Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Japan Inc.
Investigational Product: Bosutinib
Clinical Study Report Synopsis: Protocol B1871048
Protocol Title: A Phase 2, Open-Label, Single-Arm Study to Evaluate Efficacy and Safetyof Bosutinib Monotherapy in Japanese Adult Patients With Newly Diagnosed Chronic Phase
Chronic Myelogenous Leukemia
Investigators: Refer to CCI

for a list of investigators involved in this study.

Study Centers: This study was conducted at 20 centers in Japan. Refer tofor a list of sites involved in this study.

CCI

Publications Based on the Study: None.
Study Initiation Date: 15 May 2017
Study Completion Date: 12 March 2019 (Data Cut-off Date)
Report Date: 01 July 2019
Previous Report Date(s): Not applicable
Phase of Development: Phase 2
Primary and Secondary Study Objectives and Endpoints:
The study objectives and endpoints of this study are presented in Table 1.

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CLINICAL STUDY REPORT SYNOPSIS
Table 1.

Study Objectives and Endpoints

Type
Primary
Efficacy

Secondarya
Efficacy

Objectives

Endpoints

To evaluate MMR at 12 months(48 weeks) in newly diagnosed
Japanese Ph+ CP CML patients
harboring b2a2 and/or b3a2 transcripts

MMR at 12 months (48 weeks). All Ph+
CP CML patients harboring b2a2 and/or
b3a2 transcripts were assessed andfollowed up for MMR as primary
endpoint. MMR is defined as ≤0.1%
BCR-ABL on the IS by RT-qPCR

To evaluate MMR by 12 and18 months
To estimate the proportion of patientsdemonstrating CCyR by 12 months
To evaluate the duration of MMR andCCyR
To evaluate EFS
To evaluate OS
To assess the population PK
To assess correlations between troughconcentrations of bosutinib and key
efficacy and safety endpoints
To characterize the safety profile ofbosutinib in Japanese patients

MMR by 12 and 18 months
CCyR by 12 months
Duration of MMR and CCyR

EFS
OS
PK
Population PK parameters
Correlations between troughconcentrations of bosutinib and key
efficacy and safety endpoints
SafetySafety: AEs (as graded by NCI CTCAE
Version 4.03); laboratory abnormalities(as graded by NCI CTCAE
Version 4.03); vital signs (bloodpressure, pulse rate); ECGs; ECHO or
MUGAAbbreviations: AE=adverse event; BCR-ABL=fusion transcript or protein resulting from the 9;22
chromosomal translocation responsible for formation of the Philadelphia chromosome; CCyR=complete
cytogenetic response; CML=chronic myelogenous leukemia; CP=chronic phase; CTCAE=Common
Terminology Criteria for Adverse Events; ECG=electrocardiogram; ECHO=echocardiogram;
EFS=event-free survival; IS=international scale; MMR=major molecular response; MUGA=multiple gatedacquisition; NCI=National Cancer Institute; OS=overall survival; Ph=Philadelphia chromosome;
PK=pharmacokinetic; RT-qPCR=quantitative reverse transcriptase polymerase chain reaction.
a. All the efficacy analyses for secondary objectives were performed using the same population as primaryobjective, unless otherwise indicated.

