Clinical trial NCT04916769
Conditions: Healthy Participants
Keywords: Bioavailability bosutinib Maximum Observed Plasma Concentration (Cmax) Area Under the Curve (AUC)
Sponsor: Pfizer
Start date: 2021-08-13; Completion date: 2022-01-27
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is intended to estimate the relative bioavailability of a single 500 mg dose of bosutinib when administered as capsule contents mixed with applesauce or yogurt to intact capsules under fed condition in adult healthy participants. The comparisons will be performed using the pharmacokinetic parameters that define the rate and extent of absorption, those are Cmax and AUC. Statistical analyses will be performed comparing these parameters calculated after administration of a single 500 mg dose with the intact capsule formulation (100 mg x 5) as the Reference treatment and the capsule contents mixed with applesauce or yogurt (100 mg x 5) as the Test treatments.

Detailed description:

Arms: arm 1: Bosutinib capsule contents mixed with applesauce to healthy participants arm 2: Bosutinib capsule contents mixed with yogurt to healthy participants arm 3: Bosutinib intact capsules to healthy participants
Interventions: intervention 1: Bosutinib capsule intervention 2: Bosutinib capsule intervention 3: Bosutinib capsule
Intervention descriptions: intervention 1: 500 mg dose of bosutinib capsule contents mixed with applesauce intervention 2: 500 mg dose of bosutinib capsule contents mixed with yogurt intervention 3: 500 mg dose of intact bosutinib capsules

Protocol documents:
Prot_000.pdf: 
PF-05208763 
Protocol B1871063
Final Protocol, 22 March 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL, RANDOMIZED, 3-PERIOD, 6-SEQUENCE, 
CROSSOVER STUDY TO EVALUATE THE BIOAVAILABILITY OF BOSUTINIB
ADMINISTERED AS CAPSULE CONTENTS MIXED WITH APPLESAUCE OR 
YOGURT RELATIVE TO INTACT CAPSULES IN HEALTHY PARTICIPANTS 
UNDER FED CONDITION
Study Intervention Number:
PF-05208763
Study Intervention Name:
Bosutinib
US IND Number:
EudraCT Number:
2021-000500-38
ClinicalTrials.gov ID:  
N/A
Protocol Number:
B1871063
Phase:
1
Brief Title: Bioavailability of Bosutinib Administered as Capsule Contents Mixed With
Applesauce or Yogurt Relative to Intact Capsules Under Fed Condition
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Document History
Document
Version Date
Original protocol
22 March 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities .............................................................................................13
2. INTRODUCTION ...............................................................................................................17
2.1. Study Rationale .......................................................................................................17
2.2. Background .............................................................................................................17
2.2.1. Clinical Overview.......................................................................................17
2.3. Benefit/Risk Assessment.........................................................................................18
2.3.1. Risk Assessment.........................................................................................18
2.3.2. Benefit Assessment.....................................................................................20
2.3.3. Overall Benefit/Risk Conclusion................................................................20
3. OBJECTIVES AND ENDPOINTS.....................................................................................20
4. STUDY DESIGN.................................................................................................................20
4.1. Overall Design.........................................................................................................20
4.2. Scientific Rationale for Study Design.....................................................................22
4.3. Justification for Dose ..............................................................................................22
4.4. End of Study Definition ..........................................................................................23
5. STUDY POPULATION......................................................................................................23
5.1. Inclusion Criteria.....................................................................................................24
5.2. Exclusion Criteria....................................................................................................24
5.3. Lifestyle Considerations..........................................................................................27
5.3.1. Meals and Dietary Restrictions...................................................................27
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................27
5.3.3. Activity .......................................................................................................28
5.3.4. Contraception..............................................................................................28
5.4. Screen Failures ........................................................................................................28
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................28
6.1. Study Intervention(s) Administered........................................................................29
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6.1.1. Administration............................................................................................29
6.2. Preparation, Handling, Storage, and Accountability...............................................29
6.2.1. Preparation and Dispensing........................................................................31
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................31
6.3.1. Allocation to Study Intervention ................................................................31
6.4. Study Intervention Compliance...............................................................................31
6.5. Dose Modification...................................................................................................32
6.6. Continued Access to Study Intervention After the End of the Study......................32
6.7. Treatment of Overdose............................................................................................32
6.8. Concomitant Therapy..............................................................................................32
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................33
7.1. Discontinuation of Study Intervention ....................................................................33
7.2. Participant Discontinuation/Withdrawal From the Study.......................................33
7.2.1. Withdrawal of Consent...............................................................................34
7.3. Lost to Follow up ....................................................................................................34
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................34
8.1. Efficacy Assessments..............................................................................................36
8.2. Safety Assessments .................................................................................................36
8.2.1. Physical Examinations................................................................................36
8.2.2. Vital Signs ..................................................................................................36
8.2.2.1. Temperature ..............................................................................37
8.2.3. Electrocardiograms.....................................................................................37
8.2.4. Clinical Safety Laboratory Assessments ....................................................38
8.2.5. COVID-19 specific assessments.................................................................38
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................38
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......39
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................39
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................40
8.3.2. Method of Detecting AEs and SAEs ..........................................................40
8.3.3. Follow-Up of AEs and SAEs......................................................................40
8.3.4. Regulatory Reporting Requirements for SAEs...........................................40
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8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................41
8.3.5.1. Exposure During Pregnancy......................................................41
8.3.5.2. Exposure During Breastfeeding ................................................43
8.3.5.3. Occupational Exposure .............................................................43
8.3.6. Cardiovascular and Death Events...............................................................43
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................43
8.3.8. Adverse Events of Special Interest.............................................................43
8.3.8.1. Lack of Efficacy........................................................................43
8.3.9. Medical Device Deficiencies......................................................................44
8.3.10. Medication Errors.....................................................................................44
8.4. Pharmacokinetics ....................................................................................................44
8.5. Genetics...................................................................................................................45
8.5.1. Specified Genetics ......................................................................................45
8.5.2. Retained Research Samples for Genetics ...................................................45
8.6. Biomarkers ..............................................................................................................46
8.6.1. Retained Research Samples for Biomarkers...............................................46
8.7. Immunogenicity Assessments.................................................................................46
8.8. Health Economics ...................................................................................................46
9. STATISTICAL CONSIDERATIONS ................................................................................46
9.1. Statistical Hypotheses .............................................................................................46
9.2. Analysis Sets ...........................................................................................................47
9.3. Statistical Analyses .................................................................................................47
9.3.1. Pharmacokinetics Endpoint(s)....................................................................47
9.3.2. Other Safety Analyses ................................................................................49
9.4. Interim Analyses .....................................................................................................49
9.5. Sample Size Determination.....................................................................................50
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................51
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............51
10.1.1. Regulatory and Ethical Considerations ....................................................51
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................51
10.1.2. Informed Consent Process ........................................................................52
10.1.3. Data Protection .........................................................................................53
10.1.4. Committees Structure ...............................................................................53
10.1.4.1. Data Monitoring Committee ...................................................53
10.1.5. Dissemination of Clinical Study Data ......................................................53
10.1.6. Data Quality Assurance ............................................................................54
10.1.7. Source Documents....................................................................................55
10.1.8. Study and Site Start and Closure ..............................................................56
10.1.9. Publication Policy.....................................................................................57
10.1.10. Sponsor’s Qualified Medical Personnel .................................................58
10.2. Appendix 2: Clinical Laboratory Tests .................................................................59
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................61
10.3.1. Definition of AE .......................................................................................61
10.3.2. Definition of an SAE ................................................................................62
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................63
10.3.4. Reporting of SAEs....................................................................................67
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................68
10.4.1. Male Participant Reproductive Inclusion Criteria....................................68
10.4.2. Female Participant Reproductive Inclusion Criteria.................................68
10.4.3. Woman of Childbearing Potential ............................................................68
10.4.4. Contraception Methods.............................................................................69
10.5. Appendix 5: Genetics............................................................................................71
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......72
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................74
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10.9. Appendix 9: Abbreviations ...................................................................................84
11. REFERENCES ..................................................................................................................87
LIST OF TABLES
Table 1.
Schedule of Activities...............................................................................13
Table 2.
Pharmacokinetic Sampling Schema for Periods 1 through 3 ...................16
Table 3.
Study Design and Treatments...................................................................21
Table 4.
Summary of Bosutinib Formulation.........................................................29
Table 5.
Definitions of PK Parameters...................................................................47
Table 6.
Protocol-Required Safety Laboratory Assessments .................................59
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: Bioavailability of Bosutinib Administered as Capsule Contents Mixed With 
Applesauce or Yogurt Relative to Intact Capsules Under Fed Condition.
Background and Rationale
Bosutinib (PF-05208763) is an orally active Src/Abl kinase inhibitor indicated for the 
treatment of adult patients with Ph+ CML.
The pediatric development program for Bosulif® is being conducted in accordance with the 
requirements of the EU PIP (000727PIP01-09-M03) and Pediatric Written Request 
(Amendment 2 dated 30 October 2019).  In the pediatric development program for bosutinib, 
a capsule formulation has been developed as an age-appropriate dosage form and is currently 
being used in the ongoing Phase 1/2 pediatric study (ITCC-054/COG AAML1921, also 
known as BCHILD) along with the commercial immediate release film-coated tablets of 
100 mg and 500 mg strength to allow for BSA based dosing over a wide pediatric age range 
(1 to <18 years).  The ongoing BCHILD study allows for administration of capsule content 
sprinkled on applesauce or yogurt for patients with difficulty in swallowing.  The purpose of 
this study is to compare the bioavailability of bosutinib when orally administered as capsule 
contents mixed with applesauce or yogurt to oral administration of intact capsules in healthy 
participants under fed condition.
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Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
•
To estimate the relative bioavailability of a 
single 500 mg dose of bosutinib when 
administered as capsule contents mixed with 
applesauce to intact capsules under fed 
condition in adult healthy participants.
•
To estimate the relative bioavailability of a 
single 500 mg dose of bosutinib when 
administered as capsule contents mixed with 
yogurt to intact capsules under fed condition in 
adult healthy participants.
•
Plasma AUCinf and Cmax for bosutinib (AUClast
will be used as the primary estimate if AUCinf
cannot be reliably estimated).
Secondary: 
Secondary: 
•
To evaluate the PK of bosutinib when 
administered as capsule contents mixed with 
applesauce or yogurt and as intact capsules to 
healthy participants under fed condition.
•
To evaluate the safety and tolerability of 
bosutinib when administered as capsule 
contents mixed with applesauce or yogurt and 
as intact capsules to healthy participants under 
fed condition.
•
Plasma AUClast, Tmax, CL/F, Vz/F and t½ for 
bosutinib.
•
Safety laboratory tests and AE monitoring. 
 
