Clinical trial NCT01903733
Conditions: Chronic Myeloid Leukemia
Keywords: Subjects Chronic Myeloid Leukemia CML Bosutinib Extension
Sponsor: Pfizer
Start date: 2013-08-28; Completion date: 2020-06-05
Enrollment: 281 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of the study is to provide long term access to bosutinib treatment and assess long term safety, tolerability and duration of clinical benefit, without any formal hypothesis testing; therefore, there is no formal primary endpoint.

Detailed description:

Interventions: intervention 1: bosutinib
Intervention descriptions: intervention 1: The starting bosutinib dose is 500 mg once daily, however the dose can vary from 300 mg to 600 mg.

Protocol documents:
Prot_000.pdf: 
Bosutinib
B1871040
Final Protocol Amendment 2, 07 November 2016
PFIZER CONFIDENTIAL
Page 1
AN OPEN-LABEL BOSUTINIB TREATMENT EXTENSION STUDY FOR
SUBJECTS WITH CHRONIC MYELOID LEUKEMIA (CML) WHO HAVE
PREVIOUSLY PARTICIPATED IN BOSUTINIB STUDIES B1871006 OR B1871008
Compound:
PF-05208763
Compound Name:
Bosutinib
United States (US) IND Number:
68,268
European Clinical Trial Database 
(EudraCT) Number:
2013-000691-15
Protocol Number:
B1871040
Phase:
NA
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing,
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale 
Amendment 2
7 November 2016
Patients being studied in China are to be 
excluded from the pharmacokinetic (PK)
analysis and the centralized testing at 
end-of-treatment mutational analysis of the 
BCR-ABL kinase domain meant to explore 
mechanisms of underlying resistance to 
treatment.  This decision by the Sponsor is 
made due to the lack of local laboratory 
resources in China, weighed against impact of 
<10 % of overall patients enrolled in China.
PK data and genetic sequencing analysis will 
be collected from all the other patients and 
countries participating in this study.  Schedule 
of Activities as well as Assessment (Section 7)
are updated to reflect this decision.
Lifestyle guidelines and requirements for 
contraception are updated throughout the 
protocol for consistency with updated Pfizer 
SOPs; all sections updated to reflect 
requirement that patients of childbearing
potential must agree to use 2 highly effective 
method of contraception throughout the study
and for at least 28 days after the last dose of
assigned treatment. Inclusion and exclusion 
criteria, section 4.1 and 4.2 are now updated 
for consistency, as well as Lifestyle 
Guidelines, section 4.3. 
Compliance 5.4.3 and Appendix 3.  
Instructions are updated for use of (missed or 
changed) dose diary.  The protocol is updated
to specify that the dose diary is to be given to 
each patient at each visit and is no longer an 
optional tool.  A new dose diary is to be 
provided for each patient by the responsible 
site staff at each drug dispensation visit.  The 
dose diary is to be updated by the patient if the 
bosutinib dose is changed or if any bosutinib 
doses are missed.  The dose diary is to be 
reviewed by responsible site staff at each 
patient visit including phone contacts.  


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Correction of spelling throughout protocol of 
Creatine Kinase Section 8 Adverse Event 
Reporting updated per Pfizer SOPs
Section 15 Reporting requirements updated per 
Pfizer SOPs
Amendment 1
10 August 2016
Section 1:  Introduction section updated to 
reflect current information on bosutinib and 
current leukemia guidelines for standard of 
care; including protocol summary, CML 
treatment options, and background information 
on bosutinib. 
Section 2:  Study Objectives updated to fulfill a 
European Medicines Agency (EMA) 
post-approval requirement for the collection 
and analysis of the pharmacokinetics (PK) of 
bosutinib to assess correlations between trough 
concentrations of bosutinib and key efficacy 
and safety parameters.
Section 3: Study Design updated to allow for:
Extension of bosutinib dosing of all eligible 
patients to be studied for at least 10 years.
Visit window allowance widened from 4 days 
to 14 days (2 weeks between 6- and 
12-months and for telephone contacts (every 
3 months).
Schedule of Activities (SOA) Table 1 updated 
to reflect wider visit window allowance, the 
inclusion of PK sample collection, and 
assurance of contraceptive check per current 
SOPs.
Collection of data on any subsequent TKI 
therapy or other anti-cancer treatment
administered following discontinuation of 
bosutinib and the response to other treatments
(if applicable).
Section 4.3 Lifestyle Guidelines; updated 


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Contraception Language per current SOPs.
Section 4.4 Sponsor Medically Qualified 
Individual Section updated per current Protocol 
SOPs.
Section 5 updated to allow more frequent dose 
dispensation per site policy or specific patient 
needs, and IP return practice updated to allow 
IP destruction per site policy or local 
regulation. Updates also made to reflect 
current protocol SOPs.
Sections 5.4 and 5.4.1 Investigational Product 
(IP) and information updated per current 
protocol requirements and to allow for 
possibility of local sourcing of bosutinib drug 
supplies.
Section 5.6.3 Other Concomitant Treatment 
Considerations updated with current 
information on bosutinib.
Section 6 (and Section 7.1): Study Procedures 
Updated:
Sections 6.2 and 7.1 Study procedures and 
efficacy assessment sections updated for 
consistency and allowance for local practice of 
molecular response in Chronic Myeloid 
Leukemia (CML) disease assessment using 
reverse transcriptase polymerase chain reaction 
(RT-PCR) to assess BCR-ABL fusion 
transcript levels).  This update to protocol
reflects current treatment guidelines.  These 
assessments will be performed at each
investigative site’s investigative site’s local 
laboratory.
Section 7 Assessments Updated
Section 7.1, Updated study conduct plans 
requiring standardization of mutational 
analysis of the BCR-ABL kinase domain to
explore mechanisms of underlying resistance to 
treatment.  This analysis is now to be 
performed by a central laboratory as arranged 


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by Pfizer. 
Section 7 Pharmacokinetics requirements for 
each patient added to protocol amendment.
Section 8 Adverse Event and Exposure 
definitions updated per new protocol SOPs.
Section 9 Update made to Data Analysis and 
Statistical Methods sections to define diarrhea 
and PK analyses. 
Section 9.8 Data Monitoring Committee 
section updated per current protocol SOPs.
Section 12 Patients informed consent section 
updated to reflect current protocol SOPs.
Section 15 Communication of study results 
updated to reflect current protocol SOPs.
Original protocol
25 February 2013
Not applicable 


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PROTOCOL SUMMARY
Background and Rationale:
Bosutinib (Bosulif) is an orally bioavailable, potent, selective, dual Src-Abl tyrosine kinase
inhibitor (TKI) that has been developed as a tablet formulation for the treatment of adult
patients with Philadelphia positive (Ph+) chronic phase chronic myelogenous leukemia
(CML) previously treated with other tyrosine kinase therapy.
CML is the fourth most commonly occurring adult leukemia and accounts for nearly 
5,000 new cases annually in the United States.1 CML classically follows a tri-phasic course 
with most patients being diagnosed in an initial, chronic phase (CP) which eventually
progresses into a more advanced accelerated phase (AP) and culminates in a blast phase 
(BP), a highly treatment-refractory form of acute leukemia that shows either a myeloid or a 
lymphoid phenotype.
The transformation of CML from a fatal disease to a chronic illness that took place over the 
last decade has been due to the development of TKIs, small-molecule inhibitors of the kinase
activity of BCR-ABL1.2
Bosutinib is being developed for the treatment of Philadelphia chromosome positive (Ph+)
chronic myelogenous leukemia (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 subjects in clinical studies, including
subjects with Ph+ leukemias; subjects with solid tumors, including advanced or metastatic
breast cancer; subjects with autosomal dominant polycystic kidney disease; and healthy
subjects.  As presented in the May 2016 Bosutinib Investigator Brochure, 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 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 subjects, 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).
On 04 September 2012 bosutinib was approved by the US Food and Drug Administration 
(FDA) for the treatment of adult patients with chronic, accelerated, or blast-phase Ph+ CML 
with resistance or intolerance to prior therapy. More recently, on 17 January 2013, the 
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 tyrosine kinase inhibitor(s) 
and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment 
options.


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Those approvals have been granted mainly based on results obtained from the 
Phase 1/2 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 (B1871008)
comparing bosutinib with imatinib in newly diagnosed chronic phase Ph+ CML patients.
This study is a treatment-extension protocol aimed to allow long-term bosutinib treatment in 
patients with chronic or advanced phases Ph+ CML who received bosutinib in a previous 
Pfizer sponsored CML study (ie, Studies B1871006 and B1871008) and who are thought to 
have the potential, as judged by the investigator, to derive clinical benefit from continued 
treatment with bosutinib.  It will also enable the collection of subsequent TKI therapy and
long-term survival data for these patients, including those who have already discontinued 
treatment and are in the long-term follow-up phase or who have completed the parent study.  
Finally, this study will fulfill the European Medicines Agency (EMA) post approval 
requirement for the collection and analysis of safety data about diarrhea incidence after 
switch from clinical study to commercial bosutinib formulation.  Every effort should be made 
to enroll qualified patients into this extension study.  The patients enrolled in China, due to a 
lack of local resources, are excluded from the requirements for pharmacokinetic (PK) and 
mutational analyses of the BCR-ABL kinase domain testing.
Objectives:

To allow long-term bosutinib treatment in patients with chronic or advanced phases
of Ph+ CML who received bosutinib in a previous Pfizer-sponsored CML study (ie,
Studies B1871006 and B1871008) and who have the potential, as judged by the
investigator, to derive clinical benefit from continued treatment with bosutinib;

To collect long-term safety and efficacy data for bosutinib;

To assess the duration of clinical benefit for Ph+ CML patients treated with bosutinib;

To fulfill the EMA post-approval requirement for the collection and analysis of safety
data about diarrhea incidence after switch from clinical study to commercial bosutinib 
formulation.
Endpoints:
The objective of the study is to provide long-term access to bosutinib treatment and assess
long-term safety, tolerability and duration of clinical benefit, without any formal hypothesis
testing; therefore, there is no formal primary endpoint.  In addition, data to be collected are 
planned to be different in the first line CP patients relative to the later line and advanced
patients.  For all patients regardless of the line of treatment:
For all patients:

Long-term safety of bosutinib, including type, incidence, severity, timing, seriousness
and relatedness of adverse events (AEs) and laboratory abnormalities as well as 
reason of treatment discontinuation.  A special focus will be made on diarrhea in order 
to satisfy the EMA post-commitment request;


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
BCR -ABL mutations present at the time patients discontinue Bosutinib.  (Samples 
collected for all patients except those enrolled at sites in China)

Overall survival (OS);

Fulfill the EMA post-approval requirement to compare the pharmacokinetic analysis 
of Ctrough of bosutinib in this study to Ctrough of previous studies.  (Samples collected 
for all patients except those enrolled at sites in China)
For 2nd or later line patients coming from study B1871006 who are still on treatment with
bosutinib, the following efficacy endpoints will be assessed (Appendix 1):

Duration of hematologic and cytogenetic responses;

Progression-free survival;

Time to transformation to accelerated or blast phase.
Study Design:
This is an open-label bosutinib treatment extension protocol. This protocol will be offered to 
those bosutinib patients who were previously enrolled in one of the two parent CML 
bosutinib studies (B1871006 or B1871008).
Patients to be enrolled will include those who, at the time of this protocol amendment, 
approval, are still receiving bosutinib in either one of the parent studies and are benefiting 
from bosutinib treatment as judged by the investigator, as well as those patients who have 
already discontinued bosutinib as part of the parent studies and are in follow-up for survival. 
The former group will continue to receive bosutinib as part of the extension study; the latter 
group will only enter into the long-term survival follow-up part of the extension study.
In order to have the most accurate and unbiased statistical analysis of long-term survival, the 
maximum number of patients who have received bosutinib should be enrolled in the 
extension study including those who have completed the 2 years of follow-up as planned in 
Study B1871006 and then discontinued the study. For this purpose every effort should be 
made to re-contact the patients who have completed the parent Study B1871006 and offer 
them the opportunity to participate in the extension study.
Each patient will remain in the extension study, either on bosutinib treatment or in long-term 
survival follow-up phase, until the last patient has reached 10 years of follow-up, as 
calculated from the date of his/her first dose of bosutinib administered in the parent study.  
When this milestone is reached, the present study will be closed.  At that time, patients still 
benefiting from bosutinib will switch to the most appropriate therapy available at that time.


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PFIZER CONFIDENTIAL
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Study Treatment:
In this extension study, patients who are still on treatment will receive open-label bosutinib.  
The commercial formulation of bosutinib will be used in this study.  Dosing will be 
continuous and at the dose currently administered in the respective parent study. Each 
patient will receive daily bosutinib until such time as the last patient reaches 10 years of 
follow-up, unless disease progression, unacceptable toxicity, death, withdrawal of consent or 
Sponsor study discontinuation occurs.
Statistical Method:
All bosutinib patients from the parent Studies B1871006 and B1871008 that are still on
treatment, in survival follow-up or who have completed the parent study will be offered
enrollment in this extension study.
Data from the two parent studies will be combined with data from this study for the analysis
of efficacy. All bosutinib patients randomized in parent Study B1871008 or dosed in parent 
Study B1871006 will be included in the efficacy analyses.  Analyses will be presented by
disease stage (ie, CP, AP, BP) and by line of therapy.
Descriptive summaries and confidence intervals (if applicable) will be provided; no 
inferential analyses are planned for this study.
The time-to-event endpoints of overall survival, time to transformation, progression-free
survival, and duration of response will be summarized via the Kaplan-Meier method or
cumulative incidence, whichever is more appropriate, depending on the competing risks.
All patients dosed in the two parent studies will be included in the safety analyses.  Data 
from the two parent studies will be combined with data from this study for the analysis of 
safety.


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Table 1.
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.
Refer to STUDY PROCEDURES and ASSESSMENTS for detailed information on each 
procedure and assessment required for compliance with the protocol.
The investigator may schedule unplanned visits in addition to those listed on the schedule of
activities, in order to conduct evaluations or assessments required to protect the well-being of 
the patient.
A. Schedule of Activities for CML 1st-line patients coming from Study B1871008
Study Visit
Initiala
On Treatment
End of
Treatment
Long-Term
Follow-up
Schedule
28 days
from last
dose on
parent study
Site visit
Phone callc
28 days
after last
dose of
bosutinib
Every
3 monthsa
At Month 3
Every
12 monthsb
Every
3 monthsc
Visit Windowa
4 days
4 days
14 days
14 days
14 days
14 days
ICD signature
X
Eligibility criteria review
X
Bosutinib Administration
Continuous Daily Dosing
Physical Examination
Xd
X
Vital Signs
Xd
X
ECOG
Xd
X
Chest X-Ray
Xd
As clinically indicated
X
ECHO or MUGA
Xd
As clinically indicated
X
ECG
Xd
As clinically indicated
X
Hematologye
Xd
X
X
Biochemistryf
Xd
X
X
Liver function testsg
Xd
X
X
Coagulation Panelh
Xd
X
Serum pregnancy test
Xd
As clinically indicated
X
Dipstick Urinalysisi
Xd
X
AEs and concomitant
medicationsj
X
X
X
X
X
Collection of diarrhea
information
X
Xk
Survival follow-up
Xl
PK sample collectionm
Refer to footnote m
Contraception checkn
Xd
X
X
X
X
IP dispensation, dosing 
checko
X
X
X
X
(Data collection of any) 
Bone Marrow Aspirate or 
Peripheral Blood for 
Cytogenetics (Karyotyping or 
FISH) or Molecular 
Analysis per local practice 
standards)p
X
X
BCR-ABL Mutation
analysisq
X


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a.
1 month is defined as a 4-week or 28-day period. Study visit can be performed with a 2 week (14 day) window.
b.
For patients who have already discontinued bosutinib in the parent study and directly enter in the long-term follow-up 
phase of this extension study, the procedures will include ICD signature; data collection of any subsequent TKI therapy 
or anti-cancer treatment and response following discontinuation of bosutinib; and survival data.
c.
Phone call every 3 months will be performed between study visits to collect safety information, including dosing 
administration information.
d.
All end of treatment procedures performed as part of the parent study may serve as the initial/baseline assessment for 
this study as long as they are performed within 28 days prior to starting treatment on this study.  If the necessary 
assessments were not performed within the 28 days, these assessments should be performed as part of this study at 
baseline.
e.
Hematology panel including: complete blood counts (CBC) with 5-part differential, platelet count, absolute neutrophil 
count (ANC), red blood cell count (RBC), and hemoglobin (Hgb). Hematology to be repeated within 4 weeks if loss of 
CHR is seen (as applicable).
f.
Biochemistry panel 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, and magnesium.  Creatine kinase also to be performed.  Abnormally high creatine kinase values should 
be confirmed and fractionated (where possible). Supplementation is advised for potassium levels or magnesium levels 
below the lower limit of normal, with consideration of the patient’s underlying renal function.
g.
Liver Function tests including: total bilirubin, AST and ALT.
h.
Coagulation panel including: prothrombin time expressed as either prothrombin time (PT) or international normalized 
ratio (INR); and partial thromboplastin time (PTT or APTT).
i.
Microscopic exam should be done if abnormalities detected.
j.
This will include reporting of adverse events, any medication and non-pharmacological treatments.
k.
Diarrhea information will be recorded by the patient in the patient diarrhea card provided at the baseline visit. 
Completed cards will be collected after the first 3 months of treatment in this extension protocol.
l.
Follow-up will be conducted every 3 months from last dose of bosutinib.  Long-term follow-up information will be 
collected via visit or telephone contact until the last patient reaches 10 years 524 weeks of follow-up, with one month 
of treatment=28 days for study purposes) from first dose of bosutinib (including the time on parent study).  Serious 
adverse events occurring to a patient after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious events that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.
m.
Pharmacokinetic Data: One pre-dose PK sample per patient (except those at Chinese sites) will be drawn, to be 
collected at first possible occasion after at least 2 weeks of uninterrupted dosing at steady state dose level. 
n.
Contraceptive Check: patients of child-bearing potential will be required to verbally affirm the use of 2 highly effective 
methods of contraception until at least 28 days after the last dose of bosutinib.  This conversation will be documented 
in the patient’s source document.
o.
Dispensing or prescribing of bosutinib at least every 6 months, or more frequently as indicated.
p.
Data collection of either cytogenetic or residual molecular response testing.  (Molecular response monitoring using 
reverse transcriptase polymerase chain reaction (RT-PCR)  measurement of BCR-ABL fusion transcript levels in on 
peripheral blood may be performed in lieu of monitoring via cytogenetics, once molecular response is achieved, and 
according to standard of care and current treatment guidelines at investigative site).
q.
Mutation analysis of the BCR-ABLl transcript will be performed using a peripheral blood sample collected at the 
end-of-treatment visit in order to identify mutations acquired upon treatment with bosutinib. Mutations will be 
identified by direct sequencing of the BCR-ABL transcript performed at a Central Laboratory as arranged by the 
Sponsor.  Peripheral blood from all eligible patients (except from patients enrolled at sites in China) will be collected 
and shipped frozen to a central vendor for analysis.  Specific instructions for handling and shipment of these samples 
can be found in Study Reference Manual.


