Clinical trial NCT03128411
Conditions: Leukemia, Chronic Myelogenous
Keywords: Leukemia, Chronic Myelogenous
Sponsor: Pfizer
Start date: 2017-05-15; Completion date: 2021-03-04
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 2, single-arm, open-label trial. Patients will receive bosutinib for the duration of the study.

Detailed description:
The study will be open for enrollment until the planned number of approximately 60 Philadelphia Chromosome Positive (Ph+) patients have been registered. All patients will be treated and/or followed for up to approximately 3 years (144 weeks) after registration of the last patient or until study termination. Patients who discontinue study therapy early due to disease progression or intolerance to study medication will continue to be followed yearly for survival for up to approximately 3 years (144 weeks) after registration of the last patient or until study termination.

Arms: arm 1: Bosutinib monotherapy; All patients will receive bosutinib at a starting dose of 400 mg QD. The dose of bosutinib may be escalated (up to a maximum of 600 mg QD) for unsatisfactory response or reduced for toxicity.
Interventions: intervention 1: Bosutinib
Intervention descriptions: intervention 1: All patients will receive bosutinib at a starting dose of 400 mg QD.

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL
A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE EFFICACY
AND SAFETY OF BOSUTINIB MONOTHERAPY IN JAPANESE ADULT 
PATIENTS WITH NEWLY DIAGNOSED CHRONIC PHASE CHRONIC 
MYELOGENOUS LEUKEMIA
Investigational Product Number:
PF-05208763, SKI-606
Investigational Product Name:
Bosutinib
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable (N/A)
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
B1871048
Phase:
2b


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
30 Mar 2018

Made changes in study objectives/endpoints
and interim analysis.
Added “MMR by 12 months” as a 
secondary endpoint and “interim look”
prior to primary analysis to assess the 
possibility of early communication with 
regulatory authorities based on the interim 
data. This change affected Sections 2,
9.2.2.1 and 9.5.
Added “Time to MR4.0 and MR4.5” as 
exploratory objectives and endpoints in 
Section 2 to be aligned with Section 9.
Split an exploratory objective and endpoint
“MMR at 3, 6, 9, 12 (in patients with both 
Ph+ and Ph negative (-) CP CML) and 18
months” into two separated exploratory 
endpoints in Section 2 for clarification.
Removed a duplicated exploratory 
objective and endpoint related to 
evaluation of BCR-ABL mutations in 
Section 2.

Updated bosutinib information based on the 
results of Study AV001 and FDA approval for
newly diagnosed CML in Section 1.2.4.

Incorporated changes of Protocol 
Administrative Change Letters.
Clarified the required timing of 24-hour 
urine protein and microscopic assessments 
in Table 4.
Eliminated the inconsistency in the items 
of hematology tests (SoA and Section 
7.1.1) and the active collection periods of 


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AEs and SAEs (SoA and Section 8.1.4).
Clarified the definitions of “loss of MCyR 
or CCyR” and “loss of CHR” in Sections 
6.5 and 9.2.2.4.
Provided examples of the items of 
laboratory tests for the efficacy 
assessments in Section 7.1.1.

Added administrative changes, clarification 
and typographical corrections for clarity and 
consistency.
Clarified evaluable patients for the 
analyses of cytogenetic or molecular 
response in Section 9.2.
Clarified the definitions of “CHR” and 
“AP/BP CML” for statistical analyses in 
Sections 9.3.1.3 and 9.3.1.4, and 
Appendix 2.
Made other minor edits for clarity or 
consistency where appropriate throughout 
the document.
Original protocol
31 Jan 2017
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).  


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................14
1. INTRODUCTION ...............................................................................................................19
1.1. Mechanism of Action/Indication.............................................................................19
1.2. Background and Rationale ......................................................................................19
1.2.1. CML and the Treatment Options................................................................19
1.2.2. Bosutinib (BOSULIF®, Pfizer)...................................................................20
1.2.3. Bosutinib as First-Line Treatment for CP CML.........................................21
1.2.4. Study Rationale...........................................................................................22
1.3. Banked Biospecimen...............................................................................................24
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
3. STUDY DESIGN.................................................................................................................26
3.1. Study Treatment ......................................................................................................27
4. PATIENT ELIGIBILITY CRITERIA.................................................................................27
4.1. Inclusion Criteria.....................................................................................................27
4.2. Exclusion Criteria....................................................................................................29
4.3. Lifestyle Requirements ...........................................................................................30
4.4. Sponsor’s Qualified Medical Personnel..................................................................31
5. STUDY TREATMENTS.....................................................................................................32
5.1. Allocation to Treatment ..........................................................................................32
5.2. Patient Compliance .................................................................................................32
5.3. Investigational Product Supplies.............................................................................32
5.3.1. Dosage Form(s) and Packaging..................................................................32
5.3.2. Preparation and Dispensing........................................................................32
5.4. Administration.........................................................................................................33
5.4.1. Dose Escalation ..........................................................................................33
5.4.2. Dosing Interruptions and Dose Reductions ................................................35
5.5. Investigational Product Storage ..............................................................................37


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5.6. Investigational Product Accountability...................................................................38
5.6.1. Destruction of Investigational Product Supplies ........................................38
5.7. Concomitant Treatments .........................................................................................38
5.7.1. Prohibited Medications...............................................................................39
5.7.2. Permitted Medications................................................................................39
5.7.3. Other Treatment Considerations: Interaction with Other Medical 
Products and Other Forms of Interaction.........................................................40
6. STUDY PROCEDURES .....................................................................................................40
6.1. Screening.................................................................................................................40
6.1.1. Collection of Banked Biospecimen ............................................................41
6.2. Core Treatment Phase .............................................................................................41
6.3. Extension Phase.......................................................................................................41
6.4. End of Treatment/Withdrawal Visit........................................................................42
6.5. Patient Withdrawal..................................................................................................42
7. ASSESSMENTS..................................................................................................................44
7.1. Efficacy Assessment ...............................................................................................44
7.1.1. Efficacy Assessment Methods....................................................................44
7.1.1.1. Sample Collection for Molecular Response..............................45
7.1.1.2. Mutation Analysis .....................................................................46
7.2. Safety Assessment...................................................................................................46
7.2.1. Pregnancy Testing ......................................................................................46
7.2.2. Adverse Events...........................................................................................47
7.2.3. Laboratory Safety Assessment ...................................................................47
7.2.4. Physical Examinations................................................................................48
7.2.5. (12-Lead) Electrocardiograms....................................................................48
7.3. Pharmacokinetics Assessments...............................................................................49
7.4. Banked Biospecimens .............................................................................................50
7.4.1. Additional Research....................................................................................51
8. ADVERSE EVENT REPORTING......................................................................................51
8.1. Requirements...........................................................................................................51
8.1.1. Additional Details on Recording Adverse Events on the CRF...................52
8.1.2. Eliciting Adverse Event Information..........................................................52


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8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal section).............................................................................52
8.1.4. Time Period for Collecting AE/SAE Information......................................53
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................53
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF.................53
8.1.5. Causality Assessment .................................................................................53
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................54
8.2. Definitions...............................................................................................................54
8.2.1. Adverse Events ...........................................................................................54
8.2.2. Abnormal Test Findings .............................................................................55
8.2.3. Serious Adverse Events ..............................................................................55
8.2.4. Hospitalization............................................................................................56
8.3. Severity Assessment................................................................................................57
8.4. Special Situations ....................................................................................................58
8.4.1. Protocol-Specified Serious Adverse Events...............................................58
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................58
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................59
8.4.3.1. Exposure During Pregnancy......................................................59
8.4.3.2. Exposure During Breastfeeding ................................................61
8.4.3.3. Occupational Exposure .............................................................61
8.4.4. Medication Errors .......................................................................................61
8.4.4.1. Medication Errors......................................................................61
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................62
9.1. Sample Size Determination.....................................................................................62
9.2. Efficacy Analysis ....................................................................................................63
9.2.1. Analysis of Primary Endpoint ....................................................................63
9.2.2. Analysis of Secondary Endpoints...............................................................64
9.2.2.1. Other Measures of MMR ..........................................................64
9.2.2.2. Cytogenetic Response Assessment ...........................................64
9.2.2.3. Duration of Response................................................................64
9.2.2.4. Event-Free Survival and Overall Survival ................................65


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9.3. Analysis of Other Endpoints ...................................................................................66
9.3.1. Exploratory Efficacy Endpoints .................................................................66
9.3.1.1. Other Measures of MMR and Reductions in BCR-ABL 
Transcript...........................................................................................66
9.3.1.2. Time to Response......................................................................66
9.3.1.3. Time to Transformation to AP/BP CML...................................66
9.3.1.4. Hematologic Response..............................................................67
9.3.2. Mutations....................................................................................................67
9.3.3. Population Pharmacokinetic Analysis and 
Pharmacokinetic/Pharmacodynamic Modeling ...............................................67
9.4. Safety Analysis........................................................................................................67
9.4.1. Adverse Events...........................................................................................67
9.4.2. Clinical Laboratory Evaluations.................................................................68
9.4.3. Vital Signs Measurements, Physical Findings, and Other Safety 
Evaluations.......................................................................................................68
9.5. Interim Analysis ......................................................................................................68
9.6. Data Monitoring Committee ...................................................................................68
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................68
11. DATA HANDLING AND RECORD KEEPING .............................................................69
11.1. Case Report Forms/Electronic Data Record .........................................................69
11.2. Record Retention...................................................................................................70
12. ETHICS..............................................................................................................................70
12.1. Institutional Review Board/Ethics Committee......................................................70
12.2. Ethical Conduct of the Study ................................................................................70
12.3. Patient Information and Consent...........................................................................71
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................71
13. DEFINITION OF END OF TRIAL...................................................................................71
14. SPONSOR DISCONTINUATION CRITERIA ................................................................72
15. PUBLICATION OF STUDY RESULTS..........................................................................72
15.1. Communication of Results by Pfizer ....................................................................72
15.2. Publications by investigators.................................................................................73


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16. REFERENCES ..................................................................................................................74
LIST OF TABLES
Table 1.
Dose Modifications for Bosutinib ........................................................................33
Table 2.
Management of Non-Hematologic Treatment-Related Toxicity..........................36
Table 3.
Management of Hematologic Treatment-Related Toxicity..................................37
Table 4.
Safety Laboratory Tests........................................................................................48
APPENDICES
Appendix 1. Abbreviations......................................................................................................77
Appendix 2. Response Definitions ..........................................................................................80
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status .................82
Appendix 4. Summary of Drugs that are Generally Accepted to Have a Risk of Causing 
QTc Prolongation Potentially Causing Torsades de Pointes................................83
Appendix 5. Selected Strong and Moderate CYP3A4 Isoenzyme Inhibitors and 
Inducers.................................................................................................................84
Appendix 6. Guidelines for the Management of Diarrhea.......................................................85


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PROTOCOL SUMMARY
Background and Rationale
Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual Src/Abl tyrosine 
kinase inhibitor (TKI) that has been approved in Japan and multinationally for the treatment 
of adult patients with Philadelphia chromosome (Ph)-positive(+) chronic phase (CP), 
accelerated phase (AP), and blast phase (BP) chronic myelogenous leukemia (CML) 
previously treated with other TKI inhibitor therapy.1 In December 2017, bosutinib was
additionally approved for adult patients with newly diagnosed Ph+ CP CML in the US. This 
study will investigate the efficacy and safety of bosutinib as a first-line treatment for 
Japanese adult patients with Ph+ CP CML.
In Japan, patients with newly diagnosed CML are now able to be effectively treated with 
TKIs, including imatinib, dasatinib, and nilotinib, with their disease controlled for long 
periods of time. Bosutinib may represent an additional choice for such patients for treatment 
of their CML in the first-line treatment setting, which could offer these patients a better 
tolerated and possibly more sustainable treatment option than other available therapies.
Prior clinical studies with bosutinib in CML have used a starting dose of bosutinib of 500 mg 
once daily (QD). In the previous studies, a substantial number of patients experienced 
toxicities. The incidence of treatment-emergent adverse events (TEAEs) overall as well as 
unique TEAEs were lower following dose reduction from 500 mg QD to 400 mg QD, while 
the efficacy of bosutinib in patients who received dose reductions to 400 mg QD remained 
favorable. Therefore, it was hypothesized that a starting dose of 400 mg QD in this Phase 2
study in the first-line Japanese CP CML patient treatment setting will result in better 
tolerability and similar efficacy as a starting dose of 500 mg QD.
Objectives and Endpoints
Primary Objective

To evaluate major molecular response (MMR) at 12 months (48 weeks) in newly 
diagnosed Japanese Ph+ CP CML patients harboring b2a2 and/or b3a2 transcripts.
Secondary Objectives
All efficacy analyses for secondary/exploratory objectives will be performed using the same 
population as primary objective, unless otherwise indicated (detailed in Section 9). For 
detailed definitions of responses, see Appendix 2.

To evaluate MMR by 12 and 18 months.

To estimate the proportion of patients demonstrating complete cytogenetic response 
(CCyR) by 12 months.


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
To evaluate the duration of MMR and CCyR.

To evaluate event-free survival (EFS).

To evaluate overall survival (OS).

To assess the population pharmacokinetics (PK).

To assess correlations between trough concentrations of bosutinib and key efficacy and 
safety endpoints.

To characterize the safety profile of bosutinib in Japanese patients.
Exploratory Objectives

To evaluate MMR at 3, 6, 9 and 18 months.

To evaluate MMR at 12 months in patients with both Ph+ and Ph negative (-) CP CML.

To evaluate molecular response (MR)1 and MR2 at 3 months and 6 months, respectively.

To evaluate MR4.0 and MR4.5 at 3, 6, 9 and 12 months.

To evaluate time to MMR, MR4.0, MR4.5 and CCyR.

To evaluate the proportion of patients demonstrating a cumulative complete hematologic 
response (CHR) in patients with Ph+ and both Ph+ and Ph- CP CML.

To estimate the time to transformation to AP and BP CML on treatment.

To evaluate the type of BCR-ABL mutations present at treatment completion or 
discontinuation, or in case of suboptimal response.

To enable exploratory research through collection of banked biospecimen, unless 
prohibited by local regulations or ethics committee (EC) decision.
Primary Endpoint

MMR at 12 months (48 weeks). All Ph+ CP CML patients harboring b2a2 and/or b3a2 
transcripts will be assessed and follow-up for MMR as primary endpoint. MMR is 
defined as ≤0.1% BCR-ABL on the international scale (IS) by quantitative reverse 
transcriptase polymerase chain reaction (RT-qPCR).
Secondary Endpoints

MMR by 12 and 18 months.


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
CCyR by 12 months.

Duration of MMR and CCyR.

EFS

OS

Population PK parameters.

Correlations between trough concentrations of bosutinib and key efficacy and safety 
endpoints.

Safety: AEs (as graded by National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] v.4.03); laboratory abnormalities (as graded by NCI 
CTCAE v.4.03); vital signs (blood pressure, pulse rate); electrocardiograms (ECGs); 
echocardiogram (ECHO) or multiple gated acquisition (MUGA).
Exploratory Endpoints

MMR at 3, 6, 9 and 18 months.

MMR at 12 months in patients with both Ph+ and Ph- CP CML.

MR1 and MR2 at 3 months and 6 months, respectively.

MR4.0 and MR4.5 at 3, 6, 9 and 12 months.

Time to MMR, MR4.0, MR4.5 and CCyR.

Cumulative CHR in patients with Ph+ and both Ph+ and Ph- CP CML.

Time to transformation to AP and BP CML on treatment.

Type of mutations present at treatment completion/discontinuation or suboptimal 
response.

Potential results from exploratory analyses of banked biospecimen (these results may or 
may not be generated in the context of the present study).
Study Design
Study Overview
This is a Phase 2, open-label, single-arm study designed to evaluate efficacy and safety of 
bosutinib alone in Japanese adult patients with newly diagnosed CP CML. The primary 


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endpoint is MMR at 12 months in newly diagnosed Japanese Ph+ CP CML patients 
harboring b2a2 and/or b3a2 transcripts. Patients will receive bosutinib treatment at a starting 
dose of 400 mg QD. The dose of bosutinib is allowed to be escalated (up to a maximum of 
600 mg QD) for unsatisfactory response or reduced for toxicity.
This study has approximately 52 weeks of planned patient accrual. Each patient will have
12 months (48 weeks) of Core Treatment Phase and the following 24 months (96 weeks) of
Extension Phase. After treatment discontinuation, the patient enters Long-Term Follow-Up. 
The Extension Phase or Long-Term Follow-Up will continue until the end of the study.
The study will be open for enrollment until approximately 60 Ph+ CML patients harboring
b2a2 and/or b3a2 transcripts have been registered. Bone marrow aspirate to assess the Ph 
status will be obtained at screening, patients with known Ph- prior to registration are not 
eligible for this study. However, as confirmation of the Ph status prior to registration is not 
mandatory, Ph- CML patients may also be included. Approximately 3 Ph- CML patients are 
expected to be registered as approximately 5% of the patients with BCR-ABL-positive CML 
are diagnosed as Ph- CML.2,3 All patients will be treated and/or followed up to 
approximately 3 years (144 weeks) after registration of the last patient, or until study 
termination, whichever comes first. Patients who permanently discontinue study treatment
will be followed for survival, investigator-assessed transformation to AP/BP, duration of 
response and disease progression, and initiation/response to further anti-cancer therapies, 
including stem cell transplantation (where applicable).
Study Treatments
All patients will receive bosutinib at a starting dose of 400 mg QD. The dose of bosutinib 
may be escalated (up to a maximum of 600 mg QD) for unsatisfactory response or reduced 
(down to 300 mg QD, and further to a minimum of 200 mg QD only when approved by the 
sponsor) for toxicity.
Each patient will receive daily bosutinib for up to approximately 3 years after registration of 
the last patient (12 months [48 weeks] Core Treatment Phase and the following 24 months
[96 weeks] Extension Phase) or until the end of the study, treatment failure, unacceptable 
toxicity, death, or withdrawal of consent, whichever occurs first.
Statistical Methods
The primary analysis population for the efficacy evaluation will be the modified as-treated
population. The modified as-treated population will consist of all patients with Ph+ CP CML 
harboring b2a2 and/or b3a2 transcripts who received at least 1 dose of study medication.
The primary efficacy variable is MMR rate at 12 months (48 weeks) which is defined as the 
proportion of patients achieving MMR at 12 months (48 weeks). MMR is defined as BCR-
ABL expression of ≤0.1% of initial BCR-ABL transcript from standardized baseline 
measured by RT-qPCR.


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Sample Size Determination
The primary analysis will use the hypothesis test for a binomial proportion the using normal 
approximation. The study is powered at greater than 82% to test the null hypothesis that the 
true MMR rate at 12 months (48 weeks) is 25% versus the alternative hypothesis that the true 
MMR rate is 40% with one-sided alpha of 5%. A sample size of 60 Ph+ CML patients 
harboring b2a2 and/or b3a2 transcripts is required for MMR at 12 months (48 weeks). 
Rejecting the null hypothesis and accepting the alternative hypothesis in the modified as-
treated population (observing at least 21 responders out of the 60 total patients), will be 
considered to be a successful demonstration of efficacy for this study.
As cytogenetic confirmation for Ph chromosome is not required for enrollment and 5% of 
patients are expected to be Ph- CML, approximately 3 Ph- CML patients may be enrolled, 
which will not affect the primary analysis.2,3


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SCHEDULE OF ACTIVITIES
The SCHEDULE OF ACTIVITIES table provides an overview of the protocol visits and procedures.  Refer to the STUDY 
PROCEDURES and ASSESSMENTS sections 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 SCHEDULE OF ACTIVITIES table in order 
to conduct evaluations or assessments required to protect the well-being of the patient.
Visit Identifier a
Screening
Core Treatment Phase
Extension Phase
End of 
Treatment / 
Withdrawal
Month
0
0
1
1
1
1
1
2
2
3
3
4
5
6
9, 12
Every 12 weeks up to 
2 years, then every 24 
weeks thereafter
7-28 days after 
the last dose of 
study drug
Week
0
0
1
1
2
3
4
6
8
10
12
16
20
24 36, 48
Day
-28 to 
registr
ation
-14 to 
registr
ation
1
7
14
21
28
42
56
70
84
112 140 168
252, 
336
Visit Time Window
4 days
1 week
Informed consent
X
Registration
X
Inclusion/Exclusion criteria review
X
Demographic data collection
X
Sokal score calculationb
X
Medicalc/Cancer historyd review
X
Physical examinatione
X
X
X
X
X
X
X
Vital signs, weight, and height 
(screening only)f
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
Extramedullary assessmentg
X
X
X
X
X
X
Digital ECGh
X
X
X
X
X
As clinically indicated
X
Chest X-ray
X
As clinically indicated
X
Contraception checki
X
X
X
X
X
X
X
X
X
X
X
ECHO or MUGAj
X
As clinically indicated
X


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Visit Identifier a
Screening
Core Treatment Phase
Extension Phase
End of 
Treatment / 
Withdrawal
Month
0
0
1
1
1
1
1
2
2
3
3
4
5
6
9, 12
Every 12 weeks up to 
2 years, then every 24 
weeks thereafter
7-28 days after 
the last dose of 
study drug
Week
0
0
1
1
2
3
4
6
8
10
12
16
20
24 36, 48
Day
-28 to 
registr
ation
-14 to 
registr
ation
1
7
14
21
28
42
56
70
84
112 140 168
252, 
336
Visit Time Window
4 days
1 week
Laboratory Tests
Hematology including CBC with 
differentialk
X
X
X
X
X
X
X
X
X
X
X
X
X
X y
X
Chemistry panel with electrolytes 
and CKl
X
X
X
X
X
X
X
X y
X
Liver function testsm
X
X
X
X
X
X
X
X y
X
Estimated glomerular filtration 
rate
X
X
X
X
X
X
X
X y
X
Coagulation paneln
X
X
X y
X
HBV and HCV test
X
Dipstick urinalysis (microscopic if 
abnormalities detected)
X
X
X
X y
X
Serum or urine pregnancy test (for 
women of childbearing potential)
X
X
X
X
X
X
X
X
X
X y
X
Study Treatment
Study drug administrationo
Continuous daily from Day 1
Disease Assessments
Bone marrow aspiratep for 
cytogeneticsq and differential
Xp
Xq
X
Xp
X
Xp
Peripheral blood for local RT-
qPCR for BCR-ABL
Xr
Peripheral blood for central RT-
qPCR for BCR-ABLs and 
mutation analysist
X
X
X
X
X
X
Other Clinical Assessments
Adverse eventsu
X
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Concomitant medicationsv
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Other Samplings
PK blood sample collectionw
X
X
X
X
Banked blood biospecimensx
X


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Visit Identifier a
Screening
Core Treatment Phase
Extension Phase
End of 
Treatment / 
Withdrawal
Month
0
0
1
1
1
1
1
2
2
3
3
4
5
6
9, 12
Every 12 weeks up to 
2 years, then every 24 
weeks thereafter
7-28 days after 
the last dose of 
study drug
Week
0
0
1
1
2
3
4
6
8
10
12
16
20
24 36, 48
Day
-28 to 
registr
ation
-14 to 
registr
ation
1
7
14
21
28
42
56
70
84
112 140 168
252, 
336
Visit Time Window
4 days
1 week
Other
Long-term follow-upz
X
Abbreviations: = ongoing/continuous event; BCR-ABL = Fusion transcript or protein resulting from the 9;22 chromosomal translocation responsible for 
formation of the Philadelphia Chromosome; CBC = complete blood count; CK = creatine kinase; ECG = electrocardiogram; ECHO = echocardiogram; ECOG =
Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCV = hepatitis C virus; MUGA = multiple gated acquisition; PK = pharmacokinetics; RT-
qPCR = Quantitative reverse transcriptase polymerase chain reaction.
a.
Day relative to start of study treatment (Day 1).
b.
Every effort should be made in order to have Sokal score calculated prior to any anti-CML treatments (ie. at initial diagnosis of patient). Sokal formula is 
Exp (0.0116 × (age - 43.4) + 0.0345 × (spln - 7.51) + 0.188 × [(plt/700)2 - 0.563] + 0.0887 × (blasts - 2.1)); Note: Spln=centimeters below costal margin, 
plt=platelet count, 109/L, blasts=% blasts in peripheral blood. If the patient has already received anti-CML treatment prior to screening every effort should be 
made to obtain test results/data before the start of treatment in order to calculate the Sokal score. If patient did not have prior anti-CML treatment, the Sokal 
score will be calculated using data obtained at screening.
c.
Medical history review includes clinically significant past and current diagnoses (including complete cardiac history) and surgical procedures.
d.
Cancer history review includes full history of the course of the patient’s cancer including date of diagnosis and any prior treatments, history of blood and
platelet transfusions or history of lumbar punctures within 28 days prior to registration.
e.
Complete physical examination ensuring examination of liver and spleen will be performed.
f.
Vital signs include temperature (axillary), supine blood pressure, and heart rate. Height will be measured at screening only.
g.
Extramedullary assessment will include physical examination and based on this assessment and any specific evidence, appropriate imaging testing can be 
requested by the investigator. The assessment should be done at any time if extramedullary disease is suspected.
h.
Digital ECGs to be done in triplicate at each time point and should be performed at the same as PK sampling (if applicable). End of Treatment/Withdrawal
visit ECG should be done at least 5 days after the last dose of bosutinib and prior to initiating other anticancer treatment (if possible). ECG should also be 
performed if clinically significant decrease in ejection fraction is detected by ECHO/MUGA while on treatment, and otherwise as clinically indicated.
i.
Male patients who are able to father children and female patients who are of childbearing potential will need to follow the contraception guidelines in 
Section 4.3. 
j.
ECHO or MUGA to be performed at screening (within 2 weeks prior to registration) and at End of Treatment/Withdrawal or at Week 96, whichever is 
earlier. If a patient has undergone ECHO or MUGA as standard of care prior to entering the study, the procedures will not have to be repeated if results are 
available and the procedures were performed within 28 days prior to registration. To enable meaningful clinical comparison, every effort must be made to 
ensure that the imaging method used to assess cardiac function remains consistent for each individual patient through the course of the trial. 


