Clinical trial NCT02228382
Conditions: Previously Treated PH + CML
Keywords: Bosutinib Chronic Myeloid Leukemia CML Leukemia Myelogenous Chronic BC-ABL Positive
Sponsor: Pfizer
Start date: 2014-11-07; Completion date: 2020-10-13
Enrollment: 163 participants; Allocation: NA; Intervention model: 

Brief summary:
The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients with high unmet medical need, including 75 Chronic Phase, Accelerated Phase or Blast Phase patients in the fourth or later line treatment setting (i.e., after treatment with at least 3 other Tyrosine Kinase Inhibitors).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Bosutinib
Intervention descriptions: intervention 1: 100 mg and 500 mg tablets, once daily dosage up to 4 years duration

Protocol documents:
Prot_000.pdf: 
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A PHASE 4 SAFETY AND EFFICACY STUDY OF BOSUTINIB (BOSULIF®) IN 
PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE CHRONIC 
MYELOID LEUKEMIA PREVIOUSLY TREATED WITH ONE OR MORE 
TYROSINE KINASE INHIBITORS
Investigational Product Number:
PF-05208763
Investigational Product Name:
Bosutinib
United States (US) Investigational New 
Drug (IND) Number:
68,268
European Clinical Trial Database 
(EudraCT) Number:
2013-003250-25
Protocol Number:
B1871039
Phase:
Phase 4
This document and accompanying materials contain 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
Original 
protocol
21 January 2014
Not applicable (N/A)
Amendment 1
07 September 
2017
Protocol Summary, Table 1: Updated for consistency to 
reflect the revisions in the protocol body;
Protocol Summary & Section 1.2.3: Added decision to 
decrease the number of patients in the 4th-/later-line
cohort from the initial target of 75 to at least 45 
patients. 
Protocol Summary & Section 2: Added biobanked 
biospecimens as an exploratory objective as per new 
protocol template and a result of the Biospecimen 
Work Group initiative;
Protocol Summary, Table 1, and Section 7. Clarified if 
bone marrow or peripheral blood sample is required for  
mutation analysis of the tyrosine kinase domain, when 
the assessment will be performed, and that the same 
sample will be used to perform qRT-PCR and mutation 
analysis; 
Protocol Summary, Table 1, Sections 2.2 3, 6, 7.1.1.1, 
and 9.2.1:  Removed the requirement of karyotype 
imaging submissionfor independent central review; 
Protocol Summary Updated to provide scientific 
rationale regarding the inclusion of the Ph- CML 
patients in this study;
Protocol Summary, Added a definition of “Full 
Analysis Set” (FAS); 
Protocol Summary, Table 1, Section 7: Clarified 
contraceptive check requirements;
Protocol Summary, Table 1, Section 6 & 7: hepatitis B 
serology testing added to screening tests;
Protocol Summary Table 1: Updated to  add footnotes 
regarding contraception checks and coagulation tests 


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(footnotes);
Protocol Summary Updated to provide further 
clarifications to footnotes;
Protocol Summary, Table 1, Sections 6 and 7, and 
Appendices 5 and 11: Made changes reflective of the 
latest version of  European LeukemiaNet (ELN) 
recommendations for the management of chronic 
myelogenous leukemia (CML) (published in 2013);
Protocol Summary, Sections 2.1, 2.2.1.2, and 9.2.2: 
Updated to add new secondary endpoints composed of 
duration of CCyR duration of MMR and clarifications 
regarding the analysis of the primary endpoint;
Section 1.2.1: Updated to add information about 
ponatinib (Iclusig), a third-generation TKI;
Section 1.2.2: Updated the number of patients treated 
with bosutinib in clinical studies as of 01 September 
2016.
Section 1.2.2 & section  2:  Incorporated updates to the 
Biospecimens language text on biobanked 
biospecimens as per new protocol template;
Section 2: Combined the Obectives and endpoints 
section into a table format according to new protocol 
template To clearly show the relationship between each 
objective and its associated endpoint;
Section 2: Added biobanked biospecimens as an 
exploratory objective as per new protocol template and 
a result of the Biospecimen Work Group initiative;
Sections 3:Updated to include timeframe for complete 
blood count,  cytogenetic and molecular assessments;
Section 4.1: Inclusion criterion clarification: “All 
patients must have screening bone marrow (BM) 
cytogenetic analysis with conventional banding 
performed within 30 days prior to study entry”; 
Section 4.1: Inclusion criterion clarification regarding 
chronic hemolysis for the total bilirubin assessment;


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Section 4.2: New exclusion criterion added for 
hydroxyurea or anagrelide  during screening for their 
use within 72 hours preceding CML disease 
assessment; 
Section 4.3: Clarified special warnings related to QTc 
prolongation based upon recent pharmacological study 
results;
Section 4.3: Removed the sentence, “Patients on 
medications that are substrates of P-glycoprotein who 
cannot be switched to alternative medications that are 
not substrates of P-glycoprotein” as a recent 
pharmacological study did not show interaction 
between bosutinib and substrates of P-glycoprotein; 
Section 4.3: Updated information regarding the 
concomitant use of CYP3A inhibitors and inducers 
based on recent pharmacological studies results;
Section 4.3 and 5.2.2: Updated information regarding 
renal impairment during bosutinib treatment based on 
clinical study results.  Updated recommended dose 
modification in the non-hematological toxicity table if  
renal impairment to align with the product label; 
Section 4.4 Lifestydle guidelines: Contraception 
language was updated for clarity based on stakeholder 
feedback in new protocol template;
Section 5: Added definition of investigational product 
as per new protocol template to help distinguish 
between investigational products and non-
investigational products used in a study;
Section 5.1: New section added to define instructions 
on allocation to treatment process description; 
Section 5.2: Dose modification guidelines updated to 
align with clinical practice;
Section 5.3: Disease progression criteria updated 
according to the CML disease phase;
Section 5.4.3: Added language regarding vomited dose 
instructions;


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Section 5.4.1: Clarified local drug supply prescription 
requirement specifically for Ph+ CML patients, per 
local regulations in certain countries;
Section 5.4.3: Added language regarding vomited dose 
instructions;
Section 5.4.3: Medication error definition updated per 
new protocol template and moved to section 8.4.4;
Section 5.5: Updated section on IP storage and  
temperature excursion as per new protocol template;
Section 5.5.1: Added section on destruction of 
investigational product as per new protocol template;
Section 5.6.2: Clarified the use of blood cell 
transfusions and growth factors regarding CBC 
assessment for data analysis due to impact on 
assessment for response; also clarified the use of 
hydroxyurea or anagrelide during bosutinib treatment; 
and use of corticosteroids during bosutinib treatment; 
Section 5.7.3: Clarified header and reference to 
Appendix 3 regarding full list of drugs that could lead 
to QTc prolongation;
Section 6: Clarified when disease assessment should be 
performed;
Section 6.1: Clarified previous treatments data 
collection, as only previous therapies for CML should 
be recorded in the CRF;
Section 6.1: Reference to appendix 1 removed;
Section 6.1: Clarified acceptable documentation of 
CML diagnosis;
Section 6.1: Added collection of medical history, 
smoking status at screening visit;
Section 6.1: Added screening window extension for 
chest X-ray, ECHO, and MUGA scan to allow for 
flexibility;
Section 6.1: Bone marrow aspirate not needed when 


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disease status is proven to be MMR by qRT-PCR;
Section 6.1 & 6.2: Clarified whether blood or bone 
marrow sample will be used for molecular response 
and mutational analysis;
Section 6.1 & 6.2: Added Hepatitis serology at 
screening;
Section 6.1: Added serum pregnancy test as acceptable 
and contraceptive check;
Section 6.2: Clarified additional tests required if 
clinically indicated (HbA1C, cholesterol, HDLc, LDLc, 
Hepatisi B;
Section 6.2: Added contraceptive checks and 
pregnancy tests, coagulation tests;
Section 6.2 & 6.3: Added collection of current smoking 
status;
Section 6.2: Clarified that the degree of CyR is 
assessed from bone marrow exclusively until 
achievement of CCyR. Then the use of FISH until 
MMR is reached is possible. Added guidance in case of 
loss of CCyR;
Section 6.2: Added guidance when progression and/or 
failure is suspected;
Section 6.2: Added guidance on molecular response 
assessment;  
Section 6.2: Added guidance on blood and plasma for 
biobanking collection at the time of first response;
Section 6.3: Added FACT-leu administration at EOT;
Section 6.4: Clarified  bone marrow transplantation 
treatment data collection during follow-up phase; 
Updated requirements for long-term follow-up phase: 
new TKI treatment, time to disease progression, or 
Section 7.1.1.1: Clarified Cytogenic response 
assessment;
Section 7.1.1.2: Clarified CHR criteria used for 


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Accelerated Phase (AP) and Blast Phase (BP) CML;
Section 7.1.1.4: Clarified Molecular Response 
assessment;
Section 7.2: Clarified that patient diary card and Fact 
leu should be verified for potential AEs, as advised by 
PRC;
Section 8: Changes made to various sections of the AE 
Reporting Section to align with new protocol template. 
Section 8: Updated the Potential Cases of Drug-
Induced Liver Injury language; 
Section 8: The active collection periods for recording 
non-serious AEs and serious adverse events (SAEs) on 
Case Report Forms and reporting SAEs to Pfizer Safety 
have been modified according to new protocol 
template;
Section 9: updated to align with changes made to other 
sections of the protocol;
Section 9.1 updated sample size to reflect the decreased 
number of patients needed in the 4th line cohort (from 
75 to at least 45);
Section 9.5 updated to clarify review conducted on 
unblinded data in an open label study (as per new 
protocol template);
Section 9.6: Clarified  that periodic safety review will 
be applied by an internal safety review team with 
medical and statistical capabilities;
Section 10: Added the following sentence to the 
Quality Control and Quality Assurance section: The 
investigator site and investigator will promptly resolve 
any discrepancies that are identified between the study 
data and the patient's medical records. Statement added 
in conjunction with the contrat unique (France) 
process. Legal requested this sentence to be included in 
the protocol template;
Section 13.2: Updated to clarify timeframe for End of 


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Trial;
Section 16, References: 2 new references added for 
ponatinib hydrochloride; 1 new reference added for the 
treatment with growth factors defined by ASCO 
guidelines; 2 new references added for the prior ELN 
recommendations (2006 and 2009); 1 new reference 
added for the definition of hematological response for 
AP and BP CML;
Appendix 1 (former): Removed prior TKI guidelines 
defining resistance and intolerance to previous TKI and 
added guidelines for resistance or intolerance to 
previous TKIs; 
Appendix 2: Updated CYP3A4 inhibitors and inducers 
based on completion of recent bosutinib 
pharmacological studies; 
Appendix 7: Clarified criteria to Identify Phase of 
CML;
Appendix 9: Updated text for Hy’s Law, coagulation, 
pregnancy, glucose, HbA1C, and lipid tests due to 
inconsistencies, and added the requirement of 
monitoring potassium and magnesium levels to follow 
as clinically indicated;
Appendix 11: Updated text for CP CML patients per 
ELN recommendations (2013), and added a new table 
to define hematological response for AP and BP CML;
Minor administrative corrections adding clarifications 
and removing inconsistences made throughout the 
protocol;
Updated language throughout the protocol related to 
changes in the Sponsor’s clinical trial protocol 
template.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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PROTOCOL SUMMARY
Background and Rationale:
Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual Src-Abl tyrosine 
kinase inhibitor (TKI) that has been approved for the treatment of adult patients with 
Philadelphia chromosome positive (Ph+) chronic phase chronic myelogenous leukemia  
previously treated with other TKI therapy.
Chronic myelogenous leukemia (CML) is the fourth most commonly occurring adult 
leukemia. CML traditionally follows a triphasic course with most patients being diagnosed 
in an initial oligosymptomatic chronic phase (CP) which eventually progresses into a more 
advanced accelerated phase (AP) and culminates in a blast phase (BP), which resembles a 
highly treatment-refractory form of acute leukemia that generally shows either a myeloid or a 
lymphoid phenotype.  The transformation of CML from a deadly cancer 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, including imatinib, bosutinib, dasatinib, 
nilotinib, and ponatinib.1, 2, 3, 4, 5 The transition of patients with CML from CP to BP with an 
intermediate AP is becoming less standard with the chief determinants of survival being
disease stage and TKI responsiveness. 
On September 4, 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 (United States Prescribing Information 
BOSULIF®). More recently, on March 27, 2013, the European Medicines Agency (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 TKIs and 
for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options
(EMA Summary of Product Characteristics).
Furthermore, in 5%–10% of patients with of chronic myelogenous leukemia (CML), the 
Philadelphia chromosome (Ph) is not identified despite the presence of the associated BCR-
ABL molecular abnormality (Ph-negative, BCR-ABL-positive CML) because of sub-
microscopic rearrangements. Regardless, the presence of the BCR-ABL fusion gene will 
translate into a BCR-ABL fusion protein with dysregulated tyrosine kinase activity. 
Therefore, a TKI targeting BCR-ABL is also an effective treatment also for Ph negative 
CML patients. The FDA and EMA approvals were granted based on the results obtained 
from the single-arm, Phase 1/2 study (3160A4-200-WW, “Study-200”) in adult patients with 
Ph+ leukemias who had failed prior TKI therapy, and with the support of the safety results 
obtained from the Phase 3 study (3160A4-3000-WW) comparing bosutinib with imatinib in 
newly diagnosed CP Ph+ CML patients.  In addition, the EMA was provided with descriptive 
narrative information from the bosutinib compassionate use program in patients with 
Ph+CML who had received at least one prior TKI treatment and had progressed or were 
intolerant, and otherwise not considered suitable for other TKI therapy, as well as efficacy 
and safety analyses from a subset of Study-200 patients whose disease had failed prior 
imatinib and/or dasatinib or nilotinib and were contraindicated for treatment with dasatinib or 
nilotinib, as well as 4th-line CML patients on the study.


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The purpose of this phase 4 study is to fulfill the post-authorization commitment made by 
Pfizer to the EMA in providing additional safety and efficacy data in approximately 150 Ph+ 
CML patients with high unmet medical need, including approximately 75 CP, AP or BP 
patients in the 2nd/3rd-line cohort and at least 45 patients in the 4th or later line treatment
setting (i.e., after treatment with at least 3 other TKIs).
The EMA conditional approval requires completion of this post-authorization study in order 
to convert the conditional approval to a full marketing authorization approval.
Study Objectives:
Primary Objectives

To estimate the 1-year (Week 52) probability of cumulative confirmed Major 
Cytogenetic Response (MCyR) in CP Ph+ CML patients with 1 or 2 prior lines of 
TKI therapy. 

To estimate the 1-year (Week 52) probability of cumulative confirmed MCyR in 
CP Ph+ CML patients with 3 or more prior lines of TKI therapy. 

To estimate the 1-year (Week 52) probability of cumulative confirmed Overall 
Hematological Response (OHR) in AP and BP Ph+ CML patients with any prior 
TKI therapy.
Secondary Objectives

To estimate the probability of cumulative MCyR in each disease phase (CP, AP 
and BP) for Ph+ CML patients. 

To estimate the probability of cumulative confirmed OHR in each disease phase 
(AP and BP) for Ph+ CML patients by number of lines of prior therapy.

To characterize the distributions of best response (molecular, cytogenetic, or 
hematologic) in the CP, AP, and BP Ph+ CML patient populations.

To estimate the probability of MCyR at 3, 6, 12, 18, and 24 months in the CP, AP, 
and BP Ph+ CML patient populations.

To estimate the probability of confirmed OHR at 3, 6, 9, 12, 18, and 24 months in 
the AP and BP Ph+ CML patient populations.

To estimate the probability of cumulative confirmed Complete Hematological 
Response (CHR) in the CP, AP and BP Ph+ CML patient populations.

To estimate the probability of cumulative major molecular response (MMR) in 
the CP, AP and BP Ph+ CML patient populations. 

To estimate the duration of Complete Cytogenetic Response (CCyR).


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
To estimate the duration of MMR.

To evaluate the overall safety profile of bosutinib in the study population.
Exploratory Objectives

To obtain preliminary estimates of Progression Free Survival (PFS) and Overall 
Survival (OS) in 4th or later line CP, AP and BP Ph+ CML patients.

To identify BCR-ABL mutations associated with sensitivity or resistance to 
bosutinib, as well as to catalog possible acquired resistance mutations. 

To explore efficacy (hematologic and molecular response) in Ph- CML patients.  

To evaluate patient reported outcomes measures.

To collect banked biospecimens for exploratory research, unless prohibited by 
local regulations or ethics committee decision.
Primary Endpoints

Cumulative confirmed MCyR defined as Complete Cytogenetic Response 
(CCyR) or Partial Cytogenetic Response (PCyR) by 1 year (52 weeks) in 2nd and 
3rd line CP patients.

Cumulative confirmed MCyR by 1 year (52 weeks) in 4th and later-line CP 
patients.

Cumulative confirmed OHR defined as Complete Hematological Response 
(CHR) or Return to CP (RCP) by 1 year (52 weeks) in AP and BP patients.
Secondary Endpoints

Cumulative MCyR in CP, AP, and BP patients.

Cumulative confirmed OHR in AP and BP patients by line of therapy.

Cumulative best response in CP, AP, and BP patients.

MCyR at 3, 6, 12, 18, and 24 months in CP, AP, and BP patients.

Confirmed OHR at 3, 6, 9, 12, 18, and 24 months in AP and BP patients.

Cumulative confirmed CHR.

Cumulative MMR in CP, AP, and BP patients.


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
Duration of CCyR.

Duration of MMR.

Assessment of adverse events will include type, incidence, severity (graded by the 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse 
Events [CTCAE] v. 4.0), timing, seriousness, and relatedness; and laboratory 
abnormalities.
Exploratory Endpoints

PFS in 4th or later line CP patients.

OS in 4th or later line CP patients.

Presence of BCR-ABL mutations.

For Ph- CML patients, cumulative best response (CHR and MMR) anytime on 
treatment.

Patients Reported Outcome (PRO) endpoints such as those measured by 
Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu).

Collection of banked biospecimens unless prohibited by local regulations or ethics 
committee decision.  Additional information on collection and potential use is 
provided in the Banked Biospecimens section.
Study Design
This is a single-arm, open-label, non-randomized, multi-center Phase 4 study to evaluate 
bosutinib (Bosulif®) in patients with CP/AP/BP Ph+ CML whose disease has failed prior 
treatment with commercially available TKIs due to drug resistance or intolerance, or are 
otherwise contraindicated for treatment with commercially available TKIs such as imatinib, 
dasatinib, or nilotinib (i.e., presence of a BCR-ABL mutation or medical condition making 
commercially available TKIs unsuitable for a patient).  Patients will receive bosutinib for at 
least 4 years from the time of first dose, unless disease progression, unacceptable toxicity, 
patient withdrawal of consent, death or Sponsor discontinuation of study.  Patients 
discontinuing bosutinib prior to completing at least 4 years of therapy will be followed for 
survival until they complete at least 4 years of follow-up from the time of first dose. Patients 
completing at least 4 years of bosutinib with continued benefit may be switched to 
commercially available therapy at that time.
Cytogenetic and molecular assessments will be performed at baseline and every 3 months
until Week 52, then at 6- month intervals during Years 2, 3, and 4 of treatment.  Complete 
blood counts should be performed weekly for the first month, then 4 weeks later and
thereafter per the visit schedule (Table 1), and as clinically indicated.  Hematologic, 
cytogenetic and extramedullary disease assessments will be done locally, while molecular 


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monitoring of BCR-ABL transcript levels and mutational analysis of the BCR-ABL kinase 
domain will be performed by a central laboratory and carried out by independent central 
analysis.  Patient participation will conclude not more than 4 years after the first dose. 
Study Treatment
Patients will receive bosutinib 500 mg orally once dailywith food. Bosutinib commercial 
formulation of 100 mg and 500 mg tablets will be provided.
Statistical Methods
This study does not include any formal sample size determination.  Approximately 
150 patients with Ph+ CML will be enrolled including approximately 45 CP, AP, and BP 
patients in the 4th or later line treatment setting.
The primary analyses will be the percentage of cumulative confirmed MCyR (for CP Ph+
CML patients) and cumulative confirmed OHR (for AP and BP Ph+ CML patients) by 1 year
of bosutinib treatment (week 52). Confirmed MCyR will be defined as (1) the attainment of 
confirmed MCyR (CCyR or PCyR) by 1 year for patients entering the study without CCyR 
achieved on the previous TKI therapy or (2) the maintenance of confirmed CCyR (achieved 
under the previous TKI therapy) for at least 1 year after starting treatment with bosutinib or 
(3) at least MMR by 1 year and a deeper molecular response compared to baseline. Patients 
with baseline PCyR that do not achieve CCyR are included in the analysis but they would be 
counted as non-responders. Initial cytogenetic (in the absence of MMR) and hematologic 
responses must be confirmed by 2 consecutive assessments at least 28 days apart.
Secondary efficacy analyses include the percentage of cumulative MCyR, cumulative 
confirmed OHR, cumulative MMR, cumulative best response, landmark MCyR and OHR, 
cumulative confirmed CHR, duration of CCyR and duration of MMR.   
All treated Ph+ CML patients with a valid baseline efficacy assessment for the respective 
endpoint will be included in the molecular, cytogenetic, and hematologic efficacy analyses.  
All treated Ph+ CML patients will be included in the other efficacy analyses.  Analyses will 
be presented by disease stage (e.g., CP, AP, BP) and/or line of therapy (e.g., CP 2nd line 
[CP2L], CP 3rd line [CP3L], CP 4th or later line [CP4L], AP2L, AP3L, AP4L, BP2L, BP3L, 
BP4L).
Ph- CML patients will be analyzed separately and only for cumulative CHR and molecular 
endpoints.
Descriptive summaries and confidence intervals (if applicable) will be provided; no 
inferential analyses are planned for this study.
The exploratory time-to-event endpoints of OS and PFS will be summarized using the 
Kaplan-Meier method or by cumulative incidence, whichever is more relevant.


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The Full Analysis Set (FAS) will include all patients who receive at least 1 dose of study 
drug. The Evaluable Population will include all patients with a valid baseline assessment for 
the respective endpoint.  All molecular, cytogenetic, and hematologic statistical analyses will 
be based on the Evaluable Population and the remaining efficacy analyses will be based on 
the FAS.
The FACT-Leu will be scored according to the respective user’s guides and validation 
papers.  Summary statistics of the Functional Assessment of Cancer Therapy-Leukemia 
(FACT-Leu) quality of life questionnaire will be calculated at baseline and approximately 
every 3 months for the first year, and then every 6 months during year 2, 3, and 4 of 
treatment on study.   
All safety analyses will be based on the FAS.  