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B. Schedule of Activities for CML 2nd line or patients coming from Study B1871006
Study Visit
Initiala
On Treatment
End of
Treatment
Long-Term
Follow-Up
LTFU
Schedule
28 days from last
dose on parent study
Site visit
Phone call
28 days after
last dose of
bosutinib
Every
3 monthsb
At Month 3
Every
6 monthsb
Every
3 monthsc
ICD signature
X
Eligibility criteria review
X
Bosutinib Administration
Continuous Daily Dosing
Physical Examination
Xd
X
Vital Signs
Xd
X
ECOG
Xd
X
Extramedullary 
Assessment
Xd
X
X
Chest X-Ray
Xd
As clinically indicated
X
ECHO or MUGA
Xd
As clinically indicated
X
ECG
Xd
As clinically indicated
X
Hematologye
Xd
X
X
Biochemistryf
Xd
X
X
Liver function testsg
Xd
X
X
Coagulation Panelh
Xd
X
Serum pregnancy test
Xd
As clinically indicated
X
Dipstick Urinalysisi
Xd
X
Bone Marrow Aspirate or 
Peripheral Blood for 
Cytogenetics 
(Karyotyping or FISH) or 
Molecular Analysis per 
local practice standards)j
Xk
X
X
AEs and concomitant
medicationsk
X
X
X
X
X
Collection of diarrhea
informationl
X
X
Survival follow-up
Xm
PK sample collectionn
Refer to 
footnote n
Refer to 
footnote n
Refer to 
footnote n
Contraception Checko
X
X
X
X
X
IP dispensation, dosing 
checkp
X
X
X
X
Bcr-Abl Mutation
analysisq
X
a.
For patients who have already discontinued bosutinib in the parent study and directly enter in the long-term follow-up 
phase of this extension study, the procedures will include ICD signature; collection of data on any subsequent TKI 
therapy or other anti-cancer treatment and response to other treatment (if applicable) following discontinuation of 
bosutinib, and survival data.
b.
1 month is defined as a 4-week or 28-day period.  Study visit can be performed with a 2 week (14-day) window.
c.
Phone call every 3 months will be performed between study visits to collect safety information, including dosing 
administration information.
d.
All end of treatment procedures performed as part of the parent study may serve as the initial/baseline assessments for 
this study as long as they are performed within 28 days prior to starting treatment on this study. If the necessary 


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assessments were not performed within the 28 days, these assessments should be performed as part of this study at 
baseline.
e.
Hematology panel including: complete blood counts (CBC) with 5-part differential, platelet count, absolute neutrophil 
count (ANC), red blood cell count (RBC), and hemoglobin (Hgb). Hematology to be repeated within 4 weeks if loss of 
CHR is seen (as applicable).
f.
Biochemistry panel 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, and magnesium.  Creatine kinase also to be performed.  Abnormally high creatine kinase values should 
be confirmed and fractionated (where possible). Supplementation is advised for potassium levels or magnesium levels 
below the lower limit of normal, with consideration of the patient’s underlying renal function.
g.
Liver Function tests including: total bilirubin, AST and ALT.
h.
Coagulation panel including: prothrombin time expressed as either prothrombin time (PT) or international normalized 
ratio (INR); and partial thromboplastin time (PTT or APTT).
i.
Microscopic exam should be done if abnormalities detected.
j.
Bone Marrow Aspirate or Peripheral blood for Cytogenetics using Karyotyping or FISH (Florescence In Situ 
Hybridization) will be conducted locally per SOC and site practice.  Molecular response monitoring using reverse 
transcriptase polymerase chain reaction (RT-PCR) measuring BCR-ABL fusion transcript levels may be performed on 
peripheral blood.  in lieu of monitoring via cytogenetics, once molecular response is achieved and according to 
standard of care and current treatment guidelines at investigative site, and if performed data will be collected in the
eCRF.
k.
Diarrhea information will be recorded by the patient in the patient diarrhea card provided at the baseline visit.
Completed cards will be collected after the first 3 months of treatment in this extension protocol.
l.
This will include reporting of adverse events, and medications and non-pharmacological treatments. 
m.
Follow-up will be conducted every 3 months from last dose of bosutinib.  Long-term follow-up information will be 
collected via visit or telephone contact until the last patient reaches 10 years (524 weeks of follow-up, with 1 month of 
treatment=28 days for study purposes) from first dose of bosutinib (including the time on parent study).  Serious 
adverse events occurring to a patient after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious events that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.
n.
Pharmacokinetic Data One pre-dose PK sample per eligible patient (except for those from sites in China) will be 
drawn, to be collected at first occasion after at least 2 weeks of uninterrupted dosing with bosutinib at steady state dose 
level. 
o.
Contraceptive Check: patients of child-bearing potential will be required to verbally affirm their use of 2 highly 
effective methods of contraception until at least 28 days after their last dose of bosutinib.  This conversation which will 
be documented in the patient’s source document.
p.
Dispensing or prescribing of bosutinib at least every 6 months, or more frequently as indicated.
q.
Mutation analysis of the BCR-ABLl transcript will be performed using a peripheral blood sample collected at the 
end-of-treatment visit for all eligible patients (except from patients enrolled at sites in China) in order to identify 
mutations acquired upon treatment with bosutinib. Mutations will be identified by direct sequencing of the BCR-ABL 
transcript performed at a Central Laboratory as arranged by the Sponsor.  Peripheral blood for all eligible patients will 
be collected and shipped frozen to a central vendor for analysis.  Specific instructions for handling and shipment of 
these samples can be found in Study Reference Manual.


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TABLE OF CONTENTS
PROTOCOL SUMMARY.........................................................................................................6
LIST OF TABLES...................................................................................................................17
APPENDICES .........................................................................................................................17
1. INTRODUCTION ...............................................................................................................18
1.1. Indication.................................................................................................................18
1.2. Background and Rationale ......................................................................................18
1.2.1. Chronic Myeloid Leukemia........................................................................18
1.2.2. Bosutinib (Bosulif) as Therapeutic Option for CML................................19
1.2.3. Study Rationale...........................................................................................23
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................23
2.1. Objectives................................................................................................................23
2.2. Endpoints.................................................................................................................24
3. STUDY DESIGN.................................................................................................................25
4. PATIENT SELECTION......................................................................................................25
4.1. Inclusion Criteria.....................................................................................................25
4.2. Exclusion Criteria....................................................................................................26
4.3. Lifestyle Guidelines ................................................................................................27
4.4. Sponsor’s Qualified Medical Personnel..................................................................28
5. STUDY TREATMENTS.....................................................................................................28
5.1. Allocation to Treatment ..........................................................................................28
5.2. Bosutinib Dose Modifications.................................................................................29
5.2.1. Bosutinib Dose Escalation..........................................................................29
5.2.2. Bosutinib Dose Reduction and Dosing Interruptions .................................30
5.3. Bosutinib Treatment Discontinuation......................................................................31
5.4. Investigational Product Supplies.............................................................................32
5.4.1. Preparation and Dispensing........................................................................32
5.4.2. Administration............................................................................................32
5.4.3. Compliance.................................................................................................33
5.5. Investigational Product Storage and Accountability...............................................33
5.6. Concomitant Medication(s).....................................................................................34
5.6.1. Prohibited....................................................................................................34


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5.6.2. Permitted.....................................................................................................34
5.6.3. Other Concomitant Treatment Considerations: Interaction with other 
Medicinal Products and Other Forms of Interaction........................................35
6. STUDY PROCEDURES .....................................................................................................36
6.1. Initial Visit...............................................................................................................36
6.2. Study Period ............................................................................................................38
6.3. Treatment Completion Visit....................................................................................39
6.4. Long-Term Follow-up Visit....................................................................................40
6.5. Patient Withdrawal..................................................................................................40
7. ASSESSMENTS..................................................................................................................41
7.1. Efficacy Assessments..............................................................................................41
7.1.1. Efficacy Assessment Methods....................................................................41
7.2. Safety Assessments .................................................................................................42
7.2.1. Safety Assessment Methods .......................................................................42
7.2.2. Special Recording of Diarrhea Events........................................................42
7.2.3. Safety Laboratory Determinations..............................................................43
7.2.4. Contraceptive Check...................................................................................43
7.3. Pharmacokinetics ....................................................................................................43
7.3.1. Blood Collections for Plasma PK and BCR-ABL Mutation Analysis .......43
7.3.2. Pregnancy Testing ......................................................................................44
8. ADVERSE EVENT REPORTING......................................................................................44
8.1. Requirements...........................................................................................................44
8.1.1. Additional Details On Recording Adverse Events on the CRF..................45
8.1.2. Eliciting Adverse Event Information..........................................................45
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................46
8.1.4. Time Period for Collecting AE/SAE Information......................................46
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................46
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................46
8.1.5. Causality Assessment .................................................................................47
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................47
8.2. Definitions...............................................................................................................47
8.2.1. Adverse Events...........................................................................................47


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8.2.2. Abnormal Test Findings .............................................................................48
8.2.3. Serious Adverse Events ..............................................................................49
8.2.4. Hospitalization............................................................................................49
8.3. Severity Assessment................................................................................................50
8.4. Special Situations ....................................................................................................51
8.4.1. Protocol-Specified Serious Adverse Events...............................................51
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................51
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................53
8.4.3.1. Exposure During Pregnancy......................................................53
8.4.3.2. Exposure During Breastfeeding ................................................54
8.4.3.3. Occupational Exposure .............................................................54
8.4.4. Medication Errors and Lack of Efficacy ....................................................55
8.4.4.1. Medication Errors......................................................................55
8.4.4.2. Lack of Efficacy........................................................................55
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................55
9.1. Sample Size Determination.....................................................................................56
9.2. Analysis of Efficacy................................................................................................56
9.3. Overall Survival ......................................................................................................56
9.4. Time to Transformation to AP/BP ..........................................................................56
9.5. Progression-Free Survival.......................................................................................56
9.6. Duration of Response..............................................................................................57
9.7. Safety Analysis........................................................................................................57
9.8. Data Monitoring Committee ...................................................................................57
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................57
11. DATA HANDLING AND RECORD KEEPING .............................................................58
11.1. Case Report Forms/Electronic Data Record .........................................................58
11.2. Record Retention...................................................................................................58
12. ETHICS..............................................................................................................................59
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............59
12.2. Ethical Conduct of the Study ................................................................................59
12.3. Patient Information and Consent...........................................................................59


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................60
13. DEFINITION OF END OF TRIAL...................................................................................60
14. SPONSOR DISCONTINUATION CRITERIA ................................................................60
15. PUBLICATION OF STUDY RESULTS ..........................................................................61
15.1. Publications by Investigators ................................................................................62
16. REFERENCES ..................................................................................................................63
LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES ............................................................................10
Table 2.
Available Dose Levels..........................................................................................29
Table 3.
Non Hematologic Treatment Related Toxicity.....................................................30
Table 4.
Hematologic Treatment Related Toxicity ............................................................30
APPENDICES
Appendix 1. Tables Defining Responses to Treatment ...........................................................67
Appendix 2. Patient Diarrhea Card..........................................................................................69
Appendix 3. Dose Diary – ......................................................................................................74
Appendix 4. Eastern Cooperative Oncology Group (ECOG) Performance Status .................77
Appendix 5. Laboratory Tests to be performed .......................................................................78
Appendix 6. Selected Strong and Moderate CYP3A4 Isoenzyme Inhibitors and 
Inducers.................................................................................................................80


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1. INTRODUCTION
1.1. Indication
Bosutinib is an orally bioavailable, potent, selective, dual Src-Abl TKI that has been
developed as a tablet formulation for the treatment of adult patients with Philadelphia 
positive (Ph+) chronic phase CML) previously treated with other tyrosine kinase therapy.
1.2. Background and Rationale
1.2.1. Chronic Myeloid Leukemia
Chronic myelogenous leukemia (CML) is the fourth most commonly occurring adult
leukemia and accounts for nearly 5,000 new cases annually in the United States.1 CML is a
clonal myeloid neoplasm that originates from the translocation t(9;22) (q34;q11), the
consequence of which is the generation of the Philadelphia (Ph) chromosome.16 The
molecular substrate of the t(9;22) translocation is the transcription of the hybrid
BCR-ABL1 oncogene, which encodes the constitutively activated BCR-ABL1 protein that 
activates several downstream signaling pathways that mediate myeloproliferation, resistance 
to apoptosis and genetic instability.16 CML classically follows a tri-phasic course with most
patients being diagnosed in an initial chronic phase (CP) which eventually progress into a
more advanced accelerated phase (AP) and culminates into a blast phase (BP), a highly 
treatment-refractory form of acute leukemia that adopts either a myeloid or a lymphoid 
phenotype.
The transformation of CML from a fatal disease to a chronic illness that took place over the 
last decade is due to the development of tyrosine kinase inhibitors (TKIs), small-molecule
inhibitors of the kinase activity of BCR-ABL1.2
Bosutinib is being developed for the treatment of Philadelphia chromosome positive (Ph+) 
chronic myelogenous leukemia (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 subjects in clinical studies, including 
subjects with Ph+ leukemias; subjects with solid tumors, including advanced or metastatic 
breast cancer; subjects with autosomal dominant polycystic kidney disease; and healthy 
subjects.  As presented in the May 2016 Bosutinib Investigator Brochure, 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 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 subjects, most GI AEs resolved with therapy, treatment interruption, and/or dose
reduction and less frequently discontinuation of bosutinib in the case of dose-limiting
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On 04 September2012 bosutinib was approved by the US Food and Drug Administration 
(FDA) for the treatment of adult patients with chronic, accelerated, or blast-phase Ph+ CML 
with resistance or intolerance to prior therapy. More recently, on 17 January 2013, the 
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 tyrosine kinase inhibitor(s) 
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 (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 (B1871008)
comparing bosutinib with imatinib in newly diagnosed chronic phase Ph+ CML patients.
1.2.2. Bosutinib (Bosulif) as Therapeutic Option for CML
As of 03 September 2015, approximately 2478 patients, including 2141 patients with cancer, 
have received at least 1 dose of bosutinib in 24 clinical studies.  On 4 September 
2012 Bosulifwas approved by the US Food and Drug Administration (FDA) for the 
treatment of adult patients with CP, AP or BP Ph+ CML with resistance or intolerance to 
prior therapy.  More recently, on 27 March 2013, the EMA 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 tyrosine kinase inhibitor(s), and for 
whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.
Both approvals were granted based on the results obtained from the Phase 1/2 study single 
arm study (3160A4-200-WW, “B1871006 or Study 200”) in adult patients with Ph+ 
leukemias whose disease had failed prior TKI therapy, supported by the safety results 
obtained as part of the Phase 3 study (3160A4-3000-WW) comparing Bosulifwith imatinib 
in newly diagnosed CP Ph+ CML patients.  In addition, the EMA was provided descriptive 
narrative information from the bosutinib compassionate use program in patients with Ph+ 
CML who had received at least one prior TKI treatment and progressed or were intolerant, 
and otherwise not considered suitable for other TKI therapy and analyses from a subset of 
B1871006 (Study 200) patients whose disease had failed prior imatinib and/or nilotinib or 
dasatinib and were contraindicated for treatment with dasatinib or nilotinib, and 4th line 
patients.
Efficacy and safety data from the Phase 1/2 study, B1871006, and the Phase 3 study, 
B1871008 (Study 3000), are presented below according to phase of disease and line of 
therapy, as of 28 March 2011 and 15 February 2012 (B1871006) and as of 26 September 
2011 (B1871008).  Pooled safety data from B1871006, B1871008, and the 
Phase 1/2 Japanese study, B1871007 (Study 2203), are presented below as of 15 November 
2010. The most current efficacy and safety data are contained in the Investigator’s Brochure. 