METHODS
Study Design: This was a Phase 2, open-label, single-arm study designed to evaluate theefficacy and safety of bosutinib alone in Japanese adult patients with newly diagnosed
chronic phase (CP) chronic myelogenous leukemia (CML). The primary endpoint was major
molecular response (MMR) at 12 months in newly diagnosed Japanese Philadelphia
chromosome (Ph)+ CP CML patients harboring b2a2 and/or b3a2 transcripts. Patients
received bosutinib treatment at a starting dose of 400 mg once daily (QD). The dose ofbosutinib was allowed to be escalated (up to a maximum of 600 mg QD) for unsatisfactory
response or reduced (down to 300 mg QD, and further to a minimum of 200 mg QD only
when approved by the sponsor) for toxicity.
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CLINICAL STUDY REPORT SYNOPSIS
This study had approximately 52 weeks of planned patient accrual. Each patient had
12 months (48 weeks) of Core Treatment Phase and the following 24 months (96 weeks) of
Extension Phase. After treatment discontinuation, the patient entered Long-Term Follow-Up.
The Extension Phase or Long-Term Follow-Up will continue until the end of the study.
The data in this study was collected till the primary completion date (12 March 2019).
Diagnosis and Main Criteria for Inclusion: Patients with diagnosis of CP CML
of 6 months (from initial diagnosis), diagnosis of CP CML with molecular confirmation by
detection of fusion transcript or protein resulting from the 9;22 chromosomal translocation
responsible for formation of the Ph (BCR-ABL) rearrangement at Screening (cytogenetic
assessment for Ph was not required for enrollment; however, patients with known Ph- CML
prior to registration were not eligible for this study), aged 20 years, Eastern Cooperative
Oncology Group (ECOG) performance status 0 or 1, and adequate renal and liver function
were included in the study.
Patients who had any prior medical treatment for CML, including tyrosine kinase inhibitors,
with the exception of hydroxyurea treatment, which was permitted for up to 6 months prior toregistration, any past or current central nervous system involvement, including
leptomeningeal leukemia, extramedullary disease only, major surgery or radiotherapy within
14 days prior to registration, history of clinically significant or uncontrolled cardiac disease
were excluded from the study.
Study Treatment: Bosutinib tablets (100 mg dosage strength) were supplied by sponsor inhigh-density polyethylene bottles. The starting dose was 400 mg QD, orally, recommended
to be taken in the morning with a meal and with approximately 200 mL of water. Available
data show that both tolerance and absorption are greatly improved by taking bosutinib with ameal, including adequate dietary fats; no restriction was imposed on patients’ food choices.
Patients swallowed the study drug whole and did not manipulate or chew the study drug prior
to swallowing. Patients were instructed that if they missed a dose or vomited any time after
taking a dose, they were not to “make it up” with an extra dose. Instead, the patients were to
resume the subsequent doses as originally prescribed. Any missed dose could have beentaken up to 12 hours prior to the next scheduled dose, otherwise it should have been skippedand dosing resumed with subsequent doses as prescribed.
The study drug information is provided in Table 2.
Table 2.

Study Drug Information

Investigational Product Description
Bosutinib (SKI-606) 100 mg oval yellow
film coated tablet commercial formulation

Vendor Lot
Number
CCI

CCI
Page 3Sponsor Lot
NumberCCI

Strength/Potency
100 mgDosageForm
TabletFinal Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Efficacy Evaluations:Primary Efficacy Endpoint:
The primary endpoint was MMR at 12 months (48 weeks). All Philadelphia
chromosome Ph+ CP CML patients harboring b2a2 and/or b3a2 transcripts were assessed
and followed up for the MMR as the primary endpoint.
The MMR was defined as 0.1% BCR-ABL on the international scale by quantitative reverse
transcriptase polymerase chain reaction.
The analysis of MMR rate included all patients with Ph+ CML harboring b2a2 and/or b3a2
transcripts. This was anticipated to represent approximately 95% of enrolled patients; 1-2%of patients could harbor other BCR-ABL transcripts not validated for MMR assessment.
MMR at 12 months (48 weeks) was counted only if the response was demonstrated at the
12-month (48-week) visit; any MMR gained and lost before the 12-month (48-week) visit
was deemed a non-response as is the case where MMR is never achieved at or before
12 months (48 weeks).
The primary analysis was conducted 12 months after the last Ph+ CML patient harboring
b2a2 and/or b3a2 transcripts was enrolled.
Secondary Efficacy Endpoints:Complete Cytogenetic Response (CCyR) by 12 months: The CCyR is defined as absenceof detectable Ph.



MMR by 12 and 18 months (MMR by 18 months is not presented in this study).

Duration of MMR and CCyR: The duration of response (MMR and CCyR, respectively)
was measured from the first date of response until the first date of confirmed loss of
response, treatment discontinuation due to progressive disease (PD), or death due todisease progression within 28 days after the last dose. A loss of response was confirmed
by a second consecutive loss at least 4 weeks later, treatment discontinuation due to PD
or death due to PD within 28 days of the last dose. A PD was defined as investigatorassessed progression. Treatment discontinuation due to PD or death due to PD within
28 days of the last dose without loss of response was considered a confirmed loss. An
unconfirmed loss followed by treatment discontinuation due to suboptimal response wasconsidered a confirmed loss.

Event-Free Survival (EFS):

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The EFS was measured from the date of the first dose until the first occurrence of one of
the following events, censored at the earlier of the last valid hematologic or cytogenetic
assessment for those without events:


Death due to any cause;Transformation to accelerated phase (AP) or blast phase (BP);

Loss of complete hematologic response (CHR);

Loss of CHR was defined as the appearance of any of the following, confirmed bya second determination 4 weeks later (unless associated with CML-related
treatment discontinuation):White blood cell (WBC) count that rose to >20.0 × 109/L;



Platelet count that rose to 600 × 109/L;



Appearance of palpable spleen or other extramedullary involvement provenby biopsy;

Appearance of 5% myelocytes in the peripheral blood; orAppearance of blasts or promyelocytes in the peripheral blood.