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k.
Hematology including automated complete blood count (CBC) (eg, hemoglobin, RBC, WBC, platelets and hematocrit) with differential counts (eg,
neutrophils, lymphocytes, monocytes, eosinophils, basophils, metamyelocytes, myelocytes, promyelocytes, myeloblasts, unspecified blast cells and band 
cells) to be performed locally. Hematology assessments are to be performed at Screening, Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 and then every 12 weeks 
for the next 72 weeks (ie, until the end of Year 2), then every 24 weeks, and End of Treatment/Withdrawal visit. CHR must be confirmed by 2 assessments 
at least 4 weeks apart. Hematology to be repeated at least 4 weeks after achieving first CHR. 
l.
Chemistry panel to be performed locally including: sodium, potassium, chloride, carbon dioxide or bicarbonate (if available), blood urea nitrogen (BUN) or 
urea, creatinine, glucose, total protein, albumin, calcium, alkaline phosphatase, amylase, lipase, phosphorous or phosphate, and magnesium. Creatine kinase 
(CK) also to be performed locally. Abnormally high CK values should be confirmed and fractionated (where possible). Uric acid to be obtained until patient 
achieves a CHR. Supplementation is advised for potassium levels or magnesium levels below the lower limit of normal (LLN), with consideration of the 
patient’s underlying renal function. 
m. Liver Function tests to be performed locally including: total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). 
n.
Coagulation panel to be performed locally including: prothrombin time (PT) expressed as either PT or international normalized ratio (INR) and 
partial/activated partial thromboplastin time (PTT or aPTT). 
o.
The first dose of study drug should occur no later than 3 business days after registration of the patient, with the day of first study drug administration = Day 1.
p.
Bone marrow obtained as part of standard of care prior to signing informed consent document can be used at screening as long as it was collected within 28 
days prior to registration. Once CCyR or MMR has been achieved, bone marrow aspirates will be performed only if clinically indicated (eg, 
suboptimal response, suspect disease progression or failed/inadequate Week 48 assessment). Patients completing treatment for cytogenetically 
confirmed treatment failure do not need to repeat bone marrow at treatment completion. Patients ending treatment for reasons other than cytogenetically 
confirmed treatment failure must undergo treatment completion bone marrow aspirate if previous bone marrow aspirate performed >12 weeks prior. If loss 
of major molecular response occurs in combination with a 5 × PCR increase for BCR-ABL, a bone marrow aspirate for chromosome banding analysis 
(CBA) should be obtained. 
q.
Cytogenetics analysis must be performed so that dose-escalation rules can be appropriately applied (eg, patient should not have 12-week bone marrow 
aspirate before Day 84 so that at least 12 weeks from first dose is assessed). Cytogenetic assessment of bone marrow aspirate will be performed locally. If 
cytogenetics is used, it must be performed by CBA of marrow cell metaphases, counting at least 20 metaphases, at 12, 24, 36, and 48 weeks, until CCyR or 
MMR is achieved, then every 48 weeks.
r.
Local PCR result for BCR-ABL confirmation is acceptable prior to informed consent where this has already been conducted as part of initial diagnosis of a 
patient, provided this molecular diagnosis of CP CML has been made ≤6 months prior to registration. However, central PCR sample must always be 
conducted after informed consent, as this is a study-specific procedure.
s.
RT-qPCR testing for BCR-ABL will be performed at Screening, at 12, 24, 36, and 48 weeks during the Core Treatment Phase and then every 12 weeks until 
the end of Year 2, then every 24 weeks. If a ≥5-fold increase in BCR-ABL transcripts from the lowest value achieved on study along with loss of MMR is 
identified and confirmed by duplicate analysis of the same sample, an unscheduled visit sample will be collected within 4-6 weeks to confirm the results.
Fifteen (15) mL peripheral blood will be collected at each designated time-point. Additional 5 mL blood will be collected at Week 48; these will serve as 
back-up samples for the primary endpoint. For patients who achieve undetectable BCR-ABL by RT-qPCR, 20 mL of blood may be collected for PCR 
analysis. In addition, after the first documented negative BCR-ABL result, 20 mL of blood will be collected for all subsequent sampling time-points until 
BCR-ABL is no longer negative. 20 mL of blood may be collected as an unscheduled PCR sample from these patients.
t.
Mutation analysis will be performed in case of either lack of response, suboptimal response or loss of response defined as: failure to achieve MMR at 12 
months; loss of MMR AND rise in BCR-ABL transcript level by ≥5-fold from the lowest value achieved during the study; at the End of 
Treatment/Withdrawal visit. No mutation analysis will occur at screening. For patients with a positive mutation identified during therapy, follow-up 


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mutation analyses will be performed in subsequent samples. For a patient with a negative mutation result immediately following relapse, continued mutation 
analyses may be performed at a frequency of every 6 months (every 24 weeks) as needed.
u.
AEs should be documented and recorded at each visit using the NCI CTCAE version 4.03.  The time period for actively eliciting and collecting AEs and 
SAEs (“active collection period”) for each patient begins from the time the patient provides informed consent through and including a minimum of 28 
calendar days after the last investigational product administration. If a patient begins a new anticancer therapy, the period for recording non-serious AEs on 
the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active collection period must still be reported to Pfizer 
Safety and recorded on the CRF, irrespective of any intervening treatment.
v.
All concomitant medications and non-drug supportive interventions will be recorded in the CRF from 28 days prior to registration and up to 28 days after the 
last dose of study treatment.
w.
The pre-dose PK samples should be collected before (within 3 hrs of) study drug administration on Days 1, 28, 56, and 84. 3 mL of whole blood for plasma 
drawn into a tube containing potassium ethylenediaminetetraacetic acid (EDTA). See Section 7.3. On PK sampling days, the bosutinib dose should be taken 
in the hospital under the supervision of the study site personnel. The bosutinib dose should be administered after the PK sample has been collected.
x.
Blood sample will be collected for bio-banking if specifically allowed by local Institutional Review Board (IRB) or EC; 1 tube of whole blood (prep D1) 
will be collected at Screening. If not collected on the designated collection day, collect at the next available time point when bio-specimens are being 
collected in conjunction with a patient visit.
y.
For patients remaining on treatment in the Extension Phase, the investigator should continue to perform biochemistry and hematology testing, per standard 
of care for CML patients and as clinically indicated in line with local guidelines including cytogenetics when indicated by bone marrow analysis. Patients 
will have mandatory AE and SAE collection follow-up. These are expected to take place at least every 12 weeks.
z.
Long-Term Follow-Up information will be collected via telephone contact up to approximately 3 years after registration of the last patient, or until study 
termination, whichever comes first, where possible for patients who discontinue the study early. Follow-up calls should be conducted every 12 weeks in the 
first two years, and then every 24 weeks. The timing of follow-up calls is calculated with Day 1 designated as the starting point. 


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
This study will investigate the efficacy and safety of bosutinib 400 mg QD as a first-line 
treatment for Japanese adult patients with Ph+ CP CML.
Bosutinib (Bosulif®) is an orally active Src/Abl kinase inhibitor with potent antiproliferative 
and proapoptotic activity in CML cells.
1.2. Background and Rationale
1.2.1. CML and the Treatment Options
CML is one of the major types of leukemia. CML is a clonal myeloid neoplasm in which the 
leukemic cells in over 95% patients have a reciprocal translocation between chromosomes 9 
and 22 t(9;22)(q34;q11), the consequence of which is the generation of the Ph. The molecular 
product of the t(9;22) translocation is the BCR-ABL oncogene, which encodes the 
constitutively activated BCR-ABL kinase that activates several downstream signaling 
pathways that mediate myeloproliferation, resistance to apoptosis and genetic instability. 
More than 95% of CML patients have b2a2 and/or b3a2 coding for BCR-ABL kinase.4 The 
transition of patients with CML from CP to BP with an intermediate AP is becoming less 
common with the chief determinants of survival being disease stage and TKI responsiveness.
Hematopoietic stem cell transplantation (HSCT) is the only curative strategy for CML. Other 
treatments including chemotherapy, interferon alpha, and TKIs are effective in controlling 
the disease to varying degrees in all populations. The utility of HSCT is largely limited to 
pediatric and younger adult patients, especially those with matched donors. In addition to its 
limited acceptability, HSCT is associated with a substantial morbidity and mortality. The 
risks accompanying HSCT and the delay in finding or nonavailability of matched donors 
have necessitated an alternate treatment paradigm wherein agents targeting the BCR-ABL 
fusion protein, such as TKIs, are considered frontline therapy.
The first such TKI to be used successfully as a therapeutic agent was imatinib. Imatinib was 
granted approval by the European Commission in November 2001 and by the US Food and 
Drug Administration (FDA) in December 2002 for the treatment of newly diagnosed patients 
with CP CML based on results from the IRIS trial. However, despite the overall success of 
imatinib, some patients fail to achieve the desired response, experience disease progression, 
or are intolerant to imatinib treatment. After 8 years of follow-up of the IRIS trial, only 55% 
of the patients originally randomized to the imatinib treatment group remain on study drug. 
This was primarily due to failure to achieve CCyR (17%), loss of CCyR (15%) and 
intolerance to imatinib (approximately 5%).5 While several mechanisms of imatinib 
resistance have been proposed, the best known and possibly the most clinically prevalent are 
lack of adherence/compliance (which may reflect AEs in some patients) and/or the 
development of BCR-ABL mutations, which alter drug sensitivity and can be detected in 
approximately 40% to 50% of patients with CP CML in which imatinib has failed.5
Second-generation TKIs, dasatinib and nilotinib, were initially developed and approved in 
2006 and 2007, respectively, for the treatment of patients with resistance or intolerance to 


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prior therapy, including imatinib. In 2010, both dasatinib and nilotinib were additionally 
approved for adult patients with newly diagnosed Ph+ CML in CP on the basis of Phase 3 
studies that demonstrated favorable results compared with imatinib.6, 7
According to the National Comprehensive Cancer Network (NCCN) Version 2, 2014 
guidelines8 and European Leukaemia Net Recommendation,9 imatinib, dasatinib or nilotinib 
are considered the standard of care in newly diagnosed patients with Ph+ CML who are not 
eligible for stem cell transplant. Imatinib has been used as the active comparator in 
investigations of both dasatinib and nilotinib.
1.2.2. Bosutinib (BOSULIF®, Pfizer)
Bosutinib is an oral, dual Src/Abl TKI with more potent inhibitory activity against BCR-ABL 
than imatinib in CML cell lines,10, 11 with minimal inhibitory activity against c-KIT or 
platelet-derived growth factor receptor.11, 12 These are 2 nonspecific targets potentially 
associated with toxicities reported for other second-generation TKIs.
Bosutinib is being developed for the first-line treatment of Ph+ CML and to delay disease 
progression in patients with autosomal dominant polycystic kidney disease (ADPKD).  
Human experience with bosutinib is based on preliminary information obtained from patients 
in clinical studies, including patients with Ph+ leukemias; patients with solid tumors, 
including advanced or metastatic breast cancer; patients with ADPKD; and healthy subjects.  
As presented in the May 2016 Bosutinib Investigator’s Brochure (IB), approximately 2478 
patients, including 2141 patients with cancer, have received at least 1 dose of bosutinib in 24 
clinical studies.
Bosutinib has shown an acceptable safety profile in the Phase 1, Phase 2, and Phase 3 studies 
to date. In general, AEs with bosutinib have included predominantly low-grade 
gastrointestinal (GI) toxicities and general symptoms such as fatigue and asthenia.  Other 
frequent AEs include rash and increases in plasma levels of hepatic transaminase (alanine 
aminotransferase [ALT] and aspartate aminotransferase [AST]). Following continuous daily 
dose administration in cancer patients, most GI AEs resolved with therapy, treatment 
interruption, and/or dose reduction and less frequently discontinuation of bosutinib in the 
case of dose-limiting toxicities (DLTs). Serious adverse reactions reported include 
anaphylactic shock, myelosuppression, GI toxicity (diarrhea), fluid retention, hepatotoxicity, 
and rash.
The results of the Japan local Phase 1/2 study (Study B1871007) showed consistent with 
findings in Western populations. The most common AEs reported were diarrhea (95%), 
nasopharyngitis (57%), rash (57%), lymphopenia (40%), nausea (38%), vomiting (38%), 
increased ALT (38%), thrombocytopenia (33%), anaemia (30%), and increased AST (30%). 
The most common grade 3/4 AEs were lymphopenia (25%), neutropenia (21%), 
thrombocytopenia (21%), increased lipase (19%), and increased ALT (17%). 
On 04 September 2012, bosutinib was approved by the FDA for the treatment of adult 
patients with CP, AP, and BP Ph+ CML with resistance or intolerance to prior therapy.  More 
recently, on 17 January 2013, the Committee for Medicinal Products for Human Use


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(CHMP) issued a positive opinion recommending that bosutinib be granted conditional 
marketing authorization in the European Union (EU), for the treatment of adult patients with 
CP, AP, and BP Ph+ CML previously treated with one or more TKIs and for whom imatinib, 
nilotinib, and dasatinib are not considered appropriate treatment options.
Those approvals have been granted mainly based on results obtained from the Phase 1/2 
study (Study B1871006) in adult patients with Ph+ leukemias who had failed prior TKI 
therapy, with the support of the results obtained as part of the Phase 3 study (Study 
B1871008) comparing bosutinib with imatinib in newly diagnosed Ph+ CP CML patients.
In Japan, on 26 September 2014, bosutinib was approved for the treatment of patients with 
CML with resistance or intolerance to prior therapy, and this approval has been granted 
mainly based on results obtained from the Japan local Phase 1/2 study (Study B1871007) in 
adult patients with Ph+ CML who had failed prior TKI therapy.
1.2.3. Bosutinib as First-Line Treatment for CP CML
In the Phase 3 study (Study B1871008, “Bosutinib Efficacy and Safety in Newly Diagnosed 
Chronic Myeloid Leukemia” [BELA]), bosutinib (500 mg QD) was compared to imatinib in 
the first-line treatment of Ph+ CP CML. The primary objective of the study was to compare 
the complete CCyR at 1 year in CP CML patients receiving bosutinib alone versus patients 
receiving imatinib alone. The study enrolled 502 patients (250 on bosutinib and 252 on 
imatinib). No statistically significant difference was observed at 12 months of treatment 
between the bosutinib and imatinib groups regarding rates of CCyR (70% vs. 68%). 
Similarly, the cumulative CCyR rates by 24 months were virtually identical at 79% and 81%, 
respectively. However, in an intent-to treat (ITT) analysis, the MMR rates at 12 months for 
bosutinib and imatinib were 41% and 27%, and the cumulative MMR rates by 24 months 
were 61% versus 52%, respectively (p <0.05 for both comparisons). Time to CCyR and
MMR was shorter with bosutinib compared to imatinib (p <0.001 for both comparisons). 
Furthermore, the percentage of patients who experienced treatment failure (4% vs. 13%), 
progression to AP or BP (2% vs. 5%) or death (3% vs. 5%) was lower among those receiving 
bosutinib compared to those treated with imatinib. The shorter time to response is important 
for patients as it means they have a shorter time when they are vulnerable to potential 
progression to either AP or BP.
Results after a minimum follow-up of 24 months showed that 66% of patients receiving 
bosutinib and 45% of those treated with imatinib had dose interruptions. Dose reductions 
were required in 43% and 21% of patients, respectively. The rates of treatment 
discontinuation were 37% and 29%, respectively. Importantly, treatment discontinuations 
due to AEs or disease progression in the bosutinib and imatinib groups were 24% versus 4% 
and 7% versus 13%, respectively.
Compared with imatinib, bosutinib was associated with higher incidences of Grade 3/4 GI 
toxicities, including diarrhea (12% vs. 1%), vomiting (3% vs. 0%) and abdominal pain (1% 
vs. <1%), although these AEs were usually transient and manageable. Notably, diarrhea 
occurred mostly in the first 1-2 months of therapy and improved or subsided spontaneously 
over time.


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Grade 3/4 elevations of ALT (23% vs. 4%), AST (12% vs. 4%) or lipase (11% vs. 6%) were 
more frequent among patients treated with bosutinib compared to imatinib. Of those patients 
experiencing Grade 3/4 elevations in transaminase levels in the bosutinib treatment group of 
this study, 91% were rechallenged. Of these patients, 80% were successfully re-challenged. 
Overall, 14% of patients were discontinued from bosutinib treatment due to unacceptable 
transaminase elevations. Grade 3/4 neutropenia, thrombocytopenia and anaemia in the 
bosutinib and imatinib treatment groups were 10% vs. 24%, 14% vs. 15% and 8% vs. 8%, 
respectively, indicating that bosutinib is at least as safe as imatinib regarding hematologic 
toxicity.
In summary, bosutinib was associated with a toxicity profile distinct from that of imatinib. A 
higher number of patients (n=48, 19%) were discontinued from bosutinib treatment as a 
result of an AE, including 15 (31%) of 48 patients who discontinued before their first post 
baseline assessment. One of the goals of this study is to assess safety of bosutinib treatment 
compared with imatinib treatment. Early discontinuations as a result of toxicity may have 
contributed to the lower rate of CCyR associated with bosutinib in the ITT population, which 
included these patients as non-responders.
Although bosutinib therapy was associated with greater rates of diarrhea, vomiting, and 
aminotransferase elevations compared with imatinib, most instances were transient and, in 
the case of diarrhea, frequently self-limiting after the first 2 to 3 months of therapy. Fluid
retention, which has commonly been observed with dasatinib13, 14, 15, 16, 17, 18, 19, 20 and 
imatinib13, 21, 22 occurred infrequently with bosutinib. Despite the occurrence of liver function 
test abnormalities with bosutinib treatment, no cases were associated with permanent liver 
injury or liver failure. Low rates of Grade 3/4 (all causality) anaemia (6%), neutropenia 
(11%), and thrombocytopenia (14%) were reported with bosutinib. The minimal inhibition of 
c-KIT by bosutinib may have contributed to the low incidence of myelosuppressive events, 
particularly Grade 3/4 neutropenia.23 Overall, there were fewer deaths in the bosutinib 
treatment group, with no treatment-related deaths and few CML-related deaths in either 
treatment group. The trends in toxicity profile observed for bosutinib in this study were 
similar to those previously observed for bosutinib in CP CML after failure of imatinib 
treatment.24
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Bosutinib IB.
1.2.4. Study Rationale
In Japan, patients with newly diagnosed CML are now able to be effectively treated with 
TKIs, including imatinib, dasatinib, and nilotinib, with their disease controlled for long 
periods of time. Bosutinib may represent an additional choice for such patients for treatment 
of their CML in the first-line treatment setting, which could offer these patients a better 
tolerated and possibly more sustainable treatment option than other available therapies.
In the Phase 3 study (Study B1871008, BELA), which evaluated the effect of treatment in a 
first-line treatment setting, bosutinib at 500 mg QD did not meet the primary efficacy 
objective of demonstrating a superior rate of CCyR at 12 months versus imatinib. However, 


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bosutinib did demonstrate superiority across many other efficacy endpoints including MMR 
at 12 months, and importantly for patients, the percentage of patients with transformation to 
AP or BP was lower for bosutinib than imatinib.
In addition, the safety profile of bosutinib was distinct from that of imatinib in terms of 
increased GI toxicity, especially diarrhea, and increased levels of ALT/AST. However, there 
were fewer patients with hematological toxicities. Detailed management guidelines for 
diarrhea have been added to this protocol to help the management of the AE profile of this 
drug (Appendix 6). In addition, investigators will receive careful training to ensure 
appropriate understanding of the bosutinib side effect profile.
Prior clinical studies of bosutinib in CML have used a starting dose of bosutinib of 500 mg 
QD, both in first-line (Study B1871008, BELA) and in later lines of treatment (Studies 
B1871006 and B1871007). In both studies, a substantial number of patients experienced 
toxicities. However these were managed in most cases by treatment interruption and/or dose 
reduction, which allowed the subsequent reintroduction of bosutinib.
In first-line CP CML patients recruited in Study B1871008 (BELA), a total of 92 out 250 
patients (37%) treated with bosutinib had a dose reduction from 500 mg QD to 400 mg QD. 
The median time to first dose reduction to 400 mg QD was 53.5 days with a range from 2 to 
612 days.
The incidence of TEAEs overall as well as unique TEAEs were lower following dose 
reduction from 500 mg QD to 400 mg QD. The overall incidence of Grade 3/4 TEAEs 
decreased from 88% to 71%. All of the most frequently reported TEAEs (all grades) also 
decreased: diarrhea (70% to 40%), ALT increased (39% to 30%), nausea (38% to 23%), 
vomiting (33% to 24%), AST increased (33% to 23%), and thrombocytopenia (30% to 21%). 
It is notable that the median time on treatment for patients prior to dose reduction was 
53.5 days (range: 2-612 days) while the median time on treatment for patients post dose 
reduction was 449 days (range: 0-1142 days). This suggests that patients on the 400 mg dose 
are better able to maintain treatment.
The efficacy of bosutinib in patients who received dose reductions to 400 mg QD remained 
favorable with 46% of patients achieving a CCyR after the dose reduction to 400 mg QD
(compared to 58% in the ITT population) and 16% of patients maintaining a previously 
attained CCyR. In addition, 40% of patients were able to achieve a MMR while on 400 mg
QD of bosutinib (compared to 45% in the ITT population). Of those dose reduced to 400 mg
QD and who attained a CCyR and MMR, the majority of patients (68% and 71% 
respectively), were still on treatment and retaining their response at the time of the analyses.
These data from Study B1871008 (BELA) suggest that the use of a starting dose of 400 mg 
QD in this Phase 2 study in the first-line Japanese CP CML patient treatment setting will 
result in better tolerability and similar efficacy as a starting dose of 500 mg QD.
Thus, the incidence of TEAEs overall as well as unique TEAEs were lower following dose 
reduction from 500 mg QD to 400 mg QD, while the efficacy of bosutinib in patients who 
received dose reductions to 400 mg QD remained favorable. Therefore, it was hypothesized 


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that a starting dose of 400 mg QD in this Phase 2 study in the first-line Japanese CP CML 
patient treatment setting will result in better tolerability and similar efficacy as a starting dose 
of 500 mg QD.
In December 2017, bosutinib was additionally approved for adult patients with newly 
diagnosed Ph+ CP CML in the US by FDA based on the results of Phase 3 study of bosutinib 
versus imatinib (Study AV001, BFORE).  The MMR rates at 12 months for bosutinib
(starting dose of 400 mg QD) and imatinib were 47% and 37% (two-sided p=0.0200), and the 
CCyR rates by 12 months were 77% and 66% (two-sided p=0.0075) respectively, thus 
bosutinib showed superior efficacy compared to imatinib.25  In addition, the most frequently 
reported treatment-emergent adverse events (TEAEs) (all grades) are diarrhea (70%), nausea 
(35%), thrombocytopenia (35%), rash (34%), ALT increased (31%), abdominal pain (25%) 
and AST increased (23%), and this result is consistent with the known safety profile of 
bosutinib.  These results suggest that bosutinib can be an important alternative for patients 
with newly diagnosed CP CML.
1.3. Banked Biospecimen
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of patients who
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study. 
Banked biospecimens retained in the BBS also can be used in research on CML.
Providing these biospecimens is a required study activity for study sites and patients, unless 
prohibited by local regulations or by the IRB or EC decision.  


