 
• Other 
Subjects will be monitored for the following criteria which may require their withdrawal from 
some or all study procedures if continuation is not in their best interests, except when the 
withdrawal is a result of withdrawal of consent:  
• Experiencing a serious or severe AE including but not limited to: 
o QTcF of >500 ms or increase in QTcF interval of >60 ms from baseline (confirmed 
following a repeat ECG) 
o ALT concentration >3 × the upper limit of the reference range (confirmed following a 
repeat ALT blood test) 
• Termination of the study 
• Upon the subject’s request (withdrawal of consent) 
• Significant deviation from the protocol 
• Concurrent illness that would adversely affect subject safety or data integrity or requirement 
for prohibited medication 
• Evidence of current SARS-CoV-2 infection  
The study will be halted, and the risk to other subjects evaluated if any of the following criteria 
are met:  
• A serious adverse reaction (ie a SAE considered at least possibly related to the IMP 
administration) in one subject. 
• Severe non-serious adverse reactions (ie severe non-serious AE considered as, at least 
possibly related to the IMP administration) in two subjects in the same cohort, independent 
of within or not within the same system organ class. 
Relatedness to IMP will be determined by the Investigator.  
If the study is halted, a temporary halt will be submitted to the MHRA and EC in the form of a 
substantial amendment. The study may be resumed or terminated; however, it will not be 


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resumed until a further substantial amendment to resume the study is submitted and approved by 
MHRA and EC. 
The ARSAC Practitioner will also be informed of the temporary halt. 
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 the Schedule of Events (SoE; Table 1.1) for data to be collected at the time of study 
discontinuation and for any further evaluations that need to be completed. 
7.3. 
Lost to Follow-up 
Subjects will be considered lost to follow-up if they leave the CRU prior to discharge from the 
clinical unit 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 (eg three telephone calls on three separate occasions and, if necessary, an email or letter 
to the participant’s last known email/postal address). These contact attempts should be 
documented. 


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8. 
STUDY PROCEDURES 
See the SoE, Table 1.1, for the procedures conducted at specific time points during screening, the 
Treatment Period, and discharge from the clinical unit. 
If the start of the study is delayed for any reason so that the interval between screening and first 
dose exceeds 21 days, all or part of the screening procedures will be repeated at the discretion of 
the Investigator. 
There are times where the protocol requires more than one procedure to be completed at the 
same time point. In these instances the following will apply to post-dose time points: 
• PK samples should take priority over other procedures scheduled at the same time point 
• ECGs should be taken prior to vital signs when both measurements are scheduled at the same 
time point  
• Other assessments, eg physical examinations, will be performed within the required time 
windows 
As guidance, the preferred order of assessments is: 
ECGs 
 
Vitals 
 
PK blood 
sampling 
(nominal 
time) 
 
Other assessments eg 
physical examinations 
All assessments will be timed and performed relative to the start of oral dosing. 
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, ECG, and 
laboratory assessments) and compare against the eligibility criteria (Section 5.1 and Section 5.2). 
Screening and admission/pre-dose safety procedures such as safety bloods, ECGs, vital signs, 
urine drug and cotinine screens, alcohol breath tests and urinalysis can be repeated as clinically 
indicated under the discretion of the Investigator or Sub-Investigator if there is a concern 
regarding a subject’s safety or eligibility to participate in the trial. 
Reserve subjects for the first dose occasion will not require admission procedures to be repeated, 
if dosing is within 2 days. 
The subjects will be admitted to the clinical unit on the morning before dosing (Day -1). 
In addition, subjects may be required to visit the clinical unit on the day before admission for 
SARS-CoV-2 antigen tests (see Sections 2.3.3.1 and 8.6.3.3). Test results must be available prior 
to dosing; if test results are delayed, admission procedures are not required to be repeated if 
dosing is within 2 days. 
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 


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questions and receive responses to their inquiries and should have adequate time to decide 
whether or not to participate in the study. See Section 10.1.5 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) Assessments 
Pharmacokinetic blood (via an indwelling cannula or by venipuncture), urine and fecal samples 
will be collected, processed, and shipped as detailed in the SoE and in the Laboratory Processing 
Specifications as detailed in the Clinical Sample Processing Manual (CSPM; see Section 10.5). 
The total blood volume for each subject will not exceed 550 mL in a 4-week period. The first 
0.5 mL of blood withdrawn via cannula will be discarded. 
Allowable time windows for PK 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 and whole blood quizartinib, plasma and whole blood AC886, plasma 14C-quizartinib, 
plasma 14C-AC886 and plasma total radioactivity concentrations. Additionally, exploratory 
metabolite analyses may be conducted using the leftover samples after quizartinib and AC886 
analysis and reported separately from the clinical study report for this protocol. 
8.5.2. 
Pharmacodynamic Assessment(s) 
No pharmacodynamic assessments are planned for this study. 
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 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 