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Second-Line CP CML
A total of 288 CP CML patients were enrolled and treated in the second-line setting in 
B1871006.  The primary population for the efficacy response analyses was the evaluable 
population for imatinib-resistant patients, which included all treated patients with an 
adequate baseline assessment for the respective endpoint.  The major cytogenetic response 
(MCyR) rate at Week 24 in the primary cohort (imatinib-resistant second-line CP CML) for 
the evaluable population (n=186) was 35.5%, with 24.2% attaining complete cytogenetic 
response (CCyR). Cumulative MCyR (defined as any on-treatment MCyR response during 
that period) was achieved in 55.4% of patients, with 43.0% attaining a CCyR.  Cumulative 
MCyR and CCyR were newly achieved or maintained from baseline in 58% and 46% of 
patients, respectively.  For patients with imatinib-intolerant CP CML, the MCyR rate at 
Week 24 in the evaluable population (n=80) was 30.0%, with a 25% CCyR rate at Week 24.
Cumulative MCyR was achieved in 48.8% of patients, with 42.5% attaining a CCyR. 
Cumulative MCyR and CCyR were newly achieved or maintained from baseline in 61% and 
54% of patients, respectively.  In the evaluable population of second-line CP CML (n=287), 
85.0% achieved cumulative Complete Hematologic Response (CHR), a secondary endpoint 
defined as a confirmed CHR or maintenance of baseline CHR during treatment with 
bosutinib. Of the 141 patients who did not have a CHR at baseline, 77.3% achieved a 
confirmed CHR. The Kaplan-Meier (K-M) estimates of Progression-Free Survival (PFS) for 
the CP CML second-line all-treated population (n=288) were 91.3% and 80.6% at Year 1 and 
Year 2, respectively; the K-M median PFS has not been reached. The K-M estimates of 
overall survival (OS) were 96.8% and 90.6% at Years 1 and 2, respectively; the K-M median 
OS has yet to be reached.
Third-Line CP CML
A total of 115 CP CML patients who received imatinib followed by dasatinib or nilotinib 
(ie, third line) and 3 CP CML patients who received imatinib followed by dasatinib and 
nilotinib (ie, fourth line) were enrolled and treated in B1871006.  These 3 patients are 
included in all efficacy analyses presented for the third-line CP CML population.  The 
primary population for the efficacy responses analyses was the evaluable population, which 
included all patients with an adequate baseline assessment for the respective endpoint.  In the 
third-line CP CML evaluable population (n=108), 26.9% achieved MCyR by Week 24, with 
13.9% attaining CCyR. The cumulative MCyR was 32.4%, with 24.1% attaining CCyR.
Cumulative MCyR and CCyR were newly achieved or maintained from baseline in 39% and 
31% of patients, respectively.
In the dasatinib-resistant cohort (n=35), 25.7% of patients had MCyR by Week 24, with 
8.6% attaining CCyR.  In the dasatinib-intolerant cohort (n=43), 25.6% had MCyR by 
Week 24, with 18.6% attaining CCyR.  In the nilotinib resistant cohort (n=26), 26.9% had 
MCyR by Week 24, with a CCyR rate of 11.5%. 
In the evaluable population of third-line CP CML (n=116), 73.3% of patients achieved a 
confirmed CHR or maintained a baseline CHR during treatment with bosutinib.  Of the 
68 patients who did not have a CHR at baseline, 64.7% achieved a confirmed CHR.  The 


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K-M estimates of PFS for the all-treated population were 76.6% and 73.2% at Years 1 and 2, 
respectively; the K-M median PFS has not been reached.  The K-M estimates of OS for the 
all-treated population were 91.2% and 82.9% at Years 1 and 2, respectively; the K-M median 
OS has not been reached. 
Three (3) patients were enrolled who were resistant or intolerant to all currently approved 
TKIs for CML (imatinib, dasatinib, and nilotinib).  One (1) patient who was intolerant to 
imatinib, dasatinib, and nilotinib due to Grade 3 skin toxicity entered the study with a partial 
cytogenetic response (PCyR) and subsequently achieved CCyR and complete molecular 
response (CMR) within 24 weeks of starting bosutinib.  The patient has remained on 
bosutinib for over 33 months and has maintained a CCyR and CMR as of the last analysis at 
the time of the database snapshot, which is also clinically relevant, given that the patient 
previously only tolerated dasatinib for a total of 39 days and nilotinib for a total of 24 days.
Advanced Leukemias
A total of 164 patients with advanced Ph+ leukemia were enrolled and treated in B1871006. 
The primary population for the efficacy response analyses was the evaluable population, 
which included all patients with an adequate baseline assessment for the respective endpoint.  
In AP CML patients in the evaluable population (n=69), the confirmed overall hematologic 
response (OHR) rate by Week 48 was 55.1%. In BP CML patients in the evaluable 
population (n=60), the confirmed OHR rate by Week 48 was 28.3%.
Summary safety data across all patient cohorts in B1871006 showed most patients 
(560, 98%) reported at least 1 drug-related treatment-emergent adverse event (TEAE).  
Treatment-related TEAEs reported in 10% of patients were diarrhea in 454 (80%) patients, 
nausea in 238 (42%) patients, vomiting in 195 (34%) patients, thrombocytopenia in 
167 (29%) patients, rash in 157 (28%) patients, abdominal pain in 97 (17%) patients, alanine 
aminotransferase (ALT) increased in 91 (16%) patients, anemia, fatigue, and neutropenia in 
81 (14%) patients each, abdominal pain upper in 76 (13%) patients, and aspartate 
aminotransferase (AST) increased in 71 (12%) patients. 
Treatment-related TEAEs of Grade 3 or higher included thrombocytopenia in 117 (21%) 
patients, neutropenia in 58 (10%) patients, diarrhea in 44 (8%) patients, ALT increased in 
36 (6%) patients, and rash in 32 (6%) patients. 
As of February 15, 2012, 134 (23.5%) patients have permanently discontinued bosutinib 
treatment because of AEs.  The most frequent AEs that led to discontinuation were 
thrombocytopenia (26 patients, 4.6%), ALT increased (11 patients, 1.9%), neutropenia 
(8 patients, 1.4%), diarrhea and vomiting (7 patients, 1.2% each).
First-Line CP CML 
In the Phase 3 study 3160A4-3000-WW (B1871008), bosutinib was compared to imatinib in 
the frontline treatment of CP Ph+ CML.  The primary objective of the study was to compare 
the complete cytogenetic response (CCyR) at one year in CP patients receiving bosutinib 
alone versus patients receiving imatinib alone.  The study enrolled 502 pts (250 on bosutinib 


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and 252 on imatinib). Results after a minimum follow-up of 24 months showed that 66% of 
patients receiving bosutinib and 45% of those treated with imatinib had dosing 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 adverse events or disease progression in the bosutinib and imatinib 
arms were 24% versus 4% and 7% versus 13%, respectively. No statistically significant 
difference was observed after 12 months of treatment between the bosutinib and imatinib 
arms regarding rates of CCyR (70% vs. 68%).  Similarly, the cumulative CCyR rates by 
24 months were virtually identical at 79% and 81%, respectively.  However, on an 
intention-to-treat analysis, the MMR (major molecular response) rates at 12 months 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.
Compared with imatinib, bosutinib was associated with higher incidences of 
Grade 3-4 gastrointestinal toxicities, including diarrhea (12% vs. 1%), vomiting (3% vs. 0%) 
and abdominal pain (1% vs. <1%), although these adverse events were usually transient and 
manageable.  Notably, diarrhea occurred mostly in the first 1-2 months of therapy and 
improved or subsided spontaneously over time.  The rates of Grade 3-4 non-hematologic 
toxicities were 1% in both arms of the study. Grade 3-4 elevations of alanine 
aminotransferase (23% vs. 4%), aspartate aminotransferase (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 arm 
of this study, 91% were rechallenged.  Of these patients, 80% did not experience subsequent 
elevations in transaminase levels that merited treatment discontinuation.  Overall, 14% of 
patients were discontinued from bosutinib treatment due to unacceptable transaminase 
elevations.  Grade 3-4 neutropenia, thrombocytopenia and anemia in the bosutinib and 
imatinib arms 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.
Ph+ Leukemia 
Pooled safety data are reflected below (with a cutoff date of 15 November 2010).  A total of 
870 Ph+ leukemia patients across multiple, global Pfizer-sponsored clinical trials received at 
least 1 dose of single-agent bosutinib.  These patients were either newly diagnosed Ph+ 
chronic phase CML, or were patients with resistant or intolerant Ph+ chronic, accelerated, or 
blast phase CML or Ph+ acute lymphoblastic leukemia (ALL).  Of these patients, 248 are 
from the Phase 3 study in previously untreated CML patients, 570 and 52 are from two 
Phase 1/2 studies in previously treated Ph+ leukemias.  The median duration of therapy was 
16.6 months (range: 0.03 to 30.4 months) in the Phase 3 study, 11 months (range: 0.03 to 
55.1 months), and 5.5 months (range: 0.3 to 30.4 months), in the Phase 1/2 studies 
respectively.


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At least 1 adverse reaction of any toxicity grade was reported for 848 (97.5%) patients.  The 
treatment-related adverse reactions reported for 20% of patients were diarrhea (78.5%), 
nausea (42.1%), thrombocytopenia (38.5%), vomiting (37.1%), abdominal pain (33.4%), rash 
(32.4%), anaemia (27.4%), pyrexia (23.4%), and alanine aminotransferase increased 
(22.3%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 531 (61.0%) 
patients.  The Grade 3 or Grade 4 adverse reactions reported for 5% of patients were 
thrombocytopenia (25.4%), anaemia (12.3%), neutropenia (11.5%), alanine aminotransferase 
increased (10.2%), diarrhea (9.1%), rash (6.1%), lipase increased (5.2%) and aspartate 
aminotransferase increased (5.0%).
Complete information for bosutinib may be found in the Single Reference Safety Document 
(SRSD), which for this study is the Bosutinib Investigator’s Brochure. (IB).
1.2.3. Study Rationale
This study is a treatment extension protocol to allow the opportunity of long-term treatment
with bosutinib for patients who received bosutinib in previous Pfizer sponsored CML studies
B1871006 and B1871008 and who are thought to have the potential, as judged by the
investigator, to derive clinical benefit from continued treatment with bosutinib.
In addition this study:

Will allow collection of subsequent TKI therapy and long-term survival data for all 
bosutinib patients who have discontinued bosutinib treatment in parent studies
B1871006 and B1871008 but are known to be alive as of their last long-term 
follow-up visit;

Will provide the opportunity to gather additional long-term safety and selected
efficacy data for bosutinib in all CML patients, including 1st-line patients in chronic
phase, as well as second-, third- and even fourth-line patients in chronic, accelerated
and blast CML phases;

Will satisfy the EMA post-approval commitment to provide safety data about diarrhea
incidence after the patients switch from clinical study to commercial bosutinib 
formulation;

Will fulfill the EMA post-approval requirement for the collection and analysis of the
pharmacokinetics (PK) of bosutinib administered once daily.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives

To allow long-term bosutinib treatment in patients with chronic or advanced phases
Ph+ CML who received bosutinib in a previous Pfizer sponsored CML study
(ie, studies B1871006 and B1871008) and who have the potential, as judged by the
investigator, to derive clinical benefit from continued treatment with bosutinib;


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
To collect long-term safety and efficacy data for bosutinib;

To assess the duration of clinical benefit for Ph+ CML patients treated with bosutinib;

To fulfill the EMA post approval requirement for the collection and analysis of safety
data about diarrhea incidence after switch from clinical study to commercial bosutinib 
formulation;

To fulfill the EMA post-approval requirement for the analysis of the PK of bosutinib
administered once daily.
2.2. Endpoints
The objective of the study is to provide long-term access to bosutinib treatment and assess 
long-term safety, tolerability and duration of clinical benefit, without any formal hypothesis
testing; therefore, there is no formal primary endpoint.
In addition, data to be collected are planned to be different in the first line CP patients
relative to the later line and advanced patients.
For all patients regardless of the line of treatment:

Long-term safety of bosutinib, including type, incidence, severity, timing, seriousness
and relatedness of AEs and laboratory abnormalities as well as reason of treatment 
discontinuation.  A special focus will be made on diarrhea in order to satisfy the EMA
post-commitment request;

BCR -ABL mutations present at the time patients discontinue Bosutinib.  
(For all patients except those enrolled at sites in China)

Overall survival (OS);

Fulfill the EMA post-approval requirement to compare the pharmacokinetic analysis 
of Ctrough of bosutinib in this study to Ctrough of previous studies.
For 2nd or later line patients coming from study who are still on treatment with bosutinib, the 
following efficacy endpoints will be assessed (Appendix 1):

Duration of hematologic and cytogenetic responses;

Progression free survival;

Time to transformation to accelerated or blast phase.
Refer to Section 7.1.1 for more details on endpoint definitions.


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3. STUDY DESIGN
This is an open-label bosutinib treatment extension protocol.  This protocol will be offered to
those bosutinib patients who were previously enrolled in one of the two parent CML
bosutinib studies (B1871006 or B1871008).
Patients to be enrolled will include those who – at the time of this protocol approval - are still 
receiving bosutinib in either one of the parent studies and are benefiting from bosutinib 
treatment as judged by the investigator, as well as those patients who have already
discontinued bosutinib as part of the parent studies and are in long-term follow-up (LTFU) 
for survival. The former group will continue to receive bosutinib as part of the extension 
study; the latter group will only enter into the long-term survival follow-up part of the 
extension study.  Data on any subsequent therapy with TKIs or other anti-cancer therapy and 
response following bosutinib will be collected on LTFU patients, if available study.
Each patient will remain in the extension study, either on bosutinib treatment or in long-term 
survival follow-up phase, until the last patient has reached 10 years of follow-up, as 
calculated from the date of his/her first dose of bosutinib administered in the parent study.  
When this milestone is reached, the present study will be closed.  At that time patients still 
benefiting from bosutinib will switch to the most appropriate therapy available at that time.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legal representative) has been informed of all pertinent aspects of the study.
2. Previous enrollment in the bosutinib arm of one of the two Pfizer parent Studies
B1871006 or B1871008. This includes:
a.
Patients still receiving bosutinib in either StudyB1871006 or Study B1871008;
b. Patients who have discontinued bosutinib but are still in the long-term follow-up
phase of the Study B1871006 or B1871008;
c.
Patients from Study B1871006 who have discontinued bosutinib and have already 
completed the long-term follow-up period.


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3. Patients who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
4. Male and female patients of childbearing potential must agree to use 2 highly effective 
methods of contraception throughout the study and for at least 28 days after the last dose
of assigned treatment. A patient is of childbearing potential if, in the opinion of the 
investigator, he/she is biologically capable of having children and is sexually active.
In order to be considered a female of non-childbearing potential the patient 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
or 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 and documented ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are considered to be 
of childbearing potential. 
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Participation in other studies involving investigational drug(s) (Phases 1-4) while patient
in the active treatment phase of the current study.
2. Patients who are investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by the
Investigator, or patients who are Pfizer employees directly involved in the conduct of the 
trial.
3. Other severe 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.
4. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female 
subjects 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.


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4.3. Lifestyle Guidelines
In this study, fertile male subjects and female subjects who are of childbearing potential will 
receive bosutinib.  Subjects who are, in the opinion of the investigator, sexually active and at 
risk for pregnancy 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 subject, will confirm and document that the subject has 
selected 2 appropriate methods of contraception for the individual subject from the list of 
permitted contraception methods (see below) and will confirm and document that the subject 
has been instructed in their consistent and correct use.  At time points indicated in the 
Schedule Of Activities, the investigator or designee will inform the subject of the need to use 
2 highly effective methods of contraception consistently and correctly and document the 
conversation, and the subject’s affirmation, in the subject’s chart.  In addition, the 
investigator or designee will instruct the subject to call immediately if 1 or both of the 
selected contraception methods is discontinued or if pregnancy is known or suspected in the 
subject or partner. 
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 (ie, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’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 spermicide (ie, foam, gel, film, cream,
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 post-vasectomy 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).
NOTE:  Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the 
study treatments) may obviate the need for contraception ONLY if this is the preferred 
and usual lifestyle of the subject.


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4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the Study Reference Manual.
To facilitate access to appropriately qualify 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 compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event
that the investigational site staff cannot be reached to provide advice on a medical question
or problem originating from another healthcare professional not involved in the in the study.  
The help desk number can also be used by investigational staff if they are seeking advice on 
medical questions or problems, however it should only be used in the event that the 
established communication pathways between the investigational site and the study team are
not available.  It is therefore intended to augment, but not replace the established 
communication pathways between the investigational site and study team for advice on
medical questions or problems that may arise during the study.  The help desk number is not 
intended for use by the patient directly and if a patient calls that number they will be directed 
back to the investigational site.
During LTFU, patients will be assessed for survival status, as well as details of any 
subsequent TKI or other anti-cancer therapy.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
For those patients continuing on bosutinib treatment, bosutinib will be administered 
continuously on a daily basis as in parent Studies B1871006 and B1871008. Patients will 
receive the same bosutinib dose administered at the time of completion of the parent study.
In this extension study, patients who are still on treatment will receive open-label bosutinib.
The commercial formulation of bosutinib will be used in this study.  Dosing will be 
continuous and at the dose currently administered in the respective parent study unless 
disease progressions, unacceptable toxicity, death, withdrawal of consent, or Sponsor study
discontinuation occurs.
Each patient will receive daily bosutinib until such time as the last patient enrolled in one of 
the parent studies reaches 10 years of dosing follow up.
Every effort should be made to continue bosutinib without interruptions while transitioning 
the patient from the parent to the present extension study. However, if needed, allowance for 
dosing interruptions can be made for a maximum of 28 days during the transition for logistic 
reasons.


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If the patient completed the parent study while bosutinib was on hold due to toxicity, the
patient must have recovered from toxicity before resuming treatment with bosutinib in the
extension study.  Please refer to the dosing guidelines for bosutinib reintroduction
(Section 5.2).
5.2. Bosutinib Dose Modifications
The starting bosutinib dose is 500 mg once daily, however the dose can vary from 300 mg to
600 mg as described in the table below:
Table 2.
Available Dose Levels
Dose Level
Daily Bosutinib Dose
+1
600 mga
0 (Optimal bosutinib dose)
500 mg
-1
400 mgb
-2
300 mgb,c
a.
The maximum dose escalation on study is 600 mg/day. Dose escalation to a dose greater than 600 mg is prohibited.
b.
Once the dose has been reduced for a patient, the patient should remain on that dose unless an additional dose reduction 
is required or the dose is escalated as defined in the dose management instructions in case of toxicity (see Table 3 and 
Table 4 and relevant footnotes).
c.
If a patient requires a dose reduction below 300 mg, the investigator should contact the sponsor to determine if the 
patient may continue on treatment at a lower dose.  However, no dose reductions below 200 mg/day will 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/day, the patient will be discontinued from treatment and will only be followed up for survival.
5.2.1. Bosutinib Dose Escalation
As in the parent studies, patients will be allowed to dose escalate to 600 mg as long as no
grade 3/4 or persistent grade 2 adverse drug reactions are observed, and at least one of the
following lack of efficacy criteria is met:

For 1st line patients: loss of complete cytogenetic response.  Cytogenetic assessment 
done as part of standard of care practice will be used to determine the cytogenetic 
response, including loss of response.

For 2nd or 3rd line patients in chronic phase: loss of major cytogenetic response.

For all patients: loss of hematologic response defined as CHR for patients in chronic
phase and OHR for advanced Ph+ CML patients.
In addition, if it is determined via RT-PCR (conducted by local lab) that a patient who had
achieved a previous MMR now has a rising level of Bcr-Abl transcript (1 log increase), the
investigator should contact the sponsor to determine if the patient’s dose should be escalated
to improve response.


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5.2.2. Bosutinib Dose Reduction and Dosing Interruptions
As in the parent studies, the bosutinib dose can be reduced and/or dosing interrupted in case
of treatment-related toxicity according to the guidelines described in the following tables.
Table 3.
Non Hematologic Treatment Related Toxicity
Adverse Event
Action
Grade 1
Remain on current dose level
Grade 2
For persistent, clinically relevant toxicity not responding to optimal management:
Interrupt bosutinib, then reintroduce at the same dose or reduce dose by one level
upon recovery to Grade 1 within 4 weeks of stopping treatment.
Grade 3a
For persistent, clinically relevant toxicity not responding to optimal management:
Interrupt bosutinib, then dose reduce by 1 level upon recovery to Grade 1 within
4 weeks of stopping treatment.  If recovery takes longer than 4 weeks, the
investigator should contact the sponsor to determine if the patient may continue on
bosutinib.
Grade 4a
Interrupt bosutinib. Investigator and sponsor to determine if patient may continue
on bosutinib with appropriate dose reduction.
a. For patients who have required a dose reduction due to toxicity, but then have been free of the specific toxicity
(Grade 1) for at least 1 month and are otherwise tolerating bosutinib well, the investigator may choose to
re-escalate the dose by one dose level each month (ie, increase the daily dose by 100 mg/month) until the patient
is back to the starting or previous dose (whichever is higher). See Table 2 for available dose levels.
Table 4.
Hematologic Treatment Related Toxicity
Adverse Event
Action
Grade 1
Remain on current dose level
Grade 2
Remain on current dose level
Grade 3a
First episode: Interrupt bosutinib until recovery to Grade 2. If patient recovers 
within 2 weeks of treatment hold: re-introduce bosutinib at same dose. If patient
recovers within 4 weeks of treatment hold: reduce bosutinib by one dose level.
Additional episodes: Interrupt bosutinib until recovery to Grade 2 and then reduce 
bosutinib by one dose level.
In both cases, if recovery takes longer than 4 weeks, the investigator should contact 
the sponsor to determine if the patient may continue bosutinib.
Grade 4a
Withhold bosutinib.  Investigator and sponsor to determine if patient may continue
bosutinib 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 bosutinib, the investigator may choose to re-escalate the dose by
One dose level each month (ie, increase the daily dose by 100 mg/month) until the patient is back to the starting
or previous dose (whichever is higher) per dosing tables – see Table 2).
See Table 2 for available dose levels.