 
 
 
 
 
 
 
Overall Design
This will be a Phase 1, open-label, randomized, single dose, 3-period, 6-sequence, crossover 
study in healthy participants.
Number of Participants
Approximately 18 participants (3 participants per sequence) will be enrolled to study 
intervention. If there are participants who withdraw or discontinue treatment and are 
considered to be non-evaluable with respect to the primary PK objective, additional 
participants can be enrolled at the discretion of the investigator upon consultation with the 
sponsor.
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Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and screening. A participant will be considered 
enrolled if the informed consent is not withdrawn prior to participating in any study activity 
after screening.  Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.
Intervention Groups and Duration
Treatment 
Sequence
Period 1
Washout
Period 2
Washout
Period 3
1 (n=3)
C
At least 14 
days between
successive
bosutinib 
doses
A
At least 14 
days between 
successive 
bosutinib 
doses
B
2 (n=3)
B
C
A
3 (n=3)
A
B
C
4 (n=3)
B
A
C
5 (n=3)
A
C
B
6 (n=3)
C
B
A
Treatment A (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of 
applesauce under fed condition. 
Treatment B (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of full fat 
yogurt under fed condition.
Treatment C (Reference): 500 mg (100 mg x 5) bosutinib intact capsules under fed condition.
Since the mean plasma elimination t½ of bosutinib is approximately 34 hours (range 18 to 
55 hours), there will be a minimum 14-day washout period between successive doses of 
bosutinib.
Blood samples for PK analysis will be collected predose and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 
60, 72, 96, and 144 hours post the bosutinib dose.
Participants will be in the study for up to approximately 13 weeks, including the screening 
and follow-up periods.  Participants will be screened within 28 days prior to the first dose of 
the IP and if all study entry criteria are fulfilled, the participants will report to the CRU on 
the day prior to Day 1 dosing (Day -1) of Period 1.  Following an overnight fast of at least 10 
hours, on Day 1 of each period, participants will receive a high-fat and high-calorie breakfast 
prior to dosing which will need to be completely consumed within 20 minutes.  For reference 
Treatment C, bosutinib intact capsules will be administered with approximately 240 mL of 
ambient temperature water.  For Test Treatments A and B, bosutinib capsule contents will be 
administered as granules mixed with 45 mL of applesauce or yogurt followed by 
approximately 240 mL of ambient temperature water.  Intact capsules (Treatment C) and 
capsule contents mixed with applesauce or yogurt (Treatments A and B, respectively) will be 
swallowed and not chewed.
 
 
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Participants will be confined in the CRU for a minimum of 5 days until completion of the 
72 hour PK sample collection on Day 4 in each period.  Participants will be discharged at the 
discretion of the investigator.  The investigator could choose to confine participants in the 
CRU and discharge them following the 96 hour PK sample on Day 5.  Participants 
discharged on Day 5 will be required to return to the CRU for outpatient visit on Day 7 of 
each period.  Alternatively, participants may be discharged from the CRU on Day 4, 
provided that they are able to return for outpatient visits on Days 5 and 7.  A follow-up phone 
call will be made at least 28 calendar days and up to 35 calendar days after the last 
administration of the IP to capture any potential AEs, prior/concomitant treatments and 
confirm appropriate contraceptive usage.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Natural logarithm-transformed bosutinib AUCinf, AUClast and Cmax will be analyzed using a 
mixed effect model with sequence, period and treatment as fixed effects and participant
within sequence as a random effect.  Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model.  The adjusted 
mean differences and 90% CIs for the differences will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
The following 2 comparisons will be performed:
•
Treatment A (Test) vs Treatment C (Reference)
•
Treatment B (Test) vs Treatment C (Reference)
The plasma PK parameters AUCinf, Cmax, AUClast, Tmax, CL/F, Vz/F and t½ of bosutinib will 
be summarized descriptively by treatment.  For AUCinf, AUClast and Cmax, a listing of the 
individual participant ratios (Test-Reference) will be provided for the 2 comparisons 
described above.  Individual participant PK parameters for AUCinf, AUClast and Cmax will be 
plotted by treatment and overlaid with geometric mean.  Concentrations will be listed and 
summarized descriptively by PK sampling time and treatment.  Individual participant and 
median profiles of the concentration-time data will be plotted by treatment.  For summary 
statistics and median plots by sampling time, the nominal PK sampling time will be used, for 
individual participant plots by time, the actual PK sampling time will be used.
AEs, ECG, BP, pulse rate, and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants.  Any clinical laboratory, 
ECG, BP, and pulse rate abnormalities of potential clinical concern will be described.  Safety 
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data will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate.
 
 
Radar plots for each time 
point, summarizing all attributes for each soft food will be generated. Box plots of each 
attribute will be plotted against the time points. The categorical summary (frequency and 
percentage) will be provided. 
1.2. Schema
Not applicable.
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Table 1.
Schedule of Activities
Visit Identifiera
Screening
Periods 1 through 3
Follow-up
contact
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day 28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7o
28-35 
Daysb
Hours After Dose
0n
24
48
72
96
144
Informed consent
X
Review inclusion/exclusion 
criteria
X
Xp
CRU confinement
X
→
→
→
Xc
Xc
Outpatient visit to CRUd
Xc
X
Demography (including 
measurement of height and 
weight)
X
Medical historye
X
Xp
Physical examf
X
X
X
Supine BP, temperature and 
pulse rateg
X
X
X
X
Single 12-Lead ECGg
X
X
X
X
Safety laboratoryh
X
X
Xc
X
X
X
Contraception check 
X
X
Xc
X
X
X
X
FSHi
X
Urine drug screening
X
X
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Table 1.
Schedule of Activities
Visit Identifiera
Screening
Periods 1 through 3
Follow-up
contact
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day 28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7o
28-35 
Daysb
Hours After Dose
0n
24
48
72
96
144
HIV, HBsAg, HBsAb, 
HCVAb, HBcAb 
X
COVID-19 questionnaireq
X
X
X
X
COVID-19 testingj
X
X
X
Xc
X
COVID-19 check 
temperaturer
X
X
X
X
X
X
X
X
X
Bosutinib administrationk
X
 