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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 sections of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities table in order to conduct evaluations or assessments required to protect 
the well-being of the patient.
On Treatment
End of 
Treatment
Follow-Up
Protocol Activity
Screening
Week 
1, Day 
1
(pre-
dose)
Weeks
1, 2, 3, 
4, and 8 
on Day 
7
Weeks 
13,
26, 39
and 52
Weeks
78, 104, 
130, 
156, 
and 182 
Weekp
Every 3 
months 
up to 4 years 
after first dose
Visit Time Window
30 days
+/- 1 
day
+/- 7 
days
+/- 21 
days
+/- 7 days
+/- 7 days
Informed Consent
X
Medical History 
X
Cancer Diagnosis/ History
X
ECOG Performance Score
X
X
X
X
Physical Examination
X
X
X
X
Vital Signs (blood pressure, 
heart rate, height, weight)
X
X
X
X
Smoking Statusa
X
X
X
X
Contraception Checkb
X
X
X
X
X
X
Laboratory
Hematologyc
X
X
X
X
X
X
Blood Chemistry
X
X
X
X
X
X
Liver Functiond
X
X
X
X
X
X
Coagulation Testse
X
X
X
X
X
X
Pregnancy Testf
X
X
X
X
X
Chest X-rayg
X
As clinically indicated
X
ECHO or MUGA scanh
X
As clinically indicated
X
ECG
X
As clinically indicated
X
Registrationi
Xi
Bosutinib Treatment 
Continuous Daily
Efficacy Assessments
Hematologic Assessment
X
X
X
X
X
X
Cytogenetic Assessmentj
X
X
X
X
Molecular  Assessmentk
X
X
X
X
Mutation Analysisl
X
X
Extramedullary Disease
Assessmentm
X
As clinically indicatedm
X
Adverse Events
Continuous
X
Concomitant Medications
Continuous
X
FACT-Leu 
X
X
X
X
Blood and plasma for 
biobankingn
X
As clinically indicatedn
X
Hepatitis B serologyq
X
As clinically indicated
Survival
Xo
The 3-monthly visits will be performed at approximately 13-week intervals.


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a.
The use of TKIs could lead to cumulative long-term cardiovascular disease therefore smoking status will be 
collected. Past and present smoking status will include: smoking type (if the patient ever smoked), if the 
patient is a current smoker, or ex-smoker and, if appropriate, duration since the patient last stopped 
smoking, and the number of units consumed/day (e.g. number of cigarettes; number of pipes; number of 
cigars, etc.).
b.
Contraceptive Check: patients of child-bearing potential will be required to affirm their use of 2 highly 
effective methods of contraception until 28 days after their last dose of bosutinib which will be documented 
in the patient’s source document.
c.
Hematology to include complete blood count (CBC) including a WBC with differential, platelet count, and 
neutrophil count (see Appendix 9).  Complete blood counts should be performed weekly for the first 
month, then 4 weeks later and thereafter per the visit schedule, and as clinically indicated.
d.
Direct bilirubin must be collected if total bilirubin is > 1.5 x ULN and for any Hy’s Law determination, if 
appropriate (see Section Appendix 9).
e.
Coagulation tests including: either prothrombin time (PT) or international normalized ratio (INR); and 
partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT).
f.
A urine or serum pregnancy test should also be done whenever one menstrual cycle is missed during 
treatment (or potential pregnancy is otherwise suspected).  Pregnancy tests may also be repeated as per 
request of IRB/ECs or if required by local regulations.  
g.
Standard of care chest X-ray results may be used for screening if not longer than 12 weeks prior to the first 
bosutinib dose in the absence of past medical history of pulmonary disease.  If the patient has past medical
history of pulmonary disease or ongoing pulmonary co-morbidities chest X-ray should be obtained within 7 
days prior to the first bosutinib dose.
h.
Standard of care echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan results may be used for 
screening if not longer than 12 weeks prior to the first bosutinib dose in the absence of past medical history 
of cardiovascular disease and presence of normal left ventricular ejection fraction (LVEF). If the patient 
has past medical history of cardiovascular disease or ongoing cardiovascular co-morbidities, ECHO or 
MUGA scan should be obtained within 7 days prior to the first bosutinib dose.  Screening, unplanned, and 
End of Treatment assessments should be consistent (e.g. assessment should be performed with the same 
test, ECHO or MUGA scan, to evaluate cardiac function).
i.
Patients must be registered to the study after protocol eligibility is confirmed and within 3 days prior to 
receiving the first dose of bosutinib. 
j.
Conventional cytogenetic assessment:

It is required for all patients at screening, (unless the CML disease status is proven to be MMR by 
quantitative reverse transcription polymerase chain reaction (qRT-PCR). Standard of care bone 
marrow analysis (morphology and G-banding) within 30 days prior to screening may be used for 
screening results; or bone marrow aspirate must be collected for morphological assessment (% of bone 
marrow differential) and local conventional cytogenetic assessment (with at least 20 metaphases), 
Percentage (%) of Ph+ metaphases, as well as any other chromosomal abnormalities, will be 
documented. Conventional Cytogenetic assessment should be continued until MMR. Only 
chromosome banding analysis of marrow cell metaphases can be used to assess the degree of 
cytogenetic response (CyR) (with at least 20 metaphases analyzed).

Upon achieving CCyR by the conventional cytogenetic assessment, fluorescent in situ hybridization 
(FISH) of blood interphase cell nuclei with an appropriate probe (Dual-Color Dual-Fusion  or Dual-
Fusion FISH) could substitute for chromosome banding analysis of marrow cell metaphases for the 
assessment of maintenance of the CCyR (which is then defined by <1% BCR-ABL-positive nuclei of 
at least 200 nuclei) until MMR is reached, Loss of CCyR using FISH requires resumption of bone 
marrow conventional cytogenetic assessment.


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
A bone marrow aspirate for morphology (% bone marrow differential) and conventional cytogenetic 
assessment is also required for all patients at the time of suspected progression and/or failure. 
Note:The cytogenetic assessment needs to be repeated at 28 days later to confirm CCyR CML disease 
status for Ph+CML patients (when the cytogenetic response is first observed in the absence of MMR,  
e.g once CCyR is achieved by G-banding,  FISH is needed to confirm the achievement/maintenance of 
CCyR at least 28 days later).
Note: In Ph- CML patients, conventional cytogenetic assessment (to detect other potential cytogenetic 
abnormalities) and molecular cytogenetic assessments using FISH are required only at screening and at 
time of suspected progression and/or failure.
k.
qRT-PCR for molecular assessment (BCR-ABL fusion transcripts) will be performed by a central 
laboratory. For Chronic-Phase (CP) CML, the assessment will be performed using peripheral blood 
samples. For Advanced Phase CML (Accelerated Phase [AP] and Blast Phase [BP]) the assessment will be 
performed using peripheral blood and/or bone marrow samples.Confirmed loss of MMR requires 
resumption of bone marrow cytogenetic assessments.
l.
Mutational analysis of the BCR-ABL kinase domain will be performed by an independent central 
laboratory at baseline and End of Treatment for CP, AP and BP CML patients and during treatment for 
patients with baseline mutations. Mutation analysis will also be performed if there is loss of response as
indicated by a rise in BCR-ABL transcript levels of at least 5-fold that has been confirmed by more than 
one test and/or disease progression.  For CP CML, the assessment will be performed using peripheral blood 
sample. For Advanced Phase (AP and BP) CML, the assessment will be performed using peripheral blood 
and/or bone marrow samples. Mutational analysis will be performed from the peripheral blood or bone 
marrow samples that were used for the molecular response assessment.
m. Patients presenting with symptoms or signs of CNS involvement at screening must be evaluated by lumbar 
puncture to confirm eligibility. Extramedullary disease will be evaluated by chest X-ray and physical 
examination (e.g., liver, spleen, lymph nodes). Sites of extramedullary disease identified at screening 
should be followed during the course of treatment. Patients should be evaluated upon suspicion of new 
extramedullary disease.
n.
Blood and plasma samples will be collected for biobanking if specifically allowed by local EC/IRB; 1 tube 
of whole blood (prep D1) and 1 tube of plasma (prep B1) will be collected at the time points indicated in 
the Schedule of Activities. B1 and D1 samples will also be collected at the time of first response, where 
response is a major cytogenetic response for CP patients and a hematologic response for AP/BP patients
when feasible. These additional biobank response samples should be obtained at the next scheduled visit if 
the next scheduled visit occurs within 2 months after the first response. If the next scheduled visit occurs >2 
months after the first response, the sample should be collected at an unscheduled visit within 2 months after 
the first response, if feasible, unless this is the End of Treatment visit. If not collected on the designated 
collection day, collect at the next available time point when biospecimens are being collected in 
conjunction with a subject visit.  
o.
End of Treatment visit should be done at Week 208 for those patients completing 4 years on bosutinib 
therapy, or at any time the patient meets any of the criteria for early discontinuation of bosutinib, whichever 
is earlier.  Patients continuing to receive benefit from bosutinib at the time of study conclusion may switch 
to commercially available therapy. Note: 1 year = 52 weeks.
p.
Patients discontinuing treatment prior to 4 years from first dose will be followed for survival (telephone 
contact acceptable) until the patient has completed at least 4 years on study (from time of first dose) or 
sooner if the patient withdraws consent for disclosure of future information.
q.
Hepatitis B serology testing will be included in the screening tests and thorughtout the study as clinicaly 
indicated. Hepatitis B reactivation has been reported with Tyrosine Kinase Inhibitors (TKI’s).


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TABLE OF CONTENTS
TABLE OF CONTENTS.........................................................................................................18
LIST OF TABLES...................................................................................................................21
APPENDICES .........................................................................................................................21
1. INTRODUCTION ...............................................................................................................22
1.1. Indication.................................................................................................................22
1.2. Background and Rationale ......................................................................................22
1.2.1. Therapeutic Options for CML ....................................................................22
1.2.2. Bosutinib (BOSULIF®) ..............................................................................23
1.2.3. Study Rationale...........................................................................................28
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................29
3. STUDY DESIGN.................................................................................................................30
4. PATIENT SELECTION......................................................................................................31
4.1. Inclusion Criteria.....................................................................................................31
4.2. Exclusion Criteria....................................................................................................33
4.2.1. Philadelphia Chromosome Negative (Ph-) CML Patients..........................34
4.3. Special Warnings and Precautions ..........................................................................34
4.4. Life Style Guidelines...............................................................................................35
4.5. Sponsor’s Qualified Medical Personnel..................................................................36
5. STUDY TREATMENTS.....................................................................................................36
5.1. Allocation to Treatment ..........................................................................................37
5.2. Dose Modifications .................................................................................................37
5.2.1. Bosutinib Dose Escalation..........................................................................38
5.2.2. Dose Adjustments for Adverse Reactions..................................................38
5.3. Bosutinib Treatment Discontinuation .....................................................................40
5.4. Investigational product Supplies.............................................................................42
5.4.1. Formulation and Packaging........................................................................42
5.4.2. Preparation and Dispensing........................................................................43
5.4.3. Administration............................................................................................43
5.4.4. Compliance.................................................................................................43
5.5. Investigational Product Storage and Accountability...............................................43
5.5.1. Destruction of Investigational Product Supplies ........................................44


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5.6. Concomitant Medication(s).....................................................................................45
5.6.1. Prohibited....................................................................................................45
5.6.2. Permitted.....................................................................................................45
5.6.3. Other Concomitant Treatment Considerations...........................................46
5.6.4. Interaction with other Medicinal Products and Other Forms of 
Interaction ........................................................................................................46
6. STUDY PROCEDURES .....................................................................................................48
6.1. Screening.................................................................................................................48
6.2. Study Period ............................................................................................................50
6.3. End of Treatment Visit (±7 days)............................................................................53
6.4. Long-Term Follow-Up Visit ...................................................................................54
6.5. Patient Withdrawal..................................................................................................54
7. ASSESSMENTS..................................................................................................................55
7.1. Efficacy Assessments..............................................................................................55
7.1.1. Efficacy Assessment Methods....................................................................55
7.2. Safety Assessment Methods....................................................................................58
7.3. Safety Laboratory Determinations ..........................................................................58
7.4. Pregnancy Testing...................................................................................................58
7.5. Banked Biospecimens .............................................................................................59
7.5.1. Markers of Investigational Product Response............................................59
7.5.2. Additional Research....................................................................................60
7.6. Biological Samples..................................................................................................60
7.7. Health Outcomes Assessment .................................................................................61
7.7.1. Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)..........61
8. ADVERSE EVENT REPORTING......................................................................................62
8.1. Requirements...........................................................................................................62
8.1.1. Additional Details on Recording Adverse Events on the CRF...................63
8.1.2. Eliciting Adverse Event Information..........................................................63
8.1.3. Withdrawal From the Study Due to Adverse Events (see also Section 
on Patient Withdrawal) ....................................................................................63
8.1.4. Time Period for Collecting AE/SAE Information......................................63
8.1.5. Causality Assessment .................................................................................64
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................65


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8.2. Definitions...............................................................................................................65
8.2.1. Adverse Events...........................................................................................65
8.2.2. Abnormal Test Findings .............................................................................66
8.2.3. Serious Adverse Events ..............................................................................66
8.2.4. Hospitalization............................................................................................67
8.3. Severity Assessment................................................................................................68
8.4. Special Situations ....................................................................................................68
8.4.1. Protocol-Specified Serious Adverse Events...............................................68
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................69
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................70
8.4.4. Medication Errors .......................................................................................72
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................73
9.1. Sample Size Determination.....................................................................................73
9.2. Efficacy Analysis ....................................................................................................73
9.2.1. Analysis of Primary Endpoint ....................................................................73
9.2.2. Analysis of Secondary Endpoints...............................................................74
9.3. Analysis of Other Endpoints ...................................................................................75
9.4. Safety Analysis........................................................................................................75
9.5. Interim Analysis ......................................................................................................76
9.6. Data Monitoring Committee ...................................................................................76
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................76
11. DATA HANDLING AND RECORD KEEPING .............................................................77
11.1. Case Report Forms/Electronic Data Record .........................................................77
11.2. Record Retention...................................................................................................77
12. ETHICS..............................................................................................................................78
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................78
12.2. Ethical Conduct of the Study ................................................................................78
12.3. Patient Information and Consent...........................................................................78
12.4. Patient Recruitment...............................................................................................79
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................79
13. DEFINITION OF END OF TRIAL...................................................................................79


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13.1. End of Trial in a Member State.............................................................................79
13.2. End of Trial in all other Participating Countries...................................................80
14. SPONSOR DISCONTINUATION CRITERIA ................................................................80
15. PUBLICATION OF STUDY RESULTS..........................................................................80
15.1. Communication of Results by Pfizer ....................................................................80
15.2. Publications by Investigators ................................................................................81
16. REFERENCES ..................................................................................................................82
LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES ............................................................................15
Table 2.
Available Dose Levels..........................................................................................37
Table 3.
Non-Hematologic Treatment-Related Toxicity....................................................39
Table 4.
Hematologic Treatment-Related Toxicity............................................................40
APPENDICES
Appendix 1. Guidelines for Identifying Resistance and Intolerance .......................................85
Appendix 2. Selected Strong and Moderate CYP3A4 Isoenzyme Inhibitors and 
Inducers.................................................................................................................86
Appendix 3. Summary of Drugs That Are Generally Accepted to Have a Risk of 
Causing QTc Prolongation Potentially Causing Torsades de Pointes..................87
Appendix 4. Patient Information Card.....................................................................................88
Appendix 5. European Leukemia Net Definition of Response to Second-Generation 
TKIs for Chronic Phase Second-line CML Patients.............................................90
Appendix 6. Sample Patient Diary Card..................................................................................92
Appendix 7. Criteria to Identify Phase of CML ......................................................................93
Appendix 8. Eastern Cooperative Oncology Group (ECOG) Performance Status .................94
Appendix 9. Local Laboratory Collection Requirements........................................................95
Appendix 10. FACT-Leu (Version 4)......................................................................................96
Appendix 11. European LeukemiaNet Guidelines for Response in CML...............................99


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1. INTRODUCTION
1.1. Indication
Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual Src-Abl tyrosine 
kinase inhibitor (TKI) that has been approved for the treatment of adult patients with 
Philadelphia chromosome positive (Ph+) chronic phase (CP), accelerated phase (AP) and 
blast phase (BP) chronic myelogenous leukemia (CML) previously treated with other TKI
therapy.6
1.2. Background and Rationale
CML is the fourth most commonly occurring leukemia in adults.  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.  The molecular product of the t(9;22) 
translocation is the BCR-ABL1 oncogene, which encodes the constitutively activated BCR-
ABL1 kinase that activates several downstream signaling pathways that mediate 
myeloproliferation, resistance to apoptosis and genetic instability. In 5%–10% of patients 
with of chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph) is not 
identified, despite the presence of the associated BCR-ABL molecular abnormality (Ph-
negative, BCR-ABL-positive CML) because of sub-microscopic rearrangements. Regardless, 
the presence of the BCR-ABL fusion gene will translates into a BCR-ABL fusion protein 
with dysregulated tyrosine kinase activity. Therefore, TKI targeting BCR-ABL is an 
effective treatment also for Ph negative CML patients.
The transition of patients with CML from CP to BP with an intermediate AP is becoming less 
standard with the chief determinants of survival being disease stage and TKI responsiveness.
1.2.1. Therapeutic Options for CML
Imatinib (Gleevec, Glivec) has improved the prognosis for many patients with CML 
worldwide. Imatinib was granted approval by the European Commission in November 2001 
and by the United States Food and Drug Administration (FDA) in December 2002 for the 
treatment of newly diagnosed patients with CP Ph+ CML based on results from the IRIS 
trial. 
However, after 8 years of follow-up, only 55% of the patients originally randomized to the 
imatinib arm remain on study drug chiefly due to failure to achieve CCyR (17%), loss of 
CCyR (15%), and intolerance to imatinib (approximately 5%).7 While several mechanisms 
of imatinib resistance have been proposed, the best known and possibly the most clinically 
prevalent are lack of adherence/compliance (which may reflect adverse events in some 
patients) and/or the development of BCR-ABL1 mutations, which alter drug sensitivity and 
can be detected in approximately 40-50% of patients with CP CML in which imatinib has 
failed.7
In order to overcome these mechanisms of resistance, second-generation TKIs have been 
developed.8 However, despite the success of imatinib and the second-generation TKIs 
nilotinib and dasatinib, some patients are intolerant to these drugs or have disease that 


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progresses despite therapy. As with imatinib, these second generation TKIs may have their 
therapeutic potential compromised by the development of resistance, including BCR-ABL1
mutations, and/or intolerance. 
As dasatinib and nilotinib have only recently been approved for the first line treatment of CP 
CML, there are limited data regarding disease management and outcome after failure in the 
frontline treatment setting.9, 10
In the second-line treatment setting, between 40%-50% of patients with CP CML who are 
treated with dasatinib or nilotinib do not achieve a MCyR with either agent.3, 4 In AP CML, 
35% of patients treated with dasatinib and 65% of those treated with nilotinib do not achieve 
an MHR. In BP CML, for which dasatinib is an approved second-generation TKI, MHR is 
not achieved in over 50% of patients, and current therapies are inadequate.11, 12, 13 Resistance 
to both these agents likely occurs through a variety of mechanisms, including Abl kinase 
domain mutations.14
Recently, the third-generation TKI inhibitor ponatinib hydrochloride (Iclusig) was approved 
for the treatment of adult patients with T315I-positive chronic myeloid leukemia (CP, AP, or 
BP) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ 
ALL) and for treatment of adult patients with CP, AP, or BP CML or Ph+ ALL for whom no 
other tyrosine kinase inhibitor (TKI) therapy is indicated. On 20 December 2013, FDA 
began requiring several new safety measures for ponatinib hydrochloride to address the risk 
of life-threatening blood clots and severe narrowing of blood vessels with ponatinib
hydrochloride treatment.15, 16
In addition, the safety profiles of dasatinib and nilotinib potentially limit their use. A known 
toxicity associated with dasatinib is serosal inflammation (pleural and/or pericardial effusion
(SprycelUnited States Prescribing Information (USPI) or Summary of Product 
Characteristics (SmPC). In addition, uncommon cases (0.1 to 1%) of sudden deaths have 
been reported in patients with imatinib-resistant or intolerant CML in CP or AP with a past 
medical history of cardiac disease or significant cardiac risk factors when treated with 
nilotinib (TasignaUSPI or SmPC).  Myelosuppression, hepatic and/or pancreatic 
dysfunction, peripheral occlusive arterial disease, cardiac or pulmonary compromise, 
bleeding diatheses, autoimmune disorders, diabetes mellitus, and a history of other 
malignancy or immune suppression are all of concern in individual patients when considering 
dasatinib or nilotinib therapy.17, 18, 19, 20, 21, 22, 23
Therefore, there is a continued unmet medical need for CML patients, with an urgent need 
for new treatment options such as bosutinib for adult CML patients resistant or intolerant to 
currently available TKIs, which was recently approved as described below. 
1.2.2. Bosutinib (BOSULIF®)
As of 01 September 2016, approximately 2033 patients have received at least 1 dose of 
bosutinib in 28 clinical studies. These included 19 clinical pharmacology studies (17 studies 
in healthy volunteers, 1 study in patients with hepatic impairment, and 1 study in patients 
with renal impairment) and 9 clinical studies in patients with cancer. Of the clinical studies 


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conducted in patients with cancer, 3 studies were conducted in patients with advanced 
malignant solid tumors who received bosutinib as a single agent, 3 studies were conducted in 
breast cancer patients with bosutinib in combination with another anticancer agent, and 3 
studies were conducted in patients with Ph+ leukemias with bosutinib as a single agent.
On September 4, 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 March 27, 2013, the European Medicines 
Agency (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, “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 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 Study 200 patients.
Efficacy and safety data from the Phase 1/2 study, Study 200, and the Phase 3 study, Study 
3000, are presented below according to phase of disease and line of therapy, as of 28 March
2011 for efficacy and 15 February 2012 for safety (Study 200) and as of 26 September 2011
(Study 3000).  Pooled safety data from Study 200, Study 3000, and the Phase 1/2 Japanese 
study, Study 2203, are presented below as of 15 November 2010. The most current safety 
data are contained in the Investigator’s Brochure.  
Second-Line CP CML
A total of 288 CP CML patients were enrolled and treated in the second-line setting in Study 
200. 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.  


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In the evaluable population of second-line CP CML (n=287), 85.0% achieved cumulative 
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 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 
(i.e., third line) and 3 CP CML patients who received imatinib followed by dasatinib and 
nilotinib (i.e., fourth line) were enrolled and treated in Study 200. 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 
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.