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
Primary Endpoint:

To evaluate MMR at 12 months (48 weeks) 
in newly diagnosed Japanese Ph+ CP CML 
patients harboring b2a2 and/or b3a2 
transcripts.

MMR at 12 months (48 weeks). All Ph+
CP CML patients harboring b2a2 and/or 
b3a2 transcripts will be assessed and 
follow-up for MMR as primary endpoint.
MMR is defined as ≤0.1% BCR-ABL on 
the IS by RT-qPCR.
Secondary Objectivesa,b:
Secondary Endpoints:

To evaluate MMR by 12 and 18 months.

To estimate the proportion of patients 
demonstrating CCyR by 12 months.

To evaluate the duration of MMR and 
CCyR.

To evaluate EFS.

To evaluate overall survival OS.

To assess the population PK.

To assess correlations between trough 
concentrations of bosutinib and key efficacy 
and safety endpoints.

To characterize the safety profile of 
bosutinib in Japanese patients.

MMR by 12 and 18 months.

CCyR by 12 months.

Duration of MMR and CCyR.

EFS

OS

Population PK parameters.

Correlations between trough concentrations 
of bosutinib and key efficacy and safety 
endpoints.

Safety: AEs (as graded by NCI CTCAE 
v.4.03); laboratory abnormalities (as graded 
by NCI CTCAE v.4.03); vital signs (blood 
pressure, pulse rate); ECGs; ECHO or 
MUGA.
Exploratory Objectives a,b:
Exploratory Endpoints:

To evaluate MMR at 3, 6, 9 and 18 months.

To evaluate MMR at 12 months in patients 
with both Ph+ and Ph- CP CML.

To evaluate MR1 and MR2 at 3 months and 
6 months, respectively.

To evaluate MR4.0 and MR4.5 at 3, 6, 9 and 
12 months.

MMR at 3, 6, 9 and 18 months.

MMR at 12 months in patients with both 
Ph+ and Ph- CP CML.

MR1 and MR2 at 3 months and 6 months, 
respectively.

MR4.0 and MR4.5 at 3, 6, 9 and 12 months.


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
To evaluate time to MMR, MR4.0, MR4.5 and 
CCyR.

To evaluate the proportion of patients 
demonstrating a cumulative complete
hematologic response (CHR) in patients 
with Ph+ and both Ph+ and Ph- CP CML.

To estimate the time to transformation to AP 
and BP CML on treatment.

To evaluate the type of BCR-ABL 
mutations present at treatment completion or 
discontinuation, or in case of suboptimal 
response.

To enable exploratory research through 
collection of banked biospecimen, unless 
prohibited by local regulations or ethics 
committee decision.

Time to MMR, MR4.0, MR4.5 and CCyR.

Cumulative CHR in patients with Ph+ and 
both Ph+ and Ph- CP CML.

Time to transformation to AP and BP CML 
on treatment.

Type of mutations present at treatment 
completion/discontinuation or suboptimal 
response.

Potential results from exploratory analyses 
of banked biospecimen (these results may 
or may not be generated in the context of 
the present study).
a. All efficacy analyses for secondary/exploratory objectives will be performed using the same population as 
primary objective, unless otherwise indicated (detailed in Section 9). 
b. For detailed definitions of responses, see Appendix 2.
3. STUDY DESIGN
This is a Phase 2, open-label, single-arm study designed to evaluate efficacy and safety of 
bosutinib alone in Japanese adult patients with newly diagnosed CP CML. The primary 
endpoint is MMR at 12 months in newly diagnosed Japanese Ph+ CP CML patients 
harboring b2a2 and/or b3a2 transcripts. Patients will receive bosutinib treatment at a starting 
dose of 400 mg QD. The dose of bosutinib is allowed to be escalated (up to a maximum of 
600 mg QD) for unsatisfactory response or reduced (down to 300 mg QD, and further to a 
minimum of 200 mg QD only when approved by the sponsor) for toxicity.
This study has approximately 52 weeks of planned patient accrual. Each patient will have
12 months (48 weeks) of Core Treatment Phase and the following 24 months (96 weeks) of
Extension Phase. After treatment discontinuation, the patient enters Long-Term Follow-Up. 
The Extension Phase or Long-Term Follow-Up will continue until the end of the study.
The study will be open for enrollment until approximately 60 Ph+ CML patients harboring
b2a2 and/or b3a2 transcripts have been registered. Bone marrow aspirate to assess the Ph 
status will be obtained at screening. Patients with known Ph- prior to registration are not 
eligible for this study. However, as confirmation of the Ph status prior to registration is not 
mandatory, Ph- CML patients may also be included. Approximately 3 Ph- CML patients are 
expected to be registered as approximately 5% of the patients with BCR-ABL-positive CML 
are diagnosed as 
Ph-CML.2,3 All patients will be treated and/or followed up to approximately 3 years


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(144 weeks) after registration of the last patient, or until study termination, whichever comes 
first. Patients who permanently discontinue study treatment will be followed for survival, 
investigator-assessed transformation to AP/BP, duration of response and disease progression, 
and initiation/response to further anti-cancer therapies, including stem cell transplantation 
(where applicable).
The primary outcome measure, MMR, is appropriate, as achievement and maintenance of 
MMR is an important endpoint in CML therapy and it appears to predict long-term EFS. The 
selection of the patient population based on presence of BCR-ABL transcript reflects the 
current approach to diagnosis of CML, and is in line with the primary endpoint of MMR.
3.1. Study Treatment
All patients will receive bosutinib at a starting dose of 400 mg QD. The dose of bosutinib 
may be escalated (up to a maximum of 600 mg QD) for unsatisfactory response or reduced 
(down to 300 mg QD, and further to a minimum of 200 mg QD only when approved by the 
sponsor) for toxicity.
Each patient will receive daily bosutinib for up to approximately 3 years after registration of 
the last patient (12 months [48 weeks] Core Treatment Phase and the following 24 months
[96 weeks] Extension Phase) or until the end of the study, treatment failure, unacceptable 
toxicity, death, or withdrawal of consent occurs.
Details of the study treatment forms and packaging, and recommendations for dose 
modifications are included in the Study Treatments Section 5 of the protocol.
4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients 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 patient is suitable for this protocol.
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis of CP CML of ≤6 months (from initial diagnosis)

Diagnosis of CP CML with molecular confirmation by detection of BCR-ABL 
rearrangement at screening (cytogenetic assessment for Ph is not required for 
enrollment; however, patients with known Ph- CML prior to registration are not 
eligible for this study); diagnosis of CP CML will be defined as all of the 
following per European LeukemiaNet (ELN) definitions:


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a.
<15% blasts in peripheral blood and bone marrow;
b. <30% blasts plus promyelocytes in peripheral blood and bone marrow;
c.
<20% basophils in peripheral blood;
d. ≥100 × 109/L platelets (≥100,000/mm3);
e.
No evidence of extramedullary disease except hepatosplenomegaly; AND
f.
No prior diagnosis of AP or BP-CML.
2. Age ≥20 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
4. Adequate Renal Function, including:
a.
Serum creatinine 1.5 × upper limit of normal (ULN) or estimated creatinine 
clearance ≥60 mL/min as calculated using the method standard for the institution.
5. Adequate Liver Function, including:
a.
Total serum bilirubin 1.5 × ULN unless the patient has documented Gilbert 
syndrome;
b.
AST and ALT 2.5 × ULN; 5.0 × ULN if there is liver involvement by 
leukemia;
6. Able to take oral tablets.
7. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 
except for AEs not constituting a safety risk by investigator judgment.
8. Serum pregnancy test (for females of childbearing potential) negative at screening.
Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;
b.
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.


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All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
9. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Any prior medical treatment for CML, including TKIs, with the exception of 
hydroxyurea treatment, which is permitted for up to 6 months prior to registration.
2. Any past or current CNS involvement, including leptomeningeal leukemia.
3. Extramedullary disease only.
4. Major surgery or radiotherapy within 14 days prior to registration.
5. History of clinically significant or uncontrolled cardiac disease including:

History of, or active, congestive heart failure;

Uncontrolled angina or hypertension within 3 months prior to registration;

Myocardial infarction within 12 months prior to registration;

Clinically significant ventricular arrhythmia (such as ventricular tachycardia, 
ventricular fibrillation, or Torsades de pointes);

Diagnosed or suspected congenital or acquired prolonged QT interval history or 
prolonged QTc (QTcF should not exceed 500 msec);

Unexplained syncope.
6. Patients with active, uncontrolled bacterial, fungal, or viral infection, including 
hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
7. Recent or ongoing clinically significant GI disorder (eg, Crohn’s disease, ulcerative 
colitis, or prior total or partial gastrectomy).
8. History of another malignancy within 5 years prior to registration with the exception 
of basal cell carcinoma or cervical carcinoma in situ or Stage 1 or 2 cancer that is 


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considered adequately treated and currently in complete remission for at least 
12 months.
9. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects 
on the QT interval.
10. Known prior or suspected severe hypersensitivity to study drugs or any component in 
their formulations.
11. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
12. Participation in other studies involving investigational drug(s) within 30 days or 5 
half-lives of investigational product, whichever is longer, prior to registration and/or 
during study participation.
13. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
14. Pregnant female patients; breastfeeding female patients; fertile male and female 
patients of childbearing potential who are unwilling or unable to use 2 highly 
effective methods of contraception as outlined in this protocol for the duration of the 
study and for at least 28 days after the last dose of investigational product.
4.3. Lifestyle Requirements
In this study, fertile male patients and female patients who are of childbearing potential as 
applicable to the study will receive bosutinib, which has been associated with suspected 
teratogenicity/fetotoxicity.  Patients who are, in the opinion of the investigator, sexually 
active and at risk for pregnancy with their partner(s) must agree to use 2 methods of highly 
effective contraception throughout the study and for at least 28 days after the last dose of 
bosutinib.  The investigator or his or her designee, in consultation with the patient, will 
confirm that the patient has selected 2 appropriate methods of contraception for the 
individual patient and his/her partner(s) from the list of permitted contraception methods (see 
below) and will confirm that the patient has been instructed in their consistent and correct 
use.  At time points indicated in the schedule of activities table, the investigator or designee 
will inform the patient of the need to use 2 highly effective methods of contraception 
consistently and correctly and document the conversation, and the patient’s affirmation, in 
the patient’s chart.  In addition, the investigator or designee will instruct the patient to call 
immediately if 1 or both of the selected contraception methods is discontinued or if 
pregnancy is known or suspected in the patient or partner.  


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
All sexually active male patients must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.
4.4. 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 study organization.
To facilitate access to an appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.


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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use (ICH 
E6 1.33).  
For this study, the investigational product is bosutinib.
5.1. Allocation to Treatment
Registration will be performed centrally by the sponsor for all patients.  Following full 
assessment and determination that the patient meets all eligibility criteria, the investigator or 
designee will fax or email a complete Registration Form to the designated sponsor study 
team member. The sponsor will assign a patient identification number, which will be used 
on all Case Report Form (CRF) pages and other trial-related documentation or
correspondence referencing that patient and fax or email to the site.  
No patient shall receive study drug until the investigator or designee has received the
following information from the sponsor: confirmation of the patient’s enrollment.
5.2. Patient Compliance
For self-administration of bosutinib at home, compliance will be captured and completed by 
the patient.
A patient diary will be provided to the patients to aid in patient compliance with the dosing 
instructions.  The diary will be maintained by the patient to include missed or changed 
bosutinib doses.  Patients will be required to return all bottles of bosutinib every visit.  The 
number of bosutinib tablets remaining will be documented and recorded at each visit.  The 
patient diary may also be used to support this part of the bosutinib accountability process.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
Bosutinib tablets (100 mg dosage strength) will be supplied by Pfizer in high-density 
polyethylene (HDPE) bottles. The bosutinib commercial formulation will be supplied in this 
study. Bosutinib will be labeled according to local regulations.
5.3.2. Preparation and Dispensing
The study treatment should be dispensed at each visit per the schedule of treatment.  A 
qualified staff member will dispense the investigational product in the bottles provided, in 
quantities appropriate for the study visit schedule.  The patient/caregiver should be instructed 
to maintain the product in the bottle provided throughout the course of dosing, keep the 
investigational product away from children, and return the bottle to the site at the next study 
visit.


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5.4. Administration
The starting dose is 400 mg QD, orally, recommended to be taken in the morning with a meal 
and approximately 200 mL of water. Available data show that both tolerance and absorption 
are greatly improved by taking bosutinib with a meal, including adequate dietary fats; no 
restriction is imposed on patients’ food choices.
Patients will swallow the investigational product whole and will not manipulate or chew the 
investigational product prior to swallowing. Patients must be instructed that should they miss 
a dose or vomit any time after taking a dose, they must not “make it up” with an extra dose.  
Instead, resume the subsequent doses as originally prescribed.  Any missed dose may be 
taken up to 12 hours prior to the next scheduled dose, otherwise it should be skipped and 
dosing resumed with subsequent doses as prescribed.
On PK sampling days, the bosutinib dose should be taken in the hospital under the 
supervision of the study site personnel. The bosutinib dose should be administered after the 0 
hour (pre-dose) PK sample has been collected.
Dosing is continuous without planned interruptions; patients who complete 12 months (48 
weeks) Core Treatment Phase will continue dosing without interruption into the Extension 
Phase. Each patient will receive daily bosutinib for up to approximately 3 years after 
registration of last patient (12 months [48 weeks] Core Treatment Phase and the following
24 months [96 weeks] Extension Phase) or until the end of the study, treatment failure, 
unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. 
In this study, the dose of bosutinib may be escalated for unsatisfactory response or reduced 
for toxicity. Dose modifications (as summarized in Table 1) may be performed according to 
the criteria as summarized in detail in Section 5.4.1 and Section 5.4.2. For dose increases, the 
investigator must communicate directly with the patient and an additional ad hoc visit should 
be considered so as not to postpone the start of optimized dosing.
Table 1.
Dose Modifications for Bosutinib
Dose Level
Bosutinib (mg)
Second Dose Increase (+2)
600
First Dose Increase (+1)
500
Starting Dose
400
First Dose Decrease (-1)
300
Second Dose Decrease (-2)
200*
*subject to sponsor approval
5.4.1. Dose Escalation
Patients should have their dose increased to 500 mg QD and further up to a maximum of 
600 mg QD of bosutinib, as tolerated, if all of the following criteria are met:
a.
They do not demonstrate an optimal response at Month 3 (ie, BCR-ABL transcripts 
>10% and/or Ph+ metaphases >35%)


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b.
They have no Grade 3/4 adverse events at the time of dose escalation, and all prior 
Grade 3/4 events have resolved to Grade 1/2 as follows:

All Grade 3/4 hematologic toxicities have resolved to Grade ≤1.

All Grade 3/4 non-hematological toxicities have resolved to Grade ≤2 and are 
manageable with supportive therapy. Grade 3/4 non-hematological toxicities 
resolved to Grade ≤2 which would be acceptable for dose escalation are: vomiting, 
nausea, abdominal pain, rash, headache, myalgia and fatigue. All other non-
hematological toxicities should be Grade ≤1 for dose escalation.

In addition, for dose escalation to be permitted in a patient who has experienced 
such toxicities (ie, Grade 3/4 hematologic and non-hematologic), the patient must 
have been able to be successfully re-challenged (ie, not have experienced 
recurrence of that toxicity at the Grade 3/4 level) at the lower dose after recovery 
from the Grade 3/4 toxicity.
AND
c.
All Grade 2 non-hematologic toxicities have resolved to Grade ≤1.
All responses will be assessed per protocol at Month 3 for the purpose of dose escalation to 
support response. If all of the above criteria are met, dose of bosutinib will be increased.
At Month 6, it is recommended that the investigator follow existing CML guidelines (ELN or 
NCCN, see Appendix 2) to determine if dose escalation is indicated based upon failure to 
demonstrate an optimal response; however, the protocol does not mandate a dose increase; 
the decision is left to the clinical judgment of the investigator, taking into account local 
guidelines. The same safety criteria apply as for the Month 3 dose escalation.
At any time, if the patient loses a complete hematologic or complete cytogenetic response, or 
has a confirmed loss of MMR and a 5 × PCR increase, then a 1-level dose increase, up to a 
maximum of 2 dose levels, is suggested, after consultation with the sponsor. In addition,
cytogenetic assessment on bone marrow should be reintroduced in the presence of loss of 
MMR and a 5 × PCR increase and until MMR is achieved again. The same safety criteria 
apply as for the Month 3 dose escalation.
Lack of response for dose escalation (mandatory at Month 6, and recommended at Month 3)
is defined as: BCR-ABL transcripts >10% by qPCR IS and/or Ph+ metaphases >35%.
Additionally, anytime lack of optimal response is demonstrated, a BCR-ABL mutation test 
must be performed on the same sample if possible.
The BCR-ABL transcript levels (and mutation analyses when appropriate) will be assessed 
by a central laboratory throughout this study.


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5.4.2. Dosing Interruptions and Dose Reductions
The dose of bosutinib may be interrupted and/or reduced for the toxicities described below.
For bosutinib, a dose reduction from 400 mg QD to 300 mg QD is permitted. If a patient 
requires a second dose reduction from 300 mg QD to 200 mg QD, the investigator should 
contact the sponsor to determine if the patient may continue on treatment at a lower dose. 
The second dose reduction must be approved by the sponsor and will only be considered if 
the patient in question displays optimal response to bosutinib treatment at the time point at 
which the dose reduction is being considered. Patients should remain on the 200 mg dose for 
a maximum of 4 weeks or until the toxicity resolves, whichever is sooner, in line with the 
dose reduction and dose escalation guidelines. The dose may then be re-escalated following 
the escalation guidelines. Any patient on the 200 mg dose with ongoing toxicity after the 4-
week time point will be discontinued from treatment and will continue with Long-Term 
Follow-Up evaluations. Dose reductions of bosutinib below 200 mg QD will not be permitted.
If the investigator and the sponsor decide that it is not in the best interest of the patient to 
remain on treatment at a dose lower than 300 mg QD, the patient will be discontinued from 
treatment and will continue with Long-Term Follow-Up evaluations.
Once the dose has been reduced for a patient, patients should remain on that dose unless the 
toxicity resolves (Grade ≤1). In that case, the dose may be escalated to the previous starting 
dose.
Management of Non-Hematologic Treatment-Related Toxicities
The management of non-hematologic treatment-related toxicities is summarized in Table 2.
Patient instructions for the management of diarrhea are presented in Appendix 6.