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5.3. Bosutinib Treatment Discontinuation
Patients meeting any of the following criteria should discontinue bosutinib:
1. Disease progression, including:

Evolution from chronic phase (or from return to chronic phase for advanced patients)
to accelerated phase or blast crisis (on two consecutive assessments at least a week 
apart).

Evolution from accelerated phase to blast crisis (on two consecutive assessments at
least a week apart).

One of the following conditions occurring after dose escalation (as specified in 
Section 5.2.1, Dose Escalation) or presence of adverse events prohibiting dose 
escalation:

For 1st line patients, loss of complete or major cytogenetic response (need at least 
30% increase confirmed by a follow-up cytogenetic analysis >1 month later). 
Cytogenetic assessment done as part of standard of care practice will be used to 
determine the cytogenetic response status.

For 2nd or later line patients, loss of major cytogenetic response (need at least 30% 
increase).

For all lines of treatment, loss of complete hematologic response confirmed by
2 assessments at least 2 weeks apart.

For all lines of treatment, increasing WBC defined as doubling of WBC, occurring 
over a period of 1 month, with the second WBC >20 x 109/L and confirmed at 
least 1 week later.
2. Bosutinib treatment interruption for longer than 4 weeks due to treatment-related toxicity,
unless decided (and documented) otherwise by the investigator and Sponsor (see 
Table 3 and Table 4).
3. Bosutinib dose reduction below 300 mg/day.  Except if after documented discussion with
the investigator and Sponsor, it has been determined as appropriate for the patient to
continue on bosutinib dose below 300 mg/day. No dose reductions below 200 mg/day
will be permitted.
4. Withdrawal of consent.
5. Sponsor decision.
6. Pregnancy.


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7. Death.
Survival follow-up information will be obtained for all patients who discontinue bosutinib
treatment. See Treatment Completion and Follow-up section for detailed procedures to be
performed upon treatment completion and for LTFU.
5.4. Investigational Product Supplies
Formulation and Packaging
Bosutinib is commercially available in 100 mg and 500 mg tablets and central supply or 
locally obtained commercial supplies of Bosutinib will be used for this study. 
For specific countries in which approval has been granted and if not a financial hardship to 
the patient, a prescription may be provided to the Ph+ CML patients to source bosutinib for 
the study as directed by local regulations.
Bosutinib will be labeled in accordance with local regulations.
5.4.1. Preparation and Dispensing
The study site will dispense bosutinib or provide a prescription to the patient at least every 
six months, if deemed appropriate by the Investigator, to allow for per specific patient or Site 
requirements.
The investigator must ensure that the patient has an adequate supply of bosutinib to last until 
the next visit. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents.
5.4.2. Administration
Bosutinib will be self-administered by the patient, once daily, orally, with food, preferably in 
the morning. Preliminary data suggests that both tolerance and absorption may be improved 
with food, including adequate dietary fats; no restriction is imposed on patient’s food choice.  
Tablets should not be crushed, split, or dissolved and patients should be instructed to swallow 
the study medication whole without manipulation or chewing of the medication prior to 
swallowing. If a patient vomits any time after taking a dose, they are instructed not to take 
another dose and to resume subsequent doses the next day as prescribed.
Medication errors may result, in this study, from the consumption of the drug by the wrong
patient, at the wrong time, or at the wrong dosage strength. Such medication errors occurring 
to a study participant are to be captured on the adverse event (AE) page of the electronic case 
report form (eCRFs) and on the Serious Adverse Event (SAE) form when appropriate. In the 
event of medication dosing error, the sponsor should be notified immediately.


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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

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.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE eCRF page. 
5.4.3. Compliance
Compliance will be reviewed by the sponsor’s site monitor utilizing source documents, 
Dispensing and Inventory Records (DIRs) or Investigational Product Accountability Log 
(IPAL), and bosutinib electronic case report forms (eCRFs).  Site personnel will monitor 
each patient for dosing compliance and document it appropriately in the eCRF. Dose
diarieswill be provided to patients as a tool for the recording of bosutinib dose information in 
cases of missed or changed dose.  (see Appendix 3).
5.5. Investigational Product Storage and Accountability
Bosutinib should be stored at controlled room temperature (between 15-25C/59-77F or 
FOR JAPAN ONLY between 1-30C/34-86F as per the Japanese pharmacopoeia) in a 
locked storage area. Freezing is not permitted.
Storage conditions stated in the Single Reference Safety Document (SRSD) will be 
superseded by the label storage.
Investigators and site staff are reminded to check temperatures daily (ie, manually or by
using alarm systems to alert of any excursions) and ensure that temperature monitoring
device(s) is (are) working correctly as required for proper storage of investigational products.  
Any temperature excursions should be reported to the sponsor.
The investigational product(s) must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor.  
Once a deviation is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions. 
Regulatory agencies require accounting for the disposition of all investigational drugs 
received by each clinical site.  The investigator is responsible for maintaining information
related to drug disposition which at minimum consists of the date received, date dispensed,
quantity dispensed and the patient to whom the drug was dispensed.


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The investigator is also responsible for the accounting of all unused investigational product 
(IP) and used investigational product (IP) containers.
IP storage and accountability will be reviewed by the monitor during routine monitoring
visits.
Patients will be required to return all unused investigational product (IP) at the time new 
investigational product (IP) bottles are dispensed and at the end of treatment.  Returned 
medication must not be re-dispensed. All bottles must be returned to the investigator by the 
patient, and the investigator will return the bottles to Pfizer.  Local IP destruction or 
destruction via vendor is allowed, per Site or local policy or laws.
5.6. Concomitant Medication(s)
All information about concomitant treatments (medications or procedures) must be recorded
on the patient’s eCRF (including the name of the medication or procedure and the duration of 
treatment).
Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral) removal, does not need to be recorded.  Anesthetics
used for any surgical procedures performed while the patient is enrolled in the study can be
recorded as “unspecified anesthesia” on the concomitant treatment records; it is not necessary 
to list the specific anesthetics.  Non-pharmacological treatment and/or procedures 
(ie, physical therapy, etc.) will be collected only if related to an adverse event.
Palliative and supportive care for cancer-related symptoms will be offered to all patients in
this study.
5.6.1. Prohibited
All concomitant medications restrictions apply only while the patient is on the active
treatment phase of the study (ie, receiving bosutinib), and include:

Any anti-leukemia treatment other than the regimen defined in this protocol,
including donor lymphocyte infusions;

Any other investigational agents while the patient is receiving bosutinib.
5.6.2. Permitted

Any medication (other than those prohibited above) for a concurrent medical 
condition is permitted;

Treatment of diarrhea and other gastrointestinal symptoms will be optimized ie, that
diarrhea will be monitored and managed using standards of care, including
antidiarrheals, antiemetics, and/or fluid replacement;


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
Palliative and supportive care for disease-related symptoms or toxicity due to study
treatment;

Treatment with growth factors (including G-CSF and/or M-CSF in Japan) (according
to ASCO guidelines).  No prophylactic use of growth factors will be allowed;

Supplementation is advised for potassium levels or magnesium levels below the 
lower limit of normal, with consideration of the patient’s underlying renal function.
5.6.3. Other Concomitant Treatment Considerations: Interaction with other Medicinal 
Products and Other Forms of Interaction
CYP3A inhibitors
The concomitant use of bosutinib with strong or moderate CYP3A inhibitors should be 
avoided, as an increase in bosutinib plasma concentration may occur (reference Appendix 6).
Caution should be exercised if mild CYP3A inhibitors are used concomitantly with 
bosutinib. Selection of an alternate concomitant medicinal product with no or minimal 
CYP3A enzyme inhibition potential, if possible, is recommended.
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, including St. John's 
Wort. Grapefruit should also be avoided.
The concomitant use of bosutinib with strong or moderate CYP3A inducers should be 
avoided; 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 6).

For advanced leukemia patients requiring –azoles and for whom the antifungal
therapies cannot be discontinued, careful monitoring of adverse events, including QTc 
prolongation via ECG testing, is important.

Inhibitors of platelet aggregation, ie, aspirin, dipyridamole, clopidogrel, and
ticlopidine, should be used with caution.

Transfusions for anemia 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.


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Proton-pump inhibitors (PPIs)
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
Please refer to the Schedule Of Activities for a complete list of procedures to be performed 
and associated time points.
Note that all study procedures listed below will apply only to patients participating in the
active treatment phase of this extension study. For patients who have already discontinued
bosutinib in one of the parent studies but are now included in the long-term follow-up phase 
of this extension study, the procedures will include ICD signature and data collection of any 
subsequent therapy with TKIs or other anti-cancer therapy and response following bosutinib 
discontinuation, as well as long-term survival data.
All tests described below will be performed locally and all the results obtained will be
captured in the electronic case report form (eCRF).
6.1. Initial Visit
There is no screening period for this protocol.  All required initial procedures should be
performed between the EOT study visit of the parent study (B1871006 or B1871008) and
Day 1 (baseline) of this extension study (Maximum time window = 28 days).
All end of treatment procedures performed as part of the parent study may serve as the initial
or baseline assessments for this study. If the necessary assessments were not performed
within the 28 days before Day 1, these assessments should be performed as part of the
baseline visit of the extension study.
Every effort should be made to conduct the EOT visit of the parent study and the
Day 1 baseline visit of the extension study on the same day in order to allow uninterrupted
bosutinib dosing.  However, if needed, a 28-day period is allowed between the last dose of
bosutinib on the previous parent study and the first dose of bosutinib on this extension study.
The following procedures should be conducted as part of the baseline visit:

Signature of the ICD;

Review of patient’s eligibility (ie, inclusion/exclusion criteria);

Complete physical examination to include vital signs (temperature, sitting or supine
blood pressure, heart rate and weight).  ECOG performance status should also be
assessed (see Appendix 4).  Extramedullary disease assessment will also be
performed;


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
Electrocardiogram (ECG);

Echocardiogram (ECHO) or multiple gated acquisition scan (MUGA);

Chest X-ray;

Hematology panel with complete blood counts (CBC) including:

White blood cell count (WBC), with 5-part differential (with manual 
confirmation of abnormalities);

Platelet count;

Absolute neutrophil count (ANC);

Red blood cell count (RBC);

Hemoglobin (Hgb).

Chemistry panel 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
and magnesium.  Creatine kinase (CK) should also be performed.  Abnormally
high CK should be confirmed and fractionated creatine kinase performed (if
available).  Uric acid to be obtained until the patient achieves a CHR;

Liver Function Tests (LFTs) including: total bilirubin, AST and ALT;

Coagulation tests including: prothrombin time expressed as either prothrombin time
(PT) or international normalized ratio (INR); and partial thromboplastin time (PTT) 
or activated partial thromboplastin time (aPTT);

Dipstick urinalysis (microscopic if abnormal);

Serum pregnancy test (for women of childbearing potential);

Review of and implementation of the patient diarrhea card;

Review of adverse events and concomitant medications;

Contraception check.
For all patients except 1st line patients enrolled from B1871008: an additional blood 
sample to perform cytogenetic assessment by FISH, except if conventional 
cytogenetics has been performed and adequate results obtained as part of the end of 
treatment visit of the parent study. 


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
According to standard of care and current treatment guidelines, bone marrow or 
blood sample will be collected for CML disease assessment via cytogenetic
assessment by karyotype or by FISH. If appropriate, in lieu of cytogenetic 
assessment molecular response monitoring using reverse transcriptase polymerase
chain reaction (RT-PCR) for molecular assessment (of BCR-ABL fusion 
transcript levels in peripheral blood may be performed.  These assessments will 
be performed at a laboratory local to Investigational Site and data for 
B1871006 and B1871008 patients will be collected in the eCRF if available. 
Note that all abnormalities revealed by baseline testing will be managed as an adverse event
and should follow the guidelines defined in Section 5.2 and 5.3 if needed.
6.2. Study Period
Visit schedules and study procedures will be different based on the line of treatment of the
patients (ie, if enrolled from B1871006 vs. B1871008).  Study visit can be performed with a
4-day (2-week) window (1 month is defined as a 4-week or 28-day period).

1st line chronic phase patients enrolled from study B1871008 will be followed up only 
to collect safety, survival and BCR-ABL mutational status data (the latter does not 
apply to patients enrolled at China Sites).. Study visits will occur every 12 months 
(once a year), and a phone call will be implemented every 3 months between study 
visits at the site in order to collect an update on the patient’s current safety status and 
dosing and to remind the patient about use of the dosing diary and importance of 
contraception compliance. All information collected during the phone calls will be 
immediately recorded in the eCRF.
One additional study visit will be arranged after the first 3 months 4 days of
treatment in order to collect all diarrhea information reported on the patient diarrhea 
card provided at the baseline visit.
Patients who are continuing bosutinib therapy should have their disease status
assessed according to the local standard of care.

For 2nd and later line patients enrolled from study B1871006, study visits will occur 
every 6 months (twice a year) and a phone call will be implemented every 3 months,
between scheduled visits in order to get an update on current patient’s status, 
assessment of any adverse events, and dosing compliance, and a contraceptive check.
Procedures performed as part of the study visits may include:

Extramedullary disease assessment;

According to standard of care and current treatment guidelines, bone marrow or 
blood sample will be collected for CML disease assessment via cytogenetic
assessment by karyotype or by FISH. If appropriate, in lieu of cytogenetic 
assessment molecular response monitoring using reverse transcriptase polymerase


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chain reaction (RT-PCR) for molecular assessment (of BCR-ABL fusion 
transcript levels in peripheral blood may be performed. These assessments will 
be performed at a laboratory local to Investigational Site and data will be 
collected if available.

Hematology panel with complete blood counts (CBC) (see Section 6.1 for
details);

Chemistry panel (see Section 6.1 for details);

Liver Function Tests (LFTs) (see Section 6.1 for details);

Bone Marrow Aspirate for differential ONLY for patients in advanced phase;

Review of adverse events and concomitant medications.
One additional study visit will be arranged after the first 3 months on treatment in
order to collect all diarrhea information reported on the patient diarrhea card provided
at the baseline visit.
6.3. Treatment Completion Visit
The End of Treatment (EOT) visit should be performed for all patients once they have 
permanently discontinued bosutinib as described in Section 5.3. The visit should occur 
within 28 days after the last dose of bosutinib.  The following procedures are required:

Complete physical examination including vital signs, ECOG performance status and
extramedullary disease assessment;

Electrocardiogram (ECG);

Chest X-ray;

Mutation analysis of the BCR-ABLl transcript will be performed using a peripheral 
blood sample collected at the end-of-treatment visit in order to identify mutations 
acquired upon treatment with bosutinib. Mutations will be identified by direct 
sequencing of the BCR-ABL transcript performed at a Central Laboratory as arranged 
by the Sponsor.  Peripheral blood for all eligible patients (except from patients 
enrolled at sites in China) will be collected and shipped frozen to a central vendor for 
analysis.  Specific instructions for handling and shipment of these samples can be 
found in Study Reference Manual;

Cytogenetic or residual molecular response testing.  Molecular response monitoring 
using reverse transcriptase polymerase chain reaction (RT-PCR) measurement of 
BCR-ABL fusion transcript levels in peripheral blood may be performed in lieu of 
monitoring via cytogenetics, once molecular response is achieved, and according to 
standard of care and current treatment guidelines at investigative site;


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
Hematology panel with complete blood counts (CBC) (see Section 6.1 for details);

Chemistry panel(see Section 6.1 for details);

Liver Function Tests (LFTs) (see Section 6.1 for details);

Coagulation tests (see Section 6.1 for details);

Dipstick urinalysis (microscopic if abnormal);

Serum pregnancy test (for women of childbearing potential);

Contraceptive check;

Dosing compliance check;

Review of adverse events and concomitant medications.
6.4. Long-Term Follow-up Visit
Patients who discontinue treatment with bosutinib prior to the end of the study will enter into 
the Long-Term Follow-Up period. Patients will be followed for the duration of study in 
order to assess the survival status of the patient. Details of any subsequent therapy with 
TKIs or other anti-cancer therapy and response following bosutinib discontinuation will be 
collected on LTFU patients if available.
Follow-up will be conducted every 3 months from the last dose of bosutinib. Information
will be collected via clinical visit or telephone contact
6.5. Patient Withdrawal
Patients may withdraw from the study 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 or 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 why a patient may discontinue or be withdrawn from the study include, but are not
limited to, adverse event patient request, protocol violation, patient noncompliance, and study
termination by the sponsor.  When a patient discontinues or is withdrawn, the investigator 
will notify the sponsor.
The treatment completion visit must be performed for all patients who discontinue from 
receiving further bosutinib administration. Furthermore, follow-up should be performed 
unless the patient died, voluntarily withdrew consent, or the sponsor terminated the study. 
All information should be recorded on the appropriate eCRF.
If a 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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If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. In any circumstance, every effort should be made to document patient outcome, if 
possible. The investigator should inquire about the reason for withdrawal, request that the 
patient to return all unused investigational product(s), request the patient to return for a final
visit, and follow-up with the patient regarding any unresolved adverse events (AEs).
If a patient is lost to follow-up, or is voluntarily withdrawn from any study participation, 
every effort must be made to obtain any pertinent follow-up information and/or perform a 
treatment completion visit.
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, which 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 
which he/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 fashion.
7.1. Efficacy Assessments
7.1.1. Efficacy Assessment Methods
Efficacy will be determined by analysis of peripheral blood and physical examination for all
patients except those in advanced phase of the disease for whom a bone marrow differential
count will be needed.  Refer to the Schedule Of Activities for time points.  Assessments will
continue per Schedule Of Activities until treatment completion.
Automated complete blood counts and differential counts (with manual confirmation of
abnormalities), physical examination and cytogenetics by FISH will be used to determine
response to treatment as outlined in Appendix 1.
Number of Ph+ cells will be assessed by fluorescence in situ hybridization (FISH) from 
peripheral blood (PB) sample. To ensure reliable estimation of cytogenetic response, the 
cytogenetic assessment must be performed on at least 200 nuclei. PB FISH is not only more 
sensitive but also less invasive for the patient than conventional bone marrow (BM) 
cytogenetics.29 Studies have demonstrated the strong correlation between BM and PB FISH 
as well as BM conventional cytogenetics.30-37
However, conventional cytogenetics on BM, requiring at least 20 metaphases, may be 
performed when loss of cytogenetic response is suspected by PB FISH or at the end of 
therapy.  Loss of cytogenetic response must be confirmed by 2 assessments at least 4 weeks 
apart.