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Advanced Leukemias
A total of 164 patients with advanced Ph+ leukemia were enrolled and treated in Study 200. 
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%.
Pooled Second-line and Third-Line CP CML and Advanced Leukemias
Summary safety data across all patient cohorts in Study 200 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, 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 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 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%), 


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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.
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 diarrhoea (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%), diarrhoea (9.1%), rash (6.1%), lipase increased (5.2%) and aspartate 
aminotransferase increased (5.0%).
Additional information for bosutinib may be found in the Single Reference Safety Document 
(SRSD), which for this study is the Bosutinib Investigator’s Brochure.


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Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of patients who
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study. Banked biospecimens retained in the BBS also can be used in research on CML.
Providing these biospecimens is a required study activity for study sites and patients, unless 
prohibited by local regulations or ethics committee (EC) decision. 
1.2.3. Study Rationale
The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to 
the EMA in providing additional safety and efficacy data in approximately 150 patients with 
Ph+ CML whose disease had failed or who are otherwise not appropriate for treatment with 
dasatinib, nilotinib or imatinib TKI, including at least 75 patients in the 4th line treatment
setting (i.e., after treatment with at least 3 other TKIs).  The EMA conditional approval 
requires completion of this post-authorization study in order to convert the conditional 
approval to a full marketing approval. 
This study was initiated in November 2014 and the original target projection was 75 patients 
in each cohort. However, the 4th line cohort has not met its planned targeted enrollment 
objective; whereas, the 2nd /3rd-line cohort has overenrolled (n=106). Therefore, Pfizer 
decided based on CHMP feedback to stop recruitment after at least 45 patients have been 
enrolled in the 4th line cohort. It was further agreed, there are sufficient numbers of patients 
in each cohort to perform an informative descriptive analysis of the safety and efficacy and 
safety of bosutinib.


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Primary Endpoint(s):
To estimate the 1-year (52-week) probability of 
cumulative confirmed Major Cytogenetic Response 
(MCyR) in CP Ph+ CML patients with 1 or 2 prior 
lines of TKI therapy.
Cumulative confirmed MCyR defined as Complete 
Cytogenetic Response (CCyR) or Partial 
Cytogenetic Response (PCyR) by 1 year (52 weeks) 
in 2nd and 3rd line CP patients.
To estimate the 1-year (52-week) probability of 
cumulative confirmed MCyR in CP Ph+ CML 
patients with 3 or more prior lines of TKI therapy.
Cumulative confirmed MCyR by 1 year (52 weeks) 
in 4th and later line CP patients.
To estimate the 1-year (52-week) probability of 
cumulative confirmed Overall Hematological 
Response (OHR) in AP and BP Ph+ CML patients 
with any prior TKI therapy.
Cumulative confirmed OHR defined as Complete 
Hematological Response (CHR) or Return to 
Chronic Phase (RCP) by 1 year (52 weeks) in AP 
and BP patients.
Secondary Objective(s):
Secondary Endpoint(s):
Efficacy
To estimate the cumulative probability of MCyR in 
each disease phase (CP, AP and BP) for Ph+ CML 
patients.
Cumulative MCyR in CP, AP and BP patients.
To estimate the cumulative probability of confirmed 
OHR in each disease phase (AP and BP) for Ph+ 
CML patients by number of lines of prior therapy.
Cumulative confirmed OHR in AP and BP patients 
by line of therapy.
To characterize the distributions of best response 
(molecular, cytogenetic, or hematologic) in the CP, 
AP, and BP Ph+ CML patient populations.
Cumulative best response in CP, AP, and BP 
patients.
To estimate the probability of MCyR at 3, 6, 12, 18, 
and 24 months in the CP, AP, and BP Ph+ CML 
patient populations.
MCyR at 3, 6, 12, 18, and 24 months in CP, AP, and 
BP patients.
To estimate the probability of confirmed OHR at 3, 
6, 9, 12, 18, and 24 months in the AP and BP Ph+ 
CML patient populations.
Confirmed OHR at 3, 6, 9, 12, 18, and 24 months in 
AP and BP patients.
To estimate the probability of cumulative confirmed 
CHR in the CP, AP and BP Ph+ CML patient 
populations.
Cumulative confirmed CHR.
To estimate the probability of cumulative major 
molecular response (MMR) in the CP, AP, and BP 
Ph+ CML patient populations.
Cumulative MMR in CP, AP, and BP patients.
To estimate the duration of CCyR.
Duration of CCyR.
To estimate the duration of MMR.
Duration of MMR.


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Safety
To evaluate the overall safety profile of bosutinib in 
the study population.
Assessment of adverse events will include type, 
incidence, severity (graded by the National Cancer 
Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE] v. 4.0), timing, 
seriousness, and relatedness; and laboratory 
abnormalities.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):
To obtain preliminary estimates of Progression Free 
Survival (PFS) and Overall Survival (OS) in 4th or 
later line CP, AP and BP Ph+ CML patients.
PFS in 4th or later- line CP patients. 
OS in 4th or later line CP patients.
To identify BCR-ABL mutations associated with 
sensitivity or resistance to bosutinib, as well as to 
catalog possible acquired resistance mutations.
Presence of BCR-ABL mutations.
To explore efficacy (hematologic and molecular
response) in Ph- CML patients.
For Ph- CML patients, cumulative best response 
(CHR and MMR) anytime on treatment
To evaluate patient reported outcomes measures
PRO endpoints such as those measured by FACT-
Leu.
To collect banked biospecimens for exploratory 
research, unless prohibited by local regulations or 
ethics committee decision. 
Collection of banked biospecimens unless 
prohibited by local regulations or ethics committee 
decision.  Additional information on collection and 
potential use is provided in the Banked 
Biospecimens section.
Cytogenetic assessments will be carried out locally. The local cytogenetic assessments will 
be used for the primary endpoint analysis in CP patients. Molecular assessments will be 
performed at a central laboratory.  Endpoint analysis for molecular response will be carried 
out by independent central analysis. The local hematologic assessments will be used for the 
primary endpoint analysis in AP and BP patients.
3. STUDY DESIGN
This is a single-arm, open-label, non-randomized, multi-center Phase 4 study to evaluate 
bosutinib (Bosulif®) in patients with chronic or advanced CP/AP/BP Ph+ CML who have 
failed prior treatment with TKIs which are commercially available, due to drug resistance or 
intolerance, or are otherwise contraindicated for treatment with commercially available TKIs 
such as imatinib, dasatinib, and nilotinib (i.e., presence of a BCR-ABL mutation or medical 
condition making commercially available TKIs unsuitable for a patient).  Patients will 
receive bosutinib for at least 4 years from the time of first dose, unless disease progression, 
unacceptable toxicity, withdrawal of consent by patient, death or discontinuation of study by 
Sponsor.  Patients discontinuing bosutinib prior to completing 4 years of therapy will be 
followed for survival until they complete at least 4 years on studyof follow-up from the time 
of first dose.  Patients completing at least 4 years of bosutinib with continued benefit may be 
switched to commercially available therapy at that time.


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Cytogenetic and Molecular assessments will be performed at baseline and every 3 months 
until Week 52, then at 6 -month intervals during Years 2, 3, and 4 of treatment.  Complete 
blood counts should be performed weekly for the first month, then 4 weeks later and 
thereafter per the visit schedule (Table 1) and as clinically indicated.
Hematologic, cytogenetic and extramedullary disease assessments will be done locally, while 
molecular monitoring of BCR-ABL transcript levels and mutational analysis of the BCR-
ABL kinase domain will be performed by a central laboratory and carried out by independent 
central analysis.  Local cytogenetic assessment will be repeated at least 28 days later to 
confirm on-treatment CCyRCML disease status (when the CCyR is first observed in the 
absence of MMR). Patient participation will conclude no sooner than 4 years after first dose. 
Approximate Duration of Study: The end of the study will be considered to be the last visit of 
the last patient for purposes of closing out sites, informing the site or regional institutional 
review board/ethics committee (IRB/EC), and terminating distribution of Council for 
International Organizations of Medical Sciences (CIOMS) reports; however, for other 
purposes the end of the study will be the last patient last visit.
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 participation in the study is 
considered appropriate. All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
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. Cytogenetic or PCR-based diagnosis of Ph+ CML or BCR-ABL1+ if Ph- (from 
initial diagnosis). NOTE: Ph- CML patients will not count towards the 150 
patients for primary and secondary analyses, which include Ph+ CML patients 
only.
NOTE: All patients must have screening bone marrow (BM) cytogenetic analysis
with conventional G banding performed within 30 days prior to study entry
(unless CML disease status is proven to be MMR by quantitative reverse 
transcription polymerase chain reaction [qRT-PCR]).  Examination of at least 20 
metaphases is required.
2. Prior treatment with 1 or more TKIs for CML.
3. Any CML phase, as long as the patient is resistant to, intolerant of, or otherwise 
not appropriate for treatment with imatinib, dasatinib and/or nilotinib.


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4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 for 
CP patients, or 0, 1, 2, or 3 for 4th line CP (and beyond) and AP/ BP patients.
5. Adequate bone marrow function:

For 2nd and 3rd line CP CML patients: 

Absolute neutrophil count >1000/mm3 (>1 x109/L).

Platelets ≥75,000/mm3 (≥75 x109/L) absent any platelet transfusions 
during the preceding 14 days.

For 4th line CP and AP/BP CML patients:

Absolute neutrophil count >500/mm3 (>0.5 x109/L).

Platelets ≥50,000/mm3 (≥50 x109/L) absent any platelet transfusions 
during the preceding 14 days.
6. Adequate hepatic and renal function:

AST/ALT ≤2.5 x the upper limit of normal (ULN) or ALT/AST ≤5 x ULN if 
attributable to liver involvement of leukemia.

Total bilirubin ≤1.5 x ULN (unless the bilirubin is principally unconjugated
and there is a strong suspicion of subclinical hemolysis (e.g. chronic 
hemolysis without clinical symptoms), or the patient has documented Gilbert's 
Disease);

Alkaline phosphatase 2.5 x ULN.

Creatinine ≤1.5 x ULN or estimated creatinine clearance (CrCL) 60 mL/min 
as calculated using the standard method for the institution.
7. Able to take daily oral tablets.
8. Age 18 years.
9. Evidence of a personally signed and dated informed consent document indicating 
that the patient (or a legally acceptable representative/legal guardian) has been 
informed of all pertinent aspects of the study.
10. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.


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11. Male and female patients of childbearing potential must agree to use two 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.
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) (Phase 1-4) within 
14 days or 3 half-lives (whichever is longer) prior to the first dose of bosutinib.
2. Prior bosutinib or ponatinib exposure.
3. Prior hydroxyurea or anagrelide exposure within 72 hours of the baseline CML 
disease assessment.
4. Known T315I or V299L mutation in BCR-ABL1.
5. Clinically active leptomeningeal leukemia.  Patients must be free of central 
nervous system (CNS) involvement for a minimum of 2 months.  
6. Hypersensitivity to the active substance or to any of the following excipients: 
Microcrystalline cellulose (E460), Croscarmellose sodium (E468), Poloxamer 
188, Povidone (E1201), Magnesium stearate (E470b), Polyvinyl alcohol, 
Titanium dioxide (E171), Macrogol 3350, Talc (E553b), Iron oxide red (E172).
7. Pregnant or breastfeeding females.  
8. Males and females of childbearing potential who are unwilling or unable to use 
two highly effective methods of contraception as outlined in this protocol for the 
duration of the study and for at least 28 days after last dose of investigational 
product.
9. 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.
10. 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.


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4.2.1. Philadelphia Chromosome Negative (Ph-) CML Patients
Patients whose CML is BCR-ABL1 positive and Philadelphia chromosome negative (Ph-)
will be permitted to enroll.  These patients will be in addition to, and not contribute to 
analysis of, the approximately 150 Ph+ CML patients planned for this study. Due to the lack 
of data on and treatment options available for this small subset of CML patients, they will be 
classified and analyzed in a separate, stand-alone cohort. Patients must meet all other 
eligibility criteria based on their stage of disease, and will be treated in an identical manner 
as Ph+ CML patients. However, due to their lack of the Ph chromosome, they will be
followed for hematologic and molecular response only, as well as safety. 
4.3. Special Warnings and Precautions
The following are not exclusion criteria, however investigators are advised to proceed with 
caution and ensure appropriate monitoring if enrolling patients with any of the following (see 
Section 5.6.4 Interaction with other Medicinal Products and Other Forms of Interaction for
more information and Appendix 1):

Automated machine-read QTc prolongation without accompanying arrhythmia has been 
observed.  Patients who have a history of or predisposition for corrected QT (QTc)
prolongation, who have uncontrolled or significant cardiac disease including recent 
myocardial infarction, congestive heart failure, unstable angina or clinically significant 
bradycardia, or who are taking medicinal products that are known to prolong the QT 
interval (e.g., anti-arrhythmic medicinal products and other substances that may prolong 
the QT interval. See Appendix 3.  The presence of hypokalemia, hypocalcemia, and 
hypomagnesaemia may further enhance this effect.  Monitoring for an effect on the QTc 
interval is advisable and a baseline electrocardiogram (ECG) is recommended prior to 
initiation of therapy and as clinically indicated.  Hypokalemia, hypocalcemia, or 
hypomagnesaemia must be corrected prior to administration of bosutinib and should be 
monitored periodically during therapy. 

Patients with previous history of pancreatitis.

Patients with recent (within 30 days of study entry) or ongoing clinically significant 
gastrointestinal disorder (e.g., severe vomiting, severe diarrhea, and/or malabsorption), or 
prior partial or total gastrectomy.

Patients on proton pump inhibitors (PPIs) who cannot be switched to alternative 
medications that do not impact proton-pump activity.

A concomitant strong or moderate CYP3A4 inhibitor (low or minimal inhibition 
potential) should be avoided as an increase in bosutinib plasma concentration will occur.
Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition 
potential, if possible, is recommended.  If a strong or moderate CYP3A4 inhibitor must 
be administered during bosutinib treatment, an interruption or dose reduction of bosutinib 
should be considered.


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
A concomitant strong or moderate CYP3A4 inducer should be avoided as a decrease in 
bosutinib plasma concentration will occur.

Caution is warranted if mild CYP3A4 inducers are used concomitantly with bosutinib.

Treatment with bosutinib may result in a clinically significant decline in renal function in 
CML patients.  A decline over time in estimated glomerular filtration rate (eGFR) has 
been observed in CML patients with bosutinib treatment.  It is important that renal 
function is assessed prior to bosutinib treatment and closely monitored during therapy, 
with particular attention in those patients who have preexisting renal compromise or in 
those patients exhibiting risk factors for renal dysfunction, including concomitant use of 
medicinal products with potential for nephrotoxicity such as diuretics, angiotensin
converting enzyme (ACE) inhibitors, angiotensin receptor blockers and nonsteroidal anti-
inflammatory drugs (NSAIDs). Bosutinib exposures were increased in patients with 
moderately and severely impaired renal function. Dose reduction is recommended for 
patients with moderate or severe renal impairment.
4.4. Life Style Guidelines
In this study, fertile male patients and female patients who are of childbearing potential will 
receive bosutinib, which has been associated with demonstrated teratogenicity/fetotoxicity.  
Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use 2 methods of highly effective contraception 
throughout the study and for at least 28 days after the last dose of investigational product.
The investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected 2appropriate methods of contraception for the individual patient and 
his/her partner(s) from the list of permitted contraception methods (see below) and will 
confirm that the patient has been instructed in their consistent and correct use.  At time points 
indicated in the Schedule of Activities, the investigator or designee will inform the patient of 
the need to use 2 highly effective methods of contraception consistently and correctly and 
document the conversation, and the patient’s affirmation, in the patient’s chart. In addition, 
the investigator or designee will instruct the patient to call immediately if 1 or both of the
selected contraception methods is discontinued or if pregnancy is known or suspected in the 
patient or partner.  
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 (i.e., perfect use) 
and include:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the entire 
study and has been using that hormonal contraceptive for an adequate period of time to 
ensure effectiveness
2. Correctly placed copper containing intrauterine device (IUD).


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3. Male condom or female condom used WITH a separate spermicide product (ie, foam, gel, 
film, cream, or suppository).  For countries where spermicide is not available or condom 
plus spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the 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).
All sexually active male patients must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of bosutinib.
4.5. 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 qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study number, contact 
information for the investigator site and contact details for a contact center in the event that 
the investigator site staff cannot be reached to provide advice on a medical question or 
problem originating from another healthcare professional not involved in the patients 
participation in the study. The contact number can also be used by investigator staff if they 
are seeking advice on medical questions or problems, however it should only be used in the 
event that the established communication pathways between the investigator site and the 
study team are not available. It is therefore intended to augment, but not replace the 
established communication pathways between the investigator site and study team for advice 
on medical questions or problems that may arise during the study. The contact number is not 
intended for use by the patient directly and if a patient calls that number they will be directed 
back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).  
Starting dose of bosutinib therapy is 500 mg once daily (commercial formulation of 100 mg 
and 500 mg tablets provided), will be taken with food.  Patients will be provided diary cards 
to record bosutinib administration, any adverse events that occur, and concomitant 
medications.


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Bosutinib will be administered for at least 4 years from the date of first dose, unless 
treatment is discontinued early due to disease progression or unacceptable toxicity or other 
reasons outlined in Section 5.3. Patients discontinuing bosutinib prior to at least 4 years on 
treatment will be followed for survival until the patient has completed at least 4 years on 
study (from time of first dose).  Patients still deriving benefit from bosutinib at the time of 
study discontinuation may switch to commercially available product.
5.1. Allocation to Treatment
When registering a patient, an email should be sent to the study team indicating when 
screening is beginning, when screen failure occurs (if there is a screen failure), and when 
dosing occurs.  For patients being treated with bosutinib, the information in the email should 
include the eligibility worksheet, enrollment form, and patient summary. Sites will use their 
4-digit site number and assign a 4-digit patient number as follows:

The patients in 2nd- or 3rd- line Ph+ [Chronic Phase (CP), Accelerated (AP), Blast Phase 
(BP)] CML patients (e.g. 12341001 – 1234 being the site number and 1001 being the first 
Ph+ patient screened) and continue patient assignments in ascending order for subsequent 
patients in this line of treatment.

For patients with Ph+ CML 4th-line Ph+ (CP, AP, BP) CML, the patient number will 
start with 2001 (e.g., 12342001) and subsequent assignments will continue in ascending 
order for patients in this line of treatment.

For patients with Ph- CML, the patient number will start with 3001 (e.g. 12343001) and 
subsequent assignments will continue in ascending order for patients in this line of 
treatment.

It is the investigator’s determination if and when a patient meets criteria for enrollment.
5.2. Dose Modifications
The recommended starting bosutinib dosing has been defined as 500 mg once daily;
however, the daily dose can vary as described in the table below:
Table 2.
Available Dose Levels
Dose Level
Daily Bosutinib Dose 
+1
600 mga
0 (Starting 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.
Consideration may be given to reducing bosutinib to 200 mg/day for CP CML patients who are 
not tolerating the 300 mg dose but otherwise benefiting from bosutinib.  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.


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5.2.1. Bosutinib Dose Escalation
Patients will be allowed to dose escalate to 600 mg/day in the absence of any grade 3/4 or 
persistent grade 2 adverse drug reaction (or adverse event), if the response is unsatisfactory 
or there are signs of disease progression.  These include, but are not limited to:

Failure to achieve complete hematologic response (CHR) by Week 8.

Failure to achieve complete cytogenetic response (CCyR) by Week 13 (Ph+ CML 
patients only).
If it is determined via qRT-PCR that a patient who has achieved a previous MMR while on 
study now has a rising level of BCR-ABL transcripts (5 times rise, accompanied with loss of 
MMR) the investigator should contact the Sponsor to determine if the patient’s dose should 
be escalated to further optimize their response.
Dose escalation to a dose greater than 600 mg is prohibited.
5.2.2. Dose Adjustments for Adverse Reactions
Bosutinib dosing may be interrupted with or without dose reduction in case of treatment-
related toxicity according to the guidelines described in the following tables.  Dosing 
interruption and dose reduction is advised for the management of hematologic and non-
hematologic adverse drug reactions. Appendix 4 provides specific guidance to patients in the 
management of diarrhea.


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Table 3.
Non-Hematologic Treatment-Related Toxicity
Adverse Event Type 
and Severity
Action
Grade 1
Remain on current dose level.
Grade 2
For persistent clinically relevant toxicity not responding to optimal management: 
Interrupt bosutinib treatment, and reintroduce at the same dose or reduce dose by 
1 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 treatment, 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 treatment.  Investigator and Sponsor to review to determine if 
patient may continue on bosutinib with appropriate dose reduction.
Specific AEs
Elevated liver 
transaminasesb
If elevations in liver transaminases >5 × institutional upper limit of normal (ULN) 
occur, bosutinib treatment should be interrupted until recovery to ≤2.5×ULN and may 
be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, 
permanent discontinuation of bosutinib should be considered.  If transaminase 
elevations ≥3×ULN occur concurrently with bilirubin elevations >2×ULN and alkaline 
phosphatase <2×ULN, bosutinib should be permanently discontinued.
Diarrhea
For Grade 3-4 diarrhea, bosutinib treatment should be interrupted and may be resumed 
at 400 mg once daily upon recovery to grade ≤1. See Appendix 4 for further guidance 
on diarrhea management.
Renal
For Grade 3 renal impairment (CrCL 30 to 50 mL/min calculated by the Cockroft-
Gault formula), bosutinib treatment should be interrupted until recovery to Grade 1, 
then may be resumed at 400 mg once daily.
For Grade 4 renal impairment (CrCL <30 mL/min, calculated by the Cockroft-Gault 
formula), bosutinib treatment should be interrupted until recovery to Grade 1, then 
may be resumed at 300 mg once daily.
a.
Treatment should only be reintroduced when all toxicities are Grade ≤ 1 and the treating physician feels it 
is in the patient’s best interest. Pfizer must be notified by email that treatment has been restarted. For patients 
who have required a dose reduction due to toxicity, but then have been free of the specific toxicity (Grade ≤1)  
and are otherwise tolerating bosutinib well, the investigator may choose to re-escalate the dose by 1 dose level 
(if it is in the patient’s best interest)  until the patient is back to the starting or previous dose (whichever is 
higher).  See Table 2 for available dose levels.
b.
For patients with pre-existing liver transaminase baseline values above the normal range (ALT/AST ≤5 x 
ULN if attributable to liver involvement of leukaemia) who subsequently present with AST or ALT ≥2 times 
the baseline values and ≥3 times the ULN, or ≥8 times the ULN (whichever is smaller), bosutinib should be 
interrupted until recovery to baseline levels.