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Table 2.
Management of Non-Hematologic Treatment-Related Toxicity
Adverse Event
Action
Elevated liver transaminases
If elevations in ALT, AST >5× institutional ULN occur, bosutinib should be 
interrupted until recovery to ≤ 2.5×ULN and may be resumed at 400 mg QD
thereafter. If recovery takes longer than 4 weeks, discontinuation of bosutinib 
should be considered. If transaminase elevations ≥3×ULN occur concurrently 
with bilirubin elevations >2×ULN and alkaline phosphatase <2×ULN, 
bosutinib should be discontinued.
Diarrhea
For Grade 3/4 diarrhea, bosutinib should be interrupted and may be resumed at 
400 mg QD upon recovery to Grade ≤ 1.
Grade 1
Current dose level.
Grade 2
For persistent clinically relevant toxicityb not responding to optimal 
management: Temporarily interrupt treatment, and reintroduce at the same 
dose or reduce dose by 1 level upon recovery to Grade ≤1 within 4 weeks of 
stopping test article.
Grade 3a
For persistent clinically relevant toxicityb not responding to optimal 
management: Withhold treatment, then dose reduce by 1 level upon recovery 
to Grade ≤1 within 4 weeks of stopping test article. If recovery takes longer 
than 4 weeks, the investigator should contact the sponsor to determine if the
patient may continue on treatment.
Grade 4a
Withhold treatment. Investigator and sponsor to review to determine if patient 
may continue on treatment with appropriate dose reduction.
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; QD = once daily; 
ULN = upper limit of normal
a. For patients requiring dose reduction due to toxicity, who have been free of the toxicity (Grade ≤1) for at least 1 month 
and are otherwise tolerating study drug, the investigator may choose to re-escalate dose by 1 dose level back to starting dose.
b. Persistent Clinically Relevant Toxicity is defined as - symptoms of toxicity which, despite optimal medical management, 
persist for ≥14 days (“persistent”) and cause sufficient symptoms or signs of illness in the patient to warrant further 
intervention, eg, dose adjustment (“clinically relevant”).
Patients with Grade 3 non-hematological toxicity which does not respond to optimal 
management, will be managed by withholding treatment followed by dose reduction by 1 
level upon recovery to Grade ≤1. If, upon re-challenge at a reduced dose, the patient remains 
free of toxicity (Grade ≤1) for at least 1 month, the investigator may choose to re-escalate the 
dose by 1 level back to the starting dose. If, subsequently, the patient fulfills the criteria for 
dose escalation due to suboptimal response (detailed in Section 5.4.1), this will be permitted 
for vomiting, nausea, abdominal pain, rash, headache, myalgia, or fatigue provided that the 
toxicity is Grade ≤2 is manageable with supportive therapy. All other non-hematological 
toxicities should be Grade ≤1 for dose escalation.
Patients fulfilling criteria for dose escalation due to suboptimal response, but also exhibiting 
elevated liver transaminases as described in Table 2, will not be dose escalated at this time, 
and will be managed according to the instructions in Table 2.
In line with the Summary of Product Characteristics26 for bosutinib, caution is recommended 
in patients with previous history of pancreatitis and in patients with increased serum lipase in 
conjunction with abdominal symptoms. Therefore, for study patients with previous history of 
pancreatitis, in the event of elevation of lipase level >1.5 × ULN (ie, CTCAE Grade 2 or 
above), bosutinib treatment should be interrupted immediately, and additional investigations 
and lipase monitoring should be performed to exclude pancreatitis. In addition, for any study 


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patient with elevation of lipase level >1.5 × ULN in conjunction with abdominal pain, 
bosutinib treatment should be interrupted, and similar investigations to exclude pancreatitis 
performed. Bosutinib treatment may be restarted only once pancreatitis is excluded and 
lipase levels return to CTCAE Grade 1.
Management of Hematologic Treatment-Related Toxicities
Guidelines in Table 3 pertain to patients with normal or higher than normal blood counts or 
patients who have achieved CHR.
Table 3.
Management of Hematologic Treatment-Related Toxicity
Adverse Event
Action
Grade 1
Current dose level
Grade 2
Current dose level
Grade 3a
Withhold treatment:
If recovered to Grade ≤2 within 2 weeks of treatment hold: re-introduce study 
drug at same dose. If recovered within 4 weeks of treatment hold: reduce study 
drug by 1 dose level.
At subsequent occurrences of Grade 3 toxicity, dose must be reduced upon 
recovery to Grade ≤2.
If recovery takes longer than 4 weeks, the investigator should contact the 
sponsor to determine if the patient may continue on treatment.
Grade 4a
Withhold treatment. Investigator and sponsor to review to determine if patient 
may continue on treatment with appropriate dose reduction.
a. For patients requiring dose reduction due to toxicity, who have been free of the toxicity (Grade ≤1) for at least 1 month 
and are otherwise tolerating study drug, the investigator may choose to re-escalate dose by 1 dose level back to starting dose
Patients fulfilling criteria for dose escalation due to suboptimal response, but also exhibiting 
Grade 2 hematologic treatment-related toxicity, will be eligible for dose escalation; however, 
if hematologic toxicity increases to Grade 3/4 after dose escalation, the patient will be 
managed as per the instructions for Grade 3/4 hematological toxicities in Table 3.
5.5. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 


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excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Site staff will instruct patients on the proper storage requirements for take home 
investigational products.
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
All bottles of study drug must be returned to the investigator by the patient at every visit and 
at the end of the trial.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  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, and all destruction must be adequately documented.
5.7. Concomitant Treatments
All information on concomitant treatment (medications or procedures) must be recorded on 
the patient’s eCRF (including the name or the medication or procedure and duration of 
treatment).
If there is a clinical indication for one of these or other medications specifically prohibited 
during the trial, discontinuation from study therapy or medication may be required.  The final 
decision on any supportive therapy rests with the investigator and/or the patient’s primary 


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physician.  However, the decision to continue the patient on study therapy or medication 
schedule requires the mutual agreement of the investigator, the sponsor, and the patient. 
Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.
Concomitant medications and treatments will be recorded from 28 days prior to the 
registration and up to 28 days after the last dose of study treatment.  All concomitant 
medications should be recorded in the CRF including supportive care drugs (eg, antiemetic 
treatment and prophylaxis), and the drugs used to treat AEs or chronic diseases, and non-drug 
supportive interventions (eg, transfusions).
There are no prohibited therapies during the Long-Term Follow-Up Phase.
5.7.1. Prohibited Medications

Any concurrent chemotherapy, radiotherapy, or anticancer immunotherapy other than as 
defined in this protocol.

Any other anti-cancer therapy.

Any other investigational agents.

Drugs known to prolong the QT interval or predispose to Torsades de Pointes (see 
Appendix 4).

Concurrent anticoagulation therapy with warfarin or related oral anticoagulant therapy. 
Concurrent therapeutic anticoagulation with low molecular weight heparin will be 
permitted.

Prophylactic use of growth factors.
5.7.2. Permitted Medications

Any medication (other than those prohibited above or per inclusion/exclusion criteria) for 
a concurrent medical condition is permitted.

Treatment of diarrhea and other GI symptoms will be optimized.

Treatment with growth factors, eg, for neutropenia (including granulocyte colony-
stimulating factor [G-CSF] according to American Society of Clinical Oncology [ASCO] 
guidelines).

Supplementation is advised for potassium levels or magnesium levels below the LLN, 
with consideration of the patient’s underlying renal function.


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
Up to 6 months of prior hydroxyurea is permitted prior to signature of informed consent 
document.  Hydroxyurea is also permitted during the first 21 days of study treatment 
following registration.

Temporary steroid use will be permitted for treatment of AEs – limited to systemic 
steroids for no more than 10 days and at doses ≤60 mg prednisone/day or the equivalent. 
Of note, inhaled and topical steroids are permitted without limitation.
5.7.3. Other Treatment Considerations: Interaction with Other Medical Products and 
Other Forms of Interaction
The concomitant use of bosutinib with strong or moderate cytochrome P450 (CYP3A)
inhibitors (reference Appendix 5) should be avoided, as an increase in bosutinib plasma 
concentration may occur.
If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an 
interruption of bosutinib therapy and/or a dose reduction in bosutinib should be considered.  
Patients should also be strongly encouraged to avoid herbal remedies. Grapefruit and 
grapefruit juice should also be avoided.
The concomitant use of bosutinib with strong or moderate CYP3A inducers including St. 
John’s Wort should be avoided (Appendix 5); it is not recommended as it will significantly 
reduce expose to bosutinib.
Bosutinib should be used with caution in patients who have or may develop QT interval 
prolongation, including those patients taking anti-arrhythmic medicinal products (see 
Appendix 4).
Inhibitors of platelet aggregation, ie, aspirin, dipyridamole, clopidogrel, and ticlopidine, 
should be used with caution.
Transfusions for anaemia or thrombocytopenia may only be given in the interest of patient 
safety.  Transfusions will not be permitted in order to allow continued dosing of bosutinib 
when there is an indication for treatment interruption as outlined in the Dose 
Adjustment/Treatment Interruption tables (see Table 2 and Table 3).
Caution should be exercised when administering bosutinib concomitantly with proton-pump 
inhibitors (PPIs).  Short-acting antacids should be considered as an alternative to PPIs and 
administration times of bosutinib and antacids should be separated by at least 2 hours (eg, 
take bosutinib in the morning and antacids in the evening) whenever possible.
6. STUDY PROCEDURES 
As applicable, all visits must occur within the predefined time windows outlined in this 
protocol.
6.1. Screening
Informed consent must be obtained prior to undergoing any study specific procedures.


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For screening procedures, see SCHEDULE OF ACTIVITIES table and ASSESSMENTS
section.
6.1.1. Collection of Banked Biospecimen
Collect a genomic banked biospecimen.  If missed, collect at the next available time point 
when biospecimens are being collected in conjunction with a patient visit.
Blood will be collected at screening and retained in a Biobank for exploratory biomarker 
assessments, unless prohibited by local regulation or by the IRB/EC.
6.2. Core Treatment Phase
For Core Treatment Phase procedures, see SCHEDULE OF ACTIVITIES table and 
ASSESSMENTS section.
Patients will have visits at the study site on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 
and 24, then every 12 weeks for the first year of treatment in the 12 months (48 weeks Core 
Treatment Phase). Additional visits may be required for patients requiring dose increases at 
the Week 12 and Week 24 visits, these will be performed as soon as possible and within 
4 weeks of the result requiring dose change being known. Patients not requiring a dose 
change will be contacted by telephone.
6.3. Extension Phase
For Extension Phase procedures, see SCHEDULE OF ACTIVITIES table and 
ASSESSMENTS section.
All patients will be treated and/or followed up to approximately 3 years (144 weeks) after
registration of the last patient or study termination. Patients who discontinue study therapy 
early due to disease progression or intolerance to study medication will continue to be 
followed for survival for up to approximately 3 years (144 weeks) after registration of the 
last patient or until study termination.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
products, request that the patient return for a final visit, if applicable, and follow up with the 
patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival. If 
the patient withdraws from the study, and also withdraws consent 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.


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6.4. End of Treatment/Withdrawal Visit
For End of Treatment/Withdrawal visit procedures, see SCHEDULE OF ACTIVITIES table 
and ASSESSMENTS section.
Patients who discontinue from study treatment for any reason should complete an End of 
Treatment/Withdrawal visit between 7 and 28 days after the last dose of study drug, and the 
patient enters Long-Term Follow-Up.
6.5. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Section 8.1.3), behavioral reasons, or the inability of the patient to comply with the protocol-
required schedule of study visits or procedures at a given study site.
Reasons for withdrawal of study treatment may include:

Treatment failure (meeting 1 or more of the following definitions);

Transformation to AP or BP at any time (disease progression).

After dose escalation (as specified in Section 5.4.1), or documented AEs prohibiting 
dose escalation and if 1 of the following conditions is met:

Failure to achieve a CHR after a minimum of 24 weeks on treatment.

Failure to achieve at least a minimal cytogenetic response after a minimum of 24 
weeks on treatment.

Failure to achieve a major cytogenetic response (MCyR) after a minimum of 48 
weeks on treatment.

Failure to achieve a CCyR after a minimum of 72 weeks on treatment.

Loss of MCyR or CCyR (need at least 30% increase for MCyR or at least one 
Ph+ metaphase for CCyR confirmed by a follow-up cytogenetic analysis 4 
weeks later).

Loss of CHR. Loss of CHR is defined as the appearance of any of the following,
confirmed by a second determination 4 weeks later (unless associated with 
CML-related treatment discontinuation):

White blood cell count (WBC) that rises to >20.0 × 109/L.

Platelet count that rises to 600 × 109/L.


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
Appearance of palpable spleen or other extramedullary involvement proven by 
biopsy.

Appearance of 5% myelocytes in the peripheral blood.

Appearance of blasts or promyelocytes in the peripheral blood.

For patients not achieving a CHR: doubling of WBC at least 1 month apart with 
the second value >20 × 109/L and maintained in subsequent assessments for at 
least 2 weeks.

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Dose is held for longer than 4 weeks for treatment-related toxicity (without 
consultation with sponsor). Of note, in some instances, if the investigator and 
sponsor determine it is appropriate, a patient may be allowed to continue on 
treatment if recovery takes longer than 4 weeks.

Need to dose reduce below 300 mg QD. Of note, in some instances, if the 
investigator and sponsor determine it is appropriate, a patient may be allowed to 
dose reduce below 300 mg QD.

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment (follow up permitted by patient);

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow up may include:

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.


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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
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.
7.1. Efficacy Assessment
7.1.1. Efficacy Assessment Methods
Efficacy will be determined by physical examination, analysis of peripheral blood and bone 
marrow. Automated CBC (eg, hemoglobin, red blood cell (RBC), WBC, platelets, and 
hematocrit), differential counts (eg, neutrophils, basophils, eosinophils, lymphocytes, 
metamyelocytes, myelocytes, monocytes, promyelocytes, myeloblasts, unspecified blast cells
and band cells), bone marrow differential (eg, plasma cells, promyelocytes, myelocytes, 
metamyelocytes, eosinophils, lymphocytes, monocytes, myeloblasts, erythroblast, basophil, 
neutrophils, band neutrophils, unspecified blast cells, megakaryocytes, and erythroid 
precursors), molecular analysis for BCR-ABL transcripts, cytogenetics, physical examination, 
and mortality will be used to determine the response to treatment as described in Appendix 2. 
Molecular and hematologic response rates will be assessed for all patients. Cytogenetic 
response will be assessed in all Ph+ CML patients. The timing of these assessments is 
presented in the SCHEDULE OF ACTIVITIES table.
Molecular response monitoring using RT-qPCR for BCR-ABL copy number will be 
performed on peripheral blood on all patients harboring b2a2 and/or b3a2 transcripts and will 
be sent to a central vendor for performance and assessment on the IS; sample collection for 
molecular response monitoring is described in Section 7.1.1.1.
Differential count and cytogenetic assessment on bone marrow aspirate will be performed 
locally.
Bone marrow obtained as part of standard of care prior to signing the informed consent 
document may be used at screening as long as it was collected within 28 days prior to
registration. Patients completing treatment for cytogenetically confirmed treatment failure do 
not need to repeat bone marrow at treatment completion. Patients ending treatment for 
reasons other than cytogenetically confirmed treatment failure must undergo treatment 
completion bone marrow aspirate if the previous bone marrow aspirate was performed 
>12 weeks prior to treatment failure. Additional bone marrow aspirations and cytogenetics 
will be done as indicated (eg, suspect disease progression or failed/inadequate Week 48 


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[Month 12] assessment). If confirmed loss of MMR occurs in combination with a 5 × PCR 
increase for BCR-ABL, a bone marrow aspirate for cytogenetics should be obtained.
Standard cytogenetics will be used to determine the presence of the Ph and its percent 
presence in the bone marrow aspirate. Twenty (20) or more metaphases should be analyzed 
for this determination, except for the baseline sample. As noted above, cytogenetics will be 
performed locally. If bone marrow aspirate collected at Week 48 is not adequate for 
cytogenetic analysis, aspirate should be repeated within 4 weeks. Loss of cytogenetic 
response must be confirmed by 2 assessments at least 4 weeks apart.
Bone marrow aspirate cell differential will also be used to determine the blast and immature 
myeloid counts in order to define disease phase.
Mutation testing for BCR-ABL sequencing will also be performed on peripheral blood at 
study completion, discontinuation or lack of response following dose escalation 
(Section 5.4.1). Blood will be sent utilizing frozen PAXgene tubes to an approved central 
vendor for analysis. See lab manual for processing and shipping of samples.
MMR is defined as BCR-ABL ≤0.1% BCR-ABL on the IS by RT-qPCR (Appendix 2) and 
CCyR is defined as absence of detectable Ph (Appendix 2). Loss of MMR, accompanied by 
at least 5-fold increase from the smallest recorded BCR-ABL transcripts value, must be 
confirmed by 2 assessments at least 4 weeks apart.
Complete hematologic response must be of at least 4 weeks in duration and confirmed by 2 
assessments at least 4 weeks apart. Complete hematologic response will be evaluated by 
peripheral blood only utilizing local laboratory results, and clinical exclusion of 
extramedullary disease. Loss of hematologic response must also be confirmed by 2 
assessments at least 4 weeks apart.
Physical examination will be used to assess liver and spleen involvement.
EFS and OS will be obtained from data evaluating the patient’s disease status and mortality 
data.
7.1.1.1. Sample Collection for Molecular Response
In order to monitor molecular response under study treatment, 15 mL of peripheral blood will 
be collected into 6 PAXgene Blood RNA tubes at each sampling time point. Blood samples 
for BCR-ABL are to be taken at Screening, Week 12, 24, 36, 48 (with a back-up sample at 
Week 48), and then every 12 weeks until the end of Year 2, then every 24 weeks.
The samples will be sent to the central RT-qPCR laboratory to evaluate BCR-ABL transcript 
levels by RT-qPCR. All Month 12 (Week 48) samples will be analyzed in duplicate to 
confirm the results. When reduction of BCR-ABL to <0.1% of standardized baseline (MMR) 
or ≥4.0 log, or ≥4.5 log reduction in BCR-ABL transcript levels (MR4.0 or MR4.5) is achieved, 
a repeat analysis of the same sample will be performed to confirm the results. If a ≥5-fold 
increase in BCR-ABL transcripts from the lowest value achieved on study along with loss of 


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MMR is identified and confirmed by duplicate analysis of the same sample, an unscheduled 
visit sample will be collected within 4-6 weeks to confirm the results. If the 5 × increase in 
BCR-ABL is accompanied by loss of MMR, mutation analysis will be performed on the 
same sample if possible and a bone marrow aspirate sample for cytogenetics will be obtained.
For patients who achieve undetectable BCR-ABL by RT-qPCR, due to variability in sample 
quality and blood cell counts, a repeat assay using more than 10 mL of blood may be 
required to determine whether ≥4.0 log or ≥4.5 log reduction in BCR-ABL transcript levels is 
reached. Therefore, 20 mL of blood may be collected from these patients for PCR analysis. 
In addition, after the first documented negative BCR-ABL result, 20 mL of blood will be 
collected for all subsequent sampling time points until BCR-ABL is no longer negative. 20 
mL of blood may be collected as an unscheduled PCR sample from these patients.
At each sampling point, 15 mL of peripheral blood will be collected into six (6) 2.5 mL 
PAXgene Blood RNA tubes included in the sample collection kits. Two (2) additional 
PAXgene tubes will be collected at Week 48; these will serve as back-up samples for the 
primary endpoint.
7.1.1.2. Mutation Analysis
Correlation of mutations with treatment response will be studied. The blood samples 
collected for RT-qPCR will also be used for mutation analysis and will be drawn every 
3 months (every 12 weeks) up to years 2 (Core Treatment Phase and Extension Phase) and 
then every 6 months (every 24 weeks) (Extension Phase). No mutation analysis will occur at
Screening. Mutation analysis will be performed in case of either lack of response, suboptimal 
response or loss of response defined as: failure to achieve MMR at 12 months; loss of MMR 
AND rise in BCR-ABL transcript level by ≥5-fold from the lowest value achieved during the 
study; at the End of Treatment/Withdrawal visit. For patients with a positive mutation 
identified during therapy, follow-up mutation analyses will be performed in subsequent 
samples. For a patient with a negative mutation result immediately following relapse, 
continued mutation analyses may be performed at a frequency of every 6 months (every 
24 weeks) as needed.
Further mutation analyses will be performed retrospectively as appropriate on patient 
samples if mutations are identified. Alternative methodologies with improved mutation 
detection sensitivity may be used for identifying mutations in earlier samples.
7.2. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examinations, ECG (12-lead), chest X-rays, ECHO/MUGA scans, laboratory assessments, 
including pregnancy tests and verification of concomitant treatments.
7.2.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL will be performed on 2 occasions prior to starting 
administration of study treatmentonce at the start of screening and once at the baseline visit 


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immediately before starting the study treatment.  Following a negative serum pregnancy test 
result at screening, appropriate contraception must be commenced and another serum or
urine negative pregnancy test result will be required at the baseline visit before the patient 
may receive the study treatment.  Urine pregnancy tests will be repeated according to the 
SCHEDULE OF ACTIVITIES table during the active treatment period, at the end of study 
treatment, and additionally whenever 1 menstrual cycle is missed during the active treatment 
period or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may 
also be undertaken if requested by IRBs/ ECs or if required by local regulations.
In the case of a positive confirmed pregnancy, the patient will be withdrawn from 
administration of investigational product but may remain in the study.  
7.2.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the NCI 
CTCAE version 4.03) timing, seriousness, and relatedness.
7.2.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the 
SCHEDULE OF ACTIVITIES table and analyzed at local laboratories.


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Table 4.
Safety Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis****
Pregnancy 
Test
Hemoglobin
ALT
PT or INR
Urine dipstick for 
urine protein: If 
positive and 
clinically indicated,
collect 24-hr and 
microscopic 
(Reflex Testing)
For female 
patients of 
childbearing 
potential, 
serum or 
urine
Platelets
AST
PTT or aPTT
Hematocrit
Alk Phos
RBC
Sodium
WBC
Potassium
Neutrophils
Magnesium
Lymphocytes
Calcium
Monocytes
Chloride
Urine dipstick for 
urine blood: If 
positive and 
clinically indicated, 
collect a 
microscopic 
(Reflex Testing)
Eosinophils
TBili*
Basophils
BUN or Urea
Metamyelocytes
Creatinine**
Myelocytes
Creatine kinase
Promyelocytes
Fractionated creatine 
kinase if creatine kinase 
is abnormally high (if 
available)
Myeloblasts
Unspecified blast cells
Band Cells
Uric Acid***
Glucose (nonfasted)
Albumin
Phosphorous or 
Phosphate
Total protein
Amylase
Lipase
Carbon dioxide or 
bicarbonate (if available)
Other Tests: HBV and 
HCV
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; HBV = hepatitis B virus; HCV = hepatitis C virus; INR =
international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood 
cell count; TBili = total bilirubin; WBC = white blood cell count.
* For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, PT/INR, alkaline 
phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels. ** eGFR will be calculated. 
*** Uric acid will be obtained until patient achieves a CHR. **** Urinalysis and microscopic (Reflex testing) 
may include urine protein, urine pH, urine blood/hemoglobin, urine glucose, urine esterase, urine nitrites, urine 
ketones, urine specific gravity, urine red blood cells, urine white blood cells, urine crystals and urine casts.
7.2.4. Physical Examinations
Patients will undergo physical examinations to include weight, vital signs, assessment of 
ECOG performance (Appendix 3) status and height; height will be measured at baseline only.
7.2.5. (12-Lead) Electrocardiograms
Triplicate 12-lead (with a 10-second rhythm strip) tracings will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  At each time point (see SCHEDULE OF ACTIVITIES table), 3 consecutive 


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ECGs will be performed at approximately 2 minutes apart to determine the mean QTcF 
interval.  If the mean QTcF is prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs 
should be re-evaluated by a qualified person at the site for confirmation as soon as the 
finding is made, including verification that the machine reading is accurate.  If manual 
reading verifies a QTcF of >500 msec, immediate correction for reversible causes (including
electrolyte abnormalities, hypoxia and concomitant medications for drugs with the potential 
to prolong the QTcF interval) should be performed.  In addition, repeat ECGs should be 
immediately performed hourly for at least 3 hours until the QTcF interval falls below 
500 msec.  If QTcF interval reverts to less than 500 msec, and in the judgment of the 
investigator(s) and sponsor is determined to be due to cause(s) other than investigational 
product, treatment may be continued with regular ECG monitoring.  If in that timeframe the 
QTcF intervals rise above 500 msec the investigational product will be held until the QTcF 
interval decreases to 500 msec.  Patients will then restart the investigational product at the 
next lowest dose level.  If the QTcF interval has still not decreased to 500 msec after 
2 weeks, or if at any time a patient has a QTcF interval >515 msec or becomes symptomatic, 
the patient will be removed from the study.  Additional triplicate ECGs may be performed as 
clinically indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If a patient experiences any cardiac or neurologic AEs (specifically syncope, dizziness, 
seizures, or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 
7.3. Pharmacokinetics Assessments
Blood samples (3 mL) to provide a minimum of 1.0 mL plasma for PK analysis will be 
collected into appropriately labeled tubes containing potassium EDTA as outlined in the 
SCHEDULE OF ACTIVITIES table.
The pre-dose samples may be collected before (within 3 hours) study drug administration.
Refer to the SCHEDULE OF ACTIVITIES table for specific timing of the sample collection. 
Actual date and time of treatment dose and PK sampling should be recorded on the eCRF.
Detailed instructions for PK blood sample collection, processing, storage, and shipment will 
be provided in a lab manual.  PK samples must be processed and shipped as indicated in the 
lab manual to maintain sample integrity.  Any deviations from the processing steps 
(ie, sample collection and processing, 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.  