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Hematologic responses must be of at least 4 weeks in duration confirmed by 2 assessments at
least 4 weeks apart.  Hematologic response will be evaluated by peripheral blood only for
patients in chronic phase and by both peripheral blood and bone marrow for patients in
advanced phase.  Loss of hematologic response must also be confirmed by 2 assessments at
least 2 weeks apart.
Molecular response monitoring using reverse transcriptase polymerase chain reaction 
(RT-PCR) measurement of BCR-ABL fusion transcript levels may be performed on 
peripheral blood in lieu of monitoring the patient via cytogenetics, once molecular response is 
achieved, and according to standard of care and current treatment guidelines at Site.  This data
will be collected in the eCRF.
Physical examination will be used to assess hepatic and spleen involvement.
All tests described above will be performed locally.
7.2. Safety Assessments
Refer to the Schedule Of Activities for time points.
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. Patients are to be 
followed for adverse events for 28 days after last dose of bosutinib, regardless of causality. 
Furthermore, all treatment-related adverse events will be followed until Grade 1, return to 
baseline, or in the case of impairment, until the condition stabilizes.
7.2.1. Safety Assessment Methods
Safety will be assessed by physical examination (including vital signs) and laboratory tests
(see Appendix 5), including chest X-ray and ECHO/MUGA scans.
All safety assessments are outlined in the schedule of activity and include adverse event and
concomitant medication review, assessment of disease status, PK collection for all eligible 
patients (except from patients enrolled at sites in China), and ECG monitoring.
7.2.2. Special Recording of Diarrhea Events
EMA has required that ad hoc analyses are conducted in order to evaluate the incidence of
diarrhea after study patient’s transition to the bosutinib commercial formulation.  To satisfy
this request, a diarrhea card will be provided to the patients to collect the details of diarrhea
events during the first three months on study treatment (see Appendix 2).
Diarrhea cards will be provided to all patients at the baseline visit. The cards will be 
collected at the Month 3 study visit; data reported by the patient will be reviewed by the 
investigator and recorded in the eCRF.


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7.2.3. Safety Laboratory Determinations
The investigator will review laboratory test results to determine the occurrence of clinically 
important abnormalities (ie, AEs).  If laboratory values do not return to normal or baseline 
within a reasonable period, the etiology should be identified and documented appropriately.  
Only laboratories associated with the investigative site should be used by the investigator for 
all determinations, unless a special test is required.  Every effort should be made by each 
investigator to designate one primary laboratory for all determinations unless a special test is 
required.  It is the responsibility of site staff to collect valid laboratory certifications and 
normal ranges for all local laboratories used during the course of the study.
7.2.4. Contraceptive Check
Patients of child-bearing potential will be required to verbally affirm their use of 2 highly 
effective methods of contraception until at least 28 days after their last dose of bosutinib.  
This conversation which will be documented in the patient’s source records.
7.3. Pharmacokinetics
Steady-state trough concentrations (Ctrough) of bosutinib will be determined. A total of 1 PK 
sample per subject will be drawn. All eligible patients (except from patients enrolled at sites 
in China) will provide a pre-dose blood sample following at least 2 weeks of uninterrupted 
dosing with bosutinib at the same dose level.  This sample will be collected at their first 
scheduled visit following all appropriate approvals and implementation of protocol 
amendment # 1.  Biological specimen samples for pharmacokinetic analysis must be 
identified with labels provided by the sponsor.Concentrations of bosutinib will be determined 
in plasma using a Pfizer -approved and validated liquid chromatography/tandem mass 
spectrometry (LC/MS/MS) assay.
The objective of the pharmacokinetic analysis is to compare the Ctrough of bosutinib in this 
study to Ctrough of previous studies.
7.3.1. Blood Collections for Plasma PK and BCR-ABL Mutation Analysis
Blood samples (3 mL) to provide approximately 1.0 mL plasma for PK analysis will be 
collected into appropriately labeled tubes at times specified in the Schedule Of Activities.
One pre dose PK sample per eligible patient will be drawn, to be collected at first occasion 
after at least 2 weeks of uninterrupted dosing at the same dose level.  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.  
Any deviation from the specified sample handling procedure resulting in compromised 
sample integrity will be considered a protocol deviation.


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As part of understanding the PK of the study drug, samples may be used for further 
characterization and/or evaluation of the bioanalytical method. These data will be used for 
internal exploratory purposes and will not be included in the clinical report.
BCR-ABL Mutation Analysis
Analysis of the BCR-ABL transcript will be performed using a peripheral blood sample 
collected at the end-of-treatment visit from each eligible patient in order to identify mutations
acquired upon treatment with bosutinib. Mutations will be identified by direct sequencing of 
the BCR-ABL transcript performed at a Central Laboratory as arranged by the Sponsor.  
Peripheral blood will be collected and shipped frozen to a central vendor for analysis.  
Specific instructions for handling and shipment of these samples can be found in Study 
Reference Manual.
7.3.2. Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed within 28 days of the first dose of bosutinib at the 
baseline visit and at the end of treatment visit. Pregnancy tests will also be done whenever 
one menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected), repeated at the end of the study to confirm the patient has 
not become pregnant during the study. In the case of a positive hCG test, the patient will be 
withdrawn from study medication but may remain in the study.  Pregnancy tests may also be 
repeated as per request of IRB/IECs or if required by local regulations.
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)


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All observed or volunteered events regardless of] group or 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 when the investigator becomes awareof the event All events are to 
be reported to Pfizer, regardless as to causation.  In the rare situation that the investigator 
does not become immediately aware of the occurrence of an event, the investigator must 
report the event within 24 hours and document the time of his/her first awareness of the 
event.In particular, if the SAE is fatal or life-threatening, notification to Pfizer Safety must be 
made immediately upon discovery, irrespective of the extent of available event information.  
This timeframe also applies to additional new (follow-up) information on previously 
forwarded reports. 
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 
subject 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 subject/[parent(s)/legal guardian/legally acceptable representative].  In 
addition, each study subject/[parent(s)/legal guardian/legally acceptable representative] will 
be questioned about the occurrence of AEs in a non-leading manner.


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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
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 subject 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.
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 subject begins from the time the subject provides informed consent, which 
is obtained before the subject’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; except as indicated below] after the last administration of the 
investigational product.
For subjects 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 subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject 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.


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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 
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 subject 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;

Progression/worsening of underlying disease 

Drug abuse;

Drug dependency.


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Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

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.


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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.
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 subject 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 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:


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
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:

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, subject 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 subject;

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
For oncology studies, investigators report AEs using concise medical terminology (verbatim) 
as well as collect on the CRF the appropriate Common Terminology Criteria for Adverse 
Events (CTCAE) (Version 4.03, Publish Date: 14 June 2010, 
http://ctep.cancer.gov/reporting/ctc.html) listed in the Cancer Therapy Evaluation Program. 


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The investigator will use the following definitions of severity in accordance with the current 
CTCAE version to describe the maximum intensity of the adverse event. 
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
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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects 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.


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The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects 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:

Subjects 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 subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or 
ALT values >2 times the baseline values AND >3 × ULN; or >8 × ULN 
(whichever is smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × 
ULN (whichever is smaller).
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 subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, 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. 


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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:

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 subject or subject’s partner becomes or is found to be pregnant during the subject’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 subject 
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 


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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 
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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject 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 subject 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.


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8.4.4. Medication Errors and Lack of Efficacy
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors and lack of 
efficacy*
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
*For lack of efficacy (particularly for studies conducted with vaccines, contraceptives, and products used in the 
treatment of life-threatening diseases or conditions [eg, anti-infectives]), see the Lack of Efficacy section below.
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength, or 
inadvertent exposure.
Medication errors include:

Medication errors involving subject 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 subject.
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.
8.4.4.2. Lack of Efficacy 
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor. 
This document may modify the plans outlined in the protocol; however, any major 
modifications of the endpoint definition and/or its analysis will also be reflected in the 
clinical study report.


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9.1. Sample Size Determination
This study does not include any formal sample size determination. All bosutinib patients
from the two parent studies B1871006 and B871008 who are still on-treatment at the 
initiation of this study, or known to be alive as of their last LTFU visit, or who have 
completed the parent study will be offered enrollment in this extension study.
9.2. Analysis of Efficacy 
Data from the two parent studies will be combined with the data from this study for the 
analysis of efficacy.  All bosutinib patients randomized in parent Study B1871008 or dosed
in parent Study B1871006 will be included in the efficacy analyses. Analyses will be 
presented by disease stage (ie, CP, AP, BP) and by line of therapy.
Descriptive summaries and confidence intervals (if applicable) will be provided; no 
inferential analyses are planned for this study.
The time-to-event endpoints of overall survival, time to transformation, progression-free 
survival, and duration of response will be summarized via the Kaplan-Meier method or 
cumulative incidence,2 whichever is more appropriate, depending on the presence of 
competing risk.
9.3. Overall Survival
Overall survival (OS) or survival time is defined as the interval from the date of
randomization (first line patients enrolled from B1871008) or first dosing (second or later
line patients enrolled from B1871006) in the parent study to the date of death due to any
cause. Patients not known to have died are censored at the last known alive date.  OS will be
calculated for all patients enrolled in the parent study B1871008 and dosed in the parent 
study B1871006.
9.4. Time to Transformation to AP/BP
Time to transformation is defined as the time from the date of first dose in the parent study to 
the first date of confirmed transformation to AP or BP. For patients without transformation, 
censorship is at the last evaluation date.
Time to transformation will be calculated only for patients in 2nd or plus line setting while on 
treatment.
9.5. Progression-Free Survival
Progression-free survival (PFS) is the interval from the date of first dose of bosutinib in the 
parent study until the earlier date of progression or death from any cause. Patients without 
events are censored at the last evaluation date.
PFS will be calculated only for patients in 2nd or above line setting.


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9.6. Duration of Response
Duration of response (MCyR, CHR, OHR) is measured from the date of the earliest 
demonstration of a response, until the earliest date of confirmed loss of that response.  For 
patients without loss of response, censorship is at the last evaluation date. Duration of 
response will be calculated only for patients in 2nd or plus line setting who respond to 
treatment.
9.7. Safety Analysis
Treatment-emergent AE (defined as any event increasing in severity from parent study 
baseline, or any new event starting during bosutinib therapy or within 30 days of the last 
bosutinib dose) incidence rates will be described both with and without regard to causality.  
The frequency of occurrence of overall toxicity, categorized by toxicity grades, will be 
described. Listings of laboratory test results collected at baseline and during the study will 
be generated and descriptive statistics summarizing changes in laboratory tests over time will 
be presented.
The incidence of diarrhea from the 2 parent studies and the incidence of diarrhea from 
extension study will be tabulated in order to compare the clinical and commercial 
formulations of bosutinib.
The pharmacokinetic analysis (collected for all patients except those from sites in China) will
compare the Ctrough of bosutinib in this study to Ctrough of previous studies.
All patients dosed in the parent Studies B1871006 and B1871008 will be included in the 
safety analyses.  Data from the two parent studies will be combined with the data from this
study for the analysis of safety.
9.8. Data Monitoring Committee
This study will not use a Data Monitoring Committee.  The Sponsor’s procedures for 
ongoing periodic safety reviews will be applied by an internal safety review team with 
medical and statistical expertise to review individual and summary data collected in the 
safety and clinical databases.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may
review source documents to confirm that the data recorded on CRFs is 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.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent
Ethics Committee (IEC), 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.


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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 is true.  Any corrections to entries made in the CRFs, 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's or the physician's patient chart. In
these cases data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient
information to link records, ie, 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 (ie, letters, meeting minutes, telephone calls reports).  The records should be
retained by the investigator according to International Conference on Harmonisation (ICH),
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 (ie, 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 to an independent third party arranged by Pfizer.


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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 (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
ie, recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients. In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as
the general principles set forth in the International Ethical Guidelines for Biomedical
Research Involving Human Patients (Council for International Organizations of Medical
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World  
Medical Association 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline
on GCP, and 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
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Patient names, address, birth date and other identifiable data will be replaced by a numerical
code consisting of a numbering system provided by Pfizer in order to de-identify the trial
patient.  In case of data transfer, Pfizer will maintain high standards of confidentiality and
protection of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory
requirements, and legal requirements.
Whenever consent is obtained from a patient’s legally acceptable representative or legal 
guardian, the patient’s assent (affirmative agreement) must subsequently be obtained when 
the patient has the capacity to provide assent, as determined by the IRB/EC.  If the 


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investigator determines that a patient’s decisional capacity is so limited, he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the patient’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study patient does not provide 
his or her own consent, the source documents must record why the patient did not provide 
consent (ie, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the patient’s legally acceptable representative, the consent 
signer’s relationship to the study patient (ie, parent, spouse) and that the patient’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents. 
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  The informed consent document(s) used during the informed consent process 
must be reviewed by the sponsor, approved by the IRB/IEC before use, and available for 
inspection. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient’s legal representative 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
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, 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 in all participating countries is defined as Last Patient Last Visit, which will 
occur when the last patient would have spent approximately 10 years (either on treatment or 
in long-term follow-up from the first dose of bosutinib in the parent study (B1871006 or 
B1871008).  When this milestone is reached, the present study will be closed.  At that time,
the patients still benefiting from bosutinib will switch to the most appropriate therapy
available at that time.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision,
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In
addition, Pfizer retains the right to discontinue development of bosutinib at any time.


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If a study is prematurely terminated or discontinued, Pfizer will promptly notify the
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within one week of notification.  As directed by Pfizer,
all study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
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 subject 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 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.


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15.1. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigators, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigators will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigators will provide manuscripts, abstracts, or the full text of any other intended
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer
at least 30 days before they are submitted for publication or otherwise disclosed. If any
patent action is required to protect intellectual property rights, Investigators agree to delay
the disclosure for a period not to exceed an additional 60 days.
Investigators will, on request, remove any previously undisclosed Confidential Information
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigators agree that the first publication is to 
be a joint publication covering all centers. 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, Investigators are free to publish separately, patient to the other 
requirements of this Section.
For all publications relating to the Study, 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 Clinical Study Agreement between
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined
terms shall have the meanings given to them in the Clinical Study Agreement.


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Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and 
dasatinib and/or nilotinib therapy failure. H. Jean Khoury, Jorge E. Cortes, Hagop M.
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Zaritskey, Athena Countouriotis, Nadine Besson, Eric Leip, Virginia Kelly and Tim H.
Brümmendorf. 2012, Blood, Vol. 119, pp. 3403-3412.
2.
A class of k-sample tests for comparing the cumulative incidence of a competing risk.
Gray, RJ. 3, 1988, Annals of Statistics, Vol. 16, pp. 1141-1154.
3.
BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic
myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock
protein 90. Gorre, M.E., Ellwood-Yen, K., Chiosis, G., Rosen, N., Sawyers, C.L. 8,
2002, Blood 2002, Vol. 100, pp. 3041-4.
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Cancer statistics, 2010. Jemal A, Siegel R, Xu J, Ward E. . . 5, 2010, CA Cancer J Clin,
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Five-year followup of patients receiving imatinib for chronic myeloid leukemia. Druker,
B.J., Guilhot, F., O’Brien, S.G. et al. 23, 2006, N Engl J Med, Vol. 355, pp. 2408-17.
6.
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed
chronic-phase chronic myeloid leukemia. O’Brien S, Guilhot F, Larson RA, et al. 11,
2003, NEJM, Vol. 348, pp. 994-1004.
7.
Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Apperley,
J.F. 11, 2007, Lancet Oncol, Vol. 8, pp. 1018-29.
8.
International randomized study of interferon vs STI571 (IRIS) 8-year follow-up. 
Deininger, M., O’Brien, S.G., Guilhot, F. et al. 22, 2009, Blood, Vol. 114.
9.
Overriding imatinib resistance with a novel ABL kinase inhibitor. Shah, N.P., Tran, C., 
Lee, F.Y., Chen, P., Norris, D., Sawyers, C.L. 5682, 2004, Science, Vol. 305, pp. 399-
401.
10.
In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically
relevant imatinib-resistant Abl kinase domain mutants. O’Hare, T., Walters, D.K.,
Stoffregen, E.P. et al. 11, 2005, Cancer Research, Vol. 65, pp. 4500-5.
11.
ABL mutations in late chronic phase chronic myeloid leukemia patients with upfront
cytogenetic resistance to imatinib are associated with a greater likelihood of progression
to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chro. 
Soverini, S., Martinelli, G., Rosti, G. et al. 18, 2005, J Clin Oncol, Vol. 23, pp. 4100-9.
12.
Frequency and clinical significance of BCR-ABL mutations in patients with chronic
myeloid leukemia treated with imatinib mesylate. Jabbour, E., Kantarjian, H., Jones, D.
et al. 10, 2006, Leukemia, Vol. 20, pp. 1767-73.


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13.
BCR-ABL fusion transcript types and levels and their interaction with secondary
genetic changes in determining the phenotype of Philadelphia chromosome-positive
leukemias. Jones, D., Luthra, R., Cortes, J. et al. 13, 2008, Blood, Vol. 112, pp. 5190-2.
14.
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is
active in patients with imatinib-resistant or –intolerant accelerate-phase chronic
myelogenous leukemia. le Coutre P, Ottmann OG, Giles F, et al. 4, 2008, Blood, Vol.
111, pp. 1834-39.
15.
Long-term outcome of patients with chronic myeloid leukemia treated with second
generation tyrosine kinase inhibitos after imatinib failure is predicted by the in vitro
sensitivity of BCR-ABL kinase domain mutations. Jabbour E, Jones D, Kantarjian H, et
al. 10, 2009, Blood 2009, Vol. 114, pp. 2037-43.
16.
J Clin Oncol. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL
mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic
phase. 25, 2009, Vol. 27, pp. 4204-10.
17.
Dasatinib treatment of chronic phase chronic myeloid leukemia :analysis of responses
according to preexisting BCR-ABL mutations. Muller MC, Cortes JE, Kim DW, et al.
24, 2009, Blood, Vol. 114, pp. 4944-53.
18.
Molecular biology of bcrabl1- positive chronic myeloid leukemia. Quintas-Cardama, A., 
Cortes, J. 8, 2009, Blood, Vol. 113, pp. 1619-30.
19.
Myleran in chronic myeloid leukaemia; results of treatment. Galton, DA. 6753, 1953,
Lancet, Vol. 264, pp. 208–213.
20.
Therapeutic options in chronic myeloid leukaemia. Allan, NC. 1, 1989, Blood, Vol. 3,
pp. 45–52.
21.
Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of
seven randomized trials. Group, Chronic Myeloid Leukemia Trialists' Collaborative. 21,
1997, J Natl Cancer Inst, Vol. 89, pp. 1616–1620.
22.
Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation
after preparation with BuCy2. Biggs JC, Szer J, Crilley P, et al. 5, 1992, Blood, Vol. 80,
pp. 1352–1357.
23.
Discovery of N-(2- chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-
2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl 
kinase inhibitor with potent antitumor activity in preclinical assays. Lombardo, L.J.,
Lee, F.Y., Chen, P. et al. 27, 2004, J Med Chem, Vol. 47, pp. 6658-61.