PK blood sampling 
See Table 2 for detailed sampling times
X
Serious and nonserious AE 
monitoring
X
→
→
→
→
→
→
X
X
X
Prior/concomitant treatments
X
→
→
→
→
→
→
X
X
X
Retained Research Samples
(Prep D1 and Prep B2)m
X
CRU discharge 
Xc
Xc
Abbreviations used in this table may be found in Appendix 9.
a.
Visit Identifier: Day relative to start of study intervention (Day 1).
b.
Follow-up contact: May occur via telephone and must occur at least 28 calendar days and up to 35 calendar days after the last administration of the 
study intervention.
c.
CRU confinement: Participants will be required to stay in the CRU for at least 72 hours following bosutinib dosing and allowed to remain in the CRU 
through the collection of the 96 hour PK sample on Day 5. Participants may be discharged on Day 4 of each period at the discretion of the investigator 
following assessment of bosutinib PK sampling at 72 hours post dosing and completion of all other required assessments. Alternatively, if participants
remain in the CRU until the completion of the 96 hour PK sample collection, the Day 4 discharge assessments described above (except COVID-19 
testing) will be delayed until Day 5.
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Table 1.
Schedule of Activities
Visit Identifiera
Screening
Periods 1 through 3
Follow-up
contact
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day 28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7o
28-35 
Daysb
Hours After Dose
0n
24
48
72
96
144
d.
Outpatient visit: Participants who are discharged on Day 4 will be required to return to the CRU for outpatient visits on Days 5 and 7 during each 
treatment period. If participants are confined in the CRU until completion of the 96 hour PK sample and discharged on Day 5, they will be required to 
return to the CRU for outpatient visit on Day 7 during each period.
e.
Medical history: Include history of alcohol abuse, tobacco, electronic smoking device, licit and illicit drug use or dependence within 6 months of 
Screening.  
f.
Physical exam: Complete physical examination must either be conducted at Screening or upon admission of Period 1 only and brief physical 
examination must be performed on Day 7 of each period. Brief physical examinations may be performed as appropriate at other times at the 
investigator’s discretion if there are findings during the previous examination, new/open adverse events, or upon discharge/early 
termination/discontinuation.
g.
Single 12-Lead ECG and Vital signs: Collected at screening, at predose on Day 1 of Period 1 and Day 7 of Period 3 only, or upon early 
termination/discontinuation. 
h.
Safety laboratory: Screening sample must be collected within 28 days prior to first administration (see Section 8.2.4).  Safety laboratory assessments 
including urinalysis, hematology, and chemistry will be performed following at least 4 hours fasting.  Safety laboratory samples will be collected on 
Day -1 of each period, prior to discharge of each period and on each outpatient visit or if the reason for discontinuation is related to an AE if 
applicable.  Additional laboratory assessments may be required to evaluate potential cases of Hy’s Law or adverse events as deemed necessary by the 
investigator. Refer to Table 6 in Section 10.2.
i.
FSH: Will be performed at screening for postmenopausal (amenorrheic for at least 12 consecutive months) women only.
j.
COVID-19 testing: The testing for COVID-19 pathogen by PCR will be performed at each visit. The testing will be performed at screening and on 
Day -1, Day 4 and Day 7 of each period and other timepoints as deemed necessary to assess the safety at the discretion of the investigator.  Day 5 
testing will be performed only if participants are discharged on Day 4. In that case, a testing will be performed on Day 5 outpatient visit of each period.
k.
Bosutinib administration: Dosing under fed condition in each period will be separated by at least a 14-day washout interval from bosutinib dosing in 
the prior period.
 
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Table 1.
Schedule of Activities
Visit Identifiera
Screening
Periods 1 through 3
Follow-up
contact
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day 28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7o
28-35 
Daysb
Hours After Dose
0n
24
48
72
96
144
m. Retained Research Samples: Period 1 only.  Prep D1 is a Retained Research Sample for Genetics. If Prep D1 and Prep B2 are not collected on the 
designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a participant visit.
n.
Day 1 0h: Activities to be performed predose, except for study intervention administration.
o.
Day 7 (Period 3): Will be used as the end of study visit including at a minimum: safety labs, ECG assessment, supine BP, temperature and pulse rate 
assessments, the last PK sample collection, assessment of participant-reported adverse events, a review of prior/concomitant treatments, contraception 
check, COVID-19 testing, COVID-19 questionnaire, COVID-19 check temperature and a brief physical examination.
p.
Review inclusion/exclusion criteria and Medical history: Period 1 only. Review any changes from Screening.
q.
COVID-19 questionnaire: Check exposure to positive participant, and COVID-19 related signs and symptoms. To be done at screening and at each 
visit.  Day 5 questionnaire will be performed only if participants are discharged on Day 4. In that case, the questionnaire will be performed on Day 5 
outpatient visit of each period.
r.
COVID-19 check temperature: To be done at least daily during residence at CRU.
Table 2.
Pharmacokinetic Sampling Schema for Periods 1 through 3
Visit Identifier 
Periods 1 through 3
Study Day
1
2
3
4
5
7
Hours Before/After Dose
0a
1
2
3
4
6
8
12
24
36
48
60
72
96
144
Bosutinib administration
X
PK blood samplingb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Predose PK samples collected any time prior to dosing bosutinib on Day 1 of each period.
b.
Bosutinib PK blood samples (approximately 3 mL blood to yield approximately 1.0 mL plasma per sample) will be collected.
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2. INTRODUCTION
Bosutinib (PF-05208763) is an orally active Src/Abl kinase inhibitor indicated for the 
treatment of adult patients with Ph+ CML.
2.1. Study Rationale 
The pediatric development program for bosutinib is being conducted in accordance with the 
requirements of the EU PIP (000727PIP01-09-M03) and Pediatric Written Request 
(Amendment 2 dated 30 October 2019).  In the pediatric development program for bosutinib, 
a capsule formulation has been developed as an age-appropriate dosage form and is currently 
being used in the ongoing Phase 1/2 pediatric study (ITCC-054/COG AAML1921, also 
known as BCHILD) along with the commercial immediate release film-coated tablets of 
100 mg and 500 mg strength to allow for BSA based dosing over a wide pediatric age range
(1 to <18 years).  The ongoing BCHILD study allows for administration of capsule content 
sprinkled on applesauce or yogurt for patients with difficulty in swallowing.  The purpose of 
this study is to compare the bioavailability of bosutinib when orally administered as capsule 
contents mixed with applesauce or yogurt to the oral administration of intact capsules in 
healthy participants under fed condition.
2.2. Background 
2.2.1. Clinical Overview
Bosutinib (PF-05208763) is an orally active Src/Abl kinase inhibitor with potent 
antiproliferative and proapoptotic activity in cultured chronic myelogenous leukemia cells, 
and antiproliferative activity in primitive progenitor chronic myelogenous leukemia cells 
from patients.  Bosutinib is approved in the US for the treatment of newly diagnosed CP 
Ph+ CML (400 mg once daily), and adult patients with CP, AP or blast phase Ph+ CML with 
resistance or intolerance to prior therapy (500 mg once daily); and received initial conditional 
marketing authorization in the EU for the treatment of adult patients CP, AP, and blast phase 
Ph+ CML previously treated with 1 or more TKIs, and for whom imatinib, nilotinib and 
dasatinib are not considered appropriate treatment options, and an extended indication for 
patients with newly-diagnosed CP Ph+ CML.  Bosutinib exhibits dose proportional increases 
in AUC and Cmax over the dose range of 200 to 800 mg when administered as a single oral 
dose in healthy participants under fed conditions.  Bosutinib absorption was relatively slow, 
with a median Tmax of 6 hours, and mean t½ was 33 to 39 hours after single oral doses, for 
healthy participants.  Food increases plasma exposures of bosutinib and appears to improve 
tolerability of bosutinib.  Bosutinib is labeled to be taken with food.
Bosutinib has shown an acceptable safety profile in the Phase 1, Phase 2, and Phase 3 
studies.  As of 11 January 2019, bosutinib has been administered as a single dose in 17 
clinical pharmacology and biopharmaceutic studies in healthy participants.  In general, AEs 
with bosutinib have included predominantly low-grade GI toxicities and general symptoms 
such as fatigue and asthenia. Other frequent AEs include rash and increases in plasma levels 
of hepatic transaminases (ALT and AST).  In a study conducted in healthy participants who 
were treated with 500 mg bosutinib under fed condition, 36 participants out of the 40 treated 
had TEAEs.  The most frequently reported TEAEs (occurring in ≥10% participants) were GI 
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disorders, including diarrhea (67.5%), nausea (52.5%), vomiting (32.5%), dizziness (25%), 
abdominal pain (17.5%), headache (15%), and dyspepsia (12.5%).  All TEAEs were mild or 
moderate in severity. 
Additional information for this compound may be found in the SRSD, which for this study is 
the IB1.
2.3. Benefit/Risk Assessment
Bosutinib is not expected to provide any clinical benefit to healthy participants. This study is 
designed primarily to generate PK data for bosutinib capsule contents mixed with soft foods 
(applesauce and yogurt) or when administered as intact capsule to enable pediatric clinical 
development.  In this study, bosutinib will be administered at single doses of 500 mg.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of bosutinib may be found in the current version of the IB, which is 
the SRSD for this study. 
Overall, single 500 mg doses of bosutinib in healthy participants are expected to be safe and 
well tolerated in this study.
2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Intervention Bosutinib 
Potential risk of decline in 
renal function (eGFR).
The potential risk is based on 
AEs reported in Ph+ CML
patients as included in the IB.
Eligibility criteria have been selected to 
ensure that only appropriate participants 
are included in the study (see Section 5).
Clinical laboratory results will be 
monitored on an ongoing basis.  
Potential risk of elevations in 
serum transaminases (ALT, 
AST).
The potential risk is based on 
AEs reported in Ph+ CML 
patients as included in the IB.
Eligibility criteria have been selected to 
ensure that only appropriate participants 
are included in the study (see Section 5).
Clinical laboratory results will be 
monitored on an ongoing basis.  
Instructions for managing potential cases 
of drug-induced liver injury are provided 
(see Appendix 6).
Potential risk of 
gastrointestinal disorders.
The potential risk is based on 
AEs reported in Ph+ CML 
patients and healthy 
participants as included in the 
IB.
Eligibility criteria have been selected to 
ensure that only appropriate participants 
are included in the study (see Section 5).
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Potential risk to fetus.
Studies in animals have shown 
reproductive toxicity.
WOCBP, male participants with partners 
currently pregnant and male participants 
who are unwilling or unable to use a 
highly effective method of contraception 
as defined in the study protocol will be 
excluded (See Sections 5.1, 5.2 and
Appendix 4).
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2.3.2. Benefit Assessment
For healthy participants in this study, no clinical benefit is expected. 
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to study participants, the potential 
risks identified in association with administration of bosutinib is clinically acceptable.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To estimate the relative bioavailability of a 
single 500 mg dose of bosutinib when 
administered as capsule contents mixed with 
applesauce to intact capsules under fed 
condition in adult healthy participants.
•
To estimate the relative bioavailability of a 
single 500 mg dose of bosutinib when 
administered as capsule contents mixed with 
yogurt to intact capsules under fed condition in 
adult healthy participants.
•
Plasma AUCinf and Cmax for bosutinib (AUClast
will be used as the primary estimate if AUCinf
cannot be reliably estimated).
Secondary: 
Secondary: 
•
To evaluate the PK of bosutinib when 
administered as capsule contents mixed with 
applesauce or yogurt and as intact capsules to 
healthy participants under fed condition.
•
To evaluate the safety and tolerability of 
bosutinib when administered as capsule 
contents mixed with applesauce or yogurt and 
as intact capsules to healthy participants under 
fed condition.
•
Plasma AUClast, Tmax, CL/F, Vz/F and t½ for 
bosutinib.
•
Safety laboratory tests and AE monitoring. 
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This will be a Phase 1, open-label, randomized, single dose, 3-period, 6-sequence, crossover 
study in approximately 18 healthy participants.  Participants will be randomized to 1 of the 6 
sequences of treatment described in Table 3.
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Table 3.
Study Design and Treatments
Treatment 
Sequence
Period 1
Washout
Period 2
Washout
Period 3
1 (n=3)
C
At least 14 days
between 
successive 
bosutinib doses
A
At least 14 days
between 
successive 
bosutinib doses
B
2 (n=3)
B
C
A
3 (n=3)
A
B
C
4 (n=3)
B
A
C
5 (n=3)
A
C
B
6 (n=3)
C
B
A
Treatment A (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of applesauce 
under fed condition. 
Treatment B (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of full fat yogurt 
under fed condition.
Treatment C (Reference): 500 mg (100 mg x 5) bosutinib intact capsules under fed condition.
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and screening. A participant will be considered 
enrolled if the informed consent is not withdrawn prior to participating in any study activity 
after screening. Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.
Since the mean plasma elimination t½ of bosutinib is approximately 34 hours (range 18 to 
55 hours), there will be a minimum 14-day washout period between successive doses of 
bosutinib.
Blood samples for PK analysis will be collected predose and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 
60, 72, 96, and 144 hours post the bosutinib dose.
Participants will remain in the study for up to approximately 13 weeks, including the 
screening and follow-up periods.  Participants will be screened within 28 days of the first 
dose of IP and if all study entry criteria are fulfilled, the participants will report to the CRU 
on the day prior to Day 1 dosing (Day -1) of Period 1.  Following an overnight fast of at least 
10 hours, on Day 1 of each period, participants will receive a high-fat and high-calorie
breakfast (see Section 5.3.1) prior to dosing which will need to be completely consumed 
within 20 minutes.  For reference Treatment C, bosutinib intact capsules will be administered 
with approximately 240 mL of ambient temperature water. For Test Treatments A and B, 
bosutinib capsule contents will be administered as granules mixed with 45 mL of applesauce 
or yogurt, respectively, followed by approximately 240 mL of ambient temperature water. 
Intact capsules (Treatment C) and capsule contents mixed with applesauce or yogurt 
(Treatments A and B, respectively) will be swallowed and not chewed.
 