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Any deviation from the specified sample handling procedure resulting in compromised 
sample integrity will be considered a protocol deviation.
As part of understanding the PK of the investigational product, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, as well as for other 
internal exploratory purposes.  These data will not be included in the Clinical Study Report 
(CSR).
7.4. Banked Biospecimens
Banked biospecimens will be collected from patients for exploratory research relating to the 
drug response and disease/condition under study.  These collections are not typically 
associated with a planned assessment described in the protocol.  They will be handled in a 
manner that protects each patient’s privacy and confidentiality.  Banked biospecimens will be 
assigned the patient’s study identification code (ID) at the site.  The data generated from 
these banked biospecimens will also be indexed by this ID.  Biospecimens will be kept until 
destruction in facilities with access limited to authorized personnel, and biospecimen-derived 
data will be stored on password-protected computer systems.  The key between the patient’s 
ID and the patient’s direct personally identifying information (eg, name, address) will be held 
at the study site.  Biospecimens will be used only for the purposes described in the protocol 
and informed consent document; any other uses require additional ethical approval.  Unless a 
time limitation is required by local regulations or ethical requirements, biospecimens will be 
stored for many years (no time limit) to allow for research in the future, including research 
conducted during the lengthy drug-development process and also postmarketing research.  
Patients may withdraw their consent for the use of their banked biospecimens at any time by 
making a request to the investigator; in this case, any remaining biospecimens will be 
destroyed, but data already generated from the biospecimens will continue to be available to 
protect the integrity of existing analyses.  
Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic 
banked biospecimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected at the 
time specified in the schedule of activities section of the protocol to be retained for potential 
pharmacogenomic/genomic/biomarker analyses related to drug response and the 
disease/condition under study. For example, putative safety biomarkers, drug-metabolizing 
enzyme genes, drug-transport protein genes, or genes thought to be related to the mechanism 
of drug action may be examined.  The primary purpose is to examine DNA; however, the 
biospecimen may also be used to study other molecules (eg, RNA, proteins, and metabolites).
The banked biospecimens will be collected from all patients unless prohibited by local 
regulations or IRB/EC decision.  
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document that they will not be compensated 
in this event.


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7.4.1. Additional Research
Unless prohibited by local regulations or IRB/EC decision, patients will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Patients may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) non-
serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of suspected causal relationship to the 
investigational product(s) will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 


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within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this 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 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  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.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.


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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any study-
related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship on the CRF, and report such an 
assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 


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investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator’s causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.  
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.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);


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
Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result 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; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias (the primary disease under study does not qualify
for this) or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:


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
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in
the safety database. 
8.4.2. 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 patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are “susceptible” to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (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 lab 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 patient’s 
individual baseline values and underlying conditions.  Patients 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:

Patients 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 patients 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:
o
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).


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o
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).
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 patient 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.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
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 (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, 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 and liver imaging 
(eg, biliary tract) 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.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:


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
A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct 
contact with a Pfizer product in a pregnant woman (eg, a nurse reports that she 
is pregnant and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
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 pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
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 includes 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 


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SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
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 patient with the Pregnant Partner Release of Information Form to deliver to 
his partner.  The investigator must document in the source documents that the patient was 
given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  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’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported 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 does not pertain to a patient 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.
8.4.4. Medication Errors
Other exposures to the investigational product 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
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:


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
Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating patient.
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 immediately.
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 non-serious, are recorded on an 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.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (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.

Analysis Populations
The as-treated population will consist of all patients who received at least 1 dose of study 
treatment.  However, the primary analysis population for the efficacy evaluation will be the 
modified as-treated population. The modified as-treated population will consist of all 
patients with Ph+ CP CML harboring b2a2 and/or b3a2 transcripts who received at least 1 
dose of study medication.
All statistical analyses will be performed using the modified as-treated population. The 
exploratory MMR analyses at 12 months (48 weeks), time to molecular response, OS, and 
cumulative CHR will also be performed using the as-treated population including the Ph+ 
and Ph- CML patients. Details about the analysis populations will be provided in the SAP.
The safety population will consist of all patients, regardless of Ph status, who received at 
least 1 dose of study treatment.
9.1. Sample Size Determination
The primary analysis will be conducted for the modified as-treated population with the 
hypothesis test of a binomial proportion using the normal approximation. The study is 
powered at greater than 82.1% to test the null hypothesis that the true MMR rate at 
12 months (48 weeks) is 25% versus the alternative hypothesis that the true MMR rate is 


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40% with one-sided alpha of 5%.  The null MMR rate was referred to the historical rates of 
imatinib.21,27  The alternative MMR rate was derived from the null MMR rate and the 15% 
difference of MMR rates to be detected in AV001 study which is the Phase 3 randomized 
study of bosutinib versus imatinib in newly diagnosed CP CML.  For the primary analysis of 
MMR at 12 months (48 weeks), a sample size of 60 Ph+ CML patients harboring b2a2 and/or 
b3a2 transcripts is required. As cytogenetic confirmation for Ph is not required for 
enrollment and 5% of patients are expected to be Ph- CML, approximately 3 Ph- CML 
patients may be enrolled additionally, which will not affect the primary analysis.
9.2. Efficacy Analysis
In general, efficacy outcomes up to 12 months (48 weeks) will be based on data collected in 
the Core Treatment Phase of the study (first 12 months [48 weeks] on a per patient basis), 
with the exception of OS, EFS and duration of responses as measured beyond the first 
12 months follow-up. Data from the Core Treatment Phase (first 12 months) will be 
evaluated and submitted in the Core Treatment Phase study report. Data beyond the first 
12 months (48 weeks) from the Extension Phase of the study will also be evaluated and 
submitted in a final end of study report.
Continuous variables will be summarized by descriptive statistics (sample size [n], mean, 
standard deviation, median, minimum, and maximum). Categorical variables will be 
summarized in frequency tables (n, frequencies, and percentages). Individual patient data 
will be presented in listings.
Patients who are Ph- and harbor a BCR-ABL transcript other than b2a2 and/or b3a2 cannot 
be followed for either molecular (eg, MMR) or cytogenetic (eg, CCyR) response. Patients 
who are Ph+ and harbor a BCR-ABL transcript other than b2a2 and/or b3a2 are not evaluable 
for assessment of molecular response, but remain evaluable for CCyR within the Ph+ 
evaluation for cytogenetic response. All patients who harbor a BCR-ABL transcript other 
than b2a2 and/or b3a2 are treated as non-responders in the analysis of molecular response.  
Patients who are Ph- and harbor a b2a2 and/or b3a2 transcript (typical transcript) are
evaluable for MMR (not for CCyR) and will be included in the exploratory endpoint of
MMR in the Ph unrestricted evaluation for molecular response. All patients will be followed 
for hematologic response and will remain evaluable for safety endpoints.
9.2.1. Analysis of Primary Endpoint
The primary efficacy variable, MMR rate at 12 months (48 weeks), is defined as the 
proportion of patients achieving MMR at 12 months (48 weeks). MMR is defined as BCR-
ABL expression of ≤0.1% of initial BCR-ABL transcript from standardized baseline 
measured by RT-qPCR. The analysis of MMR rate will include all patients with Ph+ CML 
harboring b2a2 and/or b3a2 transcripts. This is anticipated to represent approximately 95% 
of enrolled patients; 1–2% of patients may harbor other BCR-ABL transcripts not validated 
for MMR assessment.
The null hypothesis for the primary efficacy analysis will be that the proportion of patients 
achieving MMR at 12 months (48 weeks) is 25%. The alternative hypothesis will be that the 
proportion of patients achieving MMR at 12 months (48 weeks) is 40%. Rejecting the null 


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hypothesis and accepting the alternative hypothesis in the modified as-treated population
(observing at least 21 responders out of the 60 total patients), will be considered to be a 
successful demonstration of efficacy for this study. The primary outcome measure will be 
analyzed using the hypothesis test of a binomial distribution using the normal approximation.
MMR at 12 months (48 weeks) is counted only if the response is demonstrated at the 12-
month (48-week) visit; any MMR gained and lost before the 12-month (48-week) visit is 
deemed a non-response as is the case where MMR is never achieved at or before 12 months 
(48 weeks).
The primary analysis will be conducted when all treated patients with Ph+ CML harboring 
b2a2 and/or b3a2 transcripts have either been followed for at least 12 months (48 weeks), or 
discontinued from the study prematurely.
The 2-sided 90% confidence interval (CI) of MMR rate at 12 months (48 weeks) will also be 
calculated. Efficacy outcomes of MMR up to 12 months (48 weeks) will be summarized and 
submitted in the Core Treatment Phase (when all patients have received 12 months 
treatment) CSR. Additional analysis of MMR beyond 12 months (48 weeks) will be 
performed in the Extension Phase of the study.
9.2.2. Analysis of Secondary Endpoints
9.2.2.1. Other Measures of MMR
Evaluations of MMR by 12 and 18 months will be assessed using the frequency tables.  The 
90% CI will also be calculated. 
For the analysis of MMR by 12 and 18 months, a patient is counted as a responder if MMR 
occurs at or before 12 and 18 months, respectively, even if MMR is subsequently lost at or 
before the 12- or 18-month time point. A patient never achieving MMR at or before 12 and 
18 months will be considered a non-responder, respectively.
9.2.2.2. Cytogenetic Response Assessment
Evaluations of CCyR by 12 months (48 weeks) will be assessed using the frequency tables.  
The 90% CI will also be calculated.
The CCyR rate by 12 months is defined as the proportion of patients demonstrating CCyR at 
or before 12 months (48 weeks). 
9.2.2.3. Duration of Response
The analysis of secondary endpoints relating to duration of response, such as duration of 
MMR and CCyR will be based on the estimations of the quartiles of duration and yearly rates
using the Kaplan-Meier method. For the analysis of CCyR, the proportion of patients who 
have confirmed loss of response will also be evaluated.
The duration is measured from the first date of response until the first date of confirmed loss 
of response, treatment discontinuation due to progressive disease, or death due to disease 


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progression within 28 days after last dose. An unconfirmed loss followed by treatment 
discontinuation due to suboptimal response is considered a confirmed loss.  Duration of 
response will be counted while a patient is on treatment and 28 days after last dose. If loss of 
response has not occurred, the patient will be censored at the last valid assessment.
The duration of MMR will be analyzed for the modified as-treated population and as-treated 
population separately. The duration of CCyR will be calculated using the modified as-treated
population.
9.2.2.4. Event-Free Survival and Overall Survival
The analysis of EFS and OS will be similar to that for duration of response just described. 
EFS was defined as the time from first dose to the occurrence of the earliest of the following 
events while on treatment:

Death due to any cause.

Transformation to AP or BP (on treatment).

Loss of CHR.

Loss of CHR is defined as the appearance of any of the following, confirmed by a 
second determination 4 weeks later (unless associated with CML-related 
treatment discontinuation):
WBC count that rises to >20.0 × 109/L.
Platelet count that rises to 600 × 109/L.
Appearance of palpable spleen or other extramedullary involvement
proven by biopsy.
Appearance of 5% myelocytes in the peripheral blood.
Appearance of blasts or promyelocytes in the peripheral blood.

Loss of CCyR.
Loss of CCyR is defined as at least one Ph+ metaphase confirmed by a second 
determination 4 weeks later (unless associated with CML-related treatment 
discontinuation).

For patients not achieving a CHR: doubling of WBC at least 1 month apart with the 
second value >20 × 109/L and maintained in subsequent assessments for at least 
2 weeks.
OS is defined as the time from first dose to death due to any cause.


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The EFS will be calculated using the modified as-treated population.  OS will be analyzed in
the modified as-treated population and as-treated population separately.
9.3. Analysis of Other Endpoints
9.3.1. Exploratory Efficacy Endpoints
9.3.1.1. Other Measures of MMR and Reductions in BCR-ABL Transcript
Measures of MMR and reductions in BCR-ABL transcript at different time points will be 
evaluated by frequency tables.  The 90% CI will also be calculated.
The exploratory MMR analysis at 12 months will be analyzed for the as-treated population. 
The others will be calculated using the modified as-treated population and as-treated 
population separately.
Subgroup analyses for MMR at 12 months (48 weeks) may be performed and 90% CIs will 
be presented.
9.3.1.2. Time to Response
The time to response (MMR, CCyR, MR4.0, and MR4.5) is measured from first dose to the 
first date of response. In the analysis of cumulative incidence,28 the competing risk is 
defined as treatment discontinuation without response.  Also, other patients without response 
will be censored at the last valid assessment for the respective endpoint.
The time to response will be also summarized by descriptive statistics among responding 
patients.
The time to MMR will be analyzed for the modified as-treated population and as-treated 
population separately. The time to CCyR will be calculated using the modified as-treated
population.
9.3.1.3. Time to Transformation to AP/BP CML
The analysis of the time to transformation to AP/BP CML will be similar to that of the time 
to response just described.
The time to transformation to AP/BP CML is defined as the time from first dose to the first 
date of transformation to AP or BP CML. The transformation to AP/BP will be counted 
while a patient is on treatment up to 28 days after last dose. In the analysis of cumulative 
incidence,28 the competing risk is defined as treatment discontinuation without 
transformation.  If transformation has not occurred, the patient will be censored at the last 
valid hematologic assessment.
Investigators should assess transformation to AP/BP according to the original definition of 
AP/BP CML (see Table D in Appendix 2). In a statistical analysis, some restrictions (see 
Table D footnotes in Appendix 2) are adopted in addition to the original definition.


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9.3.1.4. Hematologic Response
Evaluations of cumulative CHR will be assessed using the frequency tables.  The 90% CI 
will also be calculated.
The cumulative CHR will be analyzed for the modified as-treated population and as-treated 
population separately.
Investigators should assess hematologic response according to the original definition of CHR
(see Table A in Appendix 2).  In a statistical analysis, some restrictions (see Table A 
footnotes in Appendix 2) are adopted in addition to the original definition.
9.3.2. Mutations
Types of mutations present at treatment completion and when performed during treatment 
will be summarized.
Summaries of newly observed BCR-ABL mutations in patients post-baseline will be 
presented by visit.
9.3.3. Population Pharmacokinetic Analysis and Pharmacokinetic/Pharmacodynamic 
Modeling
PK profiles of bosutinib will be determined using a sparse sampling regimen and population 
PK analysis approach. A total of 4 PK samples per patient will be drawn. All patients will 
provide pre-dose blood samples on Day 1, Day 28, Day 56, and Day 84.
PK and pharmacodynamics data from this study may be analyzed using modeling approaches 
and may also be pooled with data from other studies to investigate any association between 
bosutinib exposure and biomarkers or significant safety and/or efficacy endpoints. The 
results of these analyses, if performed, may be reported separately.
9.4. Safety Analysis
9.4.1. Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The numbers of events and incidence rates will be tabulated by preferred term 
and system organ class. AEs will be presented with and without regard to causality. The 
frequency of overall toxicity, categorized by toxicity Grades 1 through 5, will be described. 
Additional tables will be provided for AEs that are observed with higher frequency. 
TEAEs are defined as AEs that first occurred or worsened in severity after the first 
administration of the study drug up to 28 days after last dose. AE summaries will include 
incidence of TEAEs by MedDRA preferred term and system organ class, SAEs including 
deaths, AEs that led to study drug discontinuation, and AEs by maximum severity and 
relationship to study drug.


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9.4.2. Clinical Laboratory Evaluations
Laboratory assessments will be presented as mean changes from baseline and incidence of 
abnormal values. Shift tables will be presented for selected parameters.
9.4.3. Vital Signs Measurements, Physical Findings, and Other Safety Evaluations
Other safety outcomes will be presented using descriptive statistics.
9.5. Interim Analysis
A primary analysis will be conducted after Core Treatment Phase of all treated patients and 
before the final analysis at the end of study.
An interim look will be conducted separately prior to the primary analysis to assess the 
possibility of early communication with regulatory authorities based on the interim data. This 
will not be used to judge the early study termination or any changes of study design. This 
will occur at 3 months after the first dose of the last patient.  The following endpoints for 
patients with sufficient follow-up will be summarized at the interim look:

Some efficacy endpoints

Cumulative incidence of MMR at 12 months using the cumulative incidence 
function method

MMR by 12 months

MMR at 3, 6 and 9 months

MR1 at 3 months;

All safety endpoints;

All PK endpoints except for primary endpoint related parameters (Exposure-Response 
relationship will not be included in the interim data)
Analysis of primary endpoint will not be conducted at the interim look.  No alpha will be 
spent at the interim look.  Further details are described in the statistical analysis plan.
9.6. Data Monitoring Committee
This study will not use a data monitoring committee.  For the purposes of this study, Pfizer 
procedures for periodic safety review will be applied by an internal safety review team with 
medical and statistical capabilities to review individual and summary data collected in the 
safety and clinical databases.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 


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review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 patient’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 


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In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer’s written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.


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In addition, the study will be conducted in accordance with the protocol, and any applicable 
local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The investigator 
will retain the original of each patient’s signed consent document.
12.4. 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 bosutinib, 
Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
End of trial is defined as Last Subject Last Visit.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
bosutinib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1 month.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
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 US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 


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Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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16. REFERENCES
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Tasigna [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2010.
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Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia 
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Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for 
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Quintás-Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Pleural effusion in patients 
with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin 
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Gora-Tybor J, Robak T. Targeted drugs in chronic myeloid leukemia. Curr Med Chem 
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Sprycel [package insert]. Princeton, NJ, Bristol-Myers Squibb; 2006.
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Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed 
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Gleevec [package insert]. East Hanover, NJ, Novartis; 2009.
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Bartolovic K, Balabanov S, Hartmann U, et al. Inhibitory effect of imatinib on normal 
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Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib 
(SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid 
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Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib Versus Imatinib for 
Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE 
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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ADPKD
autosomal dominant polycystic kidney disease 
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
AP
accelerated phase
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BBS
biospecimen banking system
BCR-ABL
Fusion transcript or protein resulting from the 9;22 chromosomal 
translocation responsible for formation of the Philadelphia 
Chromosome
BP
blast phase
BUN
blood urea nitrogen
CBA
chromosome banding analysis
CBC
complete blood count
CCyR
complete cytogenetic response 
CHMP
committee for medicinal products for human use
CHR
complete hematologic response
CI
confidence interval
CK
creatine kinase
CML
chronic myelogenous leukemia
CP
chronic phase
CRF
case report form
CSA
clinical study agreement
CSR
clinical study report
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EDTA
ethylenediaminetetraacetic acid
EFS
event-free survival
ELN
European LeukemiaNet


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 78
Abbreviation
Term
EU
European Union
EudraCT
European Clinical Trials Database
FDA
(United States) Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus 
HCV
hepatitis C virus 
HDPE
high-density polyethylene 
Hb
hemoglobin
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplantation
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug (application)
INR
international normalized ratio
IRB
institutional review board
IS
international scale
IUD
intrauterine device
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
LLN
lower limit of normal
MCyR
major cytogenetic response
MedDRA
Medical Dictionary for Regulatory Activities
MMR
major molecular response 
MR
molecular response
MUGA
multiple gated acquisition
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute 
OS
overall survival
PCD
primary completion date
PCR
polymerase chain reaction
Ph
philadelphia chromosome
PI
principal investigator
PK
pharmacokinetic
PPI
proton-pump inhibitor
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 79
Abbreviation
Term
QD
once daily
RBC
red blood cell
RNA
ribonucleic acid
RT-qPCR
quantitative reverse transcriptase polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SRSD
single reference safety document
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
US
United States
WBC
white blood cell


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 80
Appendix 2. Response Definitions
A. Hematologic Responses to Treatment
Hematologic Responses
Definition
Complete Hematologic Response 
(CHR)
had to meet all criteria
WBC 10 × 109/L 
Basophils <5% in blood
No myelocytes, promyelocytes, myeloblasts in the blood 
differential
Platelet count <450 × 109/L
Spleen non-palpablea
a.
In a statistical analysis, if spleen disease was not assessed, it is assumed that spleen is non-palpable.
B. Cytogenetic Responses to Treatment
Before Treatment
Cytogenetic Responses
(based on analysis of at least 20 metaphases)
% Philadelphia Chromosome 
Positive Cells
Chronic Phase
None
>95%
Minimal
66-95%
Minor
36-65%
Partial
1-35%
Complete
0%
Major
Complete + Partial Rates


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 81
C. Molecular Responses to Treatment
Before Treatment
Molecular Response
RT-PCR (BCR-ABL Ratio)
Chronic Phase
Major, or MMR
≤0.1% (corresponding to ≥3 log reduction from 
baseline*) with a minimum number of ABL transcripts 
specified by the central laboratory
MR1
A 1 log reduction in BCR-ABL transcript with a 
minimum number of ABL transcripts specified by the 
central laboratory
MR2
A 2 log reduction in BCR-ABL transcript with a 
minimum number of ABL transcripts specified by the 
central laboratory
MR4.0
Either (i) Detectable disease with ≤0.01% BCR-ABL IS 
or (ii) Undetectable disease in cDNA with a minimum 
number of ABL transcripts specified by the central 
laboratory
MR4.5
Either (i) Detectable disease with ≤0.0032% BCR-ABL 
IS or (ii) Undetectable disease in cDNA with a 
minimum number of ABL transcripts specified by the 
central laboratory in the same volume of cDNA used to 
test for BCR-ABL
* standardized baseline from central laboratory
D. Definitions of Blast Phase and Accelerated Phase
Patient meeting any of the following criteria:
Blast Phase
≥30% Blasts in blood or bone marrow
Extramedullary blast proliferation, other than in spleen
Accelerated Phase
15-29% blasts in blood or marrow, or
>30% blasts plus promyelocytes in blood or marrow with blasts <30%;
≥20% basophils in blood
Persistent thrombocytopenia (<100 × 109/L) unrelated to therapya
Clonal chromosome abnormalities in Ph+ cells (CCA/Ph+), major route, on 
treatmentb
a.
In a statistical analysis, persistent thrombocytopenia is not considered to define AP progression as the 
database does not collect data regarding the relationship between the platelet value and therapy.
b.
In a statistical analysis, clonal chromosome abnormalities alone are not considered sufficient to define 
progression to AP unless concurrent presence of another AP criterion.