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24.
Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and
improves tolerability in imatinib-resistant and - intolerant chronic-phase chronic
myeloid leukemia. Shah, N.P., Kantarjian, H.M., Kim, D.W. et al. 19, 2008, J Clin
Onco, Vol. 26, pp. 3204-12.
25.
Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.
Weisberg, E., Manley, P.W., Breitenstein, W. et al. 2, 2005, Cancer Cell, Vol. 7, pp.
129-41.
26.
Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-
CP) on nilotinib therapy at 24 months: Clinical response, safety, and long-term
outcomes. Kantarjian, H.M., Giles, F.J., Bhalla, K.N., et al. 22, 2009, Blood, Vol. 114,
p. Abst 1129. .
27.
Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. Saglio, G.,
Kim, D.W., Issaragrisil, S. et al. 24, 2010, N Engl J Med, Vol. 362, pp. 2251-9.
28.
Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.
Kantarjian, H., Shah, N.P., Hochhaus, A. et al. 24, 2010, N Engl J Med, Vol. 362, pp.
2260-70.
29.
Dasatinib or imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic
phase (CML-CP): Two-year follow-up from DASISION. Kantarjian, H., Shah, N.,
Cortes, J., et al. 2011, J Clin Oncol, p. Abst 6510.
30.
Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic
phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month
minimum follow-up of the phase 3 randomised ENESTnd trial. Kantarjian, H.M.,
Hochhaus, A., Saglio, G. et al. 9, 2011, Lancet Oncol, Vol. 12, pp. 841-51.
31.
Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia:
need for new response definitions? Kantarjian H, O’Brien S, Shan J, et al. 2008, Cancer,
Vol. 112, pp. 837-845.
32.
Fluorescence in situ hybridization on peripheral-blood specimens is a reliable method to
evaluate cytogenetic response in chronic myeloid leukemia. Le Gouill S, Talmant P,
Milpied N, et al. 2000, J Clin Oncol, Vol. 18, pp. 1533-1538.
33.
Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with
imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia.
Kantarjian HM, Talpaz M, Cortes J, et al. 2003, Clin Cancer Res, Vol. 9, pp. 160-166.
34.
Correlation of 3 methods of measuring cytogenetic response in chronic myelocytic
leukemia. Lesser ML, Dewald GW, Sison CP, et al. 2002, Cancer Genet Cytogenet,
Vol. 137, pp. 79-84.


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35.
Quantification of residual disease in chronic myelogenous leukemia patients on
interferon-alpha therapy by competitive polymerase chain reaction. Hochhaus A, Lin F,
Reiter A, et al. 1996, Blood, Vol. 87, pp. 1549-1555.
36.
Serial monitoring of BCR-ABL by peripheral blood real-time polymerase chain reaction
predicts the marrow cytogenetic response to imatinib mesylate in chronic myeloid
leukaemia. Wang L, Pearson K, Pillitteri L, et al. 2002, Br J Haematol, Vol. 118, pp.
771-777.
37.
Comparison of bone marrow high mitotic index metaphase fluorescence in situ 
hybridization to peripheral blood and bone marrow real time quantitative polymerase
chain reaction on the International Scale for detecting residual disease in chronic 
myeloid leu. Lundan T, Juvonen V, Mueller MC, et al. 2008, Haematologica, Vol. 93,
pp. 178-185.
38.
Utility of peripheral blood dual color, double fusion fluorescent in situ hybridization for
BCR/ABL fusion to assess cytogenetic remission status in chronic myeloid leukemia.
Landstrom AP, Ketterling RP, Knudson RA, et al. 2006, Leuk Lymphoma, Vol. 47, pp.
2055-2061.
39.
Peripheral Blood Monitoring of Chronic Myeloid Leukemia During Treatment With
Imatinib, Second-Line Agents, and Beyond. Lima, Lisa, Bernal-Mizrachi, Leon et
Debra Saxe, et al. 2011, Cancer, pp. 1245-52.
40.
Baccarini M, Denninger MW, Rosti G, et al. European LeukemiaNet recommendations 
for the management of Chronic Myeloid Leukemia. Blood. 122(6):872-84, 2013.
41.
Cortes, J, Rousselot, P, Dong-Wook, K, et al. Dasatinib induces complete hematologic 
and cytogenetic responses in patients with imatinib-resistant or –intolerant chronic 
myeloid leukemia in blast crisis. Blood: 109(6)3207-3213, 2007.


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APPENDICES
Appendix 1. Tables Defining Responses to Treatment
A Hematologic Responses Definition
Hematologic Responses
Definition
Return to Chronic Phase (RCP)
(or CP for subjects with CP)/
Minor Hematologic Response 
(MiHR) (for Ph+ ALL subjects)
Subjects had to meet all criteria
Disappearance of features defining accelerated and blast phases, 
but still in chronic phase as noted by:
<15% Blasts in both blood and marrow
<30% Blasts + promyelocytes in both blood and marrow
<20% Basophils in both blood and marrow (marrow not 
applicable for Ph+ ALL)
No extramedullary involvement other than liver/spleen
Accelerated Phase
had to meet at least 1 criterion
15-29% Blasts in blood or marrow
30% Blasts + promyelocytes in blood or marrow
20% Basophils in blood or marrow
only applicable to advanced phase
Platelets <100x109/L (not related to therapy) 
Blast Phase
had to meet at least 1 criterion
30% blasts in blood or bone marrow
Extramedullary involvement other than liver/spleen
No Evidence of Leukemia (NEL)
had to meet all criteria
WBC institutional ULN
450 x109/L > Platelets 20x109 /L
ANC 0.5x109/L
<20% basophils in blood
No blasts or promyelocytes in blood
Myelocytes + metamyelocytes <5% in blood
No extramedullary involvement (incl. hepato- or splenomegaly)
only applicable for advanced phase 
5% bone marrow blasts 
Complete Hematologic Response 
(CHR)
had to meet all criteria
WBC institutional ULN
Platelets <450 × 109/L
<20% basophils in blood
No blasts or promyelocytes in blood 
Myelocytes + metamyelocytes <5% in blood
No extramedullary involvement (incl. hepato- or splenomegaly)
only applicable to advanced phase
5% bone marrow blasts 
ANC 1.0 × 109/L 
Platelets 100 × 109/L
Overall Hematologic Response (OHR)
had to meet at least 1 criterion
CHR +NEL +RCP + MiHR
(if applicable)
Major Hematologic Response (MHR)
(had to meet at least 1 criterion)
CHR +NEL
Abbreviations: ANC=absolute neutrophil count, ULN=upper limit of normal range, WBC=white blood cell


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B. Cytogenetic Responses to Treatment
Cytogenetic Responses*
% Philadelphia chromosome positive cells
None
>95% 
Minimal
66-95%
Minor
36-65%
Partial
1-35%
Complete
0% from conventional cytogenetics or <1% from FISH
Major
Complete + Partial Rates
* Based on analysis of 200 nuclei if done from blood sample or based on analysis of 20 metaphases if 
done from bone marrow sample.
C. Minimal Residual Disease Assessment (Quantitative PCR performed locally)
Response by Type
Definitions
Molecular 
Deep Molecular Response 
(MR4, MR4.5, MR5)
MR4= either (i) detectable disease with 0.01% BCR-ABL1 IS or 
(ii) undetectable disease in cDNA with a minimum number of 
ABL1 transcripts specified by the local laboratory in the same volume of 
cDNA used to test for BCR-ABL1.
MR4.5 =either (i) detectable disease with 0.0032% BCR-ABL1 IS or 
(ii) undetectable disease in cDNA with a minimum number of 
ABL1 transcripts specified by the local laboratory in the same volume of
cDNA used to test for BCR-ABL1.
MR5 =either (i) detectable disease with 0.001% BCR-ABL1 IS or 
(ii) undetectable disease in cDNA with a minimum number of 
ABL1 transcripts specified by the local laboratory in the same volume of 
cDNA used to test for BCR-ABL1.
Major (MMR)
Ratio of BCR-ABLIS 0.1% with a minimum number of ABL1 transcripts 
specified by the local laboratory.
MR2
Ratio of BCR-ABLIS 1% with a minimum number of ABL1 transcripts 
specified by the local laboratory.
MR1
Ratio of BCR-ABLIS 10% with a minimum number of ABL1 transcripts 
specified by the local laboratory.


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Appendix 2. Patient Diarrhea Card 
Guidelines for the Management of Diarrhea 
for Participants in the bosutinib Extension Study
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 including your own experience from your participation in study 
B1871006 or B1871008 show that diarrhea is the most common side effect you may have while receiving bosutinib.  It has also 
been showed that diarrhea events, although frequent, are mainly low grade in severity, don’t last long, occur predominantly in 
the first month of bosutinib treatment, and managed by appropriate concomitant medications given for short duration.
We do not anticipate any specific change in gastrointestinal disorders including diarrhea, however we are interested in 
additional characterization of diarrhea after extended treatment and helping to ensure appropriate management of any new 
episode 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.


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Information to provide
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).
We will also provide you with a specific card which will help you to capture any relevant information occurring at the time 
of a diarrhea event.


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Recommendations
1. Changes to your diet 
If you have diarrhea:

Stop all lactose-containing products (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.


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Patient Diarrhea Card 1/2
Project: Bosutinib Extension study – Protocol B1871040
Patient Number: _ _ _ _ _ _ _ _ _ _ _ 
This form will help you to collect any relevant information associated with diarrhea episode
during the first 3 months on bosutinib in the extension study
Date
mmm/dd/yy
Number of 
loose stools
per day
Associated Symptoms
/ Comments
Did you take any 
anti-diarrheal 
medication?
Which dose?
Current dose 
of bosutinib
Have you 
modified/stopped 
your dose of 
bosutinib?
Re-viewer 
initials


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Patient Diarrhea Card 2/2
Project: Bosutinib Extension study – Protocol B1871040
Patient Number: _ _ _ _ _ _ _ _ _ _ _ 
This form will help you to collect any relevant information associated with diarrhea episode
during the first 3 months on bosutinib in the extension study
Compared with your previous experience in the B1781006 (3160A4-200) or B1871008 (3160A4-3000) study
how would you rate your current status with regards to diarrhea side effects?
 much better
 better
 similar
 worse
 much worse
Date: _ _ _ _ / _ _ _ _ / _ _ _ _ ( mmm/dd/yy)
Additional Comments: 


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Appendix 3. Dose Diary –
Protocol ID: B1871040                                             Subject ID:__________________ 
BOSUTINIB DOSE DIARY 
INSTRUCTIONS TO THE PATIENT
(DOSE ONLY TO BE CHANGED WHEN INSTRUCTED BY STUDY DOCTOR)
Date Diary Issued : _ _/__ __ __/_ _ _ _
(DD/MMM/YYYY)
Total Bosutinib Dose:  _____ mg Once Daily
This dose is to be made by taking the following combination of tablets :
Take  _____   100 mg tablets once daily
Date New Dose Began : _ _/__ __ __/_ _ _ _
(DD/MMM/YYYY)
Total Bosutinib Dose:  _____ mg Once Daily
This dose is to be made by taking the following combination of tablets :
Take  _____   100 mg tablets once daily
Date New Dose Began : _ _/__ __ __/_ _ _ _
(DD/MMM/YYYY)
Total Bosutinib Dose:  _____ mg Once Daily
This dose is to be made by taking the following combination of tablets :
Take  _____   100 mg tablets once daily
Date New Dose Began : _ _/__ __ __/_ _ _ _
(DD/MMM/YYYY)
Total Bosutinib Dose:  _____ mg Once Daily
This dose is to be made by taking the following combination of tablets :
Take  _____   100 mg tablets once daily


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DOSING for Bosutinib: 
Take your study drug as prescribed below:
                                                                                                                                   

Take orally, once daily, at approximately the same time every day.  

Take with a meal and water, preferably in the morning. 

Tablets should be swallowed whole.  Do not chew, crush, split, or dissolve the tablets.

Do not take the tablets if broken, cracked, or otherwise not intact. 

If you vomit any time after taking a dose, do not take another dose the same day. Restart dosing the next 
day as prescribed 
Talk to your study doctor prior to starting any prescription or over the counter medications while 
participating in this study.
MISSED DOSES:

If you miss a dose by more than 12 hours do not make up the missed dose. Just wait until the next time 
you are supposed to take it. 
STUDY VISITS:

Do not take your study drug on days of your study clinic visits; bring your study drug with you to 
the clinic. You will take the study drug at the clinic when instructed by the study nurse, after your 
blood work or other tests are done.

You must return all study drug bottles/containers, along with any unused study drug, at each study visit, 
as instructed by your study doctor and his/her study staff.
DRUG STORAGE: 

Keep your drug in the bottles provided by your study doctor and do not transfer them to any other 
container.

Store your study drug at room temperature (between 15 and 25 degrees C or 59 to 77 degrees F).

Store out of the reach of children or pets.


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DOSE DIARY INSTRUCTIONS
1.
If you have any questions about how or when to take your study drug, please call your study doctor or his/her 
study staff.
2.
If you miss a dose (s) Record the date, the number of tablets you missed
3.
Please record any information, such as “forgot to take dose” in the Dosing Notes/Comments column, as 
needed.
4.
If you miss an entire dose at any time, or are instructed by your study doctor to withhold a dose, please mark 
an “X” on that dose time.  
5.
Please return these forms and the study medication bottles with left over tablets to your study doctor, when 
you go for your next appointment.
Date
Time Dose 
Taken
Number of 100 mg 
Tablets Taken
Dosing Notes/Comments


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Appendix 4. Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG 
Grade
Description
Karnofsky Score*
0
Fully active, able to carry on all pre-disease activities without 
restriction.
100
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).
80 or 90
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.
60 or 70
3
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
40 or 50
4
Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair.
20 or 30
* Karnoksy score is provided for comparison purposes only.  Please record ECOG grade only.


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Appendix 5. Laboratory Tests to be performed
Hematology panel with complete blood count (CBC) which includes:

White blood cell count, with 5-part differential (with manual confirmation of 
abnormalities)

Platelet count

Absolute neutrophil count (ANC)

Red blood cell count (RBC)

Hemoglobin (HgB)
Chemistry panel with electrolytes which includes:

Sodium

Potassium

Chloride

Creatinine

Glucose

Total protein

Albumin

Calcium

Alkaline phosphatase

Amylase

Lipase

Phosphorous

Magnesium

Creatine kinase

Uric acid until patient achieves CHR


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
Carbon dioxide or bicarbonate (if available)

Blood urea nitrogen (BUN) or urea

Fractionated creatine kinase if creatine kinase is abnormally high (if available)
Liver Function Tests which includes:

Total Bilirubin

AST

ALT
Coagulation Tests which includes:

Prothrombin Time (PT in seconds) or INR

Partial Thromboplastin Time (PTT or APTT)
Dipstick urinalysis (microscopic if abnormal)
Serum Pregnancy Test (for women of childbearing potential)


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Appendix 6. 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

SAP_001.pdf: 
Protocol B1871040 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B1871040
AN OPEN-LABEL BOSUTINIB TREATMENT EXTENSION STUDY FOR
SUBJECTS WITH CHRONIC MYELOID LEUKEMIA (CML) WHO HAVE
PREVIOUSLY PARTICIPATED IN BOSUTINIB STUDIES B1871006 OR B1871008
Statistical Analysis Plan 
(SAP)
Version:
3.0
Author:
 PhD, 
Clinical Statistician
Date:
11-AUG-2020
PPD
PPD


Protocol B1871040 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Design .............................................................................................................4
2.2. Study Objectives .......................................................................................................5
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
5. ANALYSIS SETS .................................................................................................................6
5.1. Full Analysis Set .......................................................................................................6
5.2. ‘Per Protocol’ Analysis Set .......................................................................................6
5.3. Safety Analysis Set....................................................................................................6
5.4. Other Analysis Sets ...................................................................................................6
5.5. Treatment Misallocations..........................................................................................7
5.6. Protocol Deviations...................................................................................................7
6. ENDPOINTS AND COVARIATES .....................................................................................7
6.1. Efficacy Endpoint(s) .................................................................................................7
6.2. Safety Endpoints .....................................................................................................10
6.2.1. Exposure and Compliance..........................................................................10
6.2.2. Laboratory Evaluations, Vital Signs, and Cardiac Evaluations..................10
6.2.3. Laboratory Evaluations of Special Interest.................................................10
6.2.4. Non-study Medications...............................................................................11
6.2.5. Death...........................................................................................................11
6.2.6. Adverse Events...........................................................................................11
6.2.7. Adverse Events of Special Interest.............................................................12
6.3. Other Endpoints.......................................................................................................12
6.3.1. PK Endpoints..............................................................................................12
6.3.2. PD Endpoints..............................................................................................12
6.3.3. Outcomes Research Endpoints ...................................................................13
6.4. Covariates................................................................................................................13
7. HANDLING OF MISSING VALUES ................................................................................13
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................14


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8.1. Statistical Methods ..................................................................................................14
8.1.1. Analyses of Continuous Data .....................................................................14
8.1.2. Analyses of Categorical Data .....................................................................14
8.1.3. Analyses of Binary Endpoints ....................................................................14
8.1.4. Analyses of Time-To-Event Endpoints ......................................................15
8.2. Statistical Analyses .................................................................................................15
8.2.1. Analysis of Efficacy Endpoints ..................................................................15
8.2.2. Analysis of Safety Endpoints......................................................................16
8.2.2.1. Baseline Characteristics ............................................................16
8.2.2.2. Treatment and Compliance .......................................................16
8.2.2.3. Laboratory Evaluations, Vital Signs, and Cardiac 
Evaluations ........................................................................................17
8.2.2.4. Laboratory Evaluations of Special Interest ...............................17
8.2.2.5. Non-study Medications .............................................................17
8.2.2.6. Death .........................................................................................17
8.2.2.7. Adverse Events..........................................................................17
8.2.2.8. Adverse Events of Special Interest............................................18
8.2.2.9. Additional Safety.......................................................................18
8.2.3. Analyses of B1871040 Patient Disposition Endpoints...............................18
9. REFERENCES ....................................................................................................................19
APPENDICES .........................................................................................................................20
APPENDICES
Appendix 1. HEMATOLOGIC RESPONSE DEFINITIONS.................................................20
Appendix 2. CYTOGENETIC RESPONSE DEFINITIONS..................................................21
Appendix 3. POTENTIALLY CLINCALLY IMPORTANT EVENTS .................................22


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
The SAP version 3.0 amended the original SAP v2.0 dated November 16, 2016.  The main 
changes are COVID-19 related and additional exploratory analyses which included:

Impact on analyses from COVID-19.