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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 eCRF. 
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 
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 
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8.6.2.2. 
Time Period for Collecting Adverse Events, including Adverse Events of Special 
Interest and Serious Adverse Events 
For all enrolled subjects, all AEs occurring after the subject signs the ICF and to discharge from 
the clinical unit (i.e., Day 22), whether observed by the Investigator or reported by the subject, 
will be recorded as detailed in Section 10.1.7.2. Additionally, if a subject reports any AEs 
between discharge and 7 days post-discharge (i.e., between Day 22 and Day 29), they will also 
be recorded as detailed in Section 10.1.7.2. All AEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up. SAEs 
considered related to the IMP by the Investigator should be reported regardless of the time after 
the last dose of IMP they occurred. 
8.6.2.3. 
Reporting Procedure for Investigators 
All AEs (including adverse events of special interest [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 on a Serious AdVerse Event 
Report (SAVER) form within 24 hours of awareness to Daiichi Sankyo Clinical Safety and 
Pharmacovigilance (CSPV) at CSPV-clinical@dsi.com: 
• 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 
documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Contact the Medical Monitor (see Section 10.1.1) for any questions on SAE reporting. 
See Section 8.6.2.2 for details on the time period for collecting SAEs. 


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8.6.2.5. 
Reporting Requirement to Site and Regulatory Authorities 
Daiichi Sankyo and/or the CRO will inform Investigator(s) and regulatory authorities of any 
Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in other study centers or 
other studies of the investigational drug, as appropriate per local reporting requirements. Daiichi 
Sankyo and/or the CRO will comply with any additional local safety reporting requirements. 
The Sponsor will comply with any additional local safety reporting requirements. The Sponsor 
will report SUSARs to all Central ECs, whereas this responsibility can be delegated to the 
Investigator to inform the local EC. The Sponsor will assess if an AE is to be considered 
“unexpected” based on the “Reference Safety Information” section in the current IB (3).  
AEs considered by the Investigator to be related to COVID-19 vaccines will be reported to the 
MHRA via the Yellow Card system. 
All confirmed or suspected COVID-19 vaccine-related events must be recorded in the eCRF.  
The usual protocol-mandated SAE reporting requirements should be followed for confirmed or 
suspected COVID-19 vaccine-related AE 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 suspected COVID-19 vaccine-related AE does 
not meet any seriousness criteria as outlined in the protocol, it should be reported as a non-
serious AE in the eCRF. 
When assessing the severity of the suspected COVID-19 vaccine-related 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 suspected COVID-19 
vaccine-related AE must be recorded on the AE and drug administration eCRFs. 
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. 
If a subject reports any AEs between discharge and 7 days post-discharge (i.e., between Day 22 
and Day 29) that represent a cause for concern, they will be required to attend the clinical unit 
for a follow-up assessment as per the discretion of the Investigator or delegate. This will be an 
unscheduled visit. 


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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 ms QTcF prolongation must be monitored closely with ECGs, 
performed twice weekly for the first week of the QTcF prolongation and then weekly thereafter 
until the QTcF prolongation is resolved. QTcF prolongation ≥Grade 3, either serious or 
non-serious and whether or not causally related, must be recorded as an AE or SAE in the eCRF 
within 24 hours of the assessment, with the Investigator’s assessment of seriousness, causality, 
and a detailed narrative. 
Monitoring in subjects with QTcF prolongation will include the following: 
• Electrolytes (potassium, calcium, and magnesium) should be checked and supplementation 
given to correct any values outside the normal range. 
• Concomitant medications should be reviewed to identify and, if appropriate, discontinue any 
medication with known QT prolonging effects. 
8.6.2.8. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported to the Sponsor within 24 hours of awareness and recorded via the Serious AdVerse 
Event Report (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 
male subject’s female partner that occurs while the subject is receiving or within 115 days 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 