 
 
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Participants will be confined in the CRU for a minimum of 5 days until completion of the 
72 hour PK sample collection on Day 4 in each period.  Participants will be discharged at the 
discretion of the investigator.  The investigator could choose to confine participants in the 
CRU and discharge them following the 96 hour PK sample on Day 5.  Participants 
discharged on Day 5 will be required to return to the CRU for outpatient visit on Day 7 of 
each period.  Alternatively, participants may be discharged from the CRU on Day 4, 
provided that they are able to return for outpatient visits on Days 5 and 7.  A follow-up phone 
call will be made at least 28 calendar days and up to 35 calendar days after the last 
administration of the IP to capture any potential AE, prior/concomitant treatments and 
confirm appropriate contraceptive usage.
Tolerability and safety will be assessed for all treatments by monitoring AEs, ECGs, BP, 
pulse rate and safety laboratory data.  
If there are participants who withdraw or discontinue treatment and are considered to be 
non-evaluable with respect to the primary PK objective, additional participants can be 
enrolled at the discretion of the investigator upon consultation with the sponsor.
4.2. Scientific Rationale for Study Design
The current study aims to compare the bioavailability of bosutinib when orally administered 
as capsule contents mixed with applesauce or yogurt to the oral administration of intact 
capsules in healthy participants under fed condition.
The study is being designed as a crossover study to account for any period effect.  Between 
each sequential dosing of bosutinib, a minimum of 14-day washout is proposed to minimize 
any residual bosutinib concentrations prior to start of the next period, as bosutinib has a
plasma elimination t½ of approximately 34 hours.
Bosutinib is currently labeled to be administered with food for improved tolerability.  
Therefore, this study will be conducted under fed condition using a high-fat and high-calorie 
meal2,3.
Based on findings from animal studies and its mechanism of action, bosutinib can cause fetal 
harm when administered to a pregnant woman; therefore, females of child-bearing potential 
will be excluded from the study.  In addition, male participants with partners currently 
pregnant will be excluded and the use of a highly effective method of contraception is 
required for male participants with female partners of child bearing potential (see 
Appendix 4).
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
In the current study, bosutinib will be administered at a single dose of 500 mg mixed with
45 mL of applesauce or yogurt or as intact capsules.
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The capsule dosage form has been developed as an age-appropriate dosage form to facilitate 
administration of capsule contents mixed with soft foods as a vehicle for patients with 
difficulty in swallowing.  Since this mode of administration with soft foods is generally 
expected to be used in younger patients with a BSA between 0.3 - 1.2 m2 (approximate age 
1 - 10 years), the anticipated dose of bosutinib is in the range of 100 mg to 500 mg in this 
patient population (400 mg - 2000 mg granules).  Therefore, the maximum dose of 500 mg 
was selected in this study.
Applesauce and yogurt were chosen as they provide the necessary compatibility and stability 
for administration of bosutinib granules as a sprinkle.  Availability of both applesauce and 
yogurt would allow young patients to choose the soft food of their preference. In considering 
the volume of soft food to be used for administration, 45 mL of soft food is required to 
disperse 2000 mg granules (comprises 500 mg bosutinib) with acceptable viscosity.
Bosutinib pediatric capsules are available as 25 mg, 50 mg and 100 mg dose strengths. In 
order to minimize the manipulation of number of capsules required to make up the desired 
dose, multiples of 100 mg (100 mg × 5) capsules will be used to attain the target dose of 
500 mg in this proposed study.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the follow-up visit and the investigator has reviewed the final safety data 
and determines that no additional evaluation is required.
The end of the study is defined as the date of the follow-up visit of the last participant in the 
study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Female participants of non-childbearing potential and/or male participants must be 18 
to 55 years of age, inclusive, at the time of signing the ICD.
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including a detailed medical history, complete physical examination, vital 
signs which include BP, temperature and pulse rate measurement, clinical laboratory 
tests, and ECG.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
4. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal (eg, ulcerative colitis, irritable bowel syndrome, Crohn’s 
disease), cardiovascular, hepatic, psychiatric, neurological, dermatological, or allergic 
disease (including drug allergies, but excluding untreated, asymptomatic, seasonal 
allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
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3. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
HBcAb or HCVAb.  As an exception, a positive HBsAb as a result of participant 
vaccination is permissible.
4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
5. A history of hypersensitivity to the active compounds or to any inactive ingredients 
(excipients) contained in the formulations of bosutinib. 
Prior/Concomitant Therapy:
6. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.
Proton pump inhibitors must be discontinued at least 14 days prior to the first dose of 
study medication.
Hormone replacement therapy must be discontinued at least 28 days prior to the first 
dose of study medication.
Refer to Section 6.8 for additional details.
Prior/Concurrent Clinical Study Experience:
7. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention 
used in this study (whichever is longer).  
Diagnostic Assessments:
8. A positive urine drug test.
9. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest.  If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
10. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTcF interval 
>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial
infarction, ST-T interval changes suggestive of myocardial ischemia, second 
or -third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias).  If the 
baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected 
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using the Fridericia method and the resulting QTcF should be used for decision 
making and reporting.  If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the 
ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values 
should be used to determine the participant’s eligibility.  Computer-interpreted ECGs 
should be overread by a physician experienced in reading ECGs before excluding a 
participant.
11. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary:
•
eGFR (CKD-EPI) < 90
•
AST or ALT level ≥1.5 × ULN;
•
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.
Other Exclusions:
12. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening.  Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours.  As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces [240 mL] beer, 
1 ounce [30 mL] of 40% spirit or 3 ounces [90 mL] of wine).
13. Use of tobacco/nicotine containing products in excess of the equivalent of 
5 cigarettes/day.
14. Male participants with partners currently pregnant; male participants who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the study and for at least 28 days after the last dose of 
IP.
15. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.  
16. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
17. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions
•
Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations.
•
Following an overnight fast of at least 10 hours, a high-fat (approximately 50% of 
total caloric content of the meal), high-calorie (approximately 800 to 1000 calories) 
breakfast will be provided prior to bosutinib dosing on Day 1 of each period.
Participants should begin breakfast approximately 30 minutes prior to bosutinib
administration which should be completely consumed within 20 minutes.  Bosutinib 
will be administered approximately 30 minutes after starting the breakfast.  There will 
be no restrictions on intake of water prior to and after dosing. 
•
Lunch will be provided approximately 4 hours after bosutinib dosing on Day 1 of 
each period.
•
Dinner will be provided approximately 9 to 10 hours after bosutinib dosing on Day 1 
of each period .
•
An evening snack may be permitted.
•
Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample in each 
period.  
•
With the exception of the high-fat/high-calorie meal administered prior to dosing on 
Day 1 of each period, while participants are confined to the CRU, their total daily 
nutritional composition should be approximately 55% carbohydrate, 30% fat, and 
15% protein.  The daily caloric intake per participant should not exceed 
approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco
•
Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing and during confinement in the CRU.  
•
Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period.  Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.
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•
Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.3. Activity
•
Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
•
In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception) considering that their risk for 
pregnancy may have changed since the last visit. In addition, the investigator or designee 
will instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/enrolled in the study.  Screen 
failure data are collected and remain as source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if prior reason for not meeting the eligibility criteria has been resolved.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, the term IP may be used synonymously with study 
intervention. 
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6.1. Study Intervention(s) Administered
For this study, the study intervention is bosutinib, which will be administered as intact 
capsules or capsule contents mixed with 45 mL of applesauce or yogurt.  
Bosutinib 100 mg capsules will be supplied to the CRU in multi-dose containers and 
administered to participants in single dose labeled containers.  The bottles will be provided to 
the site for dispensing by the pharmacy.  A brief description of the bosutinib formulations 
supplied in this study is provided in Table 4.  
Table 4.
Summary of Bosutinib Formulation
Description
Label Names
Material ID/ 
Lot Number
IP to Package
Route of 
Administration
PF-05208763 100 mg Size 0 (White 
OP/Swedish Orange OP) hard
PF-05208763 
100 mg 
Capsules
D1900094/ 
20-DP-00370
100 mg × 5
bosutinib 
capsules
Oral
6.1.1. Administration
IPs will be administered orally and according to the conditions described in the SoA section 
and Meals and Dietary Restrictions section of this protocol. 
On Day 1 of each period, following an overnight fast of at least 10 hours, participants will 
receive a high-fat and high-calorie breakfast approximately 30 minutes prior to dosing which 