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 82
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG 
Grade
Description
0
Fully active, able to carry on all pre-disease activities without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (light house work, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair.


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 83
Appendix 4. Summary of Drugs that are Generally Accepted to Have a Risk of Causing 
QTc Prolongation Potentially Causing Torsades de Pointes
Generic Name 
Amiodarone 
Arsenic trioxide 
Astemizole 
Bepridil 
Chloroquine 
Chlorpromazine 
Cisapride 
Clarithromycin 
Disopyramide 
Dofetilide 
Domperidone 
Droperidol 
Erythromycin 
Halofantrine 
Haloperidol 
Ibutilide 
Levomethadyl 
Mesoridazine 
Methadone 
Moxifloxacin 
Petamidine 
Pimozide 
Probucol 
Procainamide 
Quinidine 
Sotalol 
Sparfloxacin 
Terfenadine 
Thioridazine 
Vandetanib 
Adapted from “The University of Arizona Center for Education and Research on Therapeutics” 
See the following website for an updated list – Drugs with a Risk of Torsades de Pointes: 
https://crediblemeds.org/index.php/drugsearch


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 84
Appendix 5. Selected Strong and Moderate CYP3A4 Isoenzyme Inhibitors and 
Inducers
Inhibitors:
Strong CYP3A Inhibitors
Moderate CYP3A Inhibitors
Lopinavir/ritonavir
Fluconazole
Indinavir
Darunavir/ritonavir
Nelfinavir
Erythromycin
Saquinavir
Diltiazem
Ketoconazole
Itraconazole
Atazanavir
Voriconazole
Aprepitant
Posaconazole
Amprenavir
Conivaptan
Fosamprenavir
Clarithromycin
Imatinib
Telithromycin
Verapamil
Boceprevir
Tofisopam 
Telaprevir
Ciprofloxacin
Mibefradil
Nefazodone
Grapefruit products including grapefruit juice
Inducers:  
Strong CYP3A inducers
Moderate CYP3A inducers
Rifampicin
Bosentan
Phenytoin
Nafcillin
Carbamazepine
Efavirenz
St. John’s Wort
Modafinil
Etravirine


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 85
Appendix 6. Guidelines for the Management of Diarrhea
Please be sure you understand these instructions BEFORE you leave the office and 
discuss with your study doctor if you need to obtain antidiarrheal medication before 
you go home.
Data obtained thus far from patients receiving bosutinib in prior studies performed in patients 
with CML show that diarrhea is the most common side effect you may have while receiving 
bosutinib. It has also been observed that diarrhea events, although frequent, are mainly low 
grade severity, transient, occurring predominantly in the first month of bosutinib treatment
and managed by appropriate concomitant medications given for short duration. The purpose 
of this card is to help ensure appropriate management of diarrhea.
Treating diarrhea as soon as it starts may prevent it from getting worse. Your study doctor 
may tell you to take antidiarrheal medication(s) with the first loose stool or diarrhea. Please 
contact your study doctor as soon as possible if you have an episode of diarrhea. If you are 
dizzy or weak because of diarrhea, come to the office or go to the hospital immediately.
When calling the study doctor to report an event of diarrhea you should provide as much of 
the information below as possible, in order to help your study doctor to assess your diarrhea 
and decide on the best treatment:

Number of stools per day as compared to your normal bowel habits;

Presence of diarrhea during the night;

Presence of fever, dizziness, abdominal pain/cramping or weakness;

What the stool looks like, that is, watery, bloody or mucusy;

When you took your last dose of study drug;

Any other information that could explain your diarrhea (change in diet/food, recent travel, 
contact with other people experiencing vomiting and/or diarrhea).


Bosutinib
B1871048
Final Protocol Amendment 1, 30 Mar 2018
Page 86
Recommendations
1. Dietary Changes
If you have diarrhea:
 Stop all lactose-containing products (eg, milk, yogurt, cheese);
 Drink 8 to 10 large glasses of clear liquids per day;
 Eat frequent small meals;
 Eat low fat foods including bananas, rice, applesauce and/or toast;
Your study doctor may have other suggestions.
2. Medications
Your study doctor may prescribe a medication to treat diarrhea. Take the medications as 
directed by your study doctor. In case of more severe diarrhea and any diarrhea associated 
with fever, pain, infection, or dehydration, you may receive IV fluids, antibiotics and/or other 
medications.
3. Study Medication Adjustments
Your study doctor may instruct you to change the dose of your study medication, depending 
on how severe the diarrhea is and how you respond to treatment(s) for the diarrhea.

SAP_001.pdf: 
Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 1
Protocol B1871048
A Phase 2, Open-Label, Single-Arm Study to Evaluate Efficacy and Safety of
Bosutinib Monotherapy in Japanese Adult Patients with Newly Diagnosed
Chronic Phase Chronic Myelogenous Leukemia
Statistical Analysis Plan
(SAP)
Version:
Version 4
Date:
30-JAN-2019


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION ...............................................................................................................10
2.1. Study Objectives .....................................................................................................10
2.1.1. Primary Objective.......................................................................................10
2.1.2. Secondary Objectives .................................................................................11
2.1.3. Exploratory Objectives ...............................................................................11
2.2. Study Design ...........................................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint ....................................................................................................12
3.1.1. MMR at 12 Months ....................................................................................12
3.2. Secondary Endpoints...............................................................................................12
3.2.1. MMR by 12 and 18 Months........................................................................12
3.2.2. CCyR ..........................................................................................................13
3.2.3. Duration of MMR and CCyR .....................................................................13
3.2.4. EFS .............................................................................................................13
3.2.5. OS ...............................................................................................................14
3.2.6. PK Endpoints..............................................................................................14
3.3. Other Endpoints.......................................................................................................14
3.4. Baseline Variables...................................................................................................15
3.5. Safety Endpoints .....................................................................................................15
3.5.1. Adverse Events...........................................................................................15
3.5.2. Laboratory Data..........................................................................................15
3.5.3. Vital Signs and Body Weight .....................................................................16
3.5.4. Electrocardiograms.....................................................................................16
3.5.5. Echocardiogram or Multiple Gated Acquisition.........................................16
4. ANALYSIS SETS ...............................................................................................................17
4.1. As-Treated Population.............................................................................................17
4.2. Modified as-Treated Population..............................................................................17
4.3. Safety Analysis Set..................................................................................................17


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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4.4. PK Analysis Set.......................................................................................................17
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................18
5.1. Hypotheses and Decision Rules ..............................................................................18
5.2. General Methods .....................................................................................................18
5.2.1. Analyses for Continuous Data....................................................................18
5.2.2. Analyses for Categorical Data....................................................................18
5.2.3. Analyses for Time-to-Event Data...............................................................18
5.3. Methods to Manage Missing Data ..........................................................................19
5.3.1. Molecular Response Assessment................................................................19
5.3.1.1. MMR, MR4.0 and MR4.5 at 12 months (48 weeks)....................19
5.3.1.2. MMR at 18 months (72 weeks).................................................19
5.3.1.3. MR1 and MR2 at 3 and 6 months...............................................19
5.3.1.4. MMR, MR4.0 and MR4.5 at 3 month..........................................19
5.3.1.5. MMR, MR4.0 and MR4.5 at 6 and 9 months...............................19
5.3.1.6. MMR by 12 and 18 months (48 and 72 weeks) ........................19
5.3.2. Cytogenetic Response Assessment.............................................................19
5.3.3. Hematologic Response Assessment ...........................................................19
5.3.4. Time-to-Event Data ....................................................................................20
5.3.5. Safety Endpoints.........................................................................................20
5.3.6. Other Variables...........................................................................................20
6. ANALYSES AND SUMMARIES ......................................................................................20
6.1. Primary Endpoint ....................................................................................................21
6.1.1. MMR at 12 Months ....................................................................................21
6.1.1.1. Primary Efficacy Analysis ........................................................21
6.2. Secondary Endpoints...............................................................................................21
6.2.1. MMR by 12 and 18 Months........................................................................21
6.2.2. CCyR ..........................................................................................................21
6.2.3. Duration of Response .................................................................................21
6.2.4. EFS .............................................................................................................22
6.2.5. OS ...............................................................................................................22
6.2.6. Pharmacokinetics........................................................................................22
6.3. Other Endpoint(s)....................................................................................................23


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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6.3.1. MMR at Each Pre-Specified Visit ..............................................................23
6.3.2. Molecular Response....................................................................................23
6.3.3. Time to MMR, CCyR, MR4.0 and MR4.5....................................................23
6.3.4. Cumulative CHR ........................................................................................24
6.3.5. Time to Transformation to AP and BP CML .............................................24
6.3.6. Mutations....................................................................................................24
6.4. Subset Analyses.......................................................................................................24
6.5. Baseline and Other Summaries and Analyses.........................................................25
6.5.1. Baseline Summaries....................................................................................25
6.5.2. Study Conduct and Patient Disposition......................................................25
6.5.3. Study Treatment Exposure .........................................................................25
6.5.4. Concomitant Medications and Non-Drug Treatments................................26
6.5.5. Transfusions................................................................................................27
6.5.6. ECOG Performance Status .........................................................................27
6.5.7. Extramedullary Disease..............................................................................27
6.5.8. Chest X-ray.................................................................................................27
6.6. Safety Summaries and Analyses .............................................................................27
6.6.1. Adverse Events...........................................................................................27
6.6.2. Laboratory Data..........................................................................................28
6.6.2.1. Hy’s Law...................................................................................28
6.6.3. Vital Signs and Body Weight .....................................................................28
6.6.4. ECG ............................................................................................................29
6.6.5. Echocardiogram or Multiple Gated Acquisition.........................................29
6.6.6. Physical Examination .................................................................................29
6.6.7. Death...........................................................................................................29
7. INTERIM ANALYSES.......................................................................................................29
7.1. Introduction .............................................................................................................29
7.1.1. Interim Look ...............................................................................................29
7.1.2. Primary Analysis ........................................................................................29
7.1.3. Final Analysis .............................................................................................29
7.1.4. Periodic Safety Review...............................................................................30
7.2. Interim Analyses and Summaries............................................................................30


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 5
7.2.1. Interim Look ...............................................................................................30
7.2.1.1. Timing of the Interim Look.......................................................30
7.2.1.2. Endpoints...................................................................................30
7.2.1.3. Hypotheses ................................................................................30
7.2.1.4. Analysis Sets .............................................................................30
7.2.1.5. Analysis Methods......................................................................31
7.2.1.6. Prevention of Any Bias .............................................................32
7.2.2. Primary Analysis ........................................................................................32
7.2.3. Final Analysis .............................................................................................32
7.2.4. Periodic Safety Review...............................................................................32
8. REFERENCES ....................................................................................................................32
9. APPENDICES .....................................................................................................................33
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................6
APPENDICES
Appendix 1. Response Definitions ..........................................................................................33
Appendix 1.1. Molecular Responses .......................................................................................33
Appendix 1.2. Cytogenetic Responses.....................................................................................33
Appendix 1.3. Blast Phase and Accelerated Phase..................................................................33
Appendix 1.4. Hematologic Responses ...................................................................................34
Appendix 1.5. KDIGO Categories...........................................................................................34
Appendix 2. Adverse Event of Special Interest.......................................................................35
Appendix 3. Criteria for Potentially Clinically Important Changes in Vital Signs .................37
Appendix 4. Criteria for Potentially Clinically Important Changes in ECG...........................38


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 6
1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B1871048 is based on the protocol dated 
30MAR2018.
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
(24APR2017)
Not Applicable
Not Applicable
2
(23APR2018)
Section 2.1.2:

Added MMR by 12 months.

To be consistent with the protocol.

Section 2.1.3:

Add a new sentence for MMR at 
12 months;

Clarified time points for MR1 
and MR2;

Removed the investigation of 
presence of newly observed 
BCR-ABL mutations.

To be consistent with the protocol.
Section 2.2:

Added the condition of target 
patient.

To clarify the target patient.
Section 3.2.1

Added MMR by 12 months

To be consistent with the protocol.
Section 3.2.3:

Changed the reason of death as 
event;

Declared how to handle patients 
with suboptimal response;

Removed sentences about 
confirmation of CCyR.

To be considered that death due to other than 
progressive disease is classified as the 
treatment discontinuation.

To explain how patients with suboptimal 
response are handled in analysis of the 
duration of response.

To avoid duplicated explanation.
Section 3.2.4:

Removed an endnote;

Added a reference for loss of 
CCyR.

To be consistent with the protocol.

To help a reader to confirm the definition.
Section 3.3:

Added a new sentence for MMR 
at 12 months;

Clarified time points for MR1 
and MR2;

Removed the investigation of 
presence of newly observed 
BCR-ABL mutations.

To be consistent with the protocol.
Section 3.4:

Defined the baseline.

To clarify the baseline value.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 7
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
Section 3.5.2:

Added indirect bilirubin at 
endnote of liver function.

To declare that indirect bilirubin is out of 
analysis scope 
Section 4.1:

Added a supplemental 
explanation.

To clarify that no analysis based on 
as-enrolled patients is conducted.
2
(23APR2018)
Section 5.1:

Changed the sentence about 
statistical test;

Added information about the 
rejection of null hypothesis.

To describe the statistical assumption clearer.

To provide the reference for statistical test.
Section 5.2.2:

Added details of confidence 
interval.

To describe the method of confidence interval 
using this study clearer.
Section 5.2.3:

Added percentiles of cumulative 
incidence function.

To provide useful estimates.
Section 5.3.1.5:

Corrected the condition 
considered a non-responder.

To correct wrong information.
Section 5.3.1.6:

Added MMR by 12 months.

To be added MMR by 12 months in the 
protocol.
Section 6:

Added sentences how to handle 
patients without Ph+ or the 
b2a2/b3a2 transcript.

To clarify how a patient excluded from the 
modified as-treated is used in MMR or 
cytogenetic response.
Section 6.1.1.1:

Changed the word from the 
primary analysis to the primary 
efficacy analysis.

To distinguish analyses at the interim look.
Section 6.2.1:

Added MMR by 12 months.

To be added MMR by 12 months in the 
protocol.
Section 6.2.3:

Added the proportion of patients 
with confirmed loss of response.

To be consistent with study AV001.
Section 6.2.4:

Changed the referred method 
using EFS;

Clarified on-treatment EFS.

To correct the statistical method from 
Kaplan-Meier method to the cumulative 
incidence method.

To distinguish on-treatment EFS from 
off-treatment EFS.
Section 6.3.2:

Clarified time points for MR1 
and MR2.

To be consistent with the protocol.
Section 6.3.3:

Added yearly rates and 
percentiles.

To provide useful estimates.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 8
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
Section 6.3.4:

Clarified criteria for CHR using 
investigators and sponsor, 
respectively.

To provide actually used criteria for 
investigator and the statistical analysis, 
respectively.
2
(23APR2018)
Section 6.3.5:

Changed the referred method 
using time to transformation to 
AP/BP;

Clarified criteria for 
transformation to AP/BP using 
investigators and sponsor, 
respectively.

To correct the statistical method from 
Kaplan-Meier method to the cumulative 
incidence method.

To provide actually used criteria for 
investigator and the statistical analysis, 
respectively.
Section 6.5:

Added the sentence related to
analysis population.

To avoid creating redundant TLFs.
Section 6.5.2:

Added summary of patient 
disposition.

To confirm patient disposition at 12 months.
Section 6.5.3:

Added summaries related to dose 
modification.

To be consistent with study AV001.
Section 6.6.1:

Added new summaries;

Re-defined adverse event of 
special interest.

To provide sufficient information about 
safety.

To be consistent with study AV001.
Section 6.6.3:

Added criteria for potentially 
clinically important change.

To be consistent with study AV001.
Section 6.6.4:

Added criteria for potentially
clinically important change.

To be consistent with study AV001.
Section 6.6.7:

Added summary of death.

To provide details of death with reason.
Section 7.1.1:

Added a new section for the 
interim look.

To provide information about the interim look
and to distinguish it from other 2 interim 
analyses.
Section 7.1.2:

Added a new section for the 
primary analysis.

To provide information about the primary 
analysis and to distinguish it from other 
2 interim analyses.
Section 7.1.4:

Added a new section for the 
periodic safety review.

To provide information about the periodic 
safety review and to distinguish it from other 
2 interim analyses.
Section 7.2.1:

Added a new section for the 
interim look.

To provide timing, endpoints, hypotheses, 
statistical methods and prevention of bias in 
the interim look.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
Page 9
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
Section 7.2.2:

Added a new section for the 
primary analysis.

To provide timing and statistical methods in 
the primary analysis.
Section 7.2.4

Added a new section for the 
periodic safety review.

To provide timing and methods of review in 
the periodic safety review.
2
(23APR2018)
Appendix 1.3:

Removed sentences about 
protocol from the table footnote.

To be consistent with the protocol.
Appendix 2:

Added a definition of adverse 
event of special interest.

To be consistent with study AV001.
Appendix 3:

Added criteria for potentially 
clinically important changes.

To be consistent with study AV001.
Appendix 4:

Added criteria for potentially 
clinically important changes.

To be consistent with study AV001.
3
(09JUL2018)
Section 3.5.4.:

Removed a formula for QTcF;

Added a formula for QTcB;

Added a formula for heart rate.

To be reported by a study site.

To provide a calculation of QTcB.

To provide a calculation of heart rate.
Section 6.2.6:

Corrected the document name of 
PK analysis plan.

To make the referred document for PK 
analysis clear.
Section 6.3.5:

Added an analysis population.

To make used analysis populations clear.
Section 6.3.6:

Added an analysis population.

To make used analysis populations clear.
Section 6.5:

Added analysis populations.

To make used analysis populations clear.
Section 7.2.1.2:

Added baseline variables.

To provide baseline summaries in the interim 
look.
Section 7.2.1.4.4:

Added baseline variables.

To provide information about used analysis 
populations for summarizing baseline 
variables.
Section 7.2.1.5.7:

Added baseline variables.

To provide information about baseline 
summaries in the interim look.
4
(30JAN2019)
Section 3.2.4:

Added a condition for loss of 
CCyR.

To be consistent with the protocol.
Section 5.3.6:

Added imputation method of Ph 
status at screening.

To provide imputation method about the Ph 
status.
Section 6.2.1:

Added timing of analysis for 
MMR by 18 months.

To avoid insufficient analysis due to 
immature data.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
Section 6.2.4:

Added timing of analysis for 
off-treatment EFS.

To avoid insufficient analysis due to 
immature data.
Section 6.3.1:

Added timing of analysis for 
MMR at 18 months.

To avoid insufficient analysis due to 
immature data.
Section 6.5.3:

Added a summary item;

Clarified that a planned dose 
means a starting dose (ie, 
400 mg).

To be consistent with study AV001.
Section 6.6.1:

Added incidence of clustered 
anemia/neutropenia/thrombocyto
penia/leukopenia;

Added some events into AE 
categories;

Added a listing of AEs included 
in each AESI;

Added a new figure of TEAE.

To scientifically compare results of 3 penia in 
study 1048 with those in study AV001.

To be consistent with study AV001.

To provide which PT is categorized as an 
AESI.

To compare results in study 1048 with study 
AV001.
Section 6.6.2.1:

Added a new section for an 
investigation of liver injury.

To evaluate a liver injury in Japanese 
patients.
Section 7.1.3:

Added a new section for a final 
analysis.

To make the definition of final analysis clear.
Section 7.2.3:

Added a new section for a final 
analysis.

To make endpoints summarized at the final 
analysis clear.
Appendix 2:

Added definitions of some 
AESIs.

To scientifically compare results of 3 penia in 
study 1048 with those in study AV001.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B1871048. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
2.1.1. Primary Objective
A primary study objective is to evaluate a major molecular response (MMR) at 12 months 
(48 weeks) in newly diagnosed Japanese Philadelphia chromosome (Ph)-positive (+) chronic 
phase (CP) chronic myelogenous leukemia (CML) patients harboring b2a2 and/or b3a2 
transcripts.


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2.1.2. Secondary Objectives
Secondary study objectives are:

To evaluate MMR by 12 and 18 months;

To estimate the proportion of patients demonstrating a complete cytogenetic response 
(CCyR) by 12 months;

To evaluate the duration of MMR and CCyR;

To evaluate an event-free survival (EFS);

To evaluate overall survival (OS);

To assess the population pharmacokinetic (PK);

To assess correlations between trough concentrations of bosutinib and key efficacy 
and safety endpoints, and

To characterize the safety profile of bosutinib in Japanese patients.
2.1.3. Exploratory Objectives
Exploratory study objectives are:

To evaluate MMR at 3, 6, 9 and 18 months;

To evaluate MMR at 12 months in patients with both Ph+ and Ph negative (-) CP 
CML;

To evaluate molecular response (MR)1 and MR2 at 3 and 6 months, respectively;

To evaluate MR4.0 and MR4.5 at 3, 6, 9 and 12 months;

To evaluate time to MMR, MR4.0, MR4.5 and CCyR;

To evaluate the proportion of patients demonstrating a cumulative complete 
hematologic response (CHR) in patients with Ph+ and both Ph+ and Ph- CP CML;

To estimate the time to transformation to accelerated phase (AP) and blast phase (BP)
CML on treatment;

To evaluate the type of BCR-ABL* mutations present at treatment completion or 
discontinuation, or in case of suboptimal response, and
                                                
* Fusion transcript or protein resulting from the 9;22 chromosomal translocation responsible for formation of 
the Philadelphia Chromosome


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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
To enable exploratory research through collection of banked biospecimen, unless 
prohibited by local regulations or ethics committee (EC) decision.
2.2. Study Design
This is a phase 2, open-label, single-arm study designed to evaluate efficacy and safety of 
bosutinib alone in Japanese adult patients with newly diagnosed CP CML. Patients will 
receive bosutinib treatment at a starting dose of 400 mg once daily (QD). The dose of 
bosutinib is allowed to be escalated (up to a maximum of 600 mg QD) for unsatisfactory 
response or reduced for toxicity.
This study has approximately 52 weeks of planned patient accrual. Each patient will have
12 months (48 weeks) of Core Treatment Phase and the following 24 months (96 weeks) of
Extension Phase. After treatment discontinuation, the patient enters Long-Term Follow-Up.
The Extension Phase or Long-Term Follow-Up will continue until the end of the study.
The study will be open for enrollment until approximately 60 Ph+ CML patients with b2a2 
and/or b3a2 transcripts have been registered. Bone marrow aspirate to assess the Ph status 
will be obtained at screening, patients with known Ph- prior to registration are not eligible for
this study. However, as confirmation of the Ph status prior to registration is not mandatory,
Ph- CML patients may also be included. Approximately 3 Ph- CML patients are expected to 
be registered as approximately 5% of the patients with BCR-ABL-positive CML are 
diagnosed as Ph- CML. All patients will be treated and/or followed up to approximately 
3 years (144 weeks) after registration of the last patient, or until study termination, whichever 
comes first. Patients who permanently discontinue study treatment will be followed for 
survival, investigator-assessed transformation to AP/BP, duration of response and disease 
progression, and initiation/response to further anti-cancer therapies, including stem cell 
transplantation (where applicable).
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
3.1.1. MMR at 12 Months
The primary endpoint is the MMR at 12 months (48 weeks). All Ph+ CP CML patients 
harboring b2a2 and/or b3a2 transcripts will be assessed and follow-up for the MMR as the 
primary endpoint.
The MMR is defined as 0.1% BCR-ABL on the international scale (IS) by quantitative 
reverse transcriptase polymerase chain reaction (RT-qPCR).  See Appendix 1.1 for the details.
3.2. Secondary Endpoints
3.2.1. MMR by 12 and 18 Months
The MMR by 12-month and 18-month visit will be assessed.