Analysis of molecular data.
The SAP version 2.0 amended the original SAP v1.0 dated April 24, 2013.  The main 
changes to align with protocol amendment #1 included:

Add pharmacokinetic (PK) endpoint.

Include imputation of cytogenetic response from molecular monitoring data if
cytogenetics is not performed per standard of care.

Update appendices for cytogenetic and hematologic response criteria.
2. INTRODUCTION
This study is a treatment extension protocol to allow the opportunity of long term treatment 
with bosutinib for subjects who received bosutinib in previous Pfizer sponsored CML studies 
B1871006 and B1871008 and who are thought to have the potential, as judged by the 
investigator, to derive clinical benefit from continued treatment with bosutinib. 
In addition this study:

Will allow collection of long term survival data for all bosutinib subjects who have 
discontinued bosutinib treatment in parent studies B1871006 and B1871008 but are 
known to be alive as of their last long term follow-up visit;

Will provide the opportunity to gather additional long term safety and selected 
efficacy data for bosutinib in all CML subjects, including 1st line subjects in chronic
phase, as well as second, third and even fourth line subjects in chronic, accelerated 
and blast CML phases;

Will satisfy the EMA post- approval commitment to provide safety data about 
diarrhea incidence after the subjects switch from clinical study to commercial 
bosutinib formulation. 
2.1. Study Design
This is an open-label bosutinib treatment extension protocol.  This protocol will be offered to 
those bosutinib patients who were previously enrolled in one of the two parent CML 
bosutinib studies (B1871006 or B1871008).


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Patients to be enrolled will include those who – at the time of this protocol approval - are 
still receiving bosutinib in either one of the parent studies and are benefiting from bosutinib 
treatment as judged by the investigator, as well as those patients who have already 
discontinued bosutinib as part of the parent studies and are in long-term follow-up (LTFU) 
for survival.  The former group will continue to receive bosutinib as part of the extension 
study; the latter group will only enter into the long-term survival follow-up part of the 
extension study.  Data on any subsequent therapy with TKIs or other anti-cancer therapy and 
response following bosutinib will be collected on LTFU patients, if available.
Each patient will remain in the extension study, either on bosutinib treatment or in long-term 
survival follow-up phase, until the last patient has reached 10 years of follow-up, as 
calculated from the date of his/her first dose of bosutinib administered in the parent study.  
When this milestone is reached, the present study will be closed.  At that time patients still 
benefiting from bosutinib will switch to the most appropriate therapy available at that time.
Patients are allocated to the cohort based on the derived assignment from the parent study at
the time of database lock.  Patients will be summarized separately or pooled based on these 
cohorts depending on the specific analysis.  All B1871008 patients are chronic phase CML 
first line (CP1L).  B1871006 patients are either (1) chronic phase CML second line (CP2L) 
resistant or intolerant to imatinib, (2) chronic phase CML third/fourth line (CP3L/CP4L) 
resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib, 
(3) accelerated phase CML resistant or intolerant to imatinib only (AP2L) or resistant or 
intolerant to imatinib and at least one additional TKI including dasatinib and/or nilotinib
(AP3L/AP4L), (4) blast phase CML resistant or intolerant to imatinib only (BP2L) or 
resistant or intolerant to imatinib and at least one additional TKI including dasatinib and/or 
nilotinib (BP3L/BP4L), or (5) Ph+ ALL resistant or intolerant to imatinib only or resistant or 
intolerant to imatinib and at least one additional TKI including dasatinib and/or nilotinib.  
Accelerated phase, blast phase, and Ph+ ALL combined are known as advanced patients.
All data from the 2 parent studies will be combined with data from B1871040 for analysis.  
Only baseline data from the 2 parent studies previously reported in the clinical study reports 
will not be summarized. 
2.2. Study Objectives

To allow long term bosutinib treatment in patients with chronic or advanced phases
Ph+ CML who received bosutinib in a previous Pfizer sponsored CML study
(ie, studies B1871006 and B1871008) and who have the potential, as judged by the
investigator, to derive clinical benefit from continued treatment with bosutinib;

To collect long term safety and efficacy data for bosutinib;

To assess the duration of clinical benefit for Ph+ CML patients treated with 
bosutinib;

To fulfill the European Medicines Agency (EMA) post approval requirement for the
collection and analysis of safety data about diarrhea incidence after switch from
clinical study to commercial bosutinib formulation; 


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
To fulfill the EMA post-approval requirement for the analysis of the PK of bosutinib 
administered once daily.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
There are no interim analyses planned for this study.  The interim analyses were already 
conducted as part of the parent studies, along with the unblinding for patients in B1871008.
The final analysis will be performed when all patients have finished the 10 year follow-up 
period, calculated as 10 years from first dose for B1871008 and B1871006 patients.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses in this study.
4.2. Statistical Decision Rules
There are no statistical decision rules for this study and no adjustments for multiple 
comparisons.  Confidence intervals (CI) are intended for descriptive purposes only.
5. ANALYSIS SETS
5.1. Full Analysis Set
The full analysis set is all patients randomized to the bosutinib arm from B1871008 and all 
dosed patients from B1871006.
5.2. ‘Per Protocol’ Analysis Set 
Per Protocol analyses will not be performed in this study.  The Per Protocol analyses were 
conducted as part of the parent studies for the primary (B1871008, B1871006) and secondary 
(B1871006) endpoints.
5.3. Safety Analysis Set
The safety analysis set are those patients who received at least one dose of bosutinib.  For 
B1871006 patients, this is the same as the full analysis set.
5.4. Other Analysis Sets
The evaluable analysis set are those dosed patients from B1871006 with a valid baseline 
efficacy assessment from B1871006 for the respective endpoint (ie, [1] at least 
20 metaphases or at least 1 Ph+ metaphase from the baseline bone marrow cytogenetic 
assessment or [2] a valid baseline hematologic assessment as defined in Appendix 1 or 
[3] are not from China, South Africa, Russian Federation, or India for molecular analyses as 
molecular samples were not evaluated).  This analysis set will be used as deemed appropriate 
for cytogenetic, hematologic, and molecular analyses for B1871006 patients. There is no 
potential bias expected from utilizing this analysis set as patients are included based on 
baseline information collected prior to the first dose of study medication from B1871006.


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5.5. Treatment Misallocations 
All B1871008 patients were correctly randomized to the appropriate treatment group.  Three 
bosutinib patients were randomized but not dosed.  These 3 patients will be included in the 
full analysis set but not the safety analysis set.  B1871006 was a single arm study so there 
were no treatment misallocations.  One patient was enrolled but not dosed and will be 
excluded from the full and safety analysis sets.
5.6. Protocol Deviations
Per Protocol analyses will not be performed for this study.  The full list of protocol 
deviations for the study report will be compiled prior to database closure.  A listing of
COVID-19 related protocol deviations will be provided.
6. ENDPOINTS AND COVARIATES
There is no formal hypothesis testing therefore endpoints are not designated as primary or 
secondary.
In general, the baseline value will be defined as the last non-missing value prior to first dose 
from B1871008 and B1871006, unless specifically stated otherwise.  Assessments performed 
on Week 1 day 1 will be assumed to be pre-dose per the schedule of activities in the Protocol.
An on-treatment efficacy evaluation is defined as any evaluation done during bosutinib 
therapy or within 30 days of last dose for B1871008 patients and up to date of treatment 
discontinuation for B1871006 patients.  An on-treatment safety evaluation is defined as any 
evaluation done during bosutinib therapy or within 30 days of last dose.
6.1. Efficacy Endpoint(s)

Duration of major/complete cytogenetic response (MCyR/CCyR) for 
B1871006 patients only;

Duration of major/deep molecular response (MMR/MR4) for B1871006 patients 
only; 

Duration of complete hematologic response (CHR) for B1871006 patients only;

Duration of overall hematologic response (OHR) for B1871006 advanced patients 
only;

Progression-free survival (PFS) for B1871006 patients only;

Transformation to accelerated or blast phase for B1871006 patients only;

BCR-ABL mutations present at treatment discontinuation;

Overall Survival (OS).


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Duration of response (DOR) is defined as the time from first response to confirmed loss, 
progression of disease, or on-treatment death due to any cause ([date of loss – date of first 
response]/7).  Response is unconfirmed for cytogenetic and molecular and confirmed for 
hematologic with 2 consecutive responses at least 28 days apart.  Confirmed loss is defined 
as 2 consecutive non-responses at least 28 days apart for MCyR and 14 days apart for 
hematologic, 1 non-response confirmed by progression of disease or death, or no loss of 
response and progression of disease or death.  For CCyR, confirmed loss is defined as 
2 consecutive assessments with >0 Ph+ metaphases or ≥1% positive cells from fluorescence 
in situ hybridization (FISH) at least 28 days apart or progression or death. For MMR,
confirmed loss is defined as 2 consecutive assessments at least 28 days apart with a 
<3-log (>0.1% from B1871006 or MR2 or worse denoted on the B187040 case report form 
[CRF]) reduction in transcripts from standardized baseline one of which corresponds to a
≤2-log reduction (≥1% from B1871006 or MR1 or worse denoted on the B1871040 CRF) or 
progression or death.  For MR4, confirmed loss is defined as 2 consecutive assessments at 
least 28 days apart with a <4-log (>0.01% from B1871006 or MR3 or worse denoted on the 
B187040 CRF) reduction in transcripts from standardized baseline one of which corresponds 
to a ≤3-log reduction (≥0.1% from B1871006 or MR2 or worse denoted on the B1871040 
CRF) or progression or death.  Patients without confirmed loss are censored at the last valid 
assessment where response could be assessed.  Cytogenetic and hematologic responses are 
defined in Appendix 2 and Appendix 1.  MCyR is defined as a CCyR or partial cytogenetic 
response (PCyR).  OHR is defined as CHR or return to chronic phase (RCP).  To be 
considered a responder, the patient must have an improvement from baseline or maintenance 
of baseline response for ≥5 weeks for hematologic response or ≥4 weeks for cytogenetic 
response.  Patients with a non-valid cytogenetic assessment (<20 metaphases) or missing 
baseline assessment must demonstrate the best response, CCyR or CHR, to be considered a 
responder for the respective endpoint.
Molecular response in B1871006 was based on the difference between the subject’s change 
in Bcr-Abl/Abl ratio and a laboratory reference baseline. The Quest (vendor) laboratory 
reference Bcr-Abl/Abl ratio of 4.1325 derived from a pool of 120 previously untreated CML 
subjects was used as the standardized (or reference) baseline. Molecular response was not 
analyzed for subjects in China, India, the Russian Federation, and South Africa due to 
logistical constraints in transporting samples to the central laboratory.
To be considered a responder for MMR in B1871006, a subject must have had at least a 3-log 
reduction from the Quest standardized baseline, a detectable Bcr-Abl transcript at baseline or 
any time post-baseline, and must have maintained or attained a CCyR. Additionally, as a 
conservative approach given the known variability with standard MMR analyses, a subject 
who had a non-CCyR on the same day as the MMR assessment was not considered to have a 
MMR at that time point.  MR4 was defined similar to MMR except at least a 4-log reduction 
was required. In B1871040, responders had MMR/MR4 or better denoted on the CRF as 
assessed by a local laboratory.  On-treatment response is independent of a patient’s baseline 
molecular response.


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PFS is defined as the time from first dose to progression as assessed by the investigator and 
noted as the reason for permanent treatment discontinuation on the CRF or on-treatment 
death due to any cause ([date of progression/death – first dose date]/30.4), whichever occurs 
first.  Patients without events are censored at the last cytogenetic, hematologic, or laboratory 
assessment where progression could be assessed. Progression for B1871006 patients is 
defined as:

Evolution from chronic phase (or from return to chronic phase for advanced subjects) 
to accelerated phase or blast crisis (on two consecutive assessments at least a week 
apart).

Evolution from accelerated phase to blast crisis (on two consecutive assessments at 
least a week apart).

One of the following conditions occurring after dose escalation or presence of 
adverse events prohibiting dose escalation:

For 2nd or later line subjects, loss of major cytogenetic response (need at least 
30% increase).

For all lines of treatment, loss of complete hematologic response confirmed by 
2 assessments at least 2 weeks apart.

For all lines of treatment, increasing WBC defined as doubling of WBC, 
occurring over a period of ≥1 month, with the second WBC >20 x 109/L and
confirmed at least 1 week later.
For DOR and PFS, if there is an unacceptable gap between the date of progression or death 
and the date of the most recent prior disease assessment (>48 weeks), the event will not be 
used and censorship will be at the most recent prior assessment. 
Transformation, defined by the first two progression bullets above, is the time from first dose
to confirmed transformation ([date of transformation – first dose date + 1]/7).  Confirmed 
transformation is defined as 2 consecutive assessments at least 1 week apart or 1 assessment
confirmed by progression of disease or death.  Patients without events are censored at the last 
hematologic or extramedullary assessment where transformation could be assessed.
BCR-ABL mutational status at treatment discontinuation will be assessed.  Emergent 
mutations are defined as those mutations which were not present at baseline.  
B1871006 patients who were not assessed for baseline mutations are not assessable for 
emergent mutations.  All B1871008 patients are assessable for emergent mutations.
OS is defined as the time from randomization for B1871008 patients and from first dose 
B1871006 patients to the date of death ([date of death – randomization/first dose date]/30.4).  
Patients who have not died will be censored at the last known alive date.


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6.2. Safety Endpoints
Treatment-emergent adverse events (TEAE) were defined as any event increasing in severity 
from baseline or any new event starting during bosutinib therapy or within 30 days of the last 
dose of study drug.
6.2.1. Exposure and Compliance
Exposure and compliance data will be collected during this study.  The primary exposure 
endpoints while the patient is on treatment are duration of treatment, cumulative dose 
received, and reasons for dose modifications (reduction, delay, or escalation).  Duration of 
treatment is the time from first non-zero dose to last non-zero dose ([date of last non-zero 
dose – first dose date + 1]/30.4).  Planned dose is based on the initial dose for 
B1871006 patients and randomized dose for B1871008 patients.
6.2.2. Laboratory Evaluations, Vital Signs, and Cardiac Evaluations
Laboratory values, vital signs, electrocardiogram (ECG), and left ventricular ejection fraction 
(LVEF) data from echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) will 
be collected during this study.  Collection time points for these measurements are specified in 
the protocol.  Laboratory values, vital signs, ECG, and LVEF data will be flagged according 
to the potentially clinically important (PCI) criteria for abnormal values.  The PCI criteria for 
laboratory and LVEF values are those with grade 3 or 4 from NCI CTC version 3.0.  The PCI 
criteria for vital signs and ECG are specified in Appendix 3.
For continuous ECG parameters, the average of all valid measurements among the last
performed “triplicate" ECG observed prior to taking the first dose of test article is defined as 
the baseline value.  For Overall Evaluation, the most serious of all valid measurements 
among the last performed “triplicate" ECG observed prior to taking the first dose of test 
article is defined as the baseline value.
If multiple post-baseline observations occur at the same visit, the values used for summaries
and analyses are defined as the following:

For PCI laboratory evaluations, PCI vital signs (and body weight), and PCI LVEF, 
the most serious (highest grade) evaluation will be used for all summaries and
analyses.

For PCI ECG, the mean of the “triplicate” ECGs at each visit will be calculated and 
then the most serious (highest) mean will be used for all summaries and analyses.  For 
Overall Evaluation, the most serious evaluation will be used for all summaries and 
analyses.
6.2.3. Laboratory Evaluations of Special Interest
Laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase
(AST), platelets, neutrophils, and hemoglobin will be summarized.  Endpoints for these 
parameters include distribution of maximum toxicity, time to first event (time from first dose
to date of first event including only non-partial dates), duration of any grade event (time from 
start date to stop date including only non-partial dates), and cumulative duration of grade 


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3/4 events (sum of time from start date to stop date including only non-partial dates for all 
events).
A listing will be provided for patients who potentially meet the Hy’s law criteria.  Potential is 
defined as meeting these 3 criteria any time during the study (non-concurrent): AST or ALT 
level of ≥3 x upper limit of normal (ULN), total bilirubin level of >2 x ULN, and alkaline 
phosphatase level <2 x ULN.  Total Bilirubin, AST, ALT, and alkaline phosphatase will be 
listed.
6.2.4. Non-study Medications
Non-study medications are coded using the World Health Organization (WHO) Drug 
Dictionary.  The Prior, Concomitant, After (PCA) flag for non-study medications will be 
derived: prior non-study medications are defined as any non-study medications taken before 
the first dose of test article administration; concomitant non-study medications are defined as 
any medications taken during the treatment period (includes the 30 days after the last dose of 
the test article); after non-study medications are defined as any non-study medications taken 
during the follow-up period.
6.2.5. Death
Death data will be collected during this study.  Mandatory variables captured are date of 
death and cause of death.  Deaths within 30 days of last dose and death due to AEs are safety
endpoints.
6.2.6. Adverse Events
A 3-tier approach will not be used to summarize AEs since only the bosutinib patients from 
the randomized B1871008 are eligible for this study; the imatinib patients were not offered 
enrollment to this extension protocol.  Furthermore, the B1871006 study was a single-arm 
non-comparative study.
To ensure accuracy and consistency in data analysis and reporting, all adverse events must be 
classified using the Medical Dictionary for Regulatory Activities (MedDRA) before database 
lock (DBL).  The severity of AEs will be assessed using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.  The causal 
relationship between test article and an AE will be assessed by investigator’s judgment. 
AEs will be classified as follows:

TEAEs;

AEs leading to treatment discontinuations;

TEAEs leading to dose reductions;

TEAEs leading to dose delays;

TEAEs by maximum toxicity grade (grades 1 to 5);


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
TEAEs of higher toxicity grades (grades 3 or 4);

TEAEs related to test article;

Serious adverse events (SAEs).
6.2.7. Adverse Events of Special Interest
Adverse events including ALT, AST, thrombocytopenia (including MedDRA preferred term 
[PT] Platelet Count Decreased), neutropenia (including PT Neutrophil Count Decreased), 
anemia (including PT Hemoglobin Decreased), diarrhea, nausea, vomiting, cardiac toxicity 
(definition to be determined before DBL), vascular toxicity (definition to be determined 
before DBL), and renal toxicity (definition to be determined before DBL) will be 
summarized.  Additional AEs or AE clusters may be summarized if deemed appropriate.  AE 
characteristics to be summarized include maximum toxicity, time to first event, duration of 
any grade event, cumulative duration of grade 3/4 events, and successful rechallenge (those 
patients who were re-dosed and did not discontinue bosutinib due to this AE after having a 
dose delay). 
The diarrhea characteristics will also be summarized separately for data from B1871008 and 
B1871006 compared to B1871040 in order to assess the impact of changing to the clinical 
formulation of bosutinib from the parent studies to the commercial formation in this study.  
For ongoing events at the time of the switch to commercial formulation, the stop date for the 
event attributed to the clinical formulation will be set to date of the start of commercial 
formulation minus one and the start date for the event attributed to the commercial 
formulation will be set to the start date of commercial formulation.
6.3. Other Endpoints
6.3.1. PK Endpoints 
Steady-state trough concentrations (Ctrough) of bosutinib will be determined.  A total of 1 PK 
samples per subject will be drawn.  All patients will provide a pre-dose blood sample 
following at least 2 weeks of uninterrupted dosing with bosutinib at the same dose level.  This 
sample will be collected at their first scheduled visit following all appropriate approvals and 
implementation of protocol amendment # 1.  Biological specimen samples for 
pharmacokinetic analysis must be identified with labels provided by the sponsor.
Concentrations of bosutinib will be determined in plasma using a Pfizer -approved and 
validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay.
The objective of the pharmacokinetic analysis is to compare the Ctrough of bosutinib in this 
study to Ctrough of previous studies.  Definitions of and analyses for PK parameters will be 
outlined in a formal PK analysis plan and will not be included in this SAP.
6.3.2. PD Endpoints 
There are no PD data being collected in this study.