should be completely consumed within approximately 20 minutes as outlined in Section 5.3.1
(Meals and Dietary Restrictions). The participants will then receive IP at approximately 
0800 hours (±2 hours), approximately 10 minutes after the completion of the breakfast.
Investigator site personnel will administer IP during each period.  Intact capsules 
(Treatment C) will be administered with approximately 240 mL of ambient temperature 
water.  Capsule contents will be administered as granules mixed with 45 mL of applesauce or 
yogurt (Treatments A and B, respectively) followed by approximately 240 mL of ambient 
temperature water.  See the IP manual for detailed instructions on preparation and 
administration of IP.  Participants will swallow the intact capsule and capsule contents mixed 
with applesauce or yogurt, and will not manipulate or chew the IP prior to swallowing. 
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the CRU local procedures.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers and in accordance 
with the labels. Refer to Dosing administration instructions (DAI) for capsule content 
mixed with apple sauce /yogurt.
6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.
7. Further guidance and information for the final disposition of unused study 
interventions are provided by CRU or as per local procedures. All destruction must 
be adequately documented. If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer.
8. All retained capsules should be stored by the investigator site or with a third-party 
vendor.  Sample retention is the responsibility of the entity performing the study.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
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6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Bosutinib capsules will be prepared at the CRU in the individual dosing containers by 2 
operators, 1 of whom is a pharmacist.  Prepared doses will be provided in unit dose 
containers and labeled in accordance with Pfizer regulations and the clinical site’s labeling 
requirements.
Study intervention with soft foods should be prepared by 2 operators, 1 of whom is a 
pharmacist.  Detailed instructions on the dose preparation for administration will be provided 
in a separate IP manual.  Prepared doses will be provided in unit dose containers and labeled 
in accordance with Pfizer regulations and investigator site’s labelling requirement.
Dispensing will be performed in PCRU by an appropriately qualified and experienced 
member of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacy assistant/technician, or pharmacist) as allowed by local, state, and institutional 
guidance.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of IPs.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in 
accordance with the randomization numbers, the participant will receive the study treatment 
regimen assigned to the corresponding randomization number.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
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study intervention.  Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5. Dose Modification
Dose modification for bosutinib is not allowed.
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
6.7. Treatment of Overdose
For this study, any dose of bosutinib greater than 800 mg within a 24-hour time period will 
be considered an overdose.
Experience with bosutinib overdose in clinical studies to date was limited to isolated cases.  
There were no reports of any SAEs associated with bosutinib overdoses.  Participants who 
may inadvertently receive an overdose of bosutinib in this study should be observed and 
given appropriate supportive treatment.
In the event of an overdose, the investigator/treating physician should:
1. Contact the Pfizer medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of bosutinib (whichever is 
longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
6.8. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.  Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor.  Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.
Proton pump inhibitors must be discontinued at least 14 days prior to the first dose of study 
medication and is prohibited for the duration of the study.
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Females taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since this will be a single-dose study, this section is not applicable.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:
•
Refused further study procedures;
•
Lost to follow-up;
•
Death;
•
Study terminated by sponsor;
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.  
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
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If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;
•
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;
•
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
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Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
290 mL.  Additional blood samples may be taken for safety assessments at times specified by 
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Pfizer, provided the total volume taken during the study does not exceed 550 mL during any 
period of 60 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance
including skin observation, abdominal examination, the respiratory and cardiovascular 
systems, and participant-reported symptoms. 
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA.  For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface.  Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains.  They must also remove the contents of their pockets and remain 
still during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to 8.3.3.
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mmHg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study.  Participants should be 
instructed not to speak during measurements.  
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The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.2.1. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 15 
minutes prior to the measurement.  
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex.  Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement.  All scheduled ECGs should be performed after the participant 
has rested quietly for at least 5 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline (Period 1, Day 1 predose) measurements.  Additional ECG 
monitoring will occur if a) a postdose QTc interval is increased by ≥60 msec from the 
baseline and is >450 msec; or b) an absolute QTc value is ≥500 msec for any scheduled 
ECG.  If either of these conditions occurs, then 2 additional ECGs will be collected 
approximately 2 to 4 minutes apart to confirm the original measurement.  If the QTc values 
from these repeated ECGs remain above the threshold value, then a single ECG must be 
repeated at least hourly until QTc values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If a) a postdose QTc interval remains ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator); or c) QTc intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTc intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
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ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
Participants may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.2.5. COVID-19 specific assessments
Participants will be tested for SARS-CoV-2 infection by PCR prior to being admitted to the 
clinic. A subsequent SARS-CoV-2 test will be performed after 4 days of confinement (i.e. 
upon completion of 4 × 24 hours in house), or if they develop COVID-19 like symptoms. 
Additional testing may be required by local regulations or by the Principal Investigator.  See 
Section 1.3 for additional COVID-19 related assessments including questionnaire and 
temperature check performed at times as specified in the SoA.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).
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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 to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the CT 
SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
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Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 
•
A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.
•
A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:  
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
•
If EDP occurs in a participant’s partner, the investigator must report this information 
to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental Form, 
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regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until 28 days after the last dose.
•
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
•
Spontaneous abortion including miscarriage and missed abortion;
•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 
•
A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation, or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not Applicable
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not Applicable
8.3.8. Adverse Events of Special Interest
Not Applicable
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
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8.3.9. Medical Device Deficiencies
Not Applicable
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:
•
Medication errors involving participant exposure to the study intervention;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics 
Blood samples of approximately 3 mL each, to provide approximately 1.0 mL plasma, will 
be collected for measurement of plasma concentrations of bosutinib as specified in the SoA.  
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual.  The actual date and time (24-hour clock time) of each sample will be 
recorded.
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The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF/DCT.  Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing and 
samples collected at outpatient visits (eg, Day 7) that are obtained ≤4 hours away from the 
nominal time relative to dosing will not be captured as a protocol deviation, as long as the 
exact time of the collection is noted on the source document and the CRF/DCT. 
Samples will be used to evaluate the PK of bosutinib.  Samples collected for analyses of 
bosutinib (plasma) concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of bosutinib will be analyzed 
using a validated analytical method in compliance with applicable SOPs.  
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.5. Genetics
8.5.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.5.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s).
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the lab manual and other 
supporting documentation.
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8.6. Biomarkers
8.6.1. Retained Research Samples for Biomarkers 
These Retained Research Samples will be collected in this study:
•
10 mL whole blood (Prep B2 optimized for serum).
Retained Research Samples will be collected as local regulations and IRB/ECs allow
according to the SoA.
Retained Research Samples may be used for research related to drug response and safety 
biomarkers. Genes and other analytes (eg, proteins, RNA, non-drug metabolites) may be 
studied using the retained samples.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual and 
supporting documentation.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
 