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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 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 partner of a male subject, the Exposure In Utero (EIU) 
Reporting Form (or SAE form if associated with an adverse outcome) should be completed with 
the subject number, subjects’ initials, and date of birth, and details regarding the female partner 
should be entered in the narrative section. 
8.6.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed as detailed in the SoE in Section 1.3. 
The clinical laboratory tests will include hematology, coagulation, serum chemistry, and 
urinalysis. Refer to Section 10.2 for the complete list of laboratory parameters. 
Allowable time windows for clinical laboratory tests are provided in Section 10.7. 
Abnormal laboratory values occurring during the clinical study will be followed until repeat test 
results return to normal (or baseline), stabilize, or are no longer clinically relevant. New or 
worsened clinically relevant laboratory abnormalities should be recorded as AEs. 
8.6.3.1. 
Drug Screen 
A urine drug and cotinine screen will be performed on-site using a point of care testing method 
(eg Alere Drug Screen Test Cup) as detailed in the SoE in Section 1.3. The sample will be 
collected and processed as detailed in the CSPM. Subjects will be screened for the drugs of 
abuse listed in Section 10.2. 
8.6.3.2. 
Alcohol Breath Test 
An alcohol breath test will be performed as detailed in the SoE in Section 1.3. A positive result 
will exclude the subject from dosing during that admission. 
8.6.3.3. 
SARS-CoV-2 Tests  
Testing for the SARS-CoV-2 virus will be performed based on current infection rates and 
availability of tests. Tests will be performed as detailed in the SoE in Section 1.3. The samples 
will be collected and processed as detailed in the Screening Sample Processing Manual and 
CSPM. 
Testing time points may be changed and additional time points may be added throughout the 
study as required. The decision on COVID-19 testing and the definition of the testing time points 


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will be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting 
minutes. 
8.6.4. 
Body Weight, Height and BMI 
Height, weight, and calculation of BMI will be performed as detailed in the SoE in Section 1.3. 
8.6.5. 
Physical Examinations 
Physical examinations will be performed as detailed in the SoE 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, GI, and neurological 
systems.  
In the targeted (symptom driven) physical examination, a physician will assess the subject; if the 
subject reports feeling unwell or has ongoing AEs, then the physician will examine the 
appropriate body system(s) if required. 
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. 
8.6.6. 
Vital Signs 
Vital signs will be performed as detailed in the SoE in Section 1.3. 
Allowable time windows for vital sign assessments are provided in Section 10.7. 
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 time points as 
ECGs. 
8.6.7. 
Electrocardiograms 
Electrocardiograms will be performed as detailed in the SoE 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 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 in triplicate. 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 interval, RR interval, QRS amplitude, QT interval, QTcF 
interval, and results will be recorded. 
8.7. 
Pharmacogenomic (Inherited Genetic) Analysis  
A mandatory single blood sample for pharmacogenomic (PGx) analysis will be collected 
pre-dose from each enrolled subject. Detailed instructions for the collection, handling, and 


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shipping of samples are outlined in the Laboratory Specifications Document as detailed in the 
CSPM. 
Genetic analyses will not be performed on blood samples collected for PK or safety assessments. 
Subject confidentiality will be maintained; data will be decoded and the testing lab will not have 
traceability information. 
Deoxyribonucleic acid (DNA) samples will be stored, as outlined in Section 8.7.2, for 
performing possible PGx analysis in the future, otherwise all remaining DNA samples will be 
destroyed. 
8.7.1. 
Banking of Specimens for Inherited Genetic Analysis 
Procedures for the long-term preservation (banking) of blood and/or DNA specimens extracted 
from subjects’ blood samples for each subject that consented are described in the CSPM. 
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 (at Thermo Fisher Scientific, 
United States of America [USA] or other provider selected by the Sponsor) 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. 
The samples will be destroyed in line with Thermo Fisher Scientific’s/the provider’s SOPs and in 
line with local regulations. 
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 calculations. 
8 subjects will be enrolled in the study to target at least 6 subjects to complete the PK evaluation 
(i.e., to allow for withdrawal or non-PK evaluability in up to 2 dosed subjects).  
9.3. 
Exposure and Compliance 
As the dose administration is under the control of the study site, 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 Population is defined as all subjects who received the study drug and have a 
corresponding measurable concentration. The PK Analysis Population will be used for the 
descriptive statistics of concentration data and to generate mean and individual concentration 
time profiles. 
The PK Evaluable Population includes all subjects who are evaluable as defined below and have 
a sufficient number of measurable concentrations to estimate PK parameters. An evaluable 
subject is defined as a subject who has received both the oral and IV microtracer IMPs (i.e., a 
single, oral dose of 60 mg quizartinib dihydrochloride tablets [2 x 30 mg tablets] and an IV 
administration of 50 µg 14C-quizartinib solution for infusion 10 µg/mL containing NMT 22.84 
kBq 14C in 5 mL [NMT 4.6 kBq/mL] over 15 minutes at 4 hours post-oral dose) and has 
sufficient samples for evaluation of plasma PK parameters. The PK Evaluable Population will be 
used for summaries of PK parameter estimates. 
Additional exclusions and flags may be required to address relevant protocol deviations and AEs. 
Specific exclusions may be made for the fecal and urine datasets in relation to missing 
and/spilled samples. 
9.4.2. 
Safety Population 
The safety analysis will be conducted using the Safety Population defined as all subjects who 
receive at least 1 dose of quizartinib. 
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 