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Table 4.
Hematologic Treatment-Related Toxicity
Adverse Event
Severity
Action
Grade 1
Remain on current dose level
Grade 2
Remain on current dose level
Grade 3a, b
Interrupt bosutinib treatment:
If recovered to grade ≤2 within 2 weeks of treatment hold: re-introduce bosutinib at 
same dose.  If recovered within 4 weeks of treatment hold: reduce bosutinib by one 
dose level.
In case of recurrent grade 3 toxicity, dose must be reduced upon recovery to grade ≤2.
If recovery takes longer than 4 weeks, the investigator should contact the Sponsor to 
determine if the patient may continue on bosutinib.
Grade 4a
Withhold bosutinib treatment.  Investigator and Sponsor to review to determine if 
patient may continue on bosutinib with appropriate dose reduction.
a.
For patients requiring dose reduction due to toxicity, who have been free of the toxicity (grade ≤1) and are 
otherwise tolerating bosutinib well, the investigator may choose to re-escalate the dose by 1 dose level (if it is 
in the patient’s best interest) until the patient is back to the starting or previous dose (whichever is higher) – see 
Table 2 for available dose levels.
b.
For AP and BP patients who enter the study with Grade 3 neutropenia or anemia due to underlying 
disease, bosutinib dose does not require dosing interruption/reduction, unless, in the opinion of the 
investigator, the Grade 3 event is due to bosutinib toxicity, in which case the bosutinib dosing guidelines 
should be followed.  If neutropenia, thrombocytopenia and/or anemia worsen to grade 4, bosutinib dosing 
should be interrupted, with subsequent dose reduction.  Any Grade 3 hematologic toxicity occurring after 4 or 
more weeks on treatment should be managed by interrupting/reducing bosutinib dosing as recommended.
5.3. Bosutinib Treatment Discontinuation
Patients meeting any of the following criteria should permanently discontinue bosutinib
treatment:
1. Unsatisfactory Response (after dose escalation or with no option to dose escalate due to 
ongoing toxicities).

For CP 2nd-line patients, please refer to European LeukemiaNet (ELN) definition of 
Failure (Appendix 5);

For CP 3rd or 4th-line patients, lack of CHR or lack of MCyR;

For AP and BP patients, lack of any hematologic response.
2. Disease Progression:

For CP, at least one of the following criteria:

Development of AP or BP CML;

Loss of CHR (in absence of cytogenetic response) confirmed by 2 complete blood 
counts (CBCs) at least 2 weeks apart; Loss of CHR is defined as:

WBC count that rises to > 20.0 x 109/L;


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
Platelet count that rises to ≥ 600 x 109/L;

Appearance of extramedullary disease not present at baseline including 
hepatosplenomegaly by palpation or other extramedullary involvement proven 
by biopsy;

Appearance of >=5% myelocytes + metamyelocytes in the peripheral blood or
appearance of blasts or promyelocytes in the peripheral blood.

Loss of MCyR (loss of CCyR or loss of PCyR);

Increasing white blood count (WBC) in a patient without CHR, defined as 
doubling of WBC, to >20 x 109/L on 2 occasions at least 2 weeks apart (after the 
first 4 weeks of treatment).

For AP, at least one of the following criteria:

Development of confirmed BP;

Loss of previous hematologic response over a 2-week period;

Loss of CHR is defined as:

WBC count that rises to > 20.0 x 109/L;

Platelet count that rises to ≥ 600 x 109/L;

Appearance of extramedullary disease not present at baseline including 
hepatosplenomegaly by palpation or other extramedullary involvement proven 
by biopsy;

Appearance of >=5% myelocytes + metamyelocytes in the peripheral blood or 
appearance of blasts or promyelocytes in the peripheral blood.

No decrease from baseline levels (if considered clinically relevant) in percentage 
blasts in peripheral blood or bone marrow on all assessments over a 4-week 
period.

For BP (of any phenotype):

Increasing blasts (if considered clinically relevant) peripheral blood or bone
marrow over a 4-week period;


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3. Symptomatic Deterioration:
Symptomatic deterioration is a worsening of the disease under study that does not meet 
the definition of disease progression, but in the investigator’s opinion, indicates the 
treatment is no longer effective and alternative therapeutic options should be undertaken, 
if dose escalation is not an option or has not been successful.
Dose escalations up to 600 mg daily dose are permitted for patients with unsatisfactory 
response or who show signs of disease progression and do not have concurrent grade 3 or 
4 treatment related adverse events as described in Section 5.2.1.  The patient should be 
monitored closely to assess tolerability and any improvements in efficacy on the 
increased dose.  If the patient’s disease does not improve and/or continues to worsen, the 
patient should be permanently m bosutinib treatment. 
4. 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). 
5. Bosutinib dose reduction below 200 mg/day.  No dose reductions below 200 mg/day will 
be permitted.
6. Withdrawal of consent.
7. Sponsor decision.
8. Pregnancy.
9. Death.
Survival follow-up information will be obtained for all patients who discontinue bosutinib 
treatment prior to completing at least 4 years of treatment from the time of first dose.  See 
Section 6.4 for detailed procedures.
5.4. Investigational product Supplies
5.4.1. Formulation and Packaging
Bosutinib tablets (100 mg and 500 mg dosage strength) will be supplied by the Sponsor in 
high density polyethylene (HDPE) bottles or obtained through prescription if available 
locally.  The commercial formulation of bosutinib will be used in this study. Bosutinib is 
commercially available and either central supply or locally obtained commercial supplies of 
Bosutinib will be used in accordance with local regulations.
Bosutinib will be labeled according to local regulations.
Specific countries in which approval has been granted, a prescription may be provided to the 
Ph+ CML patients to source bosutinib for the study as directed by local regulations. Ph-
CML patients will receive bosutinib from Pfizer.


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5.4.2. Preparation and Dispensing
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.
Patients will be given enough bosutinib to cover the period of administration between 
scheduled resupply visits.  Any visit delays will need to be carefully evaluated to ensure 
adequate supply of bosutinib.
5.4.3. Administration
Bosutinib will be self-administered by the patient, once daily, orally, with food. Patients will 
swallow the investigational product whole and will not manipulate or chew the 
investigational product prior to swallowing.  Both tolerance and absorption may be improved 
with food, including adequate dietary fats; no restriction is imposed on patient’s food choice; 
with the exception of grapefruit or other foods known to inhibit cytochrome P450 3A 
(CYP3A). If a dose is missed the patient should be instructed not to double the dose the next 
day. The patient should take the usual prescribed dose on the following day.  Any missed 
dose information must be indicated in the source documents and the case report forms 
(CRFs).  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.
5.4.4. 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 CRFs.  Site personnel will monitor compliance by reviewing 
compliance with each patient and documenting appropriately in the CRF. Diary cards will be 
provided to patients as an aid for the recording of bosutinib compliance (Appendix 6).
5.5. Investigational Product Storage and Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Bosutinib should be stored at controlled room temperature (between 15-25°C/59-77F) in a 
secured area with controlled access. Freezing is not permitted.
Investigational products should be stored in their original containers and in accordance with 
the labels.
Any storage conditions stated in the Single Reference Safety Document (SRSD) will be
superseded by the storage conditions stated on the product label.


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Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible. Deviations from the storage
requirements, including any actions taken, must be documented and reported to the Pfizer.
Once a deviation is identified, the investigational product must be quarantined and not used
until Pfizer provides permission to use bosutinib. It will not be considered a protocol 
deviation if Pfizer approves the use of the investigational product after the temperature 
excursion. Use of the investigational product prior to Pfizer approval will be considered a 
protocol deviation. Specific details regarding information the site should report for each 
excursion will be provided to the site.
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 investigational product disposition which at minimum consists of the date received, 
date dispensed, quantity dispensed and the patient to whom the investigational product was 
dispensed.  
The investigator is also responsible for the accounting of all unused investigational product 
(IP) and used IP containers.
Bosutinib storage and accountability will be reviewed by the monitor during routine 
monitoring visits.
Patients will be required to return all unused IP at the time new IP bottles are dispensed and 
at the End of Treatment.  Returned medication must not be re-dispensed. Site staff will 
instruct patients on the storage requirement for taking home medications including how to 
report temperature excursions outside the specified range.
5.5.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.


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5.6. Concomitant Medication(s)
All information about concomitant treatments (medications or procedures) must be recorded 
on the patient’s CRF (including the name of the medication or procedure and the duration of 
treatment). 
In addition, any transfusion (red blood cells or platelets) within 1 week prior to screening and 
during the active study treatment period should be recorded on the CRF.
Growth factors required by the patient during the active study treatment period and the 
reason for administration must be recorded on the CRF.
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 (e.g.,
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 medication restrictions apply only while the patient is on the active 
treatment phase of the study (i.e., 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;

Prophylactic use of growth factors;

Requiring concurrent treatment with immunosuppressive agents, other than 
corticosteroids prescribed for a short course of therapy (10 days).
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 (i.e., 
diarrhea will be monitored and managed using standards of care, including 
antidiarrheals, antiemetics, and/or fluid replacement). See Appendix 4 for a sample 
Patient Information Card (Guidelines for the Management of Diarrhea);


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
Palliative and supportive care for disease-related symptoms or toxicity due to study 
treatment;

Treatment with growth factors [according to American Society of Clinical Oncology 
(ASCO) guidelines].25 No prophylactic use of growth factors will be allowed;
NOTE: if an on-treatment BM assessment or CBC is scheduled within 1 week from 
the last dose of granulocyte colony-stimulating factor (G-CSF) or granulocyte-
macrophage colony-stimulating factor (CM-CSF) growth factors, it should be 
considered “not evaluable” for response assessment, and a BM evaluation or CBC 
should be repeated at least 1 week from the last dose of growth factor;

A short course of hydroxyurea or anagrelide for cytoreduction is allowed during the 
first month of treatment with bosutinib, provided that the last dose of hydroxyurea or 
anagrelide is stopped at least 72 hours before any CML disease assessment;

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
Patients should be cautioned on the following:

Patients should be strongly encouraged to avoid herbal remedies, including St John's 
Wort.  Grapefruit products should also be avoided.

For advanced leukemia patients requiring –azoles and for whom the anti-fungal 
therapies cannot be discontinued, careful monitoring of adverse events, including 
QTc prolongation via electrocardiogram (ECG), is important.

Inhibitors of platelet aggregation (e.g., 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 
Section 5.4 dose modification tables.
5.6.4. 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 (See Appendix 2). 
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.


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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.
In a study of 24 healthy patients in whom 5 daily doses of 400 mg ketoconazole were co-
administered with a single dose of 100 mg bosutinib under fasting conditions, ketoconazole 
increased bosutinib Cmax by 5.2-fold, and bosutinib area under the curve (AUC) in plasma 
by 8.6-fold, as compared with administration of bosutinib alone.
CYP3A inducers 
The concomitant use of bosutinib with strong CYP3A inducers should be avoided, as a 
decrease in bosutinib plasma concentration may occur (See Appendix 2).
Based on the large reduction in bosutinib exposure that occurred when bosutinib was co-
administered with rifampicin, increasing the dose of bosutinib when coadministering with 
strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of 
exposure.
Caution is warranted if mild CYP3A inducers are used concomitantly with bosutinib. 
Following concomitant administration of a single dose bosutinib with 6 daily doses of 
600 mg rifampicin, in 24 healthy patients in fed state bosutinib exposure (Cmax and AUC in 
plasma) decreased to 14% and 6%, respectively, of the values when bosutinib 500 mg was 
administered alone.
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 (e.g., take bosutinib in the 
morning and antacids in the evening) whenever possible.
Bosutinib displays pH-dependent aqueous solubility in vitro. When a single oral dose of 
bosutinib (400 mg) was coadministered with multiple-oral doses of lansoprazole (60 mg) in a 
study of 24 healthy fasting patients, bosutinib Cmax and AUC decreased to 54% and 74%, 
respectively, of the values seen when bosutinib (400 mg) was given alone.
Effects of other medicinal products
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 3).


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6. STUDY PROCEDURES 
Refer to the Schedule of Activities (Table 1) for the complete list of procedures to be 
performed and associated timepoints.  All patients will participate on study for at least 4
years.  In view of the very refractory nature of the patients being treated on this study, the 
investigator may delegate certain specific tests/visits to be performed at other sites closer to 
the patient’s home. The investigator will be responsible for capturing results of any study-
specified tests and visits (e.g., AE/Adverse Drug Reaction data collection) that are performed 
outside his/her site in the relevant CRFs and in the source documents maintained on site.
Disease assessments will be performed at the site at week 1, week 2, week 3, week 4 and 
week 8 during the first 2 months, afterwards (from week 13), the disease assessments will be 
performed during the 3 monthly visits and starting after week 52, performed during the 6-
monthly visit. 
6.1. Screening
Screening can be accomplished over one or multiple visits over a 4-week period (30 days). 
Stage of disease is defined as the worst phase of CML experienced by the patient, regardless 
of disease status at the time of study entry.  For example, a patient whose disease is in CP at 
study entry, but who had been previously diagnosed in AP, will be classified as AP CML.  
Refer to Appendix 7 for specific criteria for CP, AP and BP phases of disease.
Prior cancer history, including CML and any other cancer will be collected. All treatments 
received by the patient for CML (CP, AP, and BP), including dates of administration, 
dose(s), best response and tolerability (including specific intolerance(s) to each therapy) will 
be collected from the time of original diagnosis of CML.  Any additionally diagnosed 
malignancies will also be recorded at screening.
All relevant medical history and treatment received by the patient within 30 days before 
administration of bosutinib will be recorded on the patient's CRF, including the name of the 
procedure or drug and other related information.  
The following procedures should be conducted as part of the baseline screening: 

Signature of informed consent document (ICD);

Review of patient’s eligibility (i.e., protocol inclusion/exclusion criteria);

Cytogenetic confirmation of Ph+ chromosome (or BCR-ABL1+ if Ph-) CML 
diagnosis and phase.  Acceptable documentation includes results from primary CML 
diagnosis or results following discontinuation/ failure of prior CML therapy.  Either 
traditional cytogenetics for the Ph+ chromosome or fluorescence in situ hybridization
(FISH) for the BCR-ABL juxtaposition or PCR for BCR-ABL transcript 
quantification are acceptable for the diagnosis of CML;

Medical history;


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
Complete physical examination to include vital signs (sitting or supine blood 
pressure, heart rate, and height and weight);

Smoking status at screening; (Note: the use of TKIs could lead to cumulative long-
term cardiovascular disease therefore information of other risk cardiovascular factors 
like smoking status will be collected for this study);

Extramedullary disease assessment (including assessment of liver, spleen and lymph 
nodes by physical examination as well as other potential sites of extramedullary 
involvement);  

ECOG performance status (Appendix 8);

Electrocardiogram (ECG);

Echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan; Standard of 
care echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan results may 
be used for screening if not longer than 12 weeks prior to the first bosutinib dose in 
the absence of past medical history of cardiovascular disease and presence of normal 
left ventricular ejection fraction (LVEF). If the patient has past medical history of
cardiovascular disease or ongoing cardiovascular co-morbidities, ECHO or MUGA 
should be obtained within 7 days prior to the first bosutinib dose.  Screening, 
unplanned, and End of Treatment assessments should be performed with the same 
test, ECHO or MUGA scan.

Chest X-ray; Standard of Care chest X-ray results may be used for screening if not 
longer than 12 weeks prior to the first bosutinib dose in the absence of past medical 
history of pulmonary disease.  If the patient has past medical history of pulmonary 
disease or ongoing pulmonary co-morbidities, then chest X-ray should be obtained 
within 7 days prior to the first bosutinib dose;

Bone marrow aspirate sample for G-banding analysis (karyotype) and morphological 
assessment (% of bone marrow differential) is required at screening, unless the CML 
disease status is proven to be MMR by qRT-PCR.  Conventional cytogenetic 
assessment will be done locally. If a bone marrow aspirate that meets all study 
requirements was obtained within 30 days prior to screening, these data may be used 
to replace the need for a bone marrow aspirate during screening.  In Ph- CML 
patients, conventional cytogenetic assessments (to detect other potential cytogenetic 
abnormalities) and molecular cytogenetic assessments using FISH (to detect 
cryptic/variant translocations) are required at screening;

qRT-PCR for molecular response assessment (BCR-ABL fusion transcript levels) and 
mutational analysis of the BCR-ABL kinase domain will be performed by a central 
laboratory.  For CP CML, the assessments will be performed using peripheral blood 
sample.  For Advanced Phase (AP and BP) CML, the assessments will be performed 
using peripheral blood and/or bone marrow samples; mutational analysis will be 
performed from the peripheral blood or bone marrow samples  that were used for
molecular response assessment;


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
Hematology panel (Appendix 9);

Chemistry panel (Appendix 9).  In addition, baseline fasting glucose, glycosylated 
hemoglobin (HbA1c) , cholesterol, high-density lipoprotein (HDL), and low-density 
lipoprotein (LDL), potassium and magnesium should be performed and repeated if 
abnormal;

Liver Function Tests (LFTs) including: total bilirubin, AST and ALT, Alkaline
Phosphatase (Appendix 9);  

Hepatitis B serology testing should be evaluated;

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) ;

Urine or serum pregnancy test (for women of childbearing potential) (Appendix 9);

Contraceptive check: patients of child-bearing potential will be required to affirm 
their use of 2 highly effective methods of contraception which will be documented in 
the patient’s source document;

Blood and plasma collection for biobanking if specifically allowed by local EC/IRB.  
If missed, collect at the next available time point when biospecimens are being 
collected in conjunction with a subject visit;

Patient diary card review and implementation (dosing, AEs and concomitant 
medications, Appendix 6);

FACT-Leu administration (Appendix 10).
6.2. Study Period
The following procedures will be performed on treatment.  Patients must be registered to the 
study after eligibility is confirmed within 3 days prior to receiving first dose of bosutinib.
Week 1 (Day 1, pre-dose and Day 7), Week 2, Week 3, Week 4 and Week 8 (±1 day) on 
Day 7

Hematology panel (Appendix 9); complete hematological assessment response;

Liver function tests (Appendix 9);

Chemistry panel; including HbA1C, cholesterol, HDL, LDL, potassium, and 
magnesium, if clinically indicated (Appendix 9);

Coagulation tests (Appendix 9);


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
Urine or serum pregnancy test (for women of childbearing potential) (pre-dose 
Week1 Day 1 only) (Appendix 9);

Contraceptive check: patients of child-bearing potential will be required to affirm 
their use of 2 highly effective methods of contraception which will be documented in 
the patient’s source document;

Extramedullary disease assessment, if clinically indicated. Sites of extramedullary 
disease identified at screening should be followed during the course of treatment.  
Patients should be evaluated upon suspicion of new extramedullary disease;

Hepatitis B serology testing, as clinically indicated;

Patient diary card review (Appendix 6);

Bosutinib dispensation on Day 1.
Week 13, Week 26, Week 39, Week 52 (±7 days), Week 78, Week 104, Week 130, Week 
156, and Week 182 (±21 days)

Complete physical examination to include vital signs (sitting or supine blood 
pressure, heart rate and weight);  

Current smoking status.

Extramedullary disease assessment, if clinically indicated. Sites of extramedullary 
disease identified at screening should be followed during the course of treatment. 
Patients should be evaluated upon suspicion of new extramedullary disease;

Hepatitis B serology testing, as clinically indicated;

ECG assessment, if clinically indicated;

ECHO or MUGA scan assessment, if clinically indicated;

Chest X-ray, if clinically indicated;

ECOG Performance Status (Appendix 8);

Bone marrow aspirate must be collected for local conventional cytogenetic 
assessment (with at least 20 metaphases).  Percentage (%) of Ph+ metaphases, as well 
as any other chromosomal abnormalities, will be documented.  Conventional 
cytogenetic assessment should be continued until MMR. Only chromosome banding 
analysis of marrow cell metaphases can be used to assess the degree of CyR (with at 
least 20 metaphases analyzed).  Upon achieving CCyR by the conventional 
cytogenetic assessment, FISH of blood interphase nuclei with an appropriate probe 
(Dual-Color Dual-Fusion or Dual-Fusion FISH) could substitute for chromosome 


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banding analysis of marrow cell metaphases for the assessment of maintenance of the 
CCyR (which is then defined by <1% BCR-ABL1-positive nuclei of at least 200
nuclei) until MMR is reached.  Loss of CCyR using FISH requires resumption of 
bone marrow conventional cytogenetic assessment (unless the CML disease status is 
proven to be MMR by qRT-PCR);

Bone marrow aspirate for morphology (% bone marrow differential) and 
conventional cytogenetic assessment is required for all patients at the time of 
suspected progression and/or failure.  
Note: in Ph-CML patients, conventional cytogenetic assessment (to detect other 
potential cytogenetic abnormalities) and molecular cytogenetic assessments using
FISH are required at the time of suspected progression and/or failure;

qRT-PCR for molecular response assessment (BCR-ABL fusion transcript levels) and 
mutational analysis of the BCR-ABL kinase domain will be performed by a central 
laboratory.  For CP CML, the assessments will be performed using peripheral blood 
sample.  For Advanced Phase (AP and BP) CML, the assessments will be performed 
using peripheral blood and/or bone marrow samples; mutational analysis will be 
performed  from the peripheral blood or bone marrow samples  that were used for 
molecular response assessment. Loss of confirmed MMR requires resumption of 
conventional cytogenetic assessment;

Hematology panel (Appendix 9); complete hematological assessment response;

Liver function tests (Appendix 9);

Chemistry panel; including HbA1C, cholesterol, HDL, LDL, potassium, and 
magnesium, if clinically indicated (Appendix 9);

Coagulation tests (Appendix 9);

Urine or serum pregnancy test (Appendix 9);

Contraceptive check: patients of child-bearing potential will be required to affirm 
their use of 2 highly effective methods of contraception which will be documented in 
the patient’s source document;

Blood and plasma collection for biobanking, if specifically allowed by local EC/IRB;
sample should be collected at the time of first response, where response there is  
response (e.g. MCyR, CCyR, MMR, depending on the baseline CML disease status)
for CP patients and hematologic response for AP/BP patients when feasible.  This 
sample should be obtained at the next scheduled visit if the next scheduled visit 
occurs within 2 months after the first response.  If the next scheduled visit occurs >2 
months after the first response, then the sample should be collected at an unscheduled 
visit within 2 months after the first response, if feasible;


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
FACT-Leu administration (Appendix 10);

Patient diary card review;

Bosutinib dispensation.
6.3. End of Treatment Visit (±7 days)
The End of Treatment visit should be performed for all patients once they have permanently 
discontinued bosutinib.  The visit should occur within the 28 days after the last dose of 
bosutinib. For patients who discontinue bosutinib prior to Week 208, all procedures listed 
should be performed, unless collected within the previous 6 weeks.  The following 
procedures are required:

Complete physical examination including vital signs (sitting or supine blood pressure, 
heart rate, and weight);

Current smoking status;

Extramedullary disease assessment;

ECOG performance status (Appendix 7);

FACT-Leu administration (Appendix 10);

ECG;

ECHO or MUGA scan; screening and End of Treatment tests to evaluate the cardiac 
function should use the same test in both visits);

Chest X-ray;

Bone marrow aspirate for morphology (% bone marrow differential) and conventional 
cytogenetic assessment is required if the discontinuation is due to progression and/or 
failure;

qRT-PCR for molecular response assessment (BCR-ABL fusion transcript levels) and 
mutational analysis of the BCR-ABL kinase domain will be performed by a central 
laboratory.  For CP CML, the assessments will be performed using peripheral blood 
sample.  For Advanced Phase CML (AP and BP) the assessment will be performed 
using peripheral blood and/or bone marrow samples;

Hematology panel (Appendix 9); complete hematological assessment response;

Liver function tests (Appendix 9);


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
Chemistry panel; including HbA1C, cholesterol, HDL, LDL, potassium and 
magnesium, if clinically indicated (Appendix 9);

Coagulation tests (Appendix 9);

Urine or serum pregnancy test (Appendix 9);

Contraceptive check: patients of child-bearing potential will be required to affirm 
their use of 2 highly effective methods of contraception until 28 days after their final 
dose of bosutinib which will be documented in the patient’s source document;

Blood and plasma collection for biobanking, if specifically allowed by local EC/IRB, 
if feasible;

Final review of patient diary card;

Return of unused bosutinib. (Note: Ph+ CML patients who receive a prescription [per 
local regulations] will have a final compliance check for dose levels and duration of 
Bosutinib treatment).
6.4. Long-Term Follow-Up Visit
Patients who discontinue from treatment for any reason (except death, withdrawal of patient 
consent or termination of study by Sponsor) prior to completing at least 4 years will enter 
into the follow-up phase of the study. Patients will be followed for at least 4 years from the 
first dose of bosutinib and will be assessed for overall survival status only.
Follow-up will be conducted approximately every 3 months from the last dose of bosutinib 
(telephone calls acceptable). If bone marrow transplantation is performed after 
discontinuation, it should be captured during the long-term follow-up as well as treatment 
with another TKI, time to progression, and transformation to AP or BP.
Patient study participation will not conclude before 4 years after the first dose of bosutinib 
was administered.
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. 
Potential reasons why a patient may permanently discontinue or be withdrawn from study
treatment are provided in Section 5.4.
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 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).