Loss of CCyR; or

For patients not achieving a CHR: doubling of WBC at least 1 month apart with thesecond value >20 × 109/L and maintained in subsequent assessments for at least
2 weeks.

Overall Survival (OS): OS was measured from the date of the first dose until theoccurrence of death due to any cause, censored at the last known alive date for those
without events.

Pharmacokinetic Evaluations:
The objectives of the pharmacokinetic (PK) analyses were as follows:

Objective 1: Aim was to use the PK model developed in the previous population PK
reports to analyze the trough concentration data in this study to obtain population PK
parameters of bosutinib;

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Objective 2: Aim was to compare/correlate the distribution of the trough concentrations
by demographic and clinical covariates at each of the 3 time points (or cumulative
exposure); and

Objective 3: Aim was to compare the distribution of the trough concentrations bypresence of major adverse events (AEs) (all-causality) at each of the 3 time points (orcumulative exposure) and efficacy endpoints.

PK profiles of bosutinib were determined using a sparse sampling regimen. A total of 4 PK
samples per patient were drawn. All patients provided predose blood samples on Day 1,
Day 28, Day 56, and Day 84. All efforts were made to obtain the PK samples at thescheduled nominal time relative to dosing. Blood samples (3 mL) to provide a minimum of
1.0 mL plasma for PK analysis were collected into appropriately labeled tubes containing
potassium ethylenediaminetetraacetic acid.
Bosutinib samples were assayed using a validated, sensitive and specific high-performance
tandem mass spectrometry method.
Safety Evaluations:
Safety evaluations included collection of AEs, serious adverse events (SAEs), vital signs,
physical examinations, 12-lead electrocardiogram (ECG), chest X-rays,
echocardiogram/multiple gated acquisition scans, laboratory assessments, including
pregnancy tests, potential cases of drug-induced liver injury, exposure to the investigational
product during pregnancy or breastfeeding, and occupational exposure, medication errors andverification of concomitant treatments.
Statistical Methods:
Data Sets Analyzed:
The efficacy endpoints were analyzed based on modified as-treated population set. The
safety endpoints were analyzed based on as-treated population set.
As-Treated Population: The as-treated population consisted of all enrolled patients who
received at least 1 dose of the study drug. Since this was a single-arm Phase 2 study,
as-treated population was also the full analysis set.
Modified As-Treated Population: The modified as-treated population consisted of all enrolled
patients with Ph+ CP CML harboring b2a2 and/or b3a2 transcripts who received at least
1 dose of the study drug. This is the primary population for primary analysis of efficacy
endpoints.
PK endpoints were analyzed based on PK analysis set.