 
 
 
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
Not applicable.
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9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
PK Concentration
The PK concentration population is defined as all participants 
randomized and treated who have at least 1 bosutinib 
concentration in at least 1 treatment period.
PK Parameter
The PK parameter analysis population is defined as all 
participants randomized and treated who have at least 1 of the 
bosutinib PK parameters of primary interest in at least 1 
treatment period.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants 
will be analyzed according to the product they actually 
received.
9.3. Statistical Analyses
The SAP will be developed and finalized prior to database lock before any analyses are 
performed and will describe the analyses and procedures for accounting for missing, unused, 
and spurious data.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints
9.3.1. Pharmacokinetics Endpoint(s)
Bosutinib PK parameters following a single dose administration will be estimated from the 
concentration time profiles using non-compartmental methods as data permit. The various 
PK parameters to be assessed in this study, their definition, and method of determination are 
outlined in Table 5.  In all cases, actual PK sampling times will be used in the derivation of 
PK parameters.
Table 5.
Definitions of PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration time 
profile from time zero to the time of the last 
quantifiable concentration (Clast)
Linear-log trapezoidal method
AUCinfa
Area under the plasma concentration-time 
profile from time zero extrapolated to infinite 
time
AUClast + (Clast*/kel) 
where Clast* is the predicted plasma 
concentration at the last quantifiable time 
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Table 5.
Definitions of PK Parameters
Parameter
Definition
Method of Determination
point estimated from the log-linear 
regression analysis and kel is the terminal 
phase rate constant calculated by a linear 
regression through at least 3 data points in 
the terminal phase of the log-linear 
concentration-time curve.
Cmax
Maximum plasma concentration
Observed directly from the data
Tmax
Time for Cmax
Observed directly from the data as time of 
first occurrence
t½a
Terminal elimination half-life
Loge(2)/kel,  
Only those data points judged to describe 
the terminal log-linear decline will be used 
in the regression.
CL/Fa
Apparent clearance after oral dose
Dose/AUCinf after oral dose
Vz/Fa
Apparent volume of distribution after oral 
dose
Dose/(AUCinf*kel) after oral dose
a.
As data permits.
Natural logarithm-transformed AUCinf, AUClast and Cmax will be analyzed using a mixed 
effect model with sequence, period and treatment as fixed effects and participant within 
sequence as a random effect.  Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model.  The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
The following 2 comparisons will be performed:
•
Treatment A (Test) vs Treatment C (Reference)
•
Treatment B (Test) vs Treatment C (Reference)
The plasma PK parameters AUCinf, Cmax, AUClast, Tmax, CL/F, Vz/F and t½ of bosutinib will 
be summarized descriptively by treatment.  For AUCinf, AUClast and Cmax, a listing of the 
individual participant ratios (Test-Reference) will be provided for the 2 comparisons 
described above.  Individual participant PK parameters for AUCinf, AUClast and Cmax will be 
plotted by treatment and overlaid with geometric mean.  Concentrations will be listed and 
summarized descriptively by PK sampling time and treatment.  Individual participant and 
median profiles of the concentration-time data will be plotted by treatment.  For summary 
statistics and median plots by sampling time, the nominal PK sampling time will be used, for 
individual participant plots by time, the actual PK sampling time will be used.
If an individual participant has a known cause for biased estimate of a PK parameter (due, for 
example, to an event such as vomiting before all of the drug is absorbed in the body), this 
will be footnoted in summary tables and will not be included in the calculation of summary 
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statistics or statistical analyses.  Participants who vomit at or before 2 times of median Tmax
after drug administration may be excluded from PK analysis.
9.3.2. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants.  Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted.  However, any untoward findings identified on physical examination 
conducted during the active collection period will be captured as AEs, if those findings meet 
the definition of an AE.  Data collected at screening that are used for inclusion/exclusion 
criteria, such as laboratory data, ECGs, and vital signs, will be considered source data, and 
will not be required to be reported, unless otherwise noted.  Demographic data collected at 
screening will be reported.
 
 
 