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missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
No formal interim analyses are planned for this study. 
9.5.1. 
Safety Analysis 
9.5.1.1. 
Adverse Events 
Treatment-emergent adverse events are defined as new AEs that occur after the first dose of 
study drug. AEs occurring after Day 29 will not be considered TEAEs unless they are 
treatment-related. AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary (see Section 10.1.7.3). An AE will be assigned to the study day on which 
it started, even if it resolved on a subsequent day. The incidence of TEAEs will be summarized. 
The number and percentage of subjects reporting TEAEs will be calculated overall, by system 
organ class, and by preferred term. 
Treatment-emergent adverse events, or AEs that are present prior to the first dose but which 
worsen in severity after the first dose of study drug, will be further summarized by common 
terminology criteria for adverse events (CTCAE) grade and relationship to study drug. Similarly, 
the number and percentage of subjects reporting treatment-emergent SAEs and related 
treatment-emergent SAEs will be tabulated, treatment-emergent AESIs, and TEAEs leading to 
discontinuation of study drug. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to study drug 
will be provided. Deaths, SAEs, AESIs, and AEs associated with study drug discontinuation will 
be listed. 
9.5.1.2. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation, 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 for the maximum and minimum post-treatment values and the values 
at discharge from the clinical unit. 
Abnormal clinical laboratory results will be appraised by the site physician where any results of 
clinical significance will be recorded as an AE, and graded according to National Cancer 
Institute - common terminology criteria for adverse events (NCI-CTCAE) Version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing. A shift table, presenting 
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 Grade 3 or 4 results 
will be generated. 
9.5.1.3. 
Electrocardiograms 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation, 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 


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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; changes from baseline of 
≥30 ms to <60 ms, and ≥60 ms). 
A listing of ECG data will be generated. 
9.5.1.4. 
Vital Signs 
Descriptive statistics will be provided for the vital sign measurements by scheduled time of 
evaluation, 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 signs 
data will be generated. 
9.5.1.5. 
Other 
Listings of all other safety endpoints (e.g., physical examination findings) will be generated. 
9.5.2. 
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. 
9.5.2.1. 
Pharmacokinetic Parameters 
Pharmacokinetic and statistical analysis will be performed using appropriate software; e.g., 
Phoenix™ WinNonlin® (Version 8.0 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 approach. 
The following PK parameters will be calculated for plasma and whole blood quizartinib, plasma 
and whole blood AC886, plasma 14C-quizartinib, plasma 14C-AC886 and plasma total 
radioactivity, as applicable. 
Cmax 
The maximum observed concentration 
Tmax 
Time to reach maximum observed concentration 
Kel 
First order rate constant associated with the terminal portion of the concentration-
time curve. This is estimated via linear regression of time vs log concentration. 
t1/2 
Terminal half-life 
AUClast  
AUC from the time of dosing to time Tlast 
AUCinf 
AUC from the time of dosing extrapolated to infinity 
AUCextr (%) 
Percentage of AUCinf that is due to extrapolation from Tlast to infinity 
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 observed concentration 
Tlast 
Time of the last measurable (non-zero) concentration 