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If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  All attempts to contact the patient and information received during 
contact attempts must be documented in the patient’s medical record.  However it is 
anticipated that from time to time there may be circumstances, outside of the control of the 
investigator that may make it unfeasible to perform the test.  In these cases the investigator 
will take all steps necessary to ensure the safety and well being of the patient.  When a 
protocol- required test cannot be performed the investigator will document the reason for this 
and any corrective and preventive actions 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 assessments detailed in this protocol are aligned with the European LeukemiaNet 
(ELN) guidelines.26 Refer to the SCHEDULE OF ACTIVITIES for assessment of time 
points.
7.1.1.1. Cytogenetic Response Assessment
Cytogenetic analysis will be performed by conventional cytogenetics from bone marrow, 
requiring at least 20 metaphases in order to evaluate number of Ph+ cells to determine 
cytogenetic response.  Conventional cytogenetic assessment will be performed at scheduled 
visits until MMR is observed.  
Only chromosome banding analysis of marrow cell metaphases will be used to assess the 
degree of CyR.  Upon achieving CCyR by the conventional cytogenetic assessment, FISH of 
blood interphase nuclei with an appropriate probe (Dual-Color Dual-Fusion or Dual-Fusion 
FISH) could substitute for chromosome banding analysis of marrow cell metaphases for the 
assessment of maintenance of the CCyR (which is then defined by <1% BCR-ABL1-positive 
nuclei of at least 200 nuclei) until MMR is reached.  Loss of CCyR using FISH will require 
resumption of bone marrow conventional cytogenetic assessment (unless the CML disease 
status is proven to be MMR by qRT-PCR).
For Ph- CML patients, conventional cytogenetic analysis will be performed only at screening 
and at the time of suspected progression and/or failure. Conventional cytogenetic assessment   
will be used to detect other potential cytogenetic abnormalities and molecular cytogenetic 
assessment (FISH) will be used to detect cryptic/variant translocations. Cytogenetic analysis 
will be conducted locally. Note: The cytogenetic assessment needs to be repeated at least 28 
days later to confirm CCyR CML disease status for Ph+CML patients (when the cytogenetic 
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FISH is needed to confirm the achievement/maintenance of CCyR at least 28 days later ).
Loss of cytogenetic response must be confirmed by 2 assessments at least 4 weeks apart.  
(Note: if confirmation is lacking and the patient goes off treatment due to progressive 
disease, the assumption is that loss of cytogenetic response (CyR) is confirmed for this study; 
therefore, the confirmation of loss of CyR 4 weeks apart is not required in this clinical 
context).  
Karyotypic abnormalities in Ph- subclones should be recorded.  See Appendix 11 for CyR
criteria definitions.
7.1.1.2. Hematologic Response Assessment
Complete blood counts and differentials and extramedullary disease assessment (liver and 
spleen assessment) from the physical examination and bone marrow differentials will be used 
to determine response to treatment.  
Hematologic responses must be of at least 4 weeks duration confirmed by 2 assessments at 
least 4 weeks apart.  Complete hematologic response (CHR) and OHR (defined as CHR or 
RCP) will be evaluated by peripheral blood, and bone marrow differential (to define RCP) 
when available, only utilizing local laboratory results.  Loss of hematologic response must be 
confirmed by 2 assessments at least 2 weeks apart.  Note: if confirmation is lacking and the
patient goes off treatment due to progressive disease, the assumption is that loss of 
hematologic response is confirmed for this study; therefore, the confirmation of loss of 
hematologic response 2 weeks apart is not required in this clinical context.
The definition of CHR for CP CML is outlined in Appendix 11.
CHR for AP and BP CML is defined as white blood cell (WBC) count less than or equal to 
the institutional upper limit of normal (ULN); absolute neutrophil count (ANC) 1.0 x 109/L 
or higher, platelet count 100 x 109/L or higher; marrow blasts 5% or less with no peripheral 
blasts or promyelocytes; peripheral myelocytes + metamyelocytes less than 5%; basophils in 
peripheral blood less than 5%; and no evidence of extramedullary involvement.  
Note: If an on-treatment CBC is scheduled within 1 week from the last platelet 
transfusion, it should be considered “Not Evaluable” for hematological response 
assessment, and a CBC should be repeated at least 1 week from the last platelet
transfusion received.
Note: If an on treatment CBC is scheduled within 1 week from the last dose of G-CSF 
or GM-CSF growth factor, it should be considered “Not Evaluable” for response 
assessment and CBC should be repeated at least 1 week from the last dose of growth 
factor.
7.1.1.3. Extramedullary Disease
Physical examination will be carried out as part of the extramedullary disease response 
assessment to confirm hepatic, spleen or other organ involvement by CML.  Chest X-ray may 
also be performed, when clinically indicated.


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7.1.1.4. Molecular Response Assessment
Blood samples (for CP, AP, and BP CML patients) and bone marrow samples (for AP and 
BP CML patients) will be collected at each efficacy time point for qRT-PCR analysis of 
BCR-ABL transcript levels that will be reported using the International Scale.
See Appendix 11for response criteria definitions.
A BCR-ABL1 expression of 0.1% corresponds to MMR with >5,000 ABL1 transcripts.
The following criteria will be used to define deep molecular response (MR):

MR4 = either (i) detectable disease with <0.01% BCR-ABL1IS or (ii) undetectable 
disease in cDNA with >10 000 ABL1 transcripts. 

MR4.5 = either (i) detectable disease with <0.0032% BCR-ABL1IS or (ii) 
undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of 
cDNA used to test for BCR-ABL1.
Samples with a total of <10,000 ABL1 transcripts (i.e., sum of the replicates if replicate 
analysis is performed) should be considered as not evaluable for MR4 and samples with a
total of <32,000 ABL1 transcripts should be considered as not evaluable for MR4.5.
MMR is MR3.  For all patients, MR1/MR2, MR3will be used and have a working definition
of ≤10%/1%/0.1% BCR-ABL1ISwith >5 000 ABL1 transcripts.
Molecular response assessments will be carried out by an independent central laboratory at 
baseline and every 3 months until Week 52, then at 6-month intervals during Years 2, 3, and 
4 and End of Treatment, and any time there is treatment failure and/or disease progression.
Loss of MMR must be confirmed by 2 consecutive assessments, one of which is 1% on the 
International Scale. Note: if confirmation is lacking and the patient goes off treatment due to
progressive disease, the assumption is that loss of MMR is confirmed for this study.
7.1.1.5. BCR-ABL Mutation Testing
Samples will be collected at screening to identify pre-bosutinib exposure point mutations in 
the BCR-ABL kinase domain.
In addition, mutational analysis of the BCR-ABL kinase domain will be performed during 
bosutinib treatment for patients with baseline mutations and for all patients at End of 
Treatment, and any time if treatment failure occurs (as indicated by a rise in BCR-ABL 
transcript levels of at least 5-fold that has been confirmed by more than one test) and/or 
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Mutational analysis of the BCR-ABL kinase domain will be performed by an independent 
central laboratory. For CP CML, the assessment will be performed using peripheral blood
samples. For Advanced Phase (AP and BP) CML, the assessments will be performed using 
peripheral blood and/or bone marrow samples. Mutational analysis will be performed from 
the peripheral blood or bone marrow samples that were used for molecular response 
assessment.  
BCR-ABL mutation analysis and molecular response assessment will be performed by the 
same central laboratory.
7.2. Safety Assessment Methods
Safety will be assessed by physical examination (including vital signs) and laboratory tests, 
including chest X-ray and ECHO/MUGA scans. All safety assessments are outlined in the 
SCHEDULE OF ACTIVITIES which includes adverse event and concomitant medication 
review, assessment of disease status, and ECG monitoring. Patient Diary cards and FACT-
Leu should be reviewed by site staff to verify presence of any reportable safety information 
that should be assessed by the investigator and reported according to guidelines provided in 
adverse event section. 
7.3. Safety Laboratory Determinations
The investigator will review laboratory test results to determine the occurrence of clinically 
important abnormalities (i.e., adverse events [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.
7.4. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL will be performed on two occasions prior to starting study 
therapy - once at the start of screening and once at the baseline visit, immediately before 
investigational product administration.  Following a negative pregnancy result at screening, 
appropriate contraception must be commenced and a further negative pregnancy result will 
then be required at the baseline visit before the patient may receive the investigational 
product.  Pregnancy tests will also be routinely repeated every 3 or 6 months at scheduled 
visits during the active treatment period, at the end of study therapy and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken if requested by IRB/ECs or if required by 
local regulations.


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7.5. Banked Biospecimens
7.5.1. Markers of Investigational Product Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of patients who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment. Collecting biospecimens 
for exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. Providing these biospecimens is a required 
study activity for study sites and patients, unless prohibited as such by local regulations or 
ethics committee decision.
To protect patients’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the patient’s study ID number. Samples will be kept in a facility 
accessible only by badge-swipe. Data will be stored on password-protected computer 
systems. The key between the code and the patient’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information. Biospecimens will only 
be used for the purposes described here and in the informed consent document/patient
information sheet; any other uses require additional ethical approval. Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also post-marketing 
research. Patients can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses. It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants. Patients are notified in the informed consent document/patient 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator. Results will not be 
provided to family members or other physicians; nor will they be recorded in the patient’s 
medical record. There is no intention to contact patients after completion of the clinical trial.
A 4 mL blood biospecimen Prep D1 (K2 EDTA whole blood collection optimized for 
DNA analysis) will be collected at Baseline, time of response (MCyR for CP patients, 
CHR/MHR for AP/BP patients), and at the End of Treatment visits to be retained for 
potential pharmacogenomic/biomarker analyses related to drug response, unless prohibited 
by local regulations or ethics committee decision.  For example, putative safety biomarkers, 
drug metabolizing enzyme genes, drug transport protein genes, or genes thought to be related 
to the mechanism of drug action may be examined. Additional biospecimens to be retained 
for exploratory analyses in this study include Prep B1 plasma samples.  


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Prep B1 (K2 EDTA plasma collection optimized for biomarker/proteomic/metabonomic 
analysis): a 10 mL blood biospecimen will be collected at screening, at the time of first 
response, and at End of Treatment (unless within 6 weeks of prior sample collection).  This 
sample should be obtained at the next scheduled visit if the next scheduled visit occurs within 
2 months after the first response.  If the next scheduled visit occurs >2 months after the first 
response, then the sample should be collected at an unscheduled visit within 2 months after
the first response, if feasible, unless it is the End of Treatment Visit.
The Banked Biospecimens will be collected from all patients unless prohibited by local 
regulations or ethics committee decision. Detailed collection, processing, storage and 
shipment instructions are provided in the independent central laboratory manual.   
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.5.2. Additional Research
Unless prohibited by local regulations or IRB/EC decision, patients will be asked to indicate 
on the consent form whether they will allow the Banked Biospecimens to also be used for the 
following research:

Investigations of the disease under study in the clinical trial, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to Pharmacogenomics/biomarkers.
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in Markers of Investigational Product Response Section will be used.  
Patients may still participate in the clinical trial if they elect not to allow their Banked 
Biospecimens to be used for the additional purposes described in this section.
7.6. Biological Samples
Peripheral blood and bone marrow aspirate samples will be used only for scientific research.  
Each sample will be labeled with a code so that the laboratory personnel testing the samples 
will not know the patient’s identity.  Some of the samples may be stored by Pfizer for 
additional testing.  The samples will not be used for any unrelated research and no genetic 
testing will be performed.  The samples will be stored for up to 15 years after the end of the 
study and then destroyed.  
The patient or legal guardian may request that the samples, if still identifiable, be destroyed 
at any time; however, any data already collected from those samples will still be used for this 
research. The biological samples may be shared with other researchers as long as 
confidentiality is maintained.


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7.7. Health Outcomes Assessment
Cancer and its treatment often have significant effects on patients as measured by patient-
reported outcomes (PROs) (e.g., symptoms, concerns, overall well-being).  Health outcomes 
assessments will be conducted with the FACT-Leu administered at screening, Weeks 13, 26, 
39, 52, 78, 104, 130, 156, 182, and 208 (End of Treatment), where the appropriate 
translations are available. The health outcomes assessment surveys are for the purpose of
exploring the patient’s own perceptions about his or her quality of life, disease symptoms, 
aspects of their treatment, and should be completed by the patient only prior to interaction 
with health care professionals at assigned study visits.  The investigator must not influence 
the patient’s assessments.  Every effort should be made to maintain an unbiased assessment.
7.7.1. Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) 
The FACT-Leu (see Appendix 10) is a 44-item, self-reported, reliable and valid assessment 
of quality of life in patients with leukemia.23  The FACT-Leu consists of measures health 
related quality of life across 4 domains : Physical Well-being (7 items; score range, 0–28), 
Social/Family Well-being (7 items; score range, 0–28), Emotional Well-being (6 items; score 
range, 0–24), Functional Well-being (7 items; score range, 0–28 and a leukemia-specific 
subscale, which consists of 17 items (score range, 0–68) that assess patient concerns relating 
to leukemia. The total score (range, 0-176) can also be calculated.  Patients are asked rate on 
a scale from ‘0’ (“not at all”) to ‘4’ (“very much”), regarding how much each item (i.e., pain, 
fatigue, etc.) was present in the last 7 days; higher scores reflect better quality of life. The 
minimally important difference (MID), defined as the smallest change in a PRO measure that 
is perceived by patients as beneficial, or that would result in a clinician considering a change 
in treatment for this instrument are defined as: 2-3 (PWB), N/A (SWB), 2 (EWB), 
2-3 (FWB), 3-7 (FACT-G), 4-7 (Leus-specific subscale) and 6-12 (FACT-Leu Total).


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) non-
serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 


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the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient/legally acceptable representative/legal guardian.  In addition, 
each study patient/legally acceptable representative/legal guardian will be questioned about 
the occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also Section on Patient
Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any study-
related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.


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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at
the time the new treatment is started; however, SAEs must continue to be recorded on the
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in 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.


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8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include the signs or 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 reported 
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.


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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 
reporting as an AE.Serious Adverse Events
8.2.3. Serious Adverse Events
An SAE 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 patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
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 
reporting period.  Hospitalization due to signs and symptoms of disease progression should 


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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 Section on Severity Assessment).
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.
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 (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (e.g., 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 (e.g., for 
work-up of persistent pre-treatment laboratory abnormality);

Social admission (e.g., patient has no place to sleep);

Administrative admission (e.g., for yearly physical examination);

Protocol-specified admission during a study (e.g., for a procedure required by the 
study protocol);


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
Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive 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
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE 
Version 4.0, Publish Date:  May 28, 2009, http://ctep.cancer.gov/reporting/ctc.html) will be 
used to assess the severity of AEs and SAEs.
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.
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.


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8.4.2. Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  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.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST or ALT values >3 x ULN AND a TBili value >2 x 
ULN with no evidence of hemolysis and an alkaline phosphatase value <2 x ULN or 
not available;

For patients with baseline ALT or AST or TBili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline:
o
Pre-existing AST or ALT baseline values above the normal range: AST or 
ALT values >2 times the baseline values AND >3 x ULN, or >8 x ULN 
(whichever is smaller).
o
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 x ULN or the value reaches >3 x 
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.


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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or seconday) should be considered.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase, direct and indirect bilirubin, gamma-glutamyl transferase, 
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 (e.g., biliary tract) may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all 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 (e.g., 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; 
o
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).


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
A male has been exposed (e.g., because of treatment or environmental exposure) to 
the investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must submit this information to 
Pfizer Safety on the CT SAE Report Form and 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 (e.g., a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (i.e., 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 (e.g., follow-up on preterm 
infants to identify developmental delays).  In the case of paternal exposure, the investigator 
will provide the patient with the Pregnant Partner Release of Information Form to deliver to 
his partner.  The Investigator must document in the source document that the patient was 
given Pregnant Partner Release of Information Form to provide to his partner.


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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 adverse event.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not reported on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.


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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 primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
This study does not include any formal sample size determination.  Approximately 
150 patients with Ph+ CML will be enrolled including at least 45 CP, AP, and BP patients in 
the 4th or later line treatment setting.  With a subset of 45 patients, the standard deviation of 
an estimate of the probability of response is at most 0.075.  
9.2. Efficacy Analysis
All treated Ph+ CML patients with a valid baseline efficacy assessment for the respective 
endpoint (Evaluable Population) will be included in the molecular, cytogenetic, and 
hematologic efficacy analyses.  All treated Ph+ CML patients (Full Analysis Set [FAS]) will 
be included in the other efficacy endpoints.  Analyses will be presented by disease stage 
(e.g., CP, AP, BP) and/or line of therapy (e.g., CP 2nd line [CP2L], CP 3rd line [CP3L], CP 4th
or later line [CP4L], AP2L, AP3L, AP4L, BP2L, BP3L, BP4L) for Ph+ CML patients.  All 
Ph- CML patients will be analyzed separately and only for cumulative CHR and molecular 
endpoints.
Descriptive summaries and confidence intervals (if applicable) will be provided; no
inferential analyses are planned for this study.
9.2.1. Analysis of Primary Endpoint 
The primary efficacy analyses are the percentage of cumulative confirmed MCyR in CP 2nd
and 3rd line patients, cumulative confirmed MCyR in 4th and later line patients and the 
cumulative confirmed OHR in AP and BP patients by 1 year of bosutinib treatment (Week 
52) assessed from the local laboratory data. The primary analyses will be the percentage of 
cumulative confirmed MCyR (for CP Ph+ CML patients) and cumulative confirmed OHR 


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(for AP and BP Ph+ CML patients) by 1 year of bosutinib treatment (week 52). Confirmed 
MCyR will be defined as (1) the attainment of confirmed MCyR (CCyR or PCyR) by 1 year 
for patients entering the study without CCyR achieved on the previous TKI therapy or (2) the 
maintenance of confirmed CCyR (achieved under the previous TKI therapy) for at least 1 
year after starting treatment with bosutinib or (3) at least MMR by 1 year and a deeper 
molecular response compared to baseline.  Patients with baseline PCyR that do not achieve 
CCyR are included in the analysis but they would be counted as non-responders. Initial 
cytogenetic (in the absence of MMR) and hematologic responses must be confirmed by 2 
consecutive assessments at least 28 days apart.
9.2.2. Analysis of Secondary Endpoints
Percentages for the following secondary endpoints will be calculated:

Cumulative MCyR anytime on treatment in the CP, AP and BP Ph+ CML patient 
populations.

Cumulative confirmed OHR anytime on treatment in the different advanced phase 
(AP, BP) Ph+ CML patient populations by lines of prior of therapy.

Cumulative best response anytime on treatment in the different CP, AP, and BP Ph+ 
CML patient populations, also in the 4th- or later-line treatment setting.  The hierarchy 
to assess for best response is MR4.5, MR4, MMR, CCyR, PCyR, CHR, and OHR.

Landmark MCyR at 3, 6, 12, 18, and 24 months in the different CP, AP and BP Ph+ 
CML patient populations.

Landmark confirmed OHR at 3, 6, 9, 12, 18, and 24 months in the AP and BP Ph+ 
CML patient populations.

Cumulative confirmed CHR anytime on treatment in the CP, AP and BP Ph+ CML 
patient populations.

Cumulative MMR anytime on treatment in the CP, AP and BP Ph+ CML patient 
populations.

Duration of CCyR.

Duration of MMR.
Analyses of hematologic and cytogenetic response will be based on the data from the local 
laboratory assessment.  Analyses of molecular response will use the data from the 
independent central laboratory.  