 
9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment.
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9.5. Sample Size Determination
A sample size of 18 participants will provide 90% confidence intervals for the difference 
between treatments of ±0.1006 and of ±0.1501 on the natural logarithmic scale for AUCinf
and loge Cmax respectively with 90% coverage probability.  The following table presents the 
width of 90% confidence interval for different estimated effects:
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
80%
0.7234, 0.8847
0.1613
90%
0.8139, 0.9953
0.1814
95%
0.8591, 1.0506
0.1915
100%
0.9043, 1.1059
0.2016
105%
0.9495, 0.1611
0.2117
110%
0.9947, 1.2164
0.2217
120%
1.0851, 1.3270
0.2419
Cmax
80%
0.6885, 0.9296
0.2411
90%
0.7745, 1.0458
0.2712
95%
0.8176, 1.1039
0.2863
100%
0.8606, 1.1620
0.3014
105%
0.9036, 1.2201
0.3164
110%
0.9467, 1.2782
0.3315
120%
1.0327, 1.3944
0.3616
These calculations are based on estimates of within-participant standard deviations of 0.1675 
and 0.2499 for loge AUCinf and loge Cmax respectively, as average intra-participant standard 
deviations obtained from bosutinib crossover studies conducted with similar formulations 
and under similar conditions (clinical studies B1871016, B1871024, and B1871035).
If there are participants who withdraw or discontinue treatment and are considered to be 
non-evaluable with respect to the primary PK objective, additional participants can be 
enrolled at the discretion of the investigator upon consultation with the sponsor.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;
•
Applicable ICH GCP guidelines;
•
Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:
•
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;
•
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;
•
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant and answer all questions regarding the study. The 
participant should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study is fully informed about his or her right to 
access and correct his or her personal data and to withdraw consent for the processing of his 
or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened 
are required to sign a new ICD.
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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.4. Committees Structure
10.1.4.1. Data Monitoring Committee 
This study will not use a DMC.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
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EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and IQMP
maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
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Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Source Document 
Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
The investigator must maintain accurate documentation (source data) that supports the
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:
•
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;
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•
Inadequate recruitment of participants by the investigator;
•
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
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10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the CTMS.
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
CBC
Total neutrophils (abs)
Eosinophils (abs)
Monocytes (abs)
Basophils (abs)
Lymphocytes (abs)
BUN/urea and creatinine
eGFR (CKD-EPI)
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local Dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Laboratory:
Microscopy and 
Culturea
Urine drug screeningc
COVID-19 testingd
At Screening Only
FSHb
HBsAg
HBsAb
HBcAb
HCVAb
HIV
Additional Tests 
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bile acid 
(repeat)
Total bilirubin 
(repeat)
Albumin (repeat)
Alkaline 
phosphatase (repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
At Screening for confirmation of postmenopausal status only.
c.
At Screening and Admission.  The minimum requirement for drug screening includes cocaine, THC, 
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific).  Participants 
may undergo an alcohol breath test or blood alcohol test at the discretion of the investigator.
d.
At screening, Day -1, Day 4 and Day 7 of each period and other timepoints as deemed necessary to 
assess the safety at the discretion of the investigator.  Day 5 testing will be performed only if 
participants are discharged on Day 4. In that case, a testing will be performed on Day 5 outpatient 
visit of each period.
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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition
•
An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:
•
Is associated with accompanying symptoms;
•
Requires additional diagnostic testing or medical/surgical intervention;
•
Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.
•
Exacerbation of a chronic or intermittent preexisting condition, including either 
an increase in frequency and/or intensity of the condition.
•
New condition 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. Overdose per se will not be reported 
as an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition
•
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’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 
participant’s condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (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 preexisting condition that did not worsen 
from baseline is not considered an AE.
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d. 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 (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:
•
Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations, such as 
significant medical events that may jeopardize the participant 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.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Note:  Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE). **
Environmental or 
occupational exposure 
to the product under 
study to a non-
participant (not 
involving EDP or EDB).
None.  Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE 
Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational 
exposure are reported to Pfizer Safety using the CT SAE Report Form. 
•
When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
•
The investigator will then record all relevant AE or SAE information in the CRF.
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•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.
•
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
•
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
•
Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.
•
Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self care ADL. Self care ADL refers to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.
•
A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.
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•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.
•
The investigator will also consult the IB and/or product information, for 
marketed products, in his/her assessment.
•
For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
•
If the investigator does not know whether or not the study intervention caused the
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs
•
The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.
•
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.
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•
New or updated information will be recorded in the originally submitted 
documents.
•
The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool
•
The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.
•
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as the data
become available.
•
After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form
•
Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.
•
In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):
•
Refrain from donating sperm.
PLUS either:
•
Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR
•
Must agree to use contraception/barrier as detailed below:
•
Agree to use a male condom when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant.
•
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not a WOCBP (see definitions below in
Section 10.4.3).
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a WOCBP. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
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Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or WOCPB partners of male participants should be consistent with 
local availability/regulations regarding the use of contraceptive methods for those 
participating in clinical trials.
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
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3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner.
•
A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.
•
Oral;
•
Intravaginal;
•
Transdermal;
•
Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation.
•
Oral;
•
Injectable.
8. Sexual abstinence.
•
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 intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent:
•
Male or female condom with or without spermicide;
•
Cervical cap, diaphragm, or sponge with spermicide;
•
A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier method
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10.5. Appendix 5: Genetics
Use/Analysis of DNA
•
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.
•
The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.
•
The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to bosutinib or study interventions of this class to understand 
treatments for the disease(s) under study or the disease(s) themselves.
•
The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.
•
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
•
The samples will be retained as indicated:
•
Retained samples will be stored indefinitely or for another period as per local 
requirements.  
•
Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses.  
•
Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample). In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:
•
Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.
•
For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
•
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).
•
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs
•
Marked sinus bradycardia (rate <40 bpm) lasting minutes.
•
New PR interval prolongation >280 msec.
•
New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline.
•
New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.
•
New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.
•
Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs
•
QTcF prolongation >500 msec.
•
New ST-T changes suggestive of myocardial ischemia.
•
New-onset left bundle branch block (QRS >120 msec).
•
New-onset right bundle branch block (QRS >120 msec).
•
Symptomatic bradycardia.
•
Asystole:
•
In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 
•
In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
•
Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.
•
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).
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•
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)).
•
Type II second-degree (Mobitz II) AV block.
•
Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs
•
Change in pattern suggestive of new myocardial infarction.
•
Sustained ventricular tachyarrhythmias (>30 seconds’ duration).
•
Second- or third-degree AV block requiring pacemaker placement.
•
Asystolic pauses requiring pacemaker placement.
•
Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.
•
Ventricular fibrillation/flutter.
•
At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
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Page 84
10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abl
Abelson 
abs
absolute
ADL
activity of daily living
AE
adverse event
ALT
alanine aminotransferase
AP
accelerated phase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration
AV
atrioventricular
BCHILD
bosutinib in pediatric patients
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Clast
last quantifiable concentration
CL/F
apparent clearance after oral dose
Cmax
maximum observed plasma concentration
CML
chronic myeloid leukemia
CO2
carbon dioxide 
COVID-19
coronavirus disease 2019
CP
chronic phase
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CTMS
clinical trial management system
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Abbreviation
Term
DCT
data collection tool
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EC
ethics committee
ECC
Emergency Contact Card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during birth
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
H
hours
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
Identification
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product 
IPAL
Investigational Product Accountability Log
IQMP
integrated quality management plan
IRB
Institutional Review Board
IV
intravenous
kel
terminal phase rate constant
LBBB
left bundle branch block
LFT
liver function test
M
minutes
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Abbreviation
Term
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
msec
millisecond
N/A
not applicable
OP
opaque
PCR
polymerase chain reaction
Ph+
Philadelphia chromosome positive
PIMS
Phase 1 Management System
PIP
Paediatric Investigation Plan (EU) 
PK
pharmacokinetic(s)
PT
prothrombin time
PVC
premature ventricular contraction
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
SOP
standard operating procedure
Src
sarcoma
SRSD
single-reference safety document
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal phase half-life
TBili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tmax
time to reach Cmax
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution after oral dose
WBC
white blood cell
WOCBP
woman of childbearing potential
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11. REFERENCES
1.
Investigator' Brochure, Bosutinib (PF-05208763).  29 May 2019.
2.
US Food and Drug Administration, Center for Drug Evaluation and Research. 
Guidance for Industry: Food-effect bioavailability and fed bioequivalence studies. 
Available from: https://www.fda.gov/media/70945/download. Published: Dec 2002. 
Accessed on 17 Feb 2020.
3.
European Medicines Agency, Committee for Medicinal Products for Human Use 
(CHMP). Guideline on the investigation of bioequivalence.  
CPMP/EWP/QWP/1401/98 Rev. 1/Corr. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-
bioequivalence-rev1_en.pdf. Published: 20 Jan 2010. Accessed on 24 Aug 2020.
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Protocol B1871063
A PHASE 1, OPEN-LABEL, RANDOMIZED, 3-PERIOD, 6-SEQUENCE, 
CROSSOVER STUDY TO EVALUATE THE BIOAVAILABILITY OF 
BOSUTINIB ADMINISTERED AS CAPSULE CONTENTS MIXED WITH 
APPLESAUCE OR YOGURT RELATIVE TO INTACT CAPSULES IN 
HEALTHY PARTICIPANTS UNDER FED CONDITION
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
(
 Statistician 
)
Date:
26-May-2021
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
May 26, 2021
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives ........................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................8
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................8
5.1.1. Concentration Analysis Set...........................................................................8
5.1.2. Parameter Analysis Set.................................................................................8
5.2. Pharmacodynamic Analysis Set................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.5. Other Analysis Sets ...................................................................................................8
5.6. Treatment Misallocations..........................................................................................8
5.7. Protocol Deviations...................................................................................................8
5.7.1. Deviations Assessed Prior to Randomization...............................................9
5.7.2. Deviations Assessed Post-Randomization....................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................10
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7.1. Concentrations Below the Limit of Quantification.................................................10
7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods ..................................................................................................11
8.2. Statistical Analyses .................................................................................................11
8.3. Safety Analysis........................................................................................................13
8.3.1. Treatment and Disposition of Participants .................................................13
8.3.2. Demographic and Clinical Examination Data............................................14
8.3.3. Discontinuation(s).......................................................................................14
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................14
8.3.8. Other Safety Data .......................................................................................14
8.3.9. Concomitant Treatments.............................................................................14
8.3.10. Screening and Other Special Purpose Data ..............................................14
9. REFERENCES ....................................................................................................................15
10. APPENDICES ...................................................................................................................16
LIST OF TABLES
Table 1.
Study Schematics........................................................................................5
Table 2.
Noncompartmental PK Parameters...........................................................10
Table 3.
PK Parameters to be Summarized Descriptively by Treatment ...............12
LIST OF FIGURES
None
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................16
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
The purpose of this study is to compare the bioavailability of bosutinib when orally 
administered as capsule contents mixed with applesauce or yogurt to the oral administration 
of intact capsules in healthy participants under fed condition. Bosutinib (PF-05208763) is 
an orally active Src/Abl kinase inhibitor with potent antiproliferative and proapoptotic 
activity in cultured chronic myelogenous leukemia cells, and antiproliferative activity in 
primitive progenitor chronic myelogenous leukemia cells from patients.
2.1. Study Design
This will be a Phase 1, open-label, randomized, single dose, 3-period, 6-sequence, crossover 
study in approximately 18 healthy participants. Participants will be randomized to 1 of the 6 
sequences of treatment described below.
Table 1.
Study Schematics
Sequence
Period 1
Washout Period
Period 2
Washout 
Period
Period 3
1 (n=6)
C
At least 14 days
between
successive
bosutinib doses
A
At least 14 days
between
successive
bosutinib doses
B
2 (n=6)
B
C
A
3 (n=6)
A
B
C
4 (n=6)
B
A
C
5 (n=6)
A
C
B
6 (n=6)
C
B
A
n = number of participants.
Treatment A (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of 
applesauce under fed condition.
Treatment B (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of 
full fat yogurt under fed condition.
Treatment C (Reference): 500 mg (100 mg x 5) bosutinib intact capsules under fed condition.
Note: “Enrolled” means a participant’s agreement to participate in a clinical study 
following completion of the informed consent process and screening. A participant will be 
considered enrolled if the informed consent is not withdrawn prior to participating in any 
study activity after screening. Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.
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Since the mean plasma elimination t½ of bosutinib is approximately 34 hours (range 18 to
55 hours), there will be a minimum 14-day washout period between successive doses of
bosutinib.
Blood samples for PK analysis will be collected predose and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48,
60, 72, 96, and 144 hours post the bosutinib dose.
Participants will remain in the study for up to approximately 13 weeks, including the
screening and follow-up periods. Participants will be screened within 28 days of the first
dose of IP and if all study entry criteria are fulfilled, the participants will report to the CRU
on the day prior to Day 1 dosing (Day -1) of Period 1. Following an overnight fast of at 
least 10 hours, on Day 1 of each period, participants will receive a high-fat and high-calorie
breakfast (see study protocol’ Section 5.3.1) prior to dosing which will need to be completely 
consumed within 20 minutes. For reference Treatment C, bosutinib intact capsules will be 
administered with approximately 240 mL of ambient temperature water. For Test 
Treatments A and B, bosutinib capsule contents will be administered as granules mixed with 
45 mL of applesauce or yogurt, respectively, followed by approximately 240 mL of ambient 
temperature water. Intact capsules (Treatment C) and capsule contents mixed with 
applesauce or yogurt (Treatments A and B, respectively) will be swallowed and not chewed.
 