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CL 
Total body clearance following single-dose iv administration (for plasma 
14C-quizartinib only) 
CL/F 
Apparent total body clearance following single-dose extravascular administration 
(for plasma and whole blood quizartinib only) 
Vz 
Volume of distribution based on the terminal phase following a single-dose of iv 
administration (for plasma 14C-quizartinib only) 
Vz/F 
Apparent volume of distribution based on the terminal phase following a single-
dose of extravascular administration (for plasma and whole blood quizartinib 
only) 
MPR Cmax 
Metabolite-to-parent ratio for Cmax (for plasma and whole blood AC886 and 
plasma 14C-AC886 only) 
MPR AUClast 
Metabolite-to-parent ratio for AUClast (for plasma and whole blood AC886 and 
plasma 14C-AC886 only) 
MPR AUCinf 
Metabolite-to-parent ratio for AUCinf (for plasma and whole blood AC886 and 
plasma 14C-AC886 only) 
F 
The fraction of the administered dose systemically available  
Kbp 
Whole blood-to-plasma concentration ratio 
The following PK parameters will be calculated for total radioactivity quizartinib and AC886 in 
urine and feces by discrete collection interval and cumulatively as applicable. 
Ae(t1-t2) 
Amount of total radioactivity, quizartinib and AC886 excreted in urine/feces 
from time t1 to time t2 for each collection interval 
Fe(t1-t2) 
Amount of total radioactivity, quizartinib and AC886 excreted in urine/feces 
expressed as a percentage of the IV (total radioactivity) or oral (quizartinib and 
AC886) dose administered from time t1 to time t2 for each collection interval 
9.5.2.2. 
Statistical Analysis of Pharmacokinetic Endpoints 
The PK Analysis Population and the PK Evaluable Population will be used for PK analyses, 
details of which will be presented in the SAP.  
Using the PK Analysis Population, descriptive statistics will be presented for plasma and whole 
blood concentrations at each sampling time point. Plasma concentration-time data will be 
analyzed using non-compartmental methods. Whole blood-to-plasma quizartinib and AC886 
concentration ratios (Kbp) will also be calculated at each sampling time point. 
The PK Evaluable Population will be used for the calculation and summaries of the PK 
parameters listed in Section 9.5.2.1. 
Note that when percent extrapolated AUC (AUCextr (%)) is greater than 20%, AUCinf and 
related parameters will be summarized with and without those individuals having >20% 
AUCextr (%). For the primary analysis, including calculation of absolute bioavailability (F), 
individuals having >20% AUCextr (%) will be excluded. An additional subset may be required 
in order to include individuals having >20% AUCextr (%); this will be documented in the 
clinical study report. 


Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 56 
Absolute bioavailability (F) will be calculated based on the dose-normalized quizartinib plasma 
AUCinf after the oral dose (data from the cold assay [i.e., 12C-quizartinib] will be used for this 
analysis) to the dose-normalized AUCinf after the IV dose (data from the hot assay 
[i.e., 14C-quizartinib] will be used for this analysis).  


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Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 59 
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. 
10.1.6. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained. On the eCRFs or other 
documents submitted to the Sponsor, 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 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. 
10.1.7. 
Data Integrity and Quality Assurance 
10.1.7.1. 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. 


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Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 61 
10.1.7.4. 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, EC 
correspondence and approvals, approved and signed ICFs, Investigator’s agreement, clinical 
supplies receipts, distribution, and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (site specific Trial Master 
File). Source documents include all recordings and observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical study. 
These records will be retained in a secure file for the period required by local laws or regulations 
or study site policy. Prior to transfer or destruction of these records, the Sponsor must be notified 
in writing and be given the opportunity to provide further instruction. 
10.1.7.5. 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, IB, copies of relevant essential 
documents required prior to commencing a clinical study, and all correspondence to and from 
the independent EC 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. 


Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 62 
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. 
10.1.8. 
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. 
10.1.9. 
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. 
10.1.10. 
Publication and Public Disclosure Policy 


Protocol AC220-A-U107 (QSC203118) 
Version 2.0, 23 Mar 2021 
Proprietary and Confidential 
Page 63 
10.1.11. 
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 ECs. 
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 major 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 EC of deviations from the protocol in accordance 
with local procedures. 
10.1.12. 
Study and Site Closure 
The Sponsor reserves the right to close the study site and terminate the study at any time for any 
reason at the sole discretion of the Sponsor. The study site 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. 
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 EC 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. 
10.1.13. 
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 Sponsor’s SOPs for instructions and details. 


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10.1.14. 
Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available at all 
times during the study. In accordance with the current Association of the British Pharmaceutical 
Industry guidelines (10), each subject will receive a card stating the telephone number of the 
Investigator and the 24/7 contact details of the Quotient’s on-call physician. 