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Duration of response is defined as the interval from the date of first on-treatment response to 
the date of confirmed loss of response, death within 28 days of last dose, or treatment 
discontinuation due to disease progression.  Responders without loss of response will be 
censored at the last valid assessment for the respective endpoint.
The secondary time-to-event endpoint duration of response will be summarized using the 
Kaplan-Meier method or by cumulative incidence, whichever is more appropriate, depending 
on the competing risks (e.g., treatment discontinuation without disease progression in the 
analysis).
9.3. Analysis of Other Endpoints
OS or survival time is defined as the interval from the date of first dose of bosutinib to the 
date of death due to any cause.  Patients not known to have died will be censored at the last 
known alive date.  The OS distribution up to at least 4 years will be provided.
PFS is the interval from the date of first dose of bosutinib until the earlier date of disease 
progression or death from any cause.  Patients without PFS events will be censored at the last 
evaluation date.  The PFS distribution up to at least 4 years will be provided.
The exploratory time-to-event endpoints of OS and PFS will be summarized using the 
Kaplan-Meier method or by cumulative incidence, whichever is more appropriate, depending 
on the competing risks (e.g., treatment discontinuation without progression in PFS analysis).
For Ph- CML patients, cumulative best response anytime on treatment will be provided.  The 
hierarchy to assess for best response is MR 4.5, MR4, MMR, MR2, MR1, CHR, and OHR.
The percentage of patients with baseline and emergent Bcr-Abl kinase-domain mutations, 
along with the specific types of mutations, will be summarized. 
The FACT-Leu will be scored according to the respective user’s guides and validation 
papers.  Summary statistics of the Functional Assessment of Cancer Therapy-Leukemia 
(FACT-Leu) quality of life questionnaire will be calculated at baseline and approximately 
every 3 months for the first year, and every 6 months during year 2, 3 and 4 of treatment on 
study.  The mean and 95% CI and median of the observed scores and the changes from 
baseline will be reported for the FACT-Leu, individual domains, and items. 
9.4. Safety Analysis
AE incidence rates will be described both with and without regard to causality.  The 
frequency of occurrence of overall toxicity, categorized by toxicity grades (NCI CTCAE 
v4.0), 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 safety analyses will be based on the FAS. 


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9.5. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is an open-
label study, the sponsor may conduct unblinded reviews of the data during the course of the 
study for the purpose of safety assessment, facilitating dose-escalation decisions, facilitating 
pharmacokinetic (PK)/pharmacodynamic (PD) modeling, and/or to support clinical 
development.
9.6. Data Monitoring Committee 
This study will not use an external Data Monitoring Committee.  The Sponsor’s procedures 
for ongoing monthly 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. This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the Institutional Review Board (IRB)/ Ethics Committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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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, or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital'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, e.g., 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 (e.g., 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 (e.g., 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. 
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.


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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)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g.,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator File.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with 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 1996 and 2008 versions). 
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.
When study data are compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify the trial patient.  The study site 
will maintain a confidential list of patients who participated in the study linking each 
patient’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patient’s personal data consistent 
with applicable privacy laws.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.


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The investigator must ensure that each study patient, or his/her legally acceptable
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.
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 
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 (eg, 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 (eg, 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, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative or legal guardian 
when applicable before any study-specific activity is performed. The investigator will retain 
the original of each patient's signed consent document.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
regulatory 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
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (i.e., Clinical Trial Application (CTA) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.


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13.2. End of Trial in all other Participating Countries 
The end of the trial for each patient occurs no more than 4 years after the date of his/her first 
dose of study drug.  The overall End of Trial for this study in all other participating countries 
is defined as the Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of bosutinib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 14 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD)
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
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.


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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 wwwclinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator 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, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator 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, Investigator agrees 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, Investigator is free to publish separately, subject 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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16. REFERENCES
1.
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the 
BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031-7, 
2001.
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O’Brien SG, Guilhot F, Larson R, et al. Imatinib compared with interferon and low-
dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J 
Med 348(11):994-1004, 2003.
3.
Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic 
and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of 
imatinib therapy. Blood 109(6):2303-9, 2007.
4.
Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (AMN107), a highly selective 
BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia 
chromosome–positive chronic myelogenous leukemia in chronic phase following 
imatinib resistance and intolerance. Blood 110(10):3540-6, 2007.
5.
Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia 
chromosome-positive leukemias. N Engl J Med. 367(22):2075-88, 2012.
6.
Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase 
chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. 
Blood 119(15): 3403-12, 2012.
7.
Apperley JF. Part I: Mechanisms of resistance to imatinib in chronic myeloid leukemia.
Lancet Oncol 8(11):1018-29, 2007.
8.
Tokarski JS, Newitt JA, Chang CYJ, et al. The structure of dasatinib (BMS-354825) 
bound to activated ABL kinase domain elucidates its inhibitory activity against 
imatinib-resistant ABL mutation. Cancer Res 66(11):5790-97, 2006.
9.
Giles F, Mahon FX, Gjertsen B, et al. Developmental Therapeutics Consortium report 
on study design effects on trial outcomes in chronic myeloid leukaemia. Eur J Clin 
Invest. 42(9):1016-26, 2012.
10.
Guilhot J, Baccarani M, Clark RE, et al. Definitions, methodological and statistical 
issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the 
European LeukemiaNet. Blood. 119(25):5963-71, 2012.
11.
Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant 
or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 
26(5):959-62, 2012.
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le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic 
myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-
month follow-up results. Leukemia. 26(6):1189-94, 2012.


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13.
Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia 
chromosome-positive leukemias. N Engl J Med. 367(22):2075-88, 2012.
14.
Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain 
mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine 
kinase inhibitors. Blood 110(12): 4005-11, 2007.
15.
Wehrle Jl, Pahl, HL, von Bubnoff N. Ponatinib: a third generation inhibitor for 
treatment of CML. Recent Results Cancer Res. 2014;201:99-107.
16.
https://www.cancer.gov/about-cancer/treatment/drugs/ponatinibhydrochloride.
17.
Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in 
patients with chronic myeloid leukemia in the chronic phase treated with imatinib, 
nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia. 
27(6):1310-5, 2013.
18.
Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase 
chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 
27(6):1316-21, 2013.
19.
Giles FJ, O'Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the 
treatment of chronic myeloid leukemia. Leukemia. 23(10):1698-707, 2009.
20.
Cervantes F, Mauro M. Practical management of patients with chronic myeloid 
leukemia. Cancer. 117(19):4343-54, 2011.
21.
Irvine E, Williams C. Treatment-, Patient-, and Disease-Related Factors and the 
Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of 
Chronic Myeloid Leukemia. Pharmacotherapy. 33(8):868-81, 2013.
22.
Sillaber C, Herrmann H, Bennett K, et al. Immunosuppression and atypical infections in 
CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest. 39(12):1098-
109, 2009.
23.
Kelly K, Swords R, Mahalingam D et al. Serosal inflammation (pleural and pericardial 
effusions) related to tyrosine kinase inhibitors. Target Oncol. 4(2):99-105, 2009.
24.
Cella D, Jensen SE, Webster K, et al. Measuring health-related quality of life in 
leukemia: the Functional Assessment of Cancer therapy –Leukemia (FACT-Leu) 
questionnaire. Value Health 15(8):1051-8; 2012.
25.
http://www.asco.org/practice-guidelines/quality-guidelines/guidelines
26.
Baccarini M, Denninger MW, Rosti G, et al. European LeukemiaNet recommendations 
for the management of Chronic Myeloid Leukemia. Blood. 122(6):872-84, 2013.


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27.
Baccarini M, Cortes J, Pane F, et al. Chronic myeloid leukemia. An update of concepts 
and management. Recommendations of the European LeukemiaNet. J Clin Oncol. 
27:604-51, 2009.
28.
Baccarini M, Saglio G, Goldman J, et al. Evolving concepts in the management of 
chronic myeloid leukemia. recommendations from an expert panel on behalf of the 
European LeukemiaNet. Blood:108:1809-1820, 2006.
29.
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.
30.
Shah N.P. Medical management of CML. Hematology Am Soc Hematol Educ Program 
2007;:371-5.
31.
Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations 
for the management of chronic myeloid leukemia: 2013. Blood 2013; 122(6):872-84.
32.
O'Brien S, Berman E, Moore JO, et al. NCCN Task Force report: tyrosine kinase 
inhibitor therapy selection in the management of patients with chronic myelogenous 
leukemia. J Natl Compr Canc Netw 2011; 9(2):S1-25.
33.
Bhamidipati PK, Kantarjian H, Cortes J, et al. Management of imatinib-resistant 
patients with chronic myeloid leukemia. Ther Adv Hematol 2013; 4(2):103-17.
34.
Pinilla-Ibarz J, Cortes J, Mauro MJ. Intolerance to tyrosine kinase inhibitors in chronic 
myeloid leukemia: definitions and clinical implications. Cancer 2011; 117(4):688-97.


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Appendix 1. Guidelines for Identifying Resistance and Intolerance
Definition criteria for Resistance
There are two categories of resistance: 

Primary resistance is the failure to achieve a response as established by the European 
LeukemiaNet (ELN) or National Comprehensive Cancer Network (NCCN) guidelines. 
Primary resistance will be further divided into primary hematologic resistance, which 
occurs in cases who fail to normalize peripheral counts within 3–6 months of initiation of 
treatment; or primary cytogenetic resistance, in patients who fail to achieve any level of 
cytogenetic response (CyR) at 6 months, a major CyR (MCyR) at 12 months or a CCyR 
at 18 months.30

Secondary resistance is defined as those who have previously achieved and sub sequently 
lost their hematologic, molecular, or cytogenetic response in accordance with 
ELN/NCCN guidelines.31, 32
Definition of Intolerance to therapy:33,34
A patient is deemed to be intolerant to a TKI if one or more of the following criteria are 
met:

Any life threatening Grade 4 non hematological toxicity.

Any Grade 3 or 4 non hematological toxicity that persists despite dose reduction and 
optimal symptomatic measures.

Grade 3 or 4 hematological toxicity that is unresponsive to supportive measures and 
would require dose reduction below the accepted minimal effective dose.

Any combination of non hematological toxicities of any grade that persist despite 
supportive measures and in the patients and physician's opinion compromise quality of 
life to such an extent that a change of therapy is justified.


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Appendix 2. 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
atazanavir
itraconazole
Aprepitant
voriconazole
Amprenavir
posaconazole
Fosamprenavir
conivaptan
Imatinib
clarithromycin
Verapamil
telithromycin
tofisopam 
boceprevir
Ciprofloxacin
telaprevir
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


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Appendix 3. Summary of Drugs That Are Generally Accepted to Have a Risk of 
Causing QTc Prolongation Potentially Causing Torsades de Pointes
Generic Name
Brand Name
EU and Other Regions (Common 
Tradenames)
Amiodarone
Coradone/Pacerone
Coradone
Arsenic trioxide
Trisenox
Trisenox
Bepridil
Vascor  (no longer sold in the 
theUS)
-
Chloroquine
Aralen
Avlocor, Nivaquine
Chlorpromazine
Thorazine
Largactil / Megaphen
Clarithromycin
Biaxin
Binoclar, Crixan, Claritt, Clarac, Biaxin, 
Klaricid, Klacid, Klaram, Klabax, Claripen,
Clarem, Claridar, Fromilid, Clacid, Clacee, 
Vikrol, Infex, Clariwin, Resclar, Clarihexal
Disopyramide
Norpace
Rythmodan
Dofetilide
Tikosyn
-
Domperidone
Motilium
Motilium
Droperidol
Inapsine
Xomolix
Erythromycin
Erythrocin/E.E.S.
-
Halofantrine
Halfan
Halfan
Haloperidol
Haldol
Aloperidin, Bioperidolo, Brotopon, Dozic, 
Duraperidol, Einalon S, Eukystol, Haldol,
Halosten, Keselan, Linton
Ibutilide
Corvert
Corvert
Levomethadyl
  Orlaam (discontinued in the US)
-
Mesoridazine
Serentil
-
Methadone
Methadose/Dolophine
Methadose
Moxifloxacin
Avelox, Moxeza, Vigamox
-
Pentamidine
NebuPent/Pentam
-
Pimozide
Orap
Orap
Procainamide
Pronestyl/Procan
-
Quinidine
Cardioquin/Quinaglute
-
Sotalol
Betapace
Sotacor
Sparfloxacin
Zagam
-
Thioridazine
Mellaril
-
Adapted from “The University of Arizona Center for Education and Research on Therapeutics”
See the following websites for an updated List – Drugs with Risk of Torsades de Pointes:
http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm#
http://www.medicines.org.uk/emc/
http://www.ema.europa.eu/ema/index.jsp?curl=pages/home/Home_Page.jsp&murl=&mid=&jsenabled=true


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Appendix 4. Patient Information Card
Guidelines for the Management of Diarrhea
Please be sure you understand these instructions BEFORE you leave the office and 
discuss with your study doctor if you need to obtain antidiarrheal medication before 
you go home. 
Data obtained thus far from patients receiving bosutinib in prior studies performed in patients 
with CML show that diarrhea is the most common side effect you may have while receiving 
bosutinib. It has also been observed that diarrhea events, although frequent, are mainly low 
grade severity, transient, occurring predominantly in the first month of bosutinib treatment 
and managed by appropriate concomitant medications given for short duration. The purpose 
of this card is to help ensure appropriate management of diarrhea.
Treating diarrhea as soon as it starts may prevent it from getting worse. Your study doctor 
may tell you to take antidiarrheal medication(s) with the first loose stool or diarrhea. Please 
contact your study doctor as soon as possible if you have an episode of diarrhea. If you are 
dizzy or weak because of diarrhea, come to the office or go to the hospital immediately.  
When calling the study doctor to report an event of diarrhea you should provide as much of 
the information below as possible, in order to help your study doctor to assess your diarrhea 
and decide on the best treatment: 

Number of stools per day as compared to your normal bowel habits;

Presence of diarrhea during the night;

Presence of fever, dizziness, abdominal pain/cramping or weakness;

What the stool looks like, that is, watery, bloody or mucusy;

When you took your last dose of study drug;

Any other information that could explain your diarrhea (change in diet/food, recent 
travel, contact with other people experiencing vomiting and/or diarrhea).
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;


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
Eat frequent small meals;

Eat low fat foods including bananas, rice, applesauce and/or toast.
Your study doctor may have other suggestions.
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.
2. 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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Appendix 5. European Leukemia Net Definition of Response to Second-Generation 
TKIs for Chronic Phase Second-line CML Patients 
If first-line treatment was changed because of INTOLERANCE, the following table defines
Optimal Response, Warning, and Failure corresponding to SECOND-LINE TREATMENT for 
all CML patients in CP, AP, and BP26
Evaluation Time
Months
Optimal Response
Warning
Failure
Baseline
NA
High Risk
OR
CCA/Ph+, major route
NA
Month 3
BCR-ABL1IS ≤10%, 
AND/OR
Ph+ 35% (PCyR)
BCR-ABLIS >10% 
AND/OR Ph+ 36-95%
Non CHR
AND/OR
Ph+ >95%
Month 6
BCR-ABL1IS <1%, 
AND/OR Ph+ 0 (CCyR)
BCR-ABL1IS 1-10%, 
AND/OR Ph+ 1-35%
BCR-ABL1IS >10%
AND/OR Ph+ > 35%
Month 12
BCR-ABL1IS 0.1%
(MMR)
BCR-ABL1 IS >      
0.1-1%
BCR-ABL1IS >1% 
AND/OR Ph+ >0
Any Time
MMR or better**
CCA/Ph- (-7, or 7q-)
Loss of CHR
Loss of CCyR
Confirmed Loss of 
MMR*
Mutations
CCA/Ph+
Abbreviations: TKIs, tyrosine kinase inhibitors; NA, not applicable; Ph+, Philadelphia chromosome positive; 
Ph-, Philadelphia chromosome negative; CCA/Ph+, Clonal Chromosome Abnormalities in Ph+ cells; CCA/Ph-, 
Clonal Chromosome Abnormalities in Ph- cells; IS, BCR-ABL transcripts on International Scale, 
*  In two consecutive tests, of which one has a BCR-ABL1 transcripts level ≥ 1% on International Scale.
** “Better” is defined as MR4 or MR4.5 or MR5


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If first-line treatment was changed because of FAILURE, the following table defines
Optimal Response, Warning, and Failure corresponding to SECOND-LINE 
TREATMENT for all CML patients in CP AP, and BP26
Time
Optimal Response
Warning
Failure
Baseline
NA
No CHR or            
Loss of CHR on first-
line treatment or    
Lack of CCyR to first-
line TKI or High Risk
NA
3 months
BCR-ABL1IS 10%
AND/OR Ph+ <65%
BCR-ABL1IS >10%
AND/OR Ph+ 65-95%
No CHR, or
Ph+ >95%, or
New mutations
6 months
BCR-ABL1IS
10% AND/OR Ph+
<35% (PCyR)
Ph+ 35-65%
BCR-ABL1IS
>10% AND/OR Ph+
>65% AND/OR  New 
mutations
12 months
BCR-ABL1IS <1%
AND/OR Ph+ 0
(CCyR)
BCR-ABL1IS 1-10-% 
AN/OR Ph+ 1-35%
BCR-ABL1IS >10% 
AND/OR Ph+ >35%
AND/OR
New mutations
Any Time
MMR or better**
CCA/Ph-(-7 or 7q-) or 
BCR-ABL1IS > 0.1%
Loss of CHR, or
Loss of CCyR, or 
PCyR
New mutations, or
Loss of MMR*, or
CCA/Ph+
Abbreviations: TKIs, tyrosine kinase inhibitors; NA, not applicable; Ph+, Philadelphia chromosome positive; 
Ph-, Philadelphia chromosome negative; CCA/Ph+, Clonal Chromosome Abnormalities in Ph+ cells; CCA/Ph-, 
Clonal Chromosome Abnormalities in Ph- cells; IS, BCR-ABL transcripts on International Scale, 
* In two consecutive tests, of which one has a BCR-ABL1 transcripts level ≥ 1% on International Scale.
**  “Better” is defined as MR4 or MR4.5 or MR5. 


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Appendix 6. Sample Patient Diary Card
Take ____mg of the study medication every morning with food
This means ______(#) of tablets
DATE
DOSE
CHECK IF 
DOSE 
MISSED
REASON FOR MISSED DOSES
SYMPTOMS/COMMENTS
CONCOMITANT 
MEDICATIONS
Example:
4Jul07-16Jul07
500 mg
Mild headache; Tylenol 250mg 
tablet
17Jul07 + 18Jul07
0
yes
Forgot meds
Date of your next visit: _________________________________________________
SAMPLE


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Appendix 7. Criteria to Identify Phase of CML
Phase a, 27,28,
Findings
Blast Phase 
≥30% Blasts in blood or bone marrow
Extramedullary Blasts proliferation, apart from spleen
If either of these 2 criteria is present, the patient is classified as Blast Phase 
regardless of other criteria.
Accelerated 
Phase
15-29% Blasts in blood or bone marrow
OR
>30% Blasts + Promyelocytes (with Blasts <30%) in blood or bone marrow
OR
≥20% Basophils in blood or bone marrow
OR
Persistent platelets <100 x 109/L (not related to therapy)OR
Clonal chromosomal abnormalities in Ph+ cells (CCA/Ph +), major route, on 
treatment
Chronic Phase
<15% Blasts
<20% Basophils
≤30% Blasts +  Promyelocytes (with Blasts <15%) in blood or bone marrow
AND
Platelets ≥100 x 109/L (unless related to therapy)
AND
No Extramedullary Blasts (except spleen)
a
Observance of any one criterion in the worse disease phase achieves that phase as the diagnosis (e.g., 20% 
basophils alone elevates the diagnosis from CP to AP).


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Appendix 8. 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.
10, 20 or 30
* 
Karnofsky Score is provided for comparison purposes only.  Please record ECOG Grade only.


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Appendix 9. Local Laboratory Collection Requirements 
Hematology Panel
CBC (including Hemoglobin and Hematocrit)
WBC with differential
Platelets
Neutrophils
Liver Function Tests
ALT
AST
Alkaline Phosphatase
Total Serum Bilirubin *
      Direct bilirubin*
      Indirect bilirubin**
      Gamma-glutamyl transferase (GGT)**
Total bile acids**
Acetaminophen drug test and/or protein adduct levels**
Blood Chemistry Panel
Total Calcium
Cholesterol (as clinically indicated)
HDL (as clinically indicated)
LDL (as clinically indicated)
Sodium
BUN or Urea
Creatinine kinase** (as clinically indicated)
Creatinine
Albumin
Potassium (as clinically indicated)
Magnesium (as clinicallyindicated)
Glucose
HbA1C (as clinically indicated)
Phosphorous
Lipase
Amylase
Uric acid
Coagulation Tests
PT or INR
PTT or aPTT
Pregnancy Test
Serum OR Urine (sensitivity of at least 25 mIU/mL)
* Direct bilirubin must be collected if total serum bilirubin is >1.5 x ULN and for Hy’s law 
determination, if appropriate. 
**  Collected for Hy’s Law determination, if appropriate
Note: Hy’s Law definition is defined in Section 8.4.1


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CCI


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CCI


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CCI


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Appendix 11. European LeukemiaNet Guidelines for Response in CML
Definitions of Hematologic, Cytogenetic, and Molecular Response26
Response by Type
Definitions
Hematologic
Complete (CHR)
WBC <10 x 109/L
Peripheral Blood Basophils <5%
No Peripheral Blood myelocytes, promyelocytes, myeloblasts in the 
differential
Platelet count <450 x 109/L
Spleen nonpalpable
Cytogenetic *
Complete (CCyR)
Partial (PCyR)
Minor (mCyR)
Minimal (minCyR)
None (noCyR)
No Ph+ metaphases
1% to 35% Ph+ metaphases
36% to 65% Ph+ metaphases
66% to 95% Ph+ metaphases
>95% Ph+ metaphases
Molecular 
Deep Molecular Response 
(MR4, MR4.5) 
Major (MMR)
MR4= either (i) detectable disease with <0.01% BCR-ABL1 IS or  
(ii) undetectable disease in cDNA with >10 000 ABL1 transcripts 
MR4.5 =either (i) detectable disease with < 0.0032% BCR-ABL1 IS
or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts 
in the same volume of cDNA used to test for BCR-ABL1.
Ratio of BCR-ABLIS ≤0.1%**. 
Abbreviations: CHR, complete hematologic response; CCyR, complete cytogenetic response, PCyR, partial 
cytogenetic response; Ph+, Philadelphia Chromosome positive; MCyR, major cytogenetic response; mCyR, 
minor cytogenetic response; minCyR, minimal cytogenetic response; noCyR, no cytogenetic response; MR4,
MR4.5, deep molecular response; MMR, major molecular response;.  
*If bone marrow metaphases cannot be obtained or evaluated by chromosome banding analysis, the definition 
of CCyR (defined as <1% for FISH) may be based on interphase FISH of blood cells, provided that it is 
performed with Dual-Color Dual-Fusion or Dual-Fusion FISH probes and at least 200 nuclei are scored.  PCyR 
and CCyR are counted together and reported as MCyR.  
**With >=5,000 ABL1 transcripts.


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Definitions of Hematologic Response for AP and BP CML29*
CHR**
WBC ≤ institutional upper limit of normal (ULN) 
ANC 1.0 x 109/L 
Platelet count 100 x 109/L 
BM Blasts ≤ 5% ***
No peripheral blood blasts or promyelocytes; 
Peripheral blood myelocytes + metamyelocytes < 5%;
Basophils in peripheral blood < 5%*
No evidence of extramedullary involvement
*The maximum % of basophils in peripheral blood was modified from < 2 to <5% for a less restrictive
constraint and alignment with the CHR criteria for CP CML patients according to ELN guidelines.
**If an on- treatment CBC is scheduled within 1 week from the last platelet transfusion or last dose of G-CSF, 
it should be considered “Not Evaluable” for hematological response assessment, and a CBC should be repeated 
at least 1 week from the last platelet transfusion or last dose of G-CSF received.
***CHR for AP/BP that the 5% BM blasts is only required when a BM differential is available.