 
Participants will be confined in the CRU for a minimum of 5 days until completion of the
72 hour PK sample collection on Day 4 in each period. Participants will be discharged at 
the discretion of the investigator. The investigator could choose to confine participants in 
the CRU and discharge them following the 96 hour PK sample on Day 5. Participants
discharged on Day 5 will be required to return to the CRU for outpatient visit on Day 7 of
each period. Alternatively, participants may be discharged from the CRU on Day 4,
provided that they are able to return for outpatient visits on Days 5 and 7. A follow-up 
phone call will be made at least 28 calendar days and up to 35 calendar days after the last
administration of the IP to capture any potential AE, prior/concomitant treatments and
confirm appropriate contraceptive usage.
Tolerability and safety will be assessed for all treatments by monitoring AEs, ECGs, BP,
pulse rate and safety laboratory data.
If there are participants who withdraw or discontinue treatment and are considered to be
non-evaluable with respect to the primary PK objective, additional participants can be
enrolled at the discretion of the investigator upon consultation with the sponsor.
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2.2. Study Objectives
Primary:
•
To estimate the relative bioavailability of a single 500 mg dose of bosutinib when
administered as capsule contents mixed with applesauce to intact capsules under fed
condition in adult healthy participants.
•
To estimate the relative bioavailability of a single 500 mg dose of bosutinib when 
administered as capsule contents mixed with yogurt to intact capsules under fed 
condition in adult healthy participants.
Secondary:
•
To evaluate the PK of bosutinib when administered as capsule contents mixed with
applesauce or yogurt and as intact capsules to healthy participants under fed 
condition.
•
To evaluate the safety and tolerability of bosutinib when administered as capsule 
contents mixed with applesauce or yogurt and as intact capsules to healthy 
participants under fed condition.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
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5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population is defined as all participants randomized and treated who 
have at least 1 concentration in at least 1 treatment period.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all participants randomized and treated 
who have at least 1 of the bosutinib PK parameters of primary interest in at least 1 treatment 
period.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the product they actually
received.
 
5.5. Other Analysis Sets
None.
5.6. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a participant takes a treatment that is not consistent with the treatment they are assigned to, 
for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety and PK analyses, 
where applicable.
5.7. Protocol Deviations
Participants who experience events that may affect their PK profile (eg, lack of compliance 
with dosing) may be excluded from the PK analysis.  At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
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A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.7.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 5.1 and 5.2 of the protocol.
5.7.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events,
•
laboratory data,
•
vital signs data,
•
ECG results.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of bosutinib (PF-05208763) will be taken according to the 
Schedule of Activities given in the protocol.
The following PK parameters will be calculated for bosutinib (PF-05208763) (if possible) 
from the concentration-time data using standard noncompartmental methods:
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Table 2.
Noncompartmental PK Parameters
PK Parameter
Analysis Scale
Bosutinib (PF-05208763)
AUCinf*
ln
A, D
AUClast
ln
A, D
Cmax
ln
A, D
Tmax
R
D
t1/2*
R
D
CL/F*
ln
D
Vz/F*
ln
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits.
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification). 
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
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7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues). 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements.  For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
If an individual participant has a known cause for biased estimate of a PK parameter (due, for 
example, to an event such as vomiting before all of the drug is absorbed in the body), this 
will be footnoted in summary tables and will not be included in the calculations of summary 
statistics or statistical analyses. Participants who vomit at or before 2 times of median Tmax
after drug administration may be excluded from PK analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
Precision of the estimate of PK parameters will be determined by constructing 
90% confidence intervals around the estimated difference between the Test and Reference 
treatments using a mixed effects model based on natural log transformed data.  The mixed 
effects model will be implemented using SAS Proc Mixed, with REML estimation method 
and Kenward-Roger degrees of freedom algorithm.
8.2. Statistical Analyses
Natural logarithm-transformed bosutinib AUCinf, AUClast and Cmax will be analyzed using a
mixed effect model with sequence, period and treatment as fixed effects and participant
within sequence as a random effect. Estimates of the adjusted mean differences
(Test- Reference) and corresponding 90% CIs will be obtained from the model.
The adjusted mean differences and 90% CIs for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for
the ratios.
The following 2 comparisons will be performed:
•
Treatment A (Test) vs Treatment C (Reference);
•
Treatment B (Test) vs Treatment C (Reference).
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The plasma PK parameters AUCinf, Cmax, AUClast, Tmax, CL/F, Vz/F and t½ of bosutinib will
be summarized descriptively by treatment. For AUCinf, AUClast and Cmax, a listing of the
individual participant ratios (Test-Reference) will be provided for the 2 comparisons
described above. Individual participant PK parameters for AUCinf, AUClast and Cmax will be
plotted by treatment and overlaid with geometric mean. Concentrations will be listed and
summarized descriptively by PK sampling time and treatment. Individual participant and
median profiles of the concentration-time data will be plotted by treatment.
For summary statistics and median plots by sampling time, the nominal PK sampling time 
will be used, for individual participant plots by time, the actual PK sampling time will be 
used.
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers, then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
Table 3.
PK Parameters to be Summarized Descriptively by Treatment
Parameter
Summary Statistics
AUCinf, AUClast, 
Cmax, Vz/F, CL/F
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum.
For AUCinf, AUClast and Cmax a listing of the individual subject ratios (Test/Reference) will 
be provided.  Box and whisker plots for individual subject parameters (AUCinf, AUClast and 
Cmax) will be presented by treatment and overlaid with geometric means.
Supporting data from the estimation of t½ and AUCinf will be listed by treatment and analyte: 
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); 
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of 
time points used in the estimation of kel.  This data may be included in the clinical study 
report.
Presentations for bosutinib (PF-05208763) concentrations will include:
•
A listing of all concentrations sorted by subject ID, treatment and nominal time 
postdose.  The concentration listing will also include the actual times.  Deviations 
from the nominal time will be given in a separate listing.
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•
A summary of concentrations by treatment and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.
•
Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by treatment (all treatments on the same plot per scale, based 
on the summary of concentrations by treatment and time postdose).
•
Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).
•
Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment 
per scale).
•
Individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each subject (containing 
all treatments) per scale].
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
 
 
 
8.3. Safety Analysis
All participants assigned to investigational product and who take at least 1 dose of 
investigational product.  Participants will be analyzed according to the product they actually 
received.
8.3.1. Treatment and Disposition of Participants
Data will be reported in accordance with the sponsor reporting standards.
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8.3.2. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Participants’ in accordance 
with the sponsor reporting standards.
8.3.3. Discontinuation(s)
Participant discontinuations and temporary discontinuations due to adverse events will be 
detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
treatment.
8.3.5. Laboratory Data
Laboratory data will be listed and summarized in accordance with the sponsor reporting 
standards.
The baseline measurement is the last predose measurement on Day 1 of Period 1.
8.3.6. Vital Signs Data
Vital Signs data will be databased and available upon request.
The baseline measurement is the last predose measurement on Day 1 of Period 1.
8.3.7. ECG Data
ECG data will be databased and available upon request.
The baseline measurement is the last predose measurement on Day 1 of Period 1.
8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Screening and Other Special Purpose Data
Screening data will available upon request.
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9. REFERENCES
None.
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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC MIXED code is provided below:
Comparison of Treatment A (100 mg x 5 with applesauce under fed condition) and B 
(100 mg x 5 with full fat yogurt under fed condition) versus Treatment C (100 mg x 5 under 
fed condition);
proc mixed data=tab.pk;
class seq period trt subject;
model l&var=seq period trt/ ddfm=KR;
random subject(seq) /subject=subject(seq);
lsmeans trt;
estimate ‘Treatment A vs Treatment C ' trt   1  0  -1  /cl alpha=0.1;
            estimate ‘Treatment B vs Treatment C ' trt   0  1  -1  /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows;
Treatment A (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of 
applesauce under fed condition.
Treatment B (Test): Contents of 500 mg (100 mg x 5) bosutinib capsules mixed with 45 mL of 
full fat yogurt under fed condition
Treatment C (Reference): 500 mg (100 mg x 5) bosutinib intact capsules under fed condition.
*/
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