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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 by The Doctors 
Laboratory (The Halo Building, 1 Mabledon Place, London WC1H 9AX; Tel: + 44 [0]207 3077 
404). 
Venous blood and urine samples will be collected from the subjects by a trained member of the 
clinical team. Subjects will sign a study-specific ICF, in which they will consent to the use of 
these samples for the purposes of the proposed study.  
Blood and urine samples are sent for laboratory testing and are identified by the study number, 
the subject’s volunteer panel number, sample type, date of sample, and the subject’s gender and 
date of birth (for analytical reasons). This information is able to be linked directly to the 
volunteer by the Quotient research team and study monitor; however, not by the laboratory staff 
or Sponsor. 
Safety laboratory tests and virology will be carried out on blood samples, and drugs of abuse and 
cotinine tests and urinalysis will be carried out on urine samples.  
Blood and urine samples will be processed as described in the CSPM. 
Safety blood and urine samples results will be reviewed by a physician and acted upon before the 
subject is dosed or receives their next dose, or is released from the study, as is appropriate. 
Table 10.1: 
Clinical Laboratory Tests 
Test 
Analytes 
Serum Chemistry 
albumin 
albumin globulin (A/G) ratio 
alanine aminotransferase (ALT) 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
bicarbonate/CO2 
bilirubin (total) 
bilirubin (direct) 
blood urea nitrogen (BUN)/urea 
calcium (Ca) 
chloride (Cl) 
creatinine 
cholesterol (total) 
creatine phosphokinase 
gamma-glutamyl transaminase (GGT) 
glucose ([non-fasting/fasting]) 
lactate dehydrogenase 
lipase 
lipoprotein, high density (HDL) 
lipoprotein, low density (LDL; 
note: LDL value is calculated) 
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 
Activated partial thromboplastin time (aPTT)/prothrombin time (PT)/international 
normalized ratio (INR) 
Urinalysis 
(abbreviated) 
bilirubin 
glucose 
ketone bodies 
occult blood 
pH 
protein 
specific gravity 
nitrites 
urobilinogen 
sediments: 
casts  
RBC 
WBC 
Microbiology and/or urine 
microscopy (at discretion of 
Investigator based on urinalysis 
results) 
Virology 
Hepatitis B Surface Antigen (HBsAg) 
Hepatitis C Virus Antibody (HCV) 
Human Immunodeficiency Virus (HIV) 
Antibody 
Hepatitis A Virus (HAV) 
SARS-CoV-2 Antibody (if required) 
SARS-CoV-2 Antigen (if required) 
Drugs of abuse 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
Marijuana/Cannabis 
Methadone 
Methamphetamine/ecstasy 
Morphine/Opiates 
Phencyclidine 
Tricyclic Antidepressants 
Cotinine 
10.3. 
Appendix 3: Reference Standards 
10.3.1. 
Cockcroft-Gault Equation 
The estimated CrCl (mL/min) will be calculated using the Cockcroft-Gault equation based on 
[actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds):  
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) =  
 
 
[140 - age (in years)] × weight (in kg) × 1.23 
serum creatinine (in µmol/L) 


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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, coagulation, serum chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, which require investigation or 
corrective measures, or are 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 SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 


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− 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. 


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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 
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 AE and the study drug based on 
his/her clinical judgment and the following definitions. The causality assessment must be made 
based on the available information and can be updated as new information becomes available. 
• Related: 
− The AE follows a reasonable temporal sequence from study drug 
administration and cannot be reasonably explained by the subject’s 
clinical state or other factors (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. 
• 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 will be categorized as follows: 
• Quizartinib when administered alone (from 0 to 4 hours post-oral dose) 
• Quizartinib and 14C-quizartinib (after the start of IV administration at 4 hours post-oral dose) 


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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 OTC medication was required to treat the AE. 
10.4.8. 
Adverse Event Outcome 
• Recovered/Resolved 
− The subject fully recovered from the AE with no sequelae observed. 
• Recovered/Resolved with Sequelae 
− The subject fully recovered from the AE but with sequelae. 
• Recovering/Resolving 
− 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, Urine and Fecal Samples 
Collection, Processing, Storage, and Shipment 
Details of pharmacokinetic blood, urine and fecal samples collection, processing, storage, and 
shipment will be contained in the CSPM. 
Venous blood samples will be collected from the subjects by a trained member of the clinical 
team. Subjects will sign a study-specific ICF, in which they will consent to the use of these 
samples for the purposes of the proposed study. Samples will be processed to isolate plasma and 
PK analysis will be carried out on plasma samples. 
Plasma, whole blood, urine and fecal samples will be sent for laboratory testing in linked 
anonymized form (identified by identified by the study number, subject’s volunteer panel 
number/subject number, date of sample and time point of blood draw). This information is able 
to be linked directly to the volunteer by the Quotient research team and study monitor, however 
not by the laboratory staff or Sponsor. 
The pre-dose urine sample will be taken any time between admission and pre-dose. Where a 
sample is not provided, this will not be considered a deviation.  
The pre-dose fecal sample will be taken any time between admission and pre-dose. If a pre dose 
fecal sample cannot be obtained, the subject will still be dosed. Where a sample is not provided, 
this will not be considered a deviation. 
 