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6.3.3. Outcomes Research Endpoints 
There are no outcomes research data being collected in this study.
6.4. Covariates 
Subgroup analyses by gender, age (<65, ≥65), and race (Asian, Black, Other, White) will be 
explored as deemed appropriate.  Additional supportive analyses may be explored if deemed 
appropriate.
The randomization in B1871008 was stratified by region and Sokal score; however, since 
only bosutinib patients from B1871008 are eligible for B1871040, none of the CP1L analyses 
will be stratified.
7. HANDLING OF MISSING VALUES
In general, no imputation such as last observation carried forward (LOCF) will be used.  For 
the time-to-event endpoints, such as DOR, time to transformation, PFS, and OS, the primary 
missing data handling method will be censoring as described in Section 6.1.
In compliance with Pfizer standards for handling partial dates, if the month and year are 
present but day is missing, start date is set to 1st of month, and stop date is set to last day of 
month.  If year is present but day and month are missing, start date is set to January 1st, and 
stop date is set to December 31st.
Handling of missing/incomplete patient cytogenetic data from parent study B1871006 was 
done by the following procedure: for B1871006 baseline visits, only bone marrow 
information is used.  If <20 metaphases at baseline, patients with ≥8 Ph+ will be assigned a 
minor response and those with 1 to 7 Ph+ will be assigned a partial cytogenetic response
(PCyR).  For post-baseline visits in B1871006 and B1871040, bone marrow information with 
20 to 100 metaphases will be used over FISH information with at least 200 nuclei at a 
specific visit.  No conventional bone marrow cytogenetic assessment will be derived when 
>100 cells are reported as analyzed for Philadelphia chromosome as this will be considered 
an error in data entry. If on-treatment molecular monitoring is performed for visits in 
B1871040 in lieu of conventional cytogenetics or FISH, CCyR may be imputed on a specific 
date if an MMR or better is achieved and denoted on the CRF on that date.  The results of 
conventional cytogenetic testing, banding with ≥20 metaphases, will be used in preference to 
molecular testing, provided they are available and performed on the same date however 
molecular results will be used over FISH with ≥200 nuclei if results are discrepant.  Handling 
of missing/mismatched patient hematologic efficacy data for from parent study 
B1871006 was done using the following procedure: for each patient, the observations were 
sorted by visit and the relative day to first dose from B1871006.
First, for each observation, peripheral blood and/or bone marrow differentials should add up 
to 100%.  Some sites may not record 0% to reflect uncounted cell types as instructed.  
Instead, the corresponding field may appear as missing or “ND” even though data collection 
procedures have been vigorously followed.  Also, the differentials may not exactly add up to 
100%.  To correct this problem, each domain of the differentials was summed together.  


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If the total was between 98.5% and 101%, the missing values were assigned 0%.  Otherwise, 
the observation was left as is and the record was also to be reported as a data issue.
Second, for the set of variables collected to derive peripheral blood or bone marrow 
differentials at each post-baseline visit through week 12 on B1871006, if a given set were
still incomplete, a non-missing set of lab variables obtained ±3 days from the scheduled visit 
was utilized to complete the derivation.  For visits after week 12 (relative to first 
B1871006 dose) from B1871006 and B1871040, a non-missing set of lab variables obtained 
±7 days of the visit will be utilized to complete that post-baseline assessment.  For 
B1871006, the last non-missing peripheral blood or bone marrow differentials collected at 
week 1 day 1 or up to 28 days prior to week 1 day 1 was used for baseline assessment.  For 
example, if the bone marrow blast count was missing, the entire non-missing bone marrow 
assessment, not just the blast field, from another observation was used.  Some data handling
rules for data combination are specified below.

Data combination is needed only when the full dataset is not available on a single day 
at a given visit.  The full dataset includes peripheral blood differential for chronic 
phase, and both bone marrow and peripheral blood differentials for advanced phase.  
The extramedullary assessment when absent should not preclude the derivation, and 
when present should be taken into account per response criteria rules.

During the post-baseline data combination, for visits up to and including week 12
from B1871006, the ±3 window will be applied to days 1 and 7 separately; for visits 
after week 12 (relative to first B1871006 dose) from B1871006 and B1871040, the 
±7 window will be based on day 7 only.  The latest date will be used as the date of 
visit and the more conservative value will be taken if there is more than one 
measurement for a variable.  For platelet counts, in case of multiple values, the lowest
value will be taken.  If any value falls above or below normal range, the out-of range
value will be taken.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Analyses of Continuous Data
For continuous variables, the descriptive statistics include n, mean, median, standard
deviation (SD), and range (minimum, maximum).
8.1.2. Analyses of Categorical Data
For categorical variables, the descriptive statistics include the count in each category, the 
total n, and percentage.
8.1.3. Analyses of Binary Endpoints
Exact 2-sided 95% CIs will be provided for molecular, cytogenetic, and hematologic 
response rates.


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8.1.4. Analyses of Time-To-Event Endpoints
For time-to-event endpoints such as DOR, time to transformation, PFS, and OS, the method 
of analysis will either be Kaplan-Meier (K-M) or cumulative incidence of the event adjusting 
for the competing risk of treatment discontinuation due to any reason without the event 
(Gray).1
When applying the K-M method, medians and quartiles with the associated 2-sided 95% CI 
will be provided.  The CIs are based on the Brookmeyer-Crowley linear transformation 
method will be provided.  The K-M yearly rates with the associated 2-sided 95% CI based on 
Greenwood’s formula will also be provided.
When applying the cumulative incidence method, yearly rates with the associated 2-sided 
95% CI based on the delta method using a log transformation will be provided.
8.2. Statistical Analyses 
The efficacy endpoints will be analyzed according to the cohorts specified in Section 2.
8.2.1. Analysis of Efficacy Endpoints
The duration of cytogenetic, hematologic, and molecular response analyses are based on the 
full analysis set for the subset of B1871006 patients who respond for the respective endpoint.  
The K-M method, as described in Section 8.1, will be used provided most responding 
patients transferred to B1871040 remain on treatment until progression or loss of response.  
The percentage of MR4, MMR, MCyR, CCyR, and PCyR and CHR and major hematologic 
response (MHR)/OHR (advanced patients only) for the respective endpoint, along with 
confirmed losses and censored patients still on-treatment will be summarized.
The time to transformation analysis is based on the full analysis set for the 
B1871006 patients.  Cumulative incidence of transformation adjusting for the competing risk 
of treatment discontinuation due to any reason without transformation, as described in 
Section 8.1, will be used.  The percentage of transformation without treatment 
discontinuation and the percentage of treatment discontinuation due to any reason without 
transformation will be summarized.  The specific disease stage transformation (accelerated or 
blast phases) will also be listed.
The PFS analysis is based on the full analysis set for the B1871006 patients.  The K-M 
method, with or without unsatisfactory response as assessed by the investigator as an event 
and cumulative incidence of on-treatment progression or death adjusting for the competing 
risk of treatment discontinuation due to any reason without the event, as described in 
Section 8.1, will be used.  For K-M, the percentage of on-treatment death or progression, 
with or without unsatisfactory response as an event, will be summarized.  For cumulative 
incidence, the percentage of on-treatment death or progression without treatment 
discontinuation and the percentage of treatment discontinuation due to any reason without 
on-treatment progression and death will be summarized.


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The OS analysis is based on the full analysis set for all patients.  The K-M method, as 
described in Section 8.1, will be used.  The number of deaths and causes of death will be 
summarized.  Time on study from date of randomization for B1871008 patients and date of 
first dose for B1871006 patients to date of last contact, and reasons for discontinuing 
participation will also be summarized.
The percentage of patients with emergent mutations will be summarized.
Missing values and incomplete data will be handled as described in Section 7 of this analysis 
plan.
Listings for all efficacy data will also be provided.
No COVID-19 related efficacy analyses will be performed as efficacy is only summarized
for data up through 10 years after start of the parent study and all patients enrolled in 
B1871040 except one reached 10 years of follow-up prior to the March 11, 2020 COVID-19
anchor date and all China patients reached 10 years of follow-up prior to their 
January 9, 2020 anchor date.  A summary of missing molecular and cytogenetic data before 
and after the anchor dates will be summarized for patients enrolled in B1871040.
A listing of COVID-19 related study discontinuations will be provided.
8.2.2. Analysis of Safety Endpoints
The safety analysis set will be used for all safety analyses unless specifically stated 
otherwise.  The safety endpoints will be analyzed according to the cohorts specified in 
Section 2 and also analyzed as a pooled set of all treated patients from B1871006 and
B1871008.
8.2.2.1. Baseline Characteristics
Demographic, medical history, and other baseline characteristics will not be summarized for 
B1871040 as this information resides solely in the parent study databases.  This summary 
information will be taken directly from the B1871006 and B1871008 clinical study reports.
8.2.2.2. Treatment and Compliance
Descriptive statistics for continuous exposure variables treatment duration and cumulative 
received dose, and received dose over time (% receiving 600, 500, 400, 300, 200, or 0 mg at 
specific time points) will be calculated.
The number and percentage of patients with at least one dose reduction due to AE, dose 
delay due to AE, and escalation to 600 mg will be summarized.  The number and percentage 
of patients who experienced more than 1 event will also be summarized.
The number and percentage for reasons for treatment discontinuation will be summarized and 
listed.  A listing of COVID-19 related treatment discontinuations will be provided.


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8.2.2.3. Laboratory Evaluations, Vital Signs, and Cardiac Evaluations
The incidence of clinical laboratory, QTcF/QTcB, and LVEF abnormalities by maximum 
toxicity categorized by NCI CTC V3.0 grade will be presented at baseline, during the 
treatment period, and post treatment period.
Laboratory values that are outside the normal range also be flagged in the data listings.  Any
out-of-range values that are identified as being clinically significant will be presented in a
data listing. PCIs for ECG, LVEF, vital signs and body weight will also be flagged in 
listings.
A summary of missing safety data before and after the anchor dates will be summarized for 
patients enrolled in B1871040.
8.2.2.4. Laboratory Evaluations of Special Interest
The number and percentage of maximum on-treatment grade 0 through 4 for ALT, AST, 
platelets, neutrophils, and hemoglobin will be summarized.  Descriptive statistics for time to 
first event, duration of any grade event, and cumulative duration of grade 3/4 events will be 
calculated for each of these parameters. 
8.2.2.5. Non-study Medications
A listing of non-study medications data will be reported. 
8.2.2.6. Death
The number of deaths within 30 days of last dose and cause of these deaths will be 
summarized.
8.2.2.7. Adverse Events
The number and percentage of AEs listed below will be summarized overall and by 
MedDRA body system and PT.  Sorting will be done alphabetically by body system and then 
by decreasing frequency of PT.

TEAEs;

AEs leading to treatment discontinuations;

TEAEs leading to dose reductions;

TEAEs leading to dose delays;

TEAEs by maximum toxicity grade (grades 1 to 5);

TEAEs of higher toxicity grades (grades 3 or 4);

TEAEs related to test article;

Serious adverse events (SAEs);


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
COVID-19 related TEAEs.
8.2.2.8. Adverse Events of Special Interest
The number and percentage of maximum treatment-emergent CTCAE grade events and 
successful rechallenge for ALT, AST, thrombocytopenia (including MedDRA PT Platelet 
Count Decreased), neutropenia (including PT Neutrophil Count Decreased), anemia 
(including PT Hemoglobin Decreased), diarrhea, nausea, and vomiting will be summarized.  
Descriptive statistics for time to first event, duration of any grade event, and cumulative 
duration of grade 3/4 events will be calculated for each of these parameters.
The number and percentage of maximum treatment-emergent CTCAE grade events over time 
for diarrhea will be summarized.  Only patients receiving treatment within a given time 
period will be included in the denominator for this time period.  The incidence relative to the 
first dose of both the parent studies and the first dose of B1871040 will be calculated 
separately.  Furthermore, the incidence relative to the last dose of bosutinib from the parent 
studies will also be calculated in order to see the percentage of patients experiencing diarrhea
during the last 6 months prior to enrolling in B1871040.  Time to first event in B1871040, 
defined as any new event in B1871040 or any increase in severity for ongoing events from 
B1871006 or B1871008, and duration of B1871040 events will also be summarized.
8.2.2.9. Additional Safety
Listings of physical examination data, chest x-ray, and ECOG performance status will be 
provided.
8.2.3. Analyses of B1871040 Patient Disposition Endpoints
The listings of violations of B1871040 inclusion/exclusion criteria will be reported.  This 
study will include the summaries of the numbers of patients who: sign the informed consent 
form (ICF), are screening failures, are enrolled, and are part of the full/safety/evaluable 
analysis sets.  Descriptive statistics for the duration on-study (time from first dose for 
B1871006 patients and randomization for B1871008 patients to last contact and time from 
first dose on B1871040 to last contact) will also be calculated.


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9. REFERENCES 
1.
A class of k-sample tests for comparing the cumulative incidence of a competing risk. 
Gray, RJ. 3, 1988, Annals of Statistics, Vol. 16, pp. 1141-1154.


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APPENDICES 
Appendix 1. HEMATOLOGIC RESPONSE DEFINITIONS
Hematologic Responses
Definition
Return to Chronic Phase (RCP) (or CP 
for subjects with CP) 
Minor Hematologic Response (MiHR) 
(for Ph+ ALL subjects)
Subjects had to meet all criteria
Disappearance of features defining accelerated and blast 
phases, but still in chronic phase as noted by:

<15% Blasts in both blood and marrow

<30% Blasts + promyelocytes in both blood and marrow

<20% Basophils in both blood and marrow (marrow not 
applicable for Ph+ ALL)

No extramedullary involvement other than liver/spleen
Accelerated Phase
had to meet at least 1 criterion

15-29% Blasts in blood or marrow

≥30% Blasts + promyelocytes in blood or marrow

≥20% Basophils in blood or marrow
only applicable to advanced phase

Platelets <100x109/L (not related to therapy) 
Blast Phase
had to meet at least 1 criterion

≥30% blasts in blood or bone marrow

Extramedullary involvement other than liver/spleen
No Evidence of Leukemia (NEL)
had to meet all criteria

WBC ≤institutional ULN

450 x109/L > Platelets ≥20x109/L

ANC ≥0.5x109/L

<20% basophils in blood

No blasts or promyelocytes in blood

Myelocytes + metamyelocytes <5% in blood

No extramedullary involvement (incl. hepato- or 
splenomegaly)
only applicable for advanced phase 

≤5% bone marrow blasts 
Complete Hematologic Response (CHR)
had to meet all criteria

WBC ≤ institutional ULN

Platelets <450 × 109/L

<20% basophils in blood

No blasts or promyelocytes in blood 

Myelocytes + metamyelocytes <5% in blood

No extramedullary involvement (incl. hepato- or 
splenomegaly)
only applicable to advanced phase

≤5% bone marrow blasts 

ANC ≥1.0 × 109/L 

Platelets ≥100 × 109/L
Overall Hematologic Response (OHR)
had to meet at least 1 criterion
CHR +NEL +RCP + MiHR
(if applicable)
Major Hematologic Response (MHR)
(had to meet at least 1 criterion)
CHR +NEL
Abbreviations: ANC=absolute neutrophil count, ULN=upper limit of normal range, WBC=white blood cell 
count


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Appendix 2. CYTOGENETIC RESPONSE DEFINITIONS
Cytogenetic Responses*
% Philadelphia chromosome positive cells
None
>95% 
Minimal
66-95%
Minor
36-65%
Partial
1-35%
Complete
0% from conventional cytogenetics or <1% from FISH
Major
Complete + Partial Rates
* Based on analysis of 200 nuclei if done from blood sample or based on analysis of 20 metaphases if done 
from bone marrow sample.  


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Appendix 3. POTENTIALLY CLINCALLY IMPORTANT EVENTS
Potentially Clinically Important Criteria for Vital Signs and Body Weight
Variable
Criteria
Heart rate
Value <40 beats/min and value >150 beats/min
Systolic blood pressure
<80 or >210 mmHg
Diastolic blood pressure
<40 or >130 mmHg
Temperature
<32 or >40°C
Body weight
Change of greater than or equal to 10% in body weight
Respiratory Rate
<10 or >50 breaths/min
Potentially Clinically Important Criteria for Electrocardiogram Evaluations
Variable
Criteria
Heart rate
Increase >15 beats/min and value ≥120 beats/min
Decrease 15 beats/min and value 45 beats/min
PR interval
Increase of 20 msec and value 220 msec
QRS interval
Value ≥120 msec
QTcF interval  
Value >500 msec
Increase >60 msec
QTcB interval
Value >500 msec
Increase >60 msec
Abbreviations: min=minute; QTcB=QT interval corrected using the Bazett formula; QTcF=QT interval 
corrected using the Fridericia formula; VS=vital signs.