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Analysis of Efficacy Endpoints:
Analysis of Primary Endpoint:
The MMR at 12 months (48 weeks) was analyzed using the hypothesis test of a 1-sample
binomial proportion test with the normal approximation. The 2-sided asymptotic 90%
confidence interval (CI) of MMR rate at 12 months (48 weeks) was also calculated.
The MMR at 12 months (48 weeks) was counted only if the response was demonstrated at
the 12-month (48-week) visit; any MMR gained and lost before the 12-month (48-week) visit
was deemed a non-response as is the case where the MMR was never achieved at or before
12 months (48 weeks).
Sixty (60) patients would provide 82% power to detect the null hypothesis (H0) of MMR rate
at 12 months ≤25% when the true rate under H1 was ≥40% at 1-sided significance levelof 0.05. Rejecting the null hypothesis and accepting the alternative hypothesis in themodified as-treated population (observing at least 21 responders out of the 60 total patients),
was considered to be a successful demonstration of efficacy for this study.
Analysis of Secondary Endpoints:
Since this was a single-arm Phase 2 study, as-treated population was also the full analysis set.
The secondary endpoints mentioned in Table 1 were evaluated in the study.
Major Molecular Response by 12 and 18 Months:
Evaluations of MMR by 12 and 18 months were assessed using the frequency tables,
respectively. The 2-sided asymptotic 90% CI was also calculated. For the analysis of MMR
by 12 and 18 months, a patient was counted as a responder if the MMR occurred at or before
12 and 18 months, respectively, even if the MMR was subsequently lost at or before the
12-month and 18-month time points, respectively. A patient never achieving the MMR at or
before 12 and 18 months was considered a non-responder, respectively.
Complete Cytogenetic Response:
Evaluations of CCyR by 12 months (48 weeks) was assessed using the frequency tables. The
2-sided 90% CI was also calculated. The CCyR rate by 12 months was defined as the
proportion of patients demonstrating CCyR at or before 12 months (48 weeks). The
percentage of Ph+ cells was calculated according to the following formula:
Ceil (100 × the number of Ph+ cells / the number of metaphases),
where, ceil () denotes a ceiling function.
The proportion of patients who had confirmed loss of CCyR were also evaluated.
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Duration of Response:
The duration of MMR and CCyR were based on the estimations of the quartiles of durationand yearly rates using the Kaplan-Meier method.
For the analysis of MMR and CCyR, the proportion of patients who had confirmed loss of
response were also evaluated, respectively.
The duration of MMR were planned to be analyzed for MMR responders in the modified
as-treated population and those in as-treated population separately. The duration of CCyR
were planned to be analyzed for CCyR responders in the modified as-treated population.
Event-Free Survival
EFS was planned to be analyzed using the cumulative incidence method adjusting for thecompeting risk of treatment discontinuation without the event, and yearly rates andpercentiles were displayed. This was indicated as the on-treatment EFS. The transformation
to AP and BP on treatment was considered as an event in the analysis of EFS. This meansthat if the first transformation to AP and BP was occurred after 28 days from the last dose,
this was not to be considered as an event in the analysis of EFS.
As a reference, the EFS using the transformation to AP and BP occurred after 28 days fromthe last dose instead of the transformation to AP and BP on treatment was also assessed using
the same analysis method. This was indicated as the off-treatment EFS.
The on-treatment EFS and off-treatment EFS were analyzed in the modified as-treatedpopulation.
Overall Survival
The analysis of OS was similar to that for duration of response.
The OS was planned to be analyzed in the modified as-treated population and as-treatedpopulation separately.
Analysis of Pharmacokinetic Endpoints:
The PK endpoints were analyzed using PK population set. The PK population was defined
as any patient in the safety population of patients who had at least 1 concentration ofbosutinib on-treatment.
Analysis of Safety Endpoints:
The safety population consisted of all enrolled patients, regardless of Ph status, who received
at least 1 dose of the study drug. This means that the as-treated population was also the

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safety analysis set. Therefore, the as-treated population was presented in any tables, listings
and figures instead of the safety analysis set.
All AEs were coded using the latest version of the Medical Dictionary for Regulatory
Activities (MedDRA) Version 21.1 at the analysis. The toxicity was graded according to the
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03.
The numbers of events and incidence rates were tabulated by preferred term and systemorgan class (SOC). AEs were presented with and without regard to causality. The frequency
of overall toxicity, categorized by toxicity Grades 1 through Grade 5, were described.
Additional tables were provided for AEs that were observed with higher frequency.
AE summaries included incidence of treatment-emergent adverse events (TEAEs) by
MedDRA preferred term and SOC, SAEs including deaths, AEs that led to study drug
discontinuation, characteristics of AEs that led to study drug discontinuation, AEs that led to
study drug interruption, AEs that led to study drug reduction and AEs by maximum severity
and relationship to study drug. Discontinuation due to AE and death data were also listed.
AEs and AE categories including cardiac, edema, effusion, gastrointestinal, hemorrhage,
hypertension, infection, liver function, myelosuppression, rash, renal and vascular weresummarized.
RESULTS
Subject Disposition and Demography:
A total of 64 patients were screened in this study (Table 3), of which 60 patients entered thestudy. As all the 60 patients had both Ph+ and b2a2 and/or b3a2 transcripts, the as-treatedpopulation and the modified as-treated population were identical.

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Table 3.

Summary of Subject Evaluation Groups
Bosutinib(N=60)n (%)

Screened: 64
Screened Failure: 4
As-Treated Population

60 (100.0)

Modified as-Treated Population

60 (100.0)

PK Analysis Set

60 (100.0)

Cutoff Date: 12Mar2019
The As-Treated Population is identical to Safety Analysis Set.
Percentages are based on As-Treated Population.

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Overall, 19 patients (31.7%) discontinued study treatment, of which 18 patients (30.0%)
discontinued study treatment within 12 months. Forty-two (42) patients (70.0%) completed
12 months of Core Treatment Phase, of which 41 patients (68.3%) were remained in
Treatment Phase