 


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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 will be taken from each subject on Study Day 1. 
This sample will be stored for possible future PGx analysis. At screening, all potential subjects 
should be presented with the standard ICF, which will include details of these procedures. 
Details of PGx blood samples collection, processing, storage, and shipment will be contained in 
the CSPM. 
 
 
 


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10.7. 
Appendix 7: Allowable Time Windows for Pharmacokinetic Blood, 
Urine and Fecal Samples, Clinical Laboratory Safety Samples, and 
Vital Sign, and Electrocardiogram Assessments 
Table 10.4: 
Acceptable Time Windows 
Procedures  
(in order of collection) 
Allowable Time Window 
Pre-dose 
Post-dose 
ECG  
(pre-dose, 4, 24, 72 and 
504 hours post-oral 
dose) 
No more than 2 hours before oral dose; 
inclusive of  
at least 5 minutes  
of quiet rest in the supine position 
No more than ± 15 minutes from the 
nominal post-dose time point (4 
through 72 hours post-oral dose); 
inclusive of  
at least 5 minutes  
of quiet rest in the supine position 
No more than ± 1 hour from the 
nominal post-dose time point 
(504 hours post-oral dose 
[discharge]); 
inclusive of  
at least 5 minutes  
of supine rest 
Approximately 2 minutes between 
triplicate ECGs  
(i.e. 1 to 3 minutes allowed between 
each of the triplicate ECGs) 
Approximately 2 minutes between 
triplicate ECGs  
(i.e. 1 to 3 minutes allowed between 
each of the triplicate ECGs) 
Vital signs 
(pre-dose, 4, 24, 72 and 
504 hours post-oral 
dose) 
No more than 2 hours before oral dose; 
inclusive of 
at least 5 minutes 
of supine rest 
No more than ± 15 minutes from the 
nominal post-dose time point (4 
through 72 hours post-oral dose); 
inclusive of  
at least 5 minutes  
of supine rest 
No more than ± 1 hour from the 
nominal post-dose time point 
(504 hours post-oral dose 
[discharge]); 
inclusive of  
at least 5 minutes  
of supine rest 
Hematology, Serum 
Chemistry (96 and 504 
hours post-oral dose) 
Not applicable 
No more than ± 1 hour from the 
nominal post-dose time point 
Coagulation (pre-dose, 
96, and 504 hours post-
oral dose 
No more than 2 hours before oral dose 
No more than ± 1 hour from the 
nominal post-dose time point 
Urinalysis (96 and 504 
hours post-oral dose) 
Not applicable 
No more than ± 2 hours from the 
nominal post-dose time point 


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PK blood sample 
collection (pre-dose, 1, 
2, 4, 4.25, 4.5, 4.75, 5, 
6, 8, 12, 24, 48, 72, 96, 
144, 192, 240, 288, 
336, 384, 432, 480, and 
504 hours post-oral 
quizartinib dose) 
No more than 60 minutes before dosing 
(applies to all pre-dose PK blood 
samples, including the pre-dose plasma 
PK samples for total radioactivity, 14C-
quizartinib and 14C-AC886 that are to 
be taken prior to the start of the IV 
infusion) 
No more than ± 2 minutes from the 
nominal post-dose time point 
(1 through 5 hours post-oral dose) 
No more than ±10 minutes from the 
nominal post-dose time point 
(6 through 12 hours post-oral dose) 
No more than ±30 minutes from the 
nominal post-dose time point 
(24 through 504 hours post-oral dose) 
PK urine sample 
collection (pre-dose, 
0 to 4 hours, 4 to 
8 hours, 8 to 12 
hours, 12 to 24 hours 
post-oral dose and 
then daily [24 hour 
intervals] until 
discharge at 504 
hours post-oral dose 
[Day 22]) 
Any time between admission and 
pre-dose 
Nominal time window to be observed 
PK fecal sample 
collection (pre-dose 
and 24 hour intervals 
post-oral dosing until 
discharge [Day 22]) 
Any time between admission and 
pre-dose 
Nominal time window to be observed 
 
 