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3.2.2. CCyR
The CCyR by 12-month visit will be assessed.
The CCyR is defined as absence of detectable Ph.  See Appendix 1.2 for the details.
3.2.3. Duration of MMR and CCyR
The duration of response (MMR and CCyR, respectively) is measured from the first date of 
response until the first date of confirmed loss of response, treatment discontinuation due to 
progressive disease (PD), or death due to PD within 28 days after last dose. A loss of 
response must be confirmed by a second consecutive loss at least 4 weeks later, treatment 
discontinuation due to PD or death due to PD within 28 days of last dose. A PD is defined as 
investigator assessed progression reported on the case report form (CRF). Treatment 
discontinuation due to PD or death due to PD within 28 days of last dose without loss of 
response will be considered a confirmed loss.  An unconfirmed loss followed by treatment 
discontinuation due to suboptimal response is considered a confirmed loss.
For loss of MMR, the loss must be at least 5 times the smallest recorded ratio. Loss of CCyR
is defined as at least one Ph+ metaphase.
Duration of response will be counted while a patient is on treatment. If treatment ceases and
loss of response has not occurred, the patient will be censored at the last valid assessment on 
treatment for the respective endpoint.
3.2.4. EFS
The EFS is measured from the date of first dose until the first occurrence of one the 
following events, censored at the earlier of the last valid hematologic or cytogenetic 
assessment for those without events:
1. Death due to any cause;
2. Transformation to AP or BP (on treatment; see Appendix 1.3);
3. Loss of CHR.

Loss of CHR is defined as the appearance of any of the following, confirmed by a 
second determination 4 weeks later (unless associated with CML-related 
treatment discontinuation):

WBC count that rises to >20.0 × 109/L;

Pplatelet count that rises to 600 × 109/L;

Appearance of palpable spleen or other extramedullary involvement proven 
by biopsy;

Appearance of 5% myelocytes in the peripheral blood, or


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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
Appearance of blasts or promyelocytes in the peripheral blood.
4. Loss of CCyR (unless associated with CML-related treatment discontinuation; refer 
to Section 3.2.3 for the definition of loss of CCyR), or
5. For patients not achieving a CHR: doubling of white blood cell (WBC) at least 
1 month apart with the second value >20 × 109/L and maintained in subsequent 
assessments for at least 2 weeks.
3.2.5. OS
OS is measured from the date of first dose until the occurrence of death due to any cause, 
censored at the last known alive date for those without events.
3.2.6. PK Endpoints
PK profiles of bosutinib will be determined using a sparse sampling regimen and population 
PK analysis approach. A total of 4 PK samples per patient will be drawn. All patients will 
provide pre-dose blood samples on Day 1, Day 28, Day 56, and Day 84.
PK endpoints and analyses include:

Population PK of bosutinib, and

Correlations between trough concentrations of bosutinib and key efficacy and safety 
endpoints.
3.3. Other Endpoints
The following endpoints will be assessed exploratorily:

MMR at 3, 6, 9 and 18 months;

MMR at 12 months in patients with both Ph+ and Ph- CP CML;

MR1 and MR2 at 3 and 6 months, respectively;

MR4.0 and MR4.5 at 3, 6, 9 and 12 months;

Time to MMR, MR4.0, MR4.5 and CCyR;

Cumulative CHR in patients with Ph+ and both Ph+ and Ph- CP CML;

Time to transformation to AP and BP CML on treatment;

Type of mutations present at treatment completion/discontinuation or suboptimal 
response;

Potential results from exploratory analyses of banked biospecimen (these results may 
or may not be generated in the context of the present study).


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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3.4. Baseline Variables
The baseline will be defined as the last non-missing assessment prior to the first dose of 
study drug.  An assessment on Day 1 is assumed to be pre-dose of study drug unless 
otherwise specified.
The following variables will be collected only during screening period:

Demographics (gender, age and race);

Sokal score;

Medical and cancer history;

Blood chemistry (hepatitis B virus (HBV) and hepatitis C virus (HCV) test);

Height.
The age will be calculated as the number of elapsed years from date of birth to date of 
screening.
The Sokal score is derived by study sites using the following formula:
exp(0.0116(Age −43.4) + 0.0345(Spleen −7.51) + 0.188((Platelet / 700)2 −0.563) +
0.0887(Blasts −2.1)),
where units of Age, Spleen, Platelet and Blasts are years, centimeters below costal margin, 
109/L and percentage of blasts in peripheral blood, respectively.
There are no stratification factors nor covariates in this study.
3.5. Safety Endpoints
Safety endpoints are the secondary endpoints in this study.
3.5.1. Adverse Events
An adverse event (AE) is any untoward medical occurrence in a study patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.
A treatment-emergent adverse event (TEAE) is defined as an AE that first occurred or 
worsened in severity from the first dose of the study drug until 28 days after the last dose.  
TEAEs will be assessed mainly in this study.
3.5.2. Laboratory Data
The following laboratory parameters will be assessed:


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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
Complete blood count (CBC) including WBC count with 5-part differential, absolute 
neutrophil count (ANC), platelet count, red blood cell (RBC) count and hemoglobin;

Liver function measurements† including aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin;

Blood chemistry including sodium, potassium, chloride, carbon dioxide or 
bicarbonate (if available), blood urea nitrogen (BUN) or urea, creatinine, glucose, 
total protein, albumin, calcium, alkaline phosphatase, amylase, lipase, phosphorous, 
magnesium, creatine kinase and uric acid (until patient achieves CHR);

Coagulation test including prothrombin time (PT) or international normalized ratio
(INR) and partial thromboplastin time (PTT) or activated partial thromboplastin time
(aPTT);

Urinalysis including urine protein and urine blood, and

Estimated glomerular filtration rate (eGFR) calculated by study sites using the 
following Modification of Diet in Renal Disease (MDRD) formula;
32788 × (Creatinine / 88.4)−1.154 × Age−0.203 × 0.742 (if female) × 1.21 (if black).
3.5.3. Vital Signs and Body Weight
Temperature (axillary), supine blood pressure, heart rate and body weight will be assessed.
3.5.4. Electrocardiograms
Triplicate 12-lead (with a 10 second rhythm strip) tracings will be used for all 
electrocardiograms (ECGs).  A QT interval will be corrected for an RR interval using 
Fridericia’s (QTcF) and Bazett’s factors (QTcB), respectively.  Actually, QTcF will be 
reported by study sites.  On the other hand, QTcB will be derived from QT / RR1 / 2. A heart 
rate will be derived from 60000 / RR if the unit of RR is msec.
At each time point, 3 consecutive ECGs will be performed at approximately 2 minutes apart 
to determine the mean QTcF and QTcB intervals.
3.5.5. Echocardiogram or Multiple Gated Acquisition
Echocardiogram (ECHO) or multiple gated acquisition (MUGA) will be performed at 
screening (within 2 weeks prior to registration) and at End of Treatment/Withdrawal or at 
Week 96, whichever is earlier, and as clinically indicated.
                                                
† Direct and indirect bilirubin are specified in the study protocol to evaluate the liver function as needed.  
However, the result of measurement will not be collected in the CRF.  Therefore, they are removed from the 
SAP.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures.
4.1. As-Treated Population
The as-treated population will consist of all enrolled patients who received at least 1 dose of 
study drug.  Since this is a single-arm phase 2 study, as-treated population is also the full 
analysis set.
4.2. Modified as-Treated Population
The modified as-treated population will consist of all enrolled patients with Ph+ CP CML 
harboring b2a2 and/or b3a2 transcripts who received at least 1 dose of study drug.
4.3. Safety Analysis Set
The safety population will consist of all enrolled patients, regardless of Ph status, who 
received at least 1 dose of study drug.  This means that the as-treated population is also the 
safety analysis set.  Therefore, the as-treated population will be presented in any tables, 
listings and figures instead of the safety analysis set.
4.4. PK Analysis Set
The PK population will be defined as any patient in the safety population of patients who had 
at least 1 concentration of bosutinib on-treatment.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
In this study, null (H0) and alternative (H1) hypotheses are as follows:
H0: the true MMR rate at 12 months (48 weeks) is 25%;
H1: the true MMR rate at 12 months (48 weeks) is 40%.
With 60 Ph+ patients, the study is powered at greater than 82% to test this null versus 
alternative hypothesis with one-sided alpha of 5%.  The MMR rate at 12 months will be 
considered >25% if and only if the null hypothesis is rejected (observing at least 
21 responders [35%] out of the 60 total patients).  The statistical comparison will be 
performed after Core Treatment Phase of all treated patients.  No multiplicity adjustment will 
be needed.
No formal statistical hypothesis tests will be performed for any endpoints except for the 
primary endpoint.
5.2. General Methods
5.2.1. Analyses for Continuous Data
Continuous data will be summarized descriptively (n, mean, standard deviation, minimum, 
median, maximum) unless otherwise specified.
5.2.2. Analyses for Categorical Data
Categorical data will be summarized using the frequency table (the number of patients, 
frequency and percentage).  An asymptotic confidence interval (CI) of estimated proportion 
for response rate will also be presented as needed.
5.2.3. Analyses for Time-to-Event Data
Time-to-event data (duration of response and OS) will be summarized using the 
Kaplan-Meier method and estimated survival curves will be displayed graphically when 
appropriate.  Graphs will describe the number of patients at risk over time.  The median, 
quartiles and probabilities of an event at particular points in time will be estimated by the 
Kaplan-Meier method.  CIs for medians and quartiles are based on the Brookmeyer-Crowley 
method.  CIs for the estimated probability of event at a particular time point will be generated 
using the Greenwood’s formula.  When applying the cumulative incidence method (time to 
response and transformation, EFS),1 yearly rates with the associated CI based on delta 
method with log(-log) transformation method will be provided.  Percentiles of the cumulative 
incidence function (25%, 50% and 75%) will also be provided.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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5.3. Methods to Manage Missing Data
5.3.1. Molecular Response Assessment
5.3.1.1. MMR, MR4.0 and MR4.5 at 12 months (48 weeks)
If a patient is missing a molecular response assessment at 48-week visit, and patient
demonstrates response at both the 36-week and 60-week visits, then that patient will be 
considered a responder at the 48-week visit.  In other situation, a patient will be considered a 
non-responder at the 48-week visit.
5.3.1.2. MMR at 18 months (72 weeks)
The same rules apply for MMR at 18 months as they do for MMR at 12 months. In this case, 
the 60-week and 84-week visits will be used for a missing molecular assessment.
5.3.1.3. MR1 and MR2 at 3 and 6 months
If a patient is missing the assessment, they will be coded as a non-responder.
5.3.1.4. MMR, MR4.0 and MR4.5 at 3 month
If a patient is missing the assessment, they will be coded as a non-responder.
5.3.1.5. MMR, MR4.0 and MR4.5 at 6 and 9 months
If a patient is missing a molecular response assessment at the time of interest and the patient
demonstrates molecular response at both prior and subsequent visits, then that patient will be 
considered a responder at that time of interest.  If a patient is missing molecular response at 
either prior or subsequent visits, then that patient will be considered a non-responder at that 
time of interest.
5.3.1.6. MMR by 12 and 18 months (48 and 72 weeks)
If a patient is missing a molecular response at the 48-week and 72-week visits and the patient
has demonstrated a MMR at visits prior to the 48-week and 72-week visits, then the patient
will be considered a responder by the 48-week and 72-week visits, respectively.
5.3.2. Cytogenetic Response Assessment
Handling of missing bone marrow data will take the following steps:
1. If bone marrow cytogenetics results are not available and a MMR is achieved on a 
specific date, then a CCyR response will be imputed for that date.
2. If bone marrow cytogenetics results are available where <20 metaphases analyzed 
with zero Ph+ cells and a MMR is achieved on a specific date, then a CCyR response 
will be imputed for that date.
5.3.3. Hematologic Response Assessment
Handling of missing hematology data will take the following steps:


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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1. For each patient, the observations are sorted by visit and the relative day.
2. For each observation, the peripheral blood differentials should add up to 100%.  
Some sites may not record 0%.  Instead, the corresponding field may appear as 
missing or “ND.”  If myelocytes, promyelocytes and myeloblasts in the blood 
differential are reported as missing or “ND,” the following rule will be applied.  Each 
domain of the differentials will be summed together.  If the total is between 98.5% 
and 101%, the missing values will be assigned 0%.  Otherwise, the observation will 
be left as is and the record will also be reported as a data issue.
3. If CHR cannot be assessed due to one or more missing components of CHR, impute 
CHR if a patient has a MMR or a CCyR and all assessed components of CHR are 
within appropriate limits.
Furthermore, in the absence of extramedullary disease info, it is assumed that spleen is 
non-palpable.
5.3.4. Time-to-Event Data
The primary missing data handling method will be censoring.  A patient withdrawing from 
the study without experiencing the event of interest will be censored at the last valid (ie, 
evaluable) assessment of that event.  A patient who fails on treatment, after missing two or 
more assessments of both hematologic and cytogenetic response, will be censored for 
on-treatment EFS at the last hematologic or cytogenetic assessment.  A patient, who dies 
after treatment discontinuation during long-term follow-up and after missing two or more 
long-term follow-up assessments, will be censored for off-treatment EFS at the last 
assessment at which the patient was found to be alive and event-free.  See also Section 3.2.3
for duration of MMR or CCyR.
5.3.5. Safety Endpoints
Missing safety data will be handled according to Pfizer standards.
5.3.6. Other Variables
For a patient without an available Ph status data at screening, cytogenetics data of the patient 
at Month 3 will be impute as the Ph status at screening only if a study monitor is able to 
confirm the Ph status before screening and records it in an appropriate document such as a 
monitoring record.
Other variables except for endpoints described in Section 5.3 will not be imputed.
6. ANALYSES AND SUMMARIES
All efficacy analyses will be performed using the modified as-treated population unless 
otherwise specified. In case the as-treated population is completely the same as the modified 
as-treated population, analyses for efficacy endpoints using the as-treated population may be 
omitted.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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Patients without the b2a2 or b3a2 transcript will be counted as non-responders of MMR in 
the as-treated population.  Analyses including cytogenetic data will only be performed on the 
modified as-treated population as Ph- patients are not assessable for cytogenetic response.
6.1. Primary Endpoint
6.1.1. MMR at 12 Months
6.1.1.1. Primary Efficacy Analysis
The MMR at 12 months (48 week) will be analyzed using the hypothesis test of a one-sample 
binomial proportion test with the normal approximation (also refer to Section 5.1).  The 
two-sided 90% CI of MMR rate at 12 months (48 weeks) will also be calculated.
The MMR at 12 months (48 weeks) is counted only if the response is demonstrated at the 
12-month (48-week) visit; any MMR gained and lost before the 12-month (48-week) visit is 
deemed a non-response as is the case where the MMR is never achieved at or before 
12 months (48 weeks).
The modified as-treated population will be used in the primary efficacy analysis.
6.2. Secondary Endpoints
6.2.1. MMR by 12 and 18 Months
Evaluations of MMR by 12 and 18 months will be assessed using the frequency tables, 
respectively.  The two-sided 90% CI will also be calculated.  For the analysis of MMR by 12 
and 18 months, a patient is counted as a responder if the MMR occurs at or before 12 and 
18 months, respectively, even if the MMR is subsequently lost at or before the 12-month and 
18-month time point, respectively. A patient never achieving the MMR at or before 12 and 
18 months will be considered a non-responder, respectively.
The MMR by 18 months will only be summarized at the final analysis (FA; refer to 
Section 7.2.3 with respect to the FA).
6.2.2. CCyR
Evaluations of CCyR by 12 months (48 weeks) will be assessed using the frequency tables.  
The two-sided 90% CI will also be calculated.  The CCyR rate by 12 months is defined as the 
proportion of patients demonstrating CCyR at or before 12 months (48 weeks). The 
percentage of Ph+ cells will be calculated according to the following formula:
ceil(100 × the number of Ph+ cells / the number of metaphases),
where ceil() denotes a ceiling function.
The proportion of patients who have confirmed loss of CCyR will also be evaluated.
6.2.3. Duration of Response
The duration of MMR and CCyR will be based on the estimations of the quartiles of duration 
and yearly rates using the Kaplan-Meier method.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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For the analysis of MMR and CCyR, the proportion of patients who have confirmed loss of 
response will also be evaluated, respectively.
The duration of MMR will be analyzed for MMR responders in the modified as-treated 
population and those in as-treated population separately. The duration of CCyR will be 
analyzed for CCyR responders in the modified as-treated population.
6.2.4. EFS
EFS will be analyzed using the cumulative incidence method1 adjusting for the competing 
risk of treatment discontinuation without the event, and yearly rates and percentiles will be 
displayed. This will be indicated as the on-treatment EFS.  As a definition of “on-treatment”
is described in Section 6.3.5, the transformation to AP and BP on treatment will be 
considered as an event in the analysis of EFS.  This means that if the first transformation to 
AP and BP is occurred after 28 days from the last dose, this will not be considered as an 
event in the analysis of EFS.
As a reference, the EFS using the transformation to AP and BP occurred after 28 days from 
the last dose instead of the transformation to AP and BP on treatment will also be assessed 
using the same analysis method. This will be indicated as the off-treatment EFS.
The on-treatment EFS and off-treatment EFS will be analyzed in the modified as-treated 
population.
The off-treatment EFS will only be evaluated at the FA (refer to Section 7.2.3 with respect to 
the FA).
6.2.5. OS
The analysis of OS will be similar to that for duration of response just described.
The OS will be analyzed in the modified as-treated population and as-treated population 
separately.
6.2.6. Pharmacokinetics
PK profiles of bosutinib will be determined using a sampling regimen and population PK 
analysis approach. A total of 4 PK samples per patient will be drawn. All patients in the 
bosutinib treatment group will provide pre-dose blood samples on Day 1, 28, 56 and 84.
Concentrations of bosutinib will be determined in plasma using a Sponsor-approved and 
validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay.
The objectives of the population PK analysis are 1) to develop a population PK model which 
describes the PK of bosutinib in this patient population, 2) to evaluate the influence of 
demographic and clinical covariates on the exposure of bosutinib, and 3) to explore the 
relationship between trough concentrations of bosutinib with clinical safety (drug related 
adverse effects such as GI AEs, and any other major AEs) and efficacy endpoints.


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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The concentration of study drug will be analyzed using population PK methodology.
Population mean values of PK parameters (eg, clearance [CL/F], volume of distribution 
[V/F]) will be estimated. PK relationships between plasma study drug concentration and 
selected outcome measures will be characterized using a population approach.
Details of analysis of PK endpoints is referred to “B1871048 Pharmacokinetic Analysis 
Plan”, which is separetely developed.
6.3. Other Endpoint(s)
6.3.1. MMR at Each Pre-Specified Visit
Measures of MMR at 3, 6, 9, 12 and 18 months will be evaluated by frequency tables.  The 
two-sided 90% CI will also be calculated.
These analyses except for the MMR at 12 months will be performed using the modified 
as-treated population and as-treated population, respectively.
The exploratory MMR analysis at 12 months will be analyzed for the as-treated population.
The MMR at 18 months will only be summarized at the FA (refer to Section 7.2.3 with 
respect to the FA).
6.3.2. Molecular Response
Measures of MR1, MR2, MR4.0 and MR4.5 at each pre-specified visit will be evaluated by 
frequency tables.  The two-sided 90% CI will also be calculated.
Pre-specified visits for MR1 and MR2 are 3 and 6 months, respectively, while pre-specified 
visits for MR4.0 and MR4.5 are 3, 6, 9 and 12 months.
These analyses will be performed using the modified as-treated population and the as-treated 
population, respectively.
6.3.3. Time to MMR, CCyR, MR4.0 and MR4.5
The time to response (MMR, CCyR, MR4.0, and MR4.5) is measured from first dose to the 
first date of response. The time to response will be analyzed using the cumulative incidence 
method.1  Yearly rates and percentiles will be displayed.  In the analysis of cumulative 
incidence (see Section 5.2.3), the competing risk is defined as treatment discontinuation
without response.  Also, other patients without response will be censored at the last valid 
assessment for the respective endpoint.
The time to response will be also summarized by descriptive statistics among responding 
patients.
The time to MMR, MR4.0 and MR4.5 will be analyzed for the modified as-treated population
and as-treated population separately. The time to CCyR will be calculated using the 
modified as-treated population.