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SAP_001.pdf: 
Protocol B1871039 Statistical Analysis Plan (PF-05208763)
PFIZER CONFIDENTIAL
Page 1
Protocol B1871039
A PHASE 4 SAFETY AND EFFICACY STUDY OF BOSUTINIB (BOSULIF®) IN
PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE CHRONIC
MYELOID LEUKEMIA PREVIOUSLY TREATED WITH ONE OR MORE
TYROSINE KINASE INHIBITORS
Statistical Analysis Plan 
(SAP)
Version:
3.0
Author:
, PhD, 
, Clinical Statistician
Date:
12-NOV-2020
PPD
PPD


Protocol B1871039 Statistical Analysis Plan (PF-05208763)
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TABLE OF CONTENTS
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................8
4. HYPOTHESES AND DECISION RULES...........................................................................9
4.1. Statistical Hypotheses ...............................................................................................9
4.2. Statistical Decision Rules..........................................................................................9
5. ANALYSIS SETS .................................................................................................................9
5.1. Full Analysis Set .......................................................................................................9
5.2. ‘Per Protocol’ Analysis Set .......................................................................................9
5.3. Safety Analysis Set....................................................................................................9
5.4. Other Analysis Sets ...................................................................................................9
5.5. Treatment Misallocations..........................................................................................9
5.6. Protocol Deviations...................................................................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) ...............................................................................................10
6.2. Safety Endpoints .....................................................................................................14
6.2.1. Exposure and Compliance..........................................................................14
6.2.2. Laboratory Evaluations, Vital Signs, and Cardiac Evaluations..................14
6.2.3. Laboratory Evaluations of Special Interest.................................................14
6.2.4. Non-study Medications...............................................................................15
6.2.5. Cross Intolerance ........................................................................................15
6.2.6. Death...........................................................................................................15
6.2.7. Adverse Events ...........................................................................................15
6.2.8. Adverse Events of Special Interest.............................................................15
6.3. Other Endpoints.......................................................................................................16
6.3.1. Demographic, Medical History, and Baseline Characteristics...................16
6.3.2. PK Endpoints..............................................................................................16
6.3.3. PD Endpoints..............................................................................................16


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6.3.4. Biomarker Endpoints..................................................................................16
6.3.5. Outcomes Research Endpoints ...................................................................16
6.4. Covariates................................................................................................................17
7. HANDLING OF MISSING VALUES ................................................................................17
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................19
8.1. Statistical Methods ..................................................................................................19
8.1.1. Analyses of Continuous Data .....................................................................19
8.1.2. Analyses of Categorical Data .....................................................................19
8.1.3. Analyses of Binary Endpoints ....................................................................19
8.1.4. Analyses of Time-To-Event Endpoints ......................................................19
8.2. Statistical Analyses .................................................................................................20
8.2.1. Analysis of Primary Efficacy Endpoints ....................................................20
8.2.2. Analysis of Secondary Efficacy Endpoints ................................................20
8.2.3. Analysis of Exploratory Efficacy Endpoints ..............................................21
8.2.4. Analysis of Safety Endpoints......................................................................22
8.2.4.1. Baseline Characteristics ............................................................22
8.2.4.2. Treatment and Compliance .......................................................23
8.2.4.3. Laboratory Evaluations, Vital Signs, and Cardiac 
Evaluations ........................................................................................23
8.2.4.4. Laboratory Evaluations of Special Interest...............................23
8.2.4.5. Non-study Medications .............................................................23
8.2.4.6. Cross Intolerance.......................................................................23
8.2.4.7. Death .........................................................................................24
8.2.4.8. Adverse Events..........................................................................24
8.2.4.9. Adverse Events of Special Interest............................................24
8.2.4.10. Additional Safety.....................................................................24
8.2.5. Analyses of Patient Disposition Endpoints.................................................25
8.2.6. Analyses of Outcome Research Endpoints.................................................25
9. REFERENCES ....................................................................................................................26
APPENDICES
Appendix 1. CRITERIA TO IDENTIFY PHASE OF CML...................................................27


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Appendix 2. DEFINITIONS OF HEMATOLOGIC, CYTOGENETIC, AND 
MOLECULAR RESPONSE ................................................................................28


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
The SAP version 3.0 amended SAP v2.0 dated September 28, 2017.  The main changes are 
COVID-19 related and additional exploratory analyses which included:

Impact on analyses from COVID-19;

Additional analyses of deep molecular response.
The SAP version 2.0 amended the original SAP v1.0 dated March 18, 2014.  The main 
changes to align with protocol amendment #1 included:

Change the primary endpoint analysis to (1) require maintenance of baseline response 
for at least one year on-treatment for patients with complete cytogenetic response 
(CCyR) at baseline, (2) require confirmation of initial on-treatment cytogenetic 
response (in the absence of major molecular response [MMR]) by a second 
consecutive response at least 28 days apart, and (3) be based on treated patients with a 
valid baseline efficacy assessment;

Addition of secondary endpoints duration of CCyR and duration of MMR;

Include imputation of cytogenetic response from molecular monitoring data if 
cytogenetics is not performed;

Update appendices for molecular, cytogenetic and hematologic response criteria;

Update required number of 4th line patients from at least 75 to 45.
2. INTRODUCTION
On September 4, 2012, bosutinib was approved by the US Food and Drug Administration
(FDA) for the treatment of adult patients with chronic (CP), accelerated (AP), or blast phase
(BP) Philadelphia chromosome positive (Ph+) Chronic myelogenous leukemia (CML) with 
resistance or intolerance to prior therapy (United States Prescribing Information 
BOSULIF®). More recently, on March 27, 2013, the European Medicines Agency (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 inhibitors (TKIs) and for whom imatinib, nilotinib and dasatinib are not considered 
appropriate treatment options (EMA Summary of Product Characteristics).
Furthermore, in 5%–10% of patients with of chronic myelogenous leukemia (CML), the 
Philadelphia chromosome (Ph) is not identified despite the presence of the associated 
BCR-ABL molecular abnormality (Ph-negative, BCR-ABL-positive CML) because of 
submicroscopic rearrangements. Regardless, the presence of the BCR-ABL fusion gene will 
translate into a BCR-ABL fusion protein with dysregulated tyrosine kinase activity. 
Therefore, a TKI targeting BCR-ABL is also an effective treatment also for Ph negative CML 
patients. The FDA and EMA approvals were granted based on the results obtained from the 
single arm, Phase 1/2 study (3160A4-200-WW, “Study-200”) in adult patients with Ph+ 


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leukemias who had failed prior TKI therapy, and with the support of the safety results
obtained from the Phase 3 study (3160A4-3000-WW) comparing bosutinib with imatinib in 
newly diagnosed CP Ph+ CML patients. In addition, the EMA was provided with descriptive 
narrative information from the bosutinib compassionate use program in patients with 
Ph+CML who had received at least one prior TKI treatment and had progressed or were 
intolerant, and otherwise not considered suitable for other TKI therapy, as well as efficacy 
and safety analyses from a subset of Study-200 patients whose disease had failed prior 
imatinib and/or dasatinib or nilotinib and were contraindicated for treatment with dasatinib 
or nilotinib, as well as 4th-line CML patients on the study.
The purpose of this phase 4 study is to fulfill the post-authorization commitment made by
Pfizer to the EMA in providing additional safety and efficacy data in approximately 150 Ph+
CML patients with high unmet medical need, including at least 75 CP, AP or BP patients in 
the 4th or later line treatment setting (ie, after treatment with at least 3 other TKIs). The 
EMA conditional approval requires completion of this post-authorization study in order to 
convert the conditional approval to a full marketing authorization approval.
This study was initiated in November 2014 and the original target projection was 75 patients 
in each cohort. However, the 4th line cohort has not met its planned targeted enrollment 
objective; whereas, the 2nd/3rd-line cohort has overenrolled (n=106). Therefore, Pfizer 
decided based on CHMP feedback to stop recruitment after at least 45 patients have been 
enrolled in the 4th line cohort. It was further agreed, there are sufficient numbers of patients 
in each cohort to perform an informative descriptive analysis of the safety and efficacy and 
safety of bosutinib.
2.1. Study Design
This is a single-arm, open-label, non-randomized, multi-center Phase 4 study to evaluate
bosutinib (Bosulif ®) in patients with CP/AP/BP Ph+ CML whose disease has failed prior
treatment with commercially available TKIs due to drug resistance or intolerance, or are
otherwise contraindicated for treatment with commercially available TKIs such as imatinib,
dasatinib, or nilotinib (ie, presence of a BCR-ABL mutation or medical condition making
commercially available TKIs unsuitable for a patient). Patients will receive bosutinib for at
least 4 years from the time of first dose, unless disease progression, unacceptable toxicity,
patient withdrawal of consent, death or Sponsor discontinuation of study. Patients
discontinuing bosutinib prior to completing at least 4 years of therapy will be followed for
survival until they complete at least 4 years of follow-up from the time of first dose. Patients 
completing at least 4 years of bosutinib with continued benefit may be switched to 
commercially available therapy at that time.
Patients are allocated to the cohort based on the derived assignment from the baseline disease 
stage and prior TKI therapy.  Patients are either:

CP Ph+ CML second line (CP2L) resistant or intolerant to imatinib, dasatinib, or 
nilotinib;

CP Ph+ CML third line (CP3L) resistant or intolerant to imatinib and dasatinib, 
imatinib and nilotinib, or dasatinib and nilotinib;


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
CP Ph+ CML fourth or later line (CP4L) resistant or intolerant to imatinib, dasatinib, 
and nilotinib;

AP Ph+ CML second line (AP2L) resistant or intolerant to imatinib, dasatinib, or 
nilotinib;

AP Ph+ CML third line (AP3L) resistant or intolerant to imatinib and dasatinib, 
imatinib and nilotinib, or dasatinib and nilotinib;

AP Ph+ CML fourth or later line (AP4L) resistant or intolerant to imatinib, dasatinib, 
and nilotinib;

BP Ph+ CML second line (BP2L) resistant or intolerant to imatinib, dasatinib, or 
nilotinib;

BP Ph+ CML third line (BP3L) resistant or intolerant to imatinib and dasatinib, 
imatinib and nilotinib, or dasatinib and nilotinib;

BP Ph+ CML fourth or later line (BP4L) resistant or intolerant to imatinib, dasatinib, 
and nilotinib, or

Ph- CML.  
Patients will be summarized based on these cohorts or a combination of these cohorts (eg, CP 
with 1 or 2 prior lines of TKI therapy includes CP2L and CP3L, CP total includes CP2L, 
CP3L, and CP4L).  AP (AP2L, AP3L, AP4L) and BP (BP2L, BP3L, BP4L) patients 
combined are known as advanced patients. All Ph- CML patients will be summarized 
separately.  Patients who were both resistant and intolerant to the prior TKI or neither will be
considered intolerant to that TKI for analysis purposes.
2.2. Study Objectives
Primary Objectives

To estimate the 1-year (52-week) probability of cumulative confirmed Major 
Cytogenetic Response (MCyR) in CP Ph+ CML patients with 1 or 2 prior lines of TKI 
therapy.

To estimate the 1-year (52-week) probability of cumulative confirmed MCyR in CP 
Ph+ CML patients with 3 or more prior lines of TKI therapy.

To estimate the 1-year (52-week) probability of cumulative confirmed Overall 
Hematological Response (OHR) in AP and BP Ph+ CML with any prior TKI therapy.
Secondary Objectives

To estimate the cumulative probability of MCyR in each disease phase (CP, AP and 
BP) for Ph+ CML patients.


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
To estimate the cumulative probability of confirmed OHR in each disease phase (AP
and BP) for Ph+ CML patients by number of lines of prior therapy.

To characterize the distributions of best response (molecular, cytogenetic, or 
hematologic) in the CP, AP, and BP Ph+ CML patient populations.

To estimate the probability of MCyR at 3, 6, 12, 18, and 24 months in the CP, AP, 
and BP Ph+ CML patient populations.

To estimate the probability of confirmed OHR at 3, 6, 9, 12, 18, and 24 months in the 
AP and BP Ph+ CML patient populations.

To estimate the probability of cumulative confirmed complete hematologic response 
(CHR) in the CP, AP and BP Ph+ CML patient populations.

To estimate the probability of cumulative MMR in the CP, AP, and BP Ph+ CML 
patient populations.

To estimate the duration of CCyR.

To estimate the duration of MMR.

To evaluate the overall safety profile of bosutinib in the study population.
Exploratory Objectives

To obtain preliminary estimates of Progression Free Survival (PFS) and Overall 
Survival (OS) in 4th or later line CP, AP and BP Ph+ CML patients.

To identify BCR-ABL mutations associated with sensitivity or resistance to bosutinib, 
as well as to catalog possible acquired resistance mutations.

To explore efficacy (hematologic and molecular response) in Ph- CML patients.

To evaluate patient reported outcomes measures.

To collect banked biospecimens for exploratory research, unless prohibited by local 
regulations or ethics committee decision.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
There are no interim analyses planned for this study. The analysis for the primary objective 
will be done after all patients have completed one year of follow-up and all data through one 
year have been collected and processed.  There will be one follow-up analysis when all study 
data are complete.  
This is a single-arm, open-label study so unblinding is not required.


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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 hypothesis testing will be done.
5. ANALYSIS SETS
5.1. Full Analysis Set
The full analysis set is all patients who receive at least one dose of bosutinib.  This is the 
same as the safety analysis set.
5.2. ‘Per Protocol’ Analysis Set 
Per Protocol analyses will not be performed in this study.
5.3. Safety Analysis Set
The safety analysis set is all patients who received at least one dose of bosutinib.  This is the 
same as the full analysis set thus only the “full analysis set” terminology will be used.
5.4. Other Analysis Sets
The evaluable analysis set are those treated patients with a valid baseline efficacy assessment 
for the respective endpoint (ie, [1] at least 20 metaphases from the baseline bone marrow 
cytogenetic assessment or a CCyR with at least 200 cells analyzed from the fluorescence in 
situ hybridization [FISH] baseline assessment or MMR from the baseline molecular 
assessment for cytogenetic endpoints or [2] a valid baseline hematologic assessment for 
hematologic endpoints as defined in Appendix 1 or [3] a valid baseline molecular assessment 
from the central laboratory for molecular endpoints).  
5.5. Treatment Misallocations 
B1871039 is a single arm study so there were will be no treatment misallocations.  Patients 
who are enrolled but not treated will not be included in the safety or efficacy analyses.  
5.6. Protocol Deviations
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
In general, the baseline value will be defined as the last non-missing value prior to first dose, 
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 evaluation is defined as any evaluation done during bosutinib therapy or 
within 28 days of last dose.


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6.1. Efficacy Endpoint(s)
Primary

Cumulative confirmed MCyR defined as Complete Cytogenetic Response (CCyR) or 
Partial Cytogenetic Response (PCyR) by 1 year (52 weeks) in 2nd and 3rd line CP 
patients.

Cumulative confirmed MCyR by 1 year (52 weeks) in 4th and later line CP patients.

Cumulative confirmed OHR defined as Complete Hematological Response (CHR) or 
Return to Chronic Phase (RCP) by 1 year (52 weeks) in AP and BP patients.
The local cytogenetic assessments will be used for the primary endpoint analysis in CP 
patients. The local hematologic assessments will be used for the primary endpoint analysis 
in AP and BP patients. 
Cumulative response is any response on-treatment up through Week 52 (based on the date of 
assessment) with a 4 week window (≤Week 56).  Response is confirmed for cytogenetic and 
hematologic with 2 consecutive responses at least 28 days apart.  The date of confirmed 
response is the date of the first response.  Cytogenetic and hematologic responses are defined 
in Appendix 2 and Appendix 1.  MCyR is defined as a CCyR or PCyR.  OHR is defined as 
CHR or RCP.  To be considered a responder, the patient must have maintenance of baseline 
response for 5 weeks for hematologic response or 52 weeks for cytogenetic response or an 
improvement from baseline.  Patients with PCyR at baseline must attain CCyR on-treatment 
to be counted as a cytogenetic responder. Patients with at least MMR and a deeper molecular 
response than baseline are counted as confirmed CCyR.
Secondary

Cumulative MCyR in CP, AP and BP patients.

Cumulative confirmed OHR in AP and BP patients by line of therapy.

Cumulative best response in CP, AP, and BP patients.

MCyR at 3, 6, 12, 18, and 24 months in CP, AP, and BP patients.

Confirmed OHR at 3, 6, 9, 12, 18, and 24 months in AP and BP patients.

Cumulative confirmed CHR.

Cumulative MMR in CP, AP, and BP patients.

Duration of CCyR.

Duration of MMR.


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The local cytogenetic assessments will be used for the secondary endpoint analyses for all
patients. The local hematologic assessments will be used for the secondary endpoint 
analyses for all patients.  Molecular assessments will be performed at a central laboratory. 
Endpoint analysis for molecular response will be carried out by independent central 
analysis.
Cumulative response is any response on-treatment.  Landmark “at” responses need to occur 
within a 2 week window of the landmark for those before Week 39 and within a 4 week 
window for Week 39 and after (eg, Month 3 is ≥Week 11 to ≤Week 15, Month 18 is 
≥Week 74 to ≤Week 82, etc.).  Molecular responses are defined in Appendix 2.  Response is 
unconfirmed for cytogenetic and molecular and confirmed for hematologic with 
2 consecutive responses at least 28 days apart.  The date of hematologic confirmed response 
is the date of the first response.  To be considered a responder, the patient must have 
maintenance of baseline response while on-treatment or an improvement from baseline. The 
hierarchy to assess for best response from best to worst is ≥4.5-log reduction of BCR-ABL 
transcripts from standardized baseline on the international scale (MR4.5), 
MR4 (≥4-log reduction), MMR (≥3-log reduction, same as MR3), CCyR, PCyR, CHR, and 
OHR.
Duration of response (DOR) for CCyR and MMR, is defined as the time from first response 
to confirmed loss, progression of disease as assessed by the investigator, or on-treatment 
death due to any cause ([date of loss – date of first response + 1]/30.4). For CCyR, 
confirmed loss is defined as 2 consecutive assessments with >0 Ph+ metaphases at least 
28 days apart.  For MMR, confirmed loss is defined as 2 consecutive assessments at least 
28 days apart with a <3-log (>0.1%) reduction in transcripts from standardized baseline one 
of which corresponds to a ≤2-log reduction (≥1%).  The date of confirmed loss is the earlier 
of first loss, progression, or death date.  Patients without confirmed loss, progression, or 
death are censored at the last valid assessment where response could be assessed.
Exploratory

PFS.

OS.

Presence of BCR-ABL mutations.

For Ph- CML patients, cumulative best response (OHR and MMR) anytime on 
treatment.

Patient reported outcome (PRO) endpoints as measured by Functional Assessment of 
Cancer Therapy-Leukemia (FACT-Leu).

To collect banked biospecimens for exploratory research, unless prohibited by local 
regulations or ethics committee decision. Collection of banked biospecimens unless 
prohibited by local regulations or ethics committee decision. Additional information 
on collection and potential use is provided in the Banked Biospecimens section.


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
Time to MMR, MR4, MR4.5, CCyR, and MCyR.

Duration of MR4 and MCyR.

Time to confirmed transformation on-treatment.
The local cytogenetic assessments will be used for the exploratory endpoint analyses for all
patients. The local hematologic assessments will be used for the exploratory endpoint 
analyses for all patients.  Molecular assessments will be performed at a central laboratory. 
Endpoint analysis for molecular response will be carried out by independent central 
analysis.
Time to response is the time from first dose to first response, unconfirmed for molecular and 
cytogenetic ([date of first response – first dose date +1]/30.4).  Patients without events are 
censored at the last molecular or cytogenetic assessment where response could be assessed
for the respective endpoint.
DOR for MCyR follows the same rules as the secondary endpoint of DOR for CCyR.  DOR 
for MR follows the same rules as the secondary endpoint of DOR for MMR except 
confirmed loss is defined as 2 consecutive assessments at least 28 days apart with a <4-log
(>0.01%) reduction in transcripts from standardized baseline one of which corresponds to a 
≤3-log reduction (≥0.1%).
PFS is defined as the time from first dose to objective progression or relapse as assessed by 
the investigator and noted as the reason for permanent treatment discontinuation on the case 
report form (CRF) or on-treatment death due to any cause ([date of progression – first dose 
date +1]/30.4). Patients without events are censored at the last cytogenetic, hematologic, or 
laboratory assessment where progression could be assessed. Progression is defined as:

For CP, at least one of the following criteria:

Development of AP or BP CML;

Loss of CHR (in absence of cytogenetic response) confirmed by 2 complete blood 
counts (CBC) at least 2 weeks apart; Loss of CHR is defined as:

WBC count that rises to >20.0 x 109/L;

Platelet count that rises to ≥600 x 109/L;

Appearance of extramedullary disease not present at baseline including 
hepatosplenomegaly by palpation or other extramedullary involvement proven 
by biopsy;

Appearance of ≥5% myelocytes + metamyelocytes in the peripheral blood or
appearance of blasts or promyelocytes in the peripheral blood:

Loss of MCyR (loss of CCyR or loss of PCyR); 


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
Increasing white blood count (WBC) in a patient without CHR, defined as 
doubling of WBC, to >20 x 109/L on 2 occasions at least 2 weeks apart 
(after the first 4 weeks of treatment).

For AP, at least one of the following criteria:

Development of confirmed BP;

Loss of previous hematologic response over a 2-week period;

Loss of CHR is defined as:

WBC count that rises to >20.0 x 109/L;

Platelet count that rises to ≥600 x 109/L;

Appearance of extramedullary disease not present at baseline including 
hepatosplenomegaly by palpation or other extramedullary involvement proven 
by biopsy;

Appearance of ≥5% myelocytes + metamyelocytes in the peripheral blood or 
appearance of blasts or promyelocytes in the peripheral blood.

No decrease from baseline levels (if considered clinically relevant) in percentage 
blasts in peripheral blood or bone marrow on all assessments over a 4-week 
period.

For BP (of any phenotype):

Increasing blasts (if considered clinically relevant) peripheral blood or bone 
marrow over a 4-week period.
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 (>52 weeks), the event will not be 
used and censorship will be at the most recent prior assessment.  
Time to on-treatment transformation, defined by the first progression bullet above, is the time 
from first dose to confirmed transformation ([date of transformation – first dose date 
+1]/30.4).  Confirmed transformation is defined as 2 consecutive assessments at least 1 week 
apart or 1 assessment confirmed by progression of disease or death due to any cause.  The 
date of confirmed transformation is the date of the first transformation.  Patients without 
events are censored at the last hematologic or extramedullary assessment where 
transformation could be assessed.