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11. 
REFERENCES 
1. FDA Guidance: Food effect bioavailability and fed bioequivalence studies. 2002. 
2. EMA – Guidance on the investigation of bioequivalence. 20 Jan 2010. 
3. Quizartinib (AC220) Investigator’s Brochure. Edition 15.0. 29 Jan 2021. 
4. Davies NG, et al. Age-dependent effects in the transmission and control of COVID-19 
epidemics. Nat Med. 2020; 26(8): 1205–1211. 
5. Li H, et al. Age-dependent risks of incidence and mortality of COVID-19 in Hubei Province 
and other parts of China. Front Med (Lausanne). 2020; 7: 190. 
6. Liu Y, et al. Association between age and clinical characteristics and outcomes of COVID-
19. Eur Respir J. 2020; 55: 2001112. 
7. 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. 
8. Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. Statutory 
Instrument 2017 No. 1322. 
9. Heads of Medicines Agency: Clinical Trials Facilitation Group. Recommendations related to 
contraception and pregnancy testing in clinical trials. 15 Sep 2014 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
10. Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical Industry 
Guidelines. London, UK; 2018 Edition (publication date 29 May 2018). 


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12. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
14C 
carbon-14 
ADME 
absorption, distribution, metabolism, and elimination 
AE 
adverse event 
Ae(t1-t2) 
Amount excreted in urine/feces from time t1 to time t2 for each collection 
interval 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AMS 
accelerator mass spectrometry 
aPTT 
activated partial thromboplastin time 
ARSAC 
Administration of Radioactive Substances Advisory Committee 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCextr (%) 
Percentage of AUCinf that is due to extrapolation from Tlast to infinity 
AUCinf 
AUC from the time of dosing extrapolated to infinity 
AUClast  
AUC from the time of dosing to time Tlast 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CL 
Total body clearance following single-dose iv administration  
Clast 
The last observed concentration 
CL/F 
Apparent total body clearance following single-dose extravascular 
administration 
Cmax 
The maximum observed concentration 
COVID-19 
coronavirus disease 2019 
C QTc 
concentration-corrected QT interval 
CrCl 
creatinine clearance 
CRU 
clinical research unit 
CRO 
contract research organization 
CSPM 
Clinical Sample Processing Manual 
CSPV 
Clinical Safety and Pharmacovigilance 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
CYP 
cytochrome P450 


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Abbreviation 
Definition 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
ET 
early termination  
EIU 
Exposure In Utero 
EU 
European Union 
F 
The fraction of the administered dose systemically available  
FDA 
Food and Drug Administration 
Fe(t1-t2) 
Amount excreted in urine/feces expressed as a percentage of the dose 
administered from time t1 to time t2 for each collection interval 
FLT3 
Feline McDonough sarcoma-like tyrosine kinase 3 
FMS 
Feline McDonough sarcoma 
GCP 
Good Clinical Practice 
GPP3 
Good Publication Practice for Communicating Company-Sponsored Medical 
Research 
GI 
gastrointestinal 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HI 
hepatic impairment 
HIV 
human immunodeficiency virus 
HPLC MS/MS 
high-performance liquid chromatography mass spectrometry/mass spectrometry  
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICRP 
International Commission on Radiological Protection 
ICMJE 
International Council of Medical Journal Editors 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
ISF 
Investigator Site File 


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Abbreviation 
Definition 
ITD 
internal tandem duplication 
IUD 
intrauterine device 
IV 
intravenous 
Kel 
First order rate constant associated with the terminal portion of the 
concentration-time curve. This is estimated via linear regression of time vs log 
concentration. 
KIT 
KIT proto oncogene receptor tyrosine kinase 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MPR 
metabolite-to-parent ratio 
MPR AUCinf 
Metabolite-to-parent ratio for AUCinf  
MPR AUClast 
Metabolite-to-parent ratio for AUClast  
MPR Cmax 
Metabolite-to-parent ratio for Cmax  
NCI-CTCAE 
National Cancer Institute - common terminology criteria for adverse events 
NMT 
not more than 
NRU 
neutral red uptake 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PGx 
pharmacogenomic(s) 
PHE 
Public Health England 
PK 
pharmacokinetic 
PT 
prothrombin time 
QP 
Qualified Person 
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAVER 
Serious AdVerse Event Report 
SI 
International System of Units 
SoE 
Schedule of Events 
SOP 
standard operating procedure 


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Abbreviation 
Definition 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
Terminal half-life 
TdP 
Torsades de Pointes 
TEAE 
treatment-emergent adverse event 
Tlast 
Time of the last measurable (non-zero) concentration 
Tmax 
Time to reach maximum observed concentration 
TOPS 
The Over Volunteering Prevention System 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 
USA 
United States of America 
Vz 
Volume of distribution based on the terminal phase following a single-dose of 
iv administration  
Vz/F 
Apparent volume of distribution based on the terminal phase following a 
single-dose of extravascular administration  
WHO 
World Health Organization