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6.3.4. Cumulative CHR
Evaluations of cumulative CHR will be assessed using the frequency tables.  The two-sided 
90% CI will also be calculated.
The cumulative CHR will be analyzed for the modified as-treated population and as-treated 
population separately.
Investigators should assess hematologic response according to the original definition of CHR 
(see Appendix 1.4).  In a statistical analysis, some restrictions (see table footnotes in
Appendix 1.4) are adopted in addition to the original definition.
6.3.5. Time to Transformation to AP and BP CML
The analysis of the time to transformation to AP and BP CML will be similar to that of the 
time to response described above.
The time to transformation to AP and BP CML is defined as the time from first dose to the 
first date of transformation to AP or BP CML. The transformation to AP and BP will be 
counted while a patient is on treatment up to 28 days after last dose.  In the analysis of 
cumulative incidence1 (see Section 5.2.3), the competing risk is defined as treatment 
discontinuation without transformation.  If transformation has not occurred, the patient will 
be censored at the last valid hematologic assessment.
Investigators should assess transformation to AP/BP according to the original definition of 
AP/BP CML (see Appendix 1.3).  In a statistical analysis, some restrictions (see table
footnotes in Appendix 1.3) are adopted in addition to the original definition.
Time to transformiation to AP and BP CML will be analyzed for the modified as-treated 
population and as-treated population separately.
6.3.6. Mutations
Types of BCR-ABL mutations present at treatment completion and when performed during 
treatment will be summarized by frequency tables.
Summaries of newly observed BCR-ABL mutations in patients post-baseline will be 
presented by visit.
Types of BCR-ABL mutations will be summarized using the modified as-treated population
and as-treated population separately.
6.4. Subset Analyses
Subgroup analyses using Sokal score for MMR at 12 months (48 weeks) will be performed 
and two-sided 90% CIs will be presented.  Sokal score will be categorized as follows:

Low risk: Sokal score <0.8;

Intermediate risk: Socal score 0.8 to 1.2, and


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
High risk: Sokal score >1.2.
This analysis will be evaluated for the modified as-treated population and the as-treated 
population, respectively.
6.5. Baseline and Other Summaries and Analyses
Both as-treated population and modified as-treated population will be used unless otherwise
specified.  In case the as-treated population is completely the same as the modified as-treated 
population, summaries using the modified as-treated population may be omitted.
6.5.1. Baseline Summaries
Baseline variables including the body weight and Ph status at the screening period will be 
summarized descriptively for both the modified as-treated population and the as-treated 
population according to Section 5.2.1 and Section 5.2.2., respectively. The body mass index 
will be derived using the height and body weight at the screening period and will be reported 
as a baseline variable.
6.5.2. Study Conduct and Patient Disposition
The total number of enrolled patients, the number of patients who completed/discontinued 
the treatment/study and the reason for any premature discontinuation from the 
treatment/study will be presented.  In addition, the number of patients who completed the 
treatment to 12 months and discontinued the treatment within 12 months will be presented. 
The number of patients in each analysis set also be presented.
6.5.3. Study Treatment Exposure
Exposure to study drug will be evaluated by duration of treatment exposure (the number of 
doses and missed doses) for as-treated population.  In addition, actual dose intensity, and 
relative dose intensity will be evaluated.  Descriptive statistics will be presented for 
continuous exposure variables: treatment duration (the number of days on treatment), actual 
dose intensity, and relative dose intensity.  The frequency and percentage of patients with at 
least one dose reduction due to AE, temporally stopped study drug due to AE, reduction to 
300 and 200 mg, and escalation to 500 and 600 mg will also be summarized.  Further, the 
followings will be summarized:

Number of dose delay;

Number of dose reduction;

Number of dose escalation;

Time to the first dose delay;

Duration of dose delay;

Time to the first dose reduction;


Protocol B1871048 (Bosutinib) Statistical Analysis Plan
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
Duration of dose reduction, and

Time to the first dose escalation.
Cumulative dose (unit: mg) will be calculated as the summation of all administered doses.
Duration of treatment will be calculated as
Duration of Treatment (days) = DL −DF + 1;
where
DL: the date of the last non-zero dose of the study drug, and
DF: the date of the first non-zero dose of the study drug.
Actual dose intensity (unit: mg/day) will be calculated as
Actual dose intensity (mg/day) = aCD / (LDD −DF + 1),
where
aCD: actual cumulative dose in mg;
LDD: the last dose date of zero or non-zero dose of the study drug, and
DF: the date of the first non-zero dose of the study drug.
Theoretical dose intensity (unit: mg/day) will be calculated as:
Theoretical dose intensity (mg/day) = pCD / (LDD −DF + 1).
where
pCD: planned cumulative dose (ie, cumulative starting dose) in mg;
LDD: the last dose date of zero or non-zero dose of the study drug, and
DF: the date of the first non-zero dose of the study drug.
Relative dose intensity will be calculate according the following formula:
Relative dose intensity (%) = 100 × (Actual dose intensity) / (Theoretical dose intensity).
6.5.4. Concomitant Medications and Non-Drug Treatments
Summary of concomitant medications will include the frequency and percentage of patients 
by Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred term.  In 
case any specific medication does not have ATC classification level 2 coded term, it will be 
summarized under “Unavailable ATC classification” category.


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Summary of non-drug treatments will include the frequency and percentage of patients by 
Medical Dictionary for Regulatory Activities (MedDRA) preferred term.
6.5.5. Transfusions
Summary of transfusions will include the frequency and percentage of patients by the 
transfusion type.
6.5.6. ECOG Performance Status
Summary of ECOG performance status will include the frequency and percentage of patients 
at each visit.
6.5.7. Extramedullary Disease
Summary of extramedullary disease will include the frequency and percentage of patients at 
each visit by body sites.
6.5.8. Chest X-ray
Results of chest X-ray will be summarized descriptively at each visit.
6.6. Safety Summaries and Analyses
All safety analyses will be performed using the as-treated population.
6.6.1. Adverse Events
All AEs will be coded using the latest version of MedDRA dictionary at the analysis.  The 
toxicity will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03.
The numbers of events and incidence rates will be tabulated by preferred term and system 
organ class. AEs will be presented with and without regard to causality. The frequency of 
overall toxicity, categorized by toxicity Grades 1 through 5, will be described. Additional 
tables will be provided for AEs that are observed with higher frequency.
AE summaries will include incidence of TEAEs by MedDRA preferred term and system 
organ class, incidence of clustered anemia/neutropenia/thrombocytopenia defined in 
Appendix 2 and clustered leukopenia includeing PTs in leukopenia and white blood cell 
count decreased, SAEs including deaths, AEs that led to study drug discontinuation, 
characteristics of AEs that led to study drug discontinuation, AEs that led to study drug 
interruption, AEs that led to study drug reduction and AEs by maximum severity and 
relationship to study drug.  Discontinuation due to AE and death data will also be listed.
AEs and AE categories including cardiac, oedema, effusion, gastrointestinal, diarrhea, nausea, 
vomiting, hemorrhage, anemia, neutropenia, thrombocytopenia, hypersensitivity, 
hypertension, infection, liver function, ALT, AST, myelosuppression, rash, renal and 
vascular will be summarized (see Appendix 2).  A listing of AEs included in each AESI 
category will be provided by each patient.


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TEAEs leading to death within 28 days of the last dose will be summarized.
Percentage of subjects with TEAEs (diarrhea, ALT, AST and the first onset of diarrhea) by 
maximum grade will be plotted using a cumulative bar chart at each month.
6.6.2. Laboratory Data
Laboratory results including bone marrow aspirate will be classified according to the NCI 
CTCAE version 4.03.  Laboratory results that are not part of NCI CTCAE or are impossible 
to be classified according to the NCI CTCAE using laboratory data only will be presented 
according to the categories: below normal limit, within normal limits and above normal limit 
(according to the laboratory normal ranges).  Kidney Disease Improving Global Outcomes 
(KDIGO) categories (see Appendix 1.5) will be used for eGFR grading.
Laboratory assessments will be presented as mean changes from baseline and incidence of 
abnormal values. Shift tables will also be presented.
6.6.2.1. Hy’s Law
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin
that met the criteria outlined below in the absence of other causes of liver injury will be 
considered potential cases of drug induced liver injury (potential Hy’s Law cases).

Subjects with AST or ALT and total bilirubin baseline values within the normal range
who subsequently presented with AST or ALT >3 x upper limit of normal (ULN)
concurrent with a total bilirubin >2 x ULN with no evidence of hemolysis and an 
alkaline phosphatase <2 x ULN or not available.

For subjects with pre-existing ALT or AST or total bilirubin values above the ULN, 
the following threshold values were used in the definition mentioned above.
For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT >2 times the baseline values and >3 x ULN, or >8 x ULN 
(whichever was smaller).
For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by 1 x ULN or >3 x ULN (whichever was smaller).
The potential Hy’s law will be confirmed at each time point.  Further, an evaluation of 
drug-induced serious hepatotoxicity (eDISH) scatter plot of peak ALT, peak AST and peak 
ALT/AST versus peak total bilirubin will be presented.
6.6.3. Vital Signs and Body Weight
Vital signs (temperature (axillary), supine blood pressure and heart rate) and body weight
will be presented using descriptive statistics.  Criteria for potentially clinically important 
changes is shown in Appendix 3.


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6.6.4. ECG
Actual values and changed from baseline of all measured ECG parameters (an average of the 
triplicate measurements) will be presented using descriptive statistics.  Frequencies and 
percentages of patients with potentially clinically important changes in ECG will be
summarized.  Criteria for potentially clinically important changes is shown in Appendix 4.
6.6.5. Echocardiogram or Multiple Gated Acquisition
Echocardiogram or multiple gated acquisition will be presented using descriptive statistics.
6.6.6. Physical Examination
Summary of physical examination will include the frequency and percentage of patients at 
the screening period by body sites.  Presence or absence of any change from the screening 
will also be summarized using descriptive statistics at each post-screening visit.
6.6.7. Death
Deaths during the study and within 28 days from the last dose will be summarized by reason 
for death. Relevant information will also be supplied in a data listing. Deaths occurring 
beyond 28 days from the last dose will be included in a data listing.
7. INTERIM ANALYSES
7.1. Introduction
7.1.1. Interim Look
An interim look (IL) will be conducted separately prior to the PA to assess the possibility of 
early communication with regulatory authorities based on the interim data. This will not be 
used to judge the early study termination or any changes of study design.  The IL is planned 
only once in this study and the primary endpoint will not be analyzed.
7.1.2. Primary Analysis
The PA will be performed:

To verify whether the study goal is achieved, and

To submit study data to a regulatory authorities if the study drug is considered to 
show efficacy and tolerable.
All planned analyses will be performed at the PA unless otherwise specified.  The PA is 
planned only once in this study.  This study will not use a data monitoring committee.
7.1.3. Final Analysis
The FA will be performed at the end of study.  Before the FA, all data will be cleaned and the 
database will be locked/released.  Some specified endpoints will be summarized newly or 
updated from the PA at the FA.


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7.1.4. Periodic Safety Review
For the purposes of this study, Pfizer procedures for periodic safety review will be applied by 
an internal safety review team with medical and statistical capabilities.
7.2. Interim Analyses and Summaries
7.2.1. Interim Look
7.2.1.1. Timing of the Interim Look
The IL will occur at 3 months after the first dose of the last patient.
7.2.1.2. Endpoints
The following endpoints for patients with sufficient follow-up will be summarized at the IL:

Cumulative incidence of MMR at 12 months;

MMR by 12 months;

MMR at 3, 6 and 9 months;

MR1 at 3 months;

all safety endpoints;

All PK endpoints except for primary endpoint related parameters 
(Exposure-Response relationship will not be included in the interim data.), and

Baseline variables.
Analysis of primary endpoint will not be conducted at the IL.
7.2.1.3. Hypotheses
No statistical hypothesis test will be performed.  Therefore, no alpha will be spent at the IL.
7.2.1.4. Analysis Sets
7.2.1.4.1. Efficacy
For efficacy endpoints, the modified as-treated population will be used at the IL.  In addition, 
a specified subset of the modified as-treated population shown below will also be used in 
each endpoint if specified.
Endpoints
Subset Criteria

Cumulative incidence of 
MMR at 12 months

MMR by 12 months

For the patient continuing the study treatment, the assessment at 
12 months is completed.

For the patient discontinuing the study treatment, at least 332 days after 
the first dose of study drug in the patient have passed at the IL.


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Endpoints
Subset Criteria

MMR at 6 months

For the patient continuing the study treatment, the assessment at 
6 months is completed.

For the patient discontinuing the study treatment, at least 164 days after 
the first dose of study drug in the patient have passed at the IL.

MMR at 9 months

For the patient continuing the study treatment, the assessment at 
9 months is completed.

For the patient discontinuing the study treatment, at least 248 days after 
the first dose of study drug in the patient have passed at the IL.
7.2.1.4.2. Safety
For safety endpoints, the as-treated population will be used at the IL.
7.2.1.4.3. PK
For PK endpoints, the PK analysis set will be used at the IL.
7.2.1.4.4. Baseline Variables
For baseline variables, the as-treated population and the modified as-treated population will 
be used at the IL.
7.2.1.5. Analysis Methods
7.2.1.5.1. Cumulative Incidence of MMR at 12 Months
The cumulative incidence of MMR at 12 months will be estimated using the cumulative 
incidence method described in Section 6.3.3.
7.2.1.5.2. MMR by 12 Months
The MMR by 12 months will be summarized described in Section 6.2.1.
7.2.1.5.3. MMR at 3, 6 and 9 Months
The MMR at 3, 6 and 9 months will be summarized described in Section 6.3.1.
7.2.1.5.4. MR1 at 3 Months
The MR1 at 3 months will be summarized described in Section 6.3.2.
7.2.1.5.5. Safety Endpoints
All safety endpoints will be summarized described in Section 6.6.
7.2.1.5.6. PK Endpoints
All PK endpoints (excluding the Exposure-Response relation) will be summarized described 
in Section 6.2.6.
7.2.1.5.7. Baseline Variables
Baseline variables will be summarized described in Section 6.5.


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7.2.1.6. Prevention of Any Bias
The results from the IL will not be reported to the study monitors and site staff including 
investigators to prevent the mixture of any bias.
7.2.2. Primary Analysis
The PA will be conducted after Core Treatment Phase of all treated patients and before the 
FA.  All analyses described in this SAP including the primary efficacy analysis of the 
primary endpoint will be performed at the PA unless otherwise specified.  No adjustment of 
the significance level will be needed because no formal analysis is planned at the FA.
7.2.3. Final Analysis
The FA will be conducted after releasing the study database.  The endpoints described below 
will be reported at the FA.

MMR by 18 months;

Duration of MMR and CCyR;

EFS (both on-treatment and off-treatment);

OS;

MMR at 18 months;

Time to MMR, MR4.0, MR4.5 and CCyR;

Time to transformation to AP and BP CML on treatment;

Type of mutations present at treatment completion/discontinuation or suboptimal 
response;

All safety endpoints.
No statistical hypothesis test will be planned at the FA.
7.2.4. Periodic Safety Review
The team will review individual and summary data collected in the safety and clinical 
databases for periodic safety review.
8. REFERENCES
1.
Lin G, So Y, Johnston G. Analyzing survival data with competing risks using SAS
Software. Proceedings of the SASGlobal Forum 2012 Conference; 22-25 Apr 2012;
Cary, NC: SAS Institute; 2012.


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9. APPENDICES
Appendix 1. Response Definitions
Appendix 1.1. Molecular Responses
Before Treatment
Molecular Response
RT-PCR (BCR-ABL Ratio)
Chronic Phase
Major, or MMR
0.1% (corresponding to 3 log reduction from baselinea) 
with a minimum number of ABL transcripts specified by 
the central laboratory
MR1
A 1 log reduction in BCR-ABL transcript with a minimum 
number of ABL transcripts specified by the central 
laboratory
MR2
A 2 log reduction in BCR-ABL transcript with a minimum 
number of ABL transcripts specified by the central 
laboratory
MR4.0
Either (i) detectable disease with 0.01% BCR-ABL IS or 
(ii) undetectable disease in cDNA with a minimum number 
of ABL transcripts specified by the central laboratory
MR4.5
Either (i) detectable disease with 0.0032% BCR-ABL IS 
or (ii) undetectable disease in cDNA with a minimum 
number of ABL transcripts specified by the central 
laboratory in the same volume of cDNA used to test for 
BCR-ABL
a. Standardized baseline from central laboratory.
Appendix 1.2. Cytogenetic Responses
Before Treatment
Cytogenetic Responsesa
Percent of Ph+ Cells
Chronic Phase
None
>95%
Minimal
66%–95%
Minor
36%–65%
Partial
1%–35%
Complete
0%
Major
Complete + Partial Rates
a. Based on analysis of at least 20 metaphases.
Appendix 1.3. Blast Phase and Accelerated Phase
Patient meeting any of the following criteria will be judged as either a BP or an AP.


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Phase
Criteria
Blast Phase

30% blasts in blood or bone marrow.

Extramedullary blast proliferation, other than in spleen.
Accelerated Phase

15%–29% blasts in blood or marrow, or
>30% blasts plus promyelocytes in blood or marrow with blasts <30%.

20% basophils in blood.

Persistent thrombocytopenia (<100 × 109/L) unrelated to therapya.

Clonal chromosome abnormalities in Ph+ cells (CCA/Ph+), major route, on 
treatmentb.
a. Persistent thrombocytopenia is not considered to define AP progression as the database does not collect 
data regarding the relationship between the platelet value and therapy.
b. Clonal chromosome abnormalities alone are not considered sufficient to define progression to AP unless
concurrent presence of another AP criterion.
Appendix 1.4. Hematologic Responses
Hematologic Responsesa
Definition
Complete Hematologic Response, or CHR

WBC 10 × 109/L.

Basophils <5% in blood.

No myelocytes, promyelocytes, myeloblasts in 
the blood differential.

Platelet count <450 × 109/L.

Spleen non palpableb.
a. Had to meet all criteria indicated in the Definition column
b. In the absence of extramedullary disease info, it is assumed that that spleen is non-palpable.
Appendix 1.5. KDIGO Categories
eGFR Category
eGFR (ml/min/1.73 m2)
Terms
1
90
Normal or high
2
60–89
Mildly decreased
3a
45–59
Mildly to moderately decreased
3b
30–44
Moderately to severely decreased
4
15–29
Severely decreased
5
<15
Kidney failure


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Appendix 2. Adverse Event of Special Interest
The table below is presented criteria for adverse event of special interest.  This was actually 
used in the study AV001.  Though AE criteria listed below were defined using MedDRA 
version 19.0, the latest version of MedDRA at the time of analysis will be used.  Therefore, 
criteria may possible be updated.  Actual criteria used in this study will be reported in the 
clinical study report.
AE Category
AE Criteria
Cardiac

HLGTs in Cardiac arrhythmias, Heart failures, Pericardial disorders.

PTs in Cardiac death, Sudden cardiac death, Sudden death, Ejection fraction decreased.

MedDRA SMQ (Narrow): Torsade de pointes/QT prolongation.
Oedema

PTs contain Oedema, Weight increased.
Effusion

PTs in Pleural effusion, Pericardial effusion.
Gastrointestinal

PTs in Nausea, Regurgitation, Retching, Vomiting, Vomiting projectile, Diarrhoea, 
Defaecation urgency, Frequent bowel movements, Gastrointestinal hypermotility.
Diarrhoea

PT in Diarrhoea.
Nausea

PT in Nausea.
Vomiting

PT in Vomiting.
Hemorrhage

PTs in Gastric occult blood positive, Occult blood positive.

MedDRA SMQ (Narrow): Haemorrhage terms (excl laboratory terms).
Anemia

PTs in Anaemia, Hemoglobin decreased.
Neutropenia

PTs in Neutropenia, Neutrophil count decreased.
Thrombocytopenia

PTs in Thrombocytopenia, Platelet count decreased.
Hypersensitivity

HLGT in Allergic conditions.
Hypertension

HLGT in Vascular hypertensive disorders.

PTs in Blood pressure abnormal, Blood pressure ambulatory abnormal, Blood pressure 
ambulatory increased, Blood pressure diastolic abnormal, Blood pressure diastolic 
increased, Blood pressure increased, Blood pressure systolic abnormal, Blood pressure 
systolic increased.
Infection

SOC in Infections and infestations.
Liver Function

MedDRA (SMQ) Hepatic disorders: Sub-SMQs (Narrow) in Cholestasis and jaundice of 
hepatic origin; Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions; Hepatitis, non-infectious; Liver related investigations, signs and symptoms
(selected relevant).

PTs: Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate 
aminotransferase abnormal, Aspartate aminotransferase increased, Bilirubin conjugated 
abnormal, Bilirubin conjugated increased, Blood bilirubin abnormal, Blood bilirubin 
increased, Blood bilirubin unconjugated increased, Hepatic enzyme abnormal, Hepatic 
enzyme increased, Hepatic function abnormal, Hyperbilirubinaemia, 
Hypertransaminasaemia, Liver function test abnormal, Transaminases abnormal, 
Transaminases increased, Blood alkaline phosphatase abnormal, Blood alkaline 
phosphatase increased, liver function test increased.
ALT

PT in Alanine aminotransferase increased.
AST

PT in Aspartate aminotransferase increased.
Myelosuppressiona

MedDRA SMQs (Narrow): Haematopoietic cytopenias affecting more than one type of 
blood cell, Haematopoietic erythropenia, Haematopoietic leukopenia, Haematopoietic 
thrombocytopenia.

PTs in Bone marrow toxicity, Haematocrit decreased, Haemoglobin decreased, 
Haematotoxicity, Anaemia.
Rash

HLTs in Rashes, eruptions and exanthems NEC; Erythemas; Acnes; Dermatitis and eczema.
Renal

HLT in Renal failure and impairment.

PTs in Blood creatinine abnormal, Blood creatinine increased, Creatinine renal clearance 
abnormal, Creatinine renal clearance decreased, Glomerular filtration rate abnormal,
Glomerular filtration rate decreased.


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AE Category
AE Criteria
Vascular

HLGTs in Coronary artery disorders; Arteriosclerosis, stenosis, vascular insufficiency and 
necrosis; Embolism and thrombosis.

HLTs in Arterial therapeutic procedures (excl aortic), Central nervous system haemorrhages 
and cerebrovascular accidents, Central nervous system vascular disorders NEC, Non-site 
specific vascular disorders NEC, Peripheral vascular disorders NEC (excluding the 2 PTs 
Flushing and Hot flush), Transient cerebrovascular events, Vascular imaging procedures 
NEC, Vascular therapeutic procedures NEC.
a. The following MedDRA PTs will be used for cytopenias: anemia (Anaemia), thrombocytopenia (Thrombocytopenia, 
Acquired amegakaryocytic thrombocytopenia), neutropenia (Cyclic neutropenia, Febrile neutropenia, Idiopathic 
neutropenia, Neutropenia).
Abbreviations: HLT=high level term; HLGT=high level group term; MedDRA=medical dictionary for regulatory 
activities; NEC=not elsewhere classified; PT=preferred term; SMQ=standard MedDRA query; SOC=system organ class.


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Appendix 3. Criteria for Potentially Clinically Important Changes in Vital Signs
Variable
Criteria
Systolic blood pressure
<80 or >210 mmHg
Diastolic blood pressure
<40 or >130 mmHg
Heart rate
<40 or >150 bpm
Temperature
<32C or >40C
Body weight
10% change from baseline value
Abbreviation: bpm=beats per minute.


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Appendix 4. Criteria for Potentially Clinically Important Changes in ECG
ECG Parameter
Criteria
Heart rate
Increase of >15 bpm from baseline value and 120 bpm
Decrease of >15 bpm from baseline value and 45 bpm
PR interval
Change of 20 msec from baseline value and 220 msec
QRS interval
120 msec
QTcB interval
>500 msec
Increase of >60 msec from baseline
QTcF interval
>500 msec
Increase of >60 msec from baseline
450 msec (Men) or 470 msec (Women)
>450 msec (Men) or >470 msec (Women)
Overall evaluation – center reported
Abnormal clinically significant
Abbreviations: bpm=beats per minute; PR interval=measure of the time between the start of the P wave and
the beginning of the QRS complex; QRS=the part of the electrocardiogram comprising the Q, R, and S
wave, together representing ventricular depolarization; QTc=corrected QT.