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BCR-ABL mutational status at baseline and treatment discontinuation will be assessed.  
Emergent mutations are defined as those mutations which were not present at baseline.  
Patients who were not assessed for baseline mutations are not assessable for emergent 
mutations.
OS is defined as the time from first dose to the date of death ([date of death – first dose date 
+1]/30.4).  Patients who have not died will be censored at the last known alive date.
For Ph- CML patients, cumulative best response anytime on treatment will be provided. The
hierarchy to assess for best response is MR4.5, MR4, MMR, MR2 (≥2-log reduction), 
MR1 (≥1-log reduction), CHR, and OHR.
PRO endpoints are defined in the outcomes research section.
6.2. Safety Endpoints
Treatment-emergent adverse events (TEAE) are defined as any event increasing in severity 
from baseline or any new event starting during bosutinib therapy or within 28 days of the last 
dose of study drug (using 28 day lag).   
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, dose over time, reasons for dose modifications (reduction, delay, or escalation), and 
reasons for treatment discontinuation.  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 500 mg/day.
6.2.2. Laboratory Evaluations, Vital Signs, and Cardiac Evaluations
Laboratory values, electrocardiogram (ECG) data, and left ventricular ejection fraction 
(LVEF) data from echocardiogram (ECHO) or multiple gated acquisition (MUGA) scans
will be collected during this study from local laboratories. Collection time points for these 
measurements are specified in the protocol. Laboratory values and LVEF data will be graded 
according to NCI CTC version 4.03.  ECG assessments (time intervals) will be graded as 
Normal: <450, Grade 1: ≥450-480, Grade 2: >480-500, and Grade 3: >500 milliseconds.
If multiple post-baseline observations occur at the same visit, the most serious (highest 
grade) evaluation will be used for all summaries.
6.2.3. Laboratory Evaluations of Special Interest
Laboratory parameters including but not limited to alanine aminotransferase (ALT), aspartate
aminotransferase (AST), serum creatinine, estimated glomerular filtration rate (eGFR), 
platelets, neutrophils, WBC, and hemoglobin will be summarized.  Endpoints 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 3b/4/5 events 
for eGFR and grade 3/4 events for others (sum of time from start dates to stop dates
including only non-partial dates for all events).


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eGFR will be derived based on the Modification of Diet in Renal Disease (MDRD) study 
formula: 175 x SerumCreatinine-1.154 * age-0.203 * 1.212 (if patient is black) * 0.742 (if 
female), creatinine measured in mg/dL. eGFR will be graded according to the Kidney 
Disease Improving Global Outcomes (KDIGO) Kidney function stages (Grade 1: ≥90, 
Grade 2: 60-<90, Grade 3a: 45-<60, Grade 3b: 30-<45, Grade 4: 15-<30, and Grade 5:
<15 mL/min/1.73 m2).
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 28 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 (more than 28 days after last dose).
6.2.5. Cross Intolerance
Patients who discontinued prior TKI therapy due to intolerance of imatinib, dasatinib, or 
nilotinib and who discontinue bosutinib due to the same AE or AE cluster will be classified 
as having cross intolerance.
6.2.6. Death
Death data will be collected during this study. Mandatory variables captured are date of 
death and cause of death. Deaths within 28 days of last dose and death due to study 
treatment toxicity are safety endpoints.
6.2.7. Adverse Events
A 3-tier approach will not be used to classify AEs since this study is 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 4.0. The 
causal relationship between test article and an AE will be assessed by investigator’s 
judgment. 
6.2.8. 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), 
leukopenia (including PT White Blood Cell 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 


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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). 
6.3. Other Endpoints
6.3.1. Demographic, Medical History, and Baseline Characteristics
Demographic and baseline variables will include the following:

Age ([the date of the signing of the informed consent form – the birth date]/365.25 in
integer years), sex, race, height, and weight;

Medical history;

Cancer history (prior cancer history including CML and initial and current CML
disease stage);

Prior cancer therapies (interferon, imatinib, dasatinib, and nilotinib) and 
resistance/intolerance status for prior TKIs;

Eastern Cooperative Oncology Group (ECOG) performance status.
6.3.2. PK Endpoints 
There are no PK data being collected in this study.
6.3.3. PD Endpoints
There are no PD data being collected in this study.
6.3.4. Biomarker Endpoints 
Blood and plasma samples will be collected for biobanking if specifically allowed by local 
EC/IRB. These samples will be retained for potential pharmacogenomic/biomarker analyses 
related to drug response, unless prohibited by local regulations or ethics committee decision.  
Formal analysis plans will be developed at a later date and will not be included in this SAP.
6.3.5. Outcomes Research Endpoints 
Health Outcomes are measured using the FACT-Leu. The FACT-Leu will be administered at 
screening, weeks 13, 26, 39, 52, 78, 104, 130, 156, 182 and 208 (End of treatment) where the 
appropriate translations are available. The health outcomes assessment surveys are for the 
purpose of exploring the patient’s own perceptions about his or her quality of life, and should 
be completed by the patient only prior to interaction with health care professionals at 
assigned study visits.
The FACT-Leu is a 44-item, self-reported, reliable and valid assessment of quality of life in 
patients with leukemia.  The FACT-Leu consists of measures health related quality of life
across 4 domains: Physical Well-being (7 items; score range, 0–28), Social/Family 
Well-being (7 items; score range, 0–28), Emotional Well-being (6 items; score range, 


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0–24), Functional Well-being (7 items; score range, 0–28 and a leukemia-specific subscale, 
which consists of 17 items (score range, 0–68) that assess patient concerns relating to 
leukemia. The total score (range, 0-176) can also be calculated. Patients are asked to rate on
a scale from ‘0’ (“not at all”) to ‘4’ (“very much”), regarding how much each item (ie, pain,
fatigue, etc.) was present in the last 7 days; higher scores reflect better quality of life. The
minimally important difference (MID), defined as the smallest change in a PRO measure that
is perceived by patients as beneficial, or that would result in a clinician considering a change
in treatment for this instrument are defined as: 2-3 (PWB), N/A (SWB), 2 (EWB),
2-3 (FWB), 3-7 (FACT-G), 4-7 (LeuS-specific subscale) and 6-12 (FACT-Leu Total).
Each item in FACT-Leu is scored on a scale of 0, 1, 2, 3, and 4 for “not at all” to “very 
much”.
The score for each subscale is the sums of the scores of the items in that subscale. Because 
some of the items are positively stated and some negatively stated, the scores of the 
negatively stated items must be reversed so that the larger total scores will always indicate
better health state. The FACT-Leu scoring guide identifies those items which must be 
reversed before being added to obtain subscale totals. The score for FACT-G is the sum of 
the subscale scores for PWB, SWB, EWB, and FWB. The score for FACT-Leu is the sum of 
the score for FACT-G plus the score for the subscale leukemia. FACT-Leukemia Trial 
Outcome Index (FACT-Leu TOI) will be calculated as sum of the PWB, FWB and LeuS 
sub-scale scores.
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.
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 time to response, 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.
If there are missing items for the PRO endpoints, subscale scores can be prorated. This is 
done by multiplying the sum of subscale by the number of items in the subscale, then 
dividing by the number of items actually answered. This can be done on the scoring guide or 
by using the formula below:
Prorated subscale score = [Sum of item scores] x [N of items in subscale] ÷ [N of items
answered]


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When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the items were answered (eg, a minimum of 4 of 7 items, 4 of 6 items, etc). The 
total score is then calculated as the sum of the unweighted subscale scores. The FACT scale 
is considered to be an acceptable indicator of patient quality of life as long as overall item 
response rate is greater than 80% (eg, at least 22 of 27 FACT-G items completed). This is 
not to be confused with individual subscale item response rate, which allows a subscale score 
to be prorated for missing items if greater than 50% of items are answered.
Handling of missing/incomplete patient central molecular data will be done by the following 
procedure: for post-baseline visits, assessments at a specific visit without a minimum number 
of ABL transcripts specified by the central laboratory will be not used for analysis.
Handling of missing/incomplete patient local cytogenetic data will be done by the following 
procedure: for baseline visits, only bone marrow information with ≥20 metaphases will be 
used, otherwise the baseline response will be set to missing.  For post-baseline visits, bone 
marrow information with 20 to 99 metaphases will be used over FISH information with at 
least 200 nuclei at a specific visit.  FISH will only be used to assess CCyR.  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 in lieu of conventional cytogenetics or 
FISH, CCyR may be imputed on a specific date if a MMR is achieved on that date. The 
results of conventional cytogenetic testing, FISH with 200 nuclei or banding with 
20 metaphases, will be used in preference to molecular testing, provided they are available 
and performed on the same date.
Handling of missing/mismatched patient hematologic efficacy data will be done using the 
following procedure: for each patient, the observations will be sorted by visit and the relative 
day to first dose.  
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 will be summed together. If 
the total is between 98.5% and 101%, the missing values are assigned 0%. Otherwise, the 
observation is left as is and the record is 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 up to week 13, if a given set are still incomplete, a 
non-missing set of lab variables obtained ±3 days from the scheduled visit will be utilized to 
complete the derivation. For visits on or after week 13, a non-missing set of lab variables 
obtained ±7 days of the visit will be utilized to complete that post-baseline assessment. The
last non-missing peripheral blood or bone marrow differentials collected at week 1 day 1 or 
up to 30 days prior to week 1 day 1 will be 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 will be used. Some data handling rules for data 
combination are specified below.


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
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 (when available) 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, 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.
8.1.4. Analyses of Time-To-Event Endpoints
For time-to-event endpoints such as time to response, 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 based on the Brookmeyer-Crowley log(-log) transformation 
method will be provided. The K-M yearly rates up through year 4 with the associated
2-sided 95% CI based on Greenwood’s formula using a log(-log) transformation will also be 
provided.
When applying the cumulative incidence method, yearly rates up through year 4 with the 
associated 2-sided 95% CI based on the delta method using a log(-log) transformation will be 
provided.


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8.2. Statistical Analyses 
The efficacy endpoints will be analyzed according to the cohorts or a combination of these 
cohorts specified in Section 2.  Ph- CML patients will be summarized separately.
8.2.1. Analysis of Primary Efficacy Endpoints
The response rate analyses are based on the evaluable analysis set for Ph+ CML patients 
only.  The primary efficacy analysis is the percentage of responders by Week 52, done 
separately for:

Confirmed MCyR for combined CP2L and CP3L;

Confirmed MCyR for CP4L;

Confirmed OHR separately for AP and BP.
Any patient not demonstrating a response by Week 52 is deemed a non-responder.  
8.2.2. Analysis of Secondary Efficacy Endpoints
The response rate and DOR analyses are based on the evaluable analysis set for Ph+ CML 
patients only.  The efficacy analysis is the percentage of responders cumulative anytime 
on-treatment or at a specific landmark, for:

Cumulative MCyR separately for CP, AP, and BP;

Cumulative confirmed OHR separately for AP2L, AP3L, AP4L, BP2L, BP3L, BP4L;

Best response separately for CP, AP, and BP;

Landmark MCyR at 3, 6, 12, 18, and 24 months separately for CP, AP, and BP;

Landmark confirmed OHR at 3, 6, 9, 12, 18, and 24 months separately for AP and 
BP;

Cumulative confirmed CHR separately for CP, AP, and BP;

Cumulative MMR separately for CP, AP, and BP;

Duration of CCyR separately for CP, AP, and BP;

Duration of MMR separately for CP, AP, and BP.
Any patient not demonstrating a response on-treatment for cumulative and at the specific 
visit for landmark is deemed a non-responder for the respective analysis.  For landmark
analyses, if the patient is missing the landmark assessment however the patient is responding 
at the scheduled before and after visit (eg, missing Month 6/Week 26 but responding at 
Week 13 and Week 39, missing Month 18/Week 78 but responding at Week 52 and


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Week 104, etc.), then the patient will be deemed a responder for that landmark.  For 
cumulative MMR (including MR4 and MR4.5) and MCyR (including CCyR), supportive 
analyses will be provided excluding patients with baseline response and also for patients who 
responded before and after initial dose reduction to 400 mg, 300 mg, and 200 mg due to an 
AE
The duration of cytogenetic and molecular response analyses are based on the evaluable 
analysis set for the subset of patients who respond for the respective endpoint. The K-M 
method, as described in Section 8.1, will be used for estimation of the distributions of 
duration provided most responding patients remain on treatment until progression or loss of 
response. The percentages of CCyR and MMR for the respective endpoint, along with 
percent of censored patients still on-treatment and percent of reasons for failure will be 
summarized.
No COVID-19 related efficacy analyses will be performed as the primary endpoint only 
summarizes data up through Week 52 and all patients reached that milestone prior to the
March 11, 2020 COVID-19 anchor date and for secondary endpoints, >80% of patients were 
already off treatment as of the anchor date.  A summary of missing data before and after the 
anchor date will be summarized.
A listing of COVID-19 related study discontinuations will be provided.
8.2.3. Analysis of Exploratory Efficacy Endpoints
The time to molecular and cytogenetic response analyses are based on the evaluable analysis 
set.  Cumulative incidence of response adjusting for the competing risk of treatment 
discontinuation due to any reason without response, as described in Section 8.1, will be used.  
The percentage of responders without treatment discontinuation and the percentage of 
treatment discontinuation without response will be summarized.   
The duration of cytogenetic and molecular response exploratory analyses follow the same 
rules as the secondary DOR analyses except the percentages of MCyR, CCyR, and PCyR and 
MR4 will be summarized.
The time to transformation analysis is based on the full analysis set.  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 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.  The K-M method, with or without 
insufficient clinical response as assessed by the investigator as an event or cumulative 
incidence of on-treatment progression or death adjusting for the competing risk of treatment 
discontinuation without the event, as described in Section 8.1, will be used.


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The OS analysis is based on the full analysis set.  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 first dose to date of last contact and reasons for discontinuing 
participation will also be summarized.
The percentage of patients with baseline and emergent mutations, along with the specific 
types of mutations, will be summarized.  The percentage of patients with cumulative MCyR, 
CHR, MMR, and OHR (AP and BP patients only) by baseline mutation status will be 
provided.  The distributions of PFS and OS will also be displayed for patients with a baseline 
mutation versus those assessed but without a baseline mutation.  
The percentage of Ph- CML patients in each best response category 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.
8.2.4. Analysis of Safety Endpoints
The full analysis set will be used for all safety analyses unless specifically stated otherwise.  
The safety endpoints will be analyzed according to the cohorts or a combination of these 
cohorts as specified in Section 2.
8.2.4.1. Baseline Characteristics
Listings of demography and baseline characteristics data will be provided. The baseline 
variables listed below will be summarized using descriptive statistics.

Age in years;

Race;

Sex;

Weight (kg);

Height (cm);

ECOG performance status;

Cancer history (prior cancer history including CML, initial and current CML disease 
stage, duration since CML diagnosis);

Prior cancer therapies (number of prior regimens for interferon, imatinib, dasatinib, 
and nilotinib), duration of prior therapy, and reasons for resistance/intolerance status
of prior TKIs;

Medical history by MedDRA System Organ Class (SOC) and PT.


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8.2.4.2. Treatment and Compliance
Descriptive statistics for continuous exposure variable treatment duration and cumulative 
dose received and the 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 600mg 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.
8.2.4.3. Laboratory Evaluations, Vital Signs, and Cardiac Evaluations
The incidence of clinical laboratory, QTcF/QTcB, and LVEF abnormalities by maximum 
toxicity grade will be presented at baseline, during the treatment period, and post treatment
period.  Shifts from baseline to maximum on-treatment grade for QTcF/QTcB and LVEF will 
also be presented.
Laboratory values and vital signs will be provided in the data listings.
8.2.4.4. Laboratory Evaluations of Special Interest
The number and percentage of maximum on-treatment grade 0 through 4 for serum 
creatinine, ALT, AST, platelets, neutrophils, WBC, and hemoglobin and grade 1 through 
5 for eGFR will be summarized.  Descriptive statistics for time to first event, duration of any 
grade event, and cumulative duration of grade 3b/4/5 for eGFR and grade 3/4 events for 
others will be calculated.  Shifts from baseline to maximum on-treatment grade will also be 
presented.
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.
8.2.4.5. Non-study Medications
The percentage of patients using non-study medications prior to, during, and after the 
treatment period will be summarized.  
A listing of non-study medications data will be reported. 
8.2.4.6. Cross Intolerance
The percentage of patients experiencing cross intolerance to imatinib, dasatinib. or nilotinib 
will be summarized overall and by AE.  The recurrence percentage of those grade 3/4 TEAEs 
during treatment with bosutinib will also be estimated.


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8.2.4.7. Death
The number of deaths within 28 days of last dose and cause of these deaths will be 
summarized.
8.2.4.8. Adverse Events
The number and percentage of AEs listed below will be summarized overall and by 
MedDRA SOC and PT.  Sorting will be done alphabetically by SOC and then by decreasing 
frequency of PT.  AEs may also be summarized by other levels if deemed appropriate (eg,
Higher Level Group Term [HLGT]). 

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);

COVID-19 related TEAEs;

TEAEs before and after initial dose reduction to 400 mg, 300 mg, and 200 mg due to 
an AE.
8.2.4.9. 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), leukopenia 
(including PT White Blood Cell Count Decreased), anemia (including PT Hemoglobin 
Decreased), diarrhea, nausea, vomiting, cardiac toxicity, vascular toxicity, and renal toxicity
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 selected parameters.
8.2.4.10. Additional Safety
Listings of physical examination data, chest x-ray, and ECOG performance status will be 
provided.


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8.2.5. Analyses of Patient Disposition Endpoints
Listings of violations of 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/evaluable analysis sets.  The number 
of subjects discontinuing study participation, along with the reason, and descriptive statistics 
for the duration on-study (time from first dose to last contact) will also be calculated.
8.2.6. Analyses of Outcome Research Endpoints
All health outcomes analysis will be based on patients in the Full Analysis Set with available
data.
The Outcomes Research endpoints are FACT-Leu overall, FACT-G overall, FACT-G
subscales, Leukemia subscale (LeuS), and FACT-Leu Trial Outcome index. Univariate 
descriptive statistics will be used in the analysis of all the above endpoints. 
For each of the endpoints listed above, summary statistics including Mean, Median, Standard 
Deviation, Minimum, Maximum, 95% CI will be reported at each time point. This will be 
done based on observed values as well as based on changes from baseline. A graphical 
display of the observed means over time for each of the endpoints will also be provided. 
The above analyses will be done separately for each cohort and combined.


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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. CRITERIA TO IDENTIFY PHASE OF CML
Phase a
Findings
Blast Phase 
≥30% Blasts in blood or bone marrow
Extramedullary Blasts proliferation, apart from spleen
If either of these 2 criteria is present, the patient is classified as Blast Phase regardless 
of other criteria.
Accelerated Phase
15-29% Blasts in blood or bone marrow
or
>30% Blasts + Promyelocytes (with Blasts <30%) in blood or bone marrow
OR
≥20% Basophils in blood
OR 
Persistent platelets <100 x 109/L (not related to therapy) OR
Clonal chromosomal abnormalities in Ph+ cells (CCA/Ph +), major route, on treatment
Chronic Phase
<15% Blasts
<20% Basophils
≤30% Blasts + Promyelocytes (with Blasts <15%) in blood or bone marrow
AND
Platelets ≥100 x 109/L (unless related to therapy)
AND
No Extramedullary Blasts (except spleen)
a
Observance of any one criterion in the worse disease phase achieves that phase as the diagnosis (eg, 
20% basophils alone elevates the diagnosis from CP to AP).


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Appendix 2. DEFINITIONS OF HEMATOLOGIC, CYTOGENETIC, AND 
MOLECULAR RESPONSE
Response by Type
Definitions
Hematologic
Complete (CHR)
WBC <10 x 109/L
Peripheral Blood Basophils <5%
No Peripheral Blood myelocytes, promyelocytes, myeloblasts in the 
differential
Platelet count <450 x 109/L
Spleen nonpalpable
Cytogenetic *
Complete (CCyR)
Partial (PCyR)
Minor (mCyR)
Minimal (minCyR)
None (noCyR)
No Ph+ metaphases
1% to 35% Ph+ metaphases
36% to 65% Ph+ metaphases
66% to 95% Ph+ metaphases
>95% Ph+ metaphases
Molecular 
Deep Molecular Response 
(MR4, MR4.5) 
Major (MMR)
MR4= either (i) detectable disease with <0.01% BCR-ABL1 IS or (ii) 
undetectable disease in cDNA with >10 000 ABL1 transcripts 
MR4.5 =either (i) detectable disease with < 0.0032% BCR-ABL1 IS or (ii) 
undetectable disease in cDNA with >32,000 ABL1 transcripts in the same 
volume of cDNA used to test for BCR-ABL1.
Ratio of BCR-ABLIS ≤0.1%**. 
Abbreviations: CHR, complete hematologic response; CCyR, complete cytogenetic response, PCyR, partial 
cytogenetic response; Ph+, Philadelphia Chromosome positive; MCyR, major cytogenetic response; mCyR, 
minor cytogenetic response; minCyR, minimal cytogenetic response; noCyR, no cytogenetic response; MR4, 
MR4.5, deep molecular response; MMR, major molecular response.  
*If bone marrow metaphases cannot be obtained or evaluated by chromosome banding analysis, the definition 
of CCyR (defined as <1% for FISH) may be based on interphase FISH of blood cells, provided that it is 
performed with Dual-Color Dual-Fusion or Dual-Fusion FISH probes and at least 200 nuclei are scored.  
PCyR and CCyR are counted together and reported as MCyR.  
**With ≥5,000 ABL1 transcripts.


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Definitions of Hematologic Response for AP and BP CML*
CHR**
WBC ≤ institutional upper limit of normal (ULN) 
ANC 1.0 x 109/L 
Platelet count 100 x 109/L 
BM Blasts ≤5%***
No peripheral blood blasts or promyelocytes; 
Peripheral blood myelocytes + metamyelocytes <5%;
Basophils in peripheral blood <5%*
No evidence of extramedullary involvement
*The maximum % of basophils in peripheral blood was modified from <2 to <5% for a less restrictive 
constraint and alignment with the CHR criteria for CP CML patients according to ELN guidelines.
**If an on- treatment CBC is scheduled within 1 week from the last platelet transfusion or last dose of G-CSF, 
it should be considered “Not Evaluable” for hematological response assessment, and a CBC should be 
repeated at least 1 week from the last platelet transfusion or last dose of G-CSF received.
***CHR for AP/BP that the 5% BM blasts is only required when a BM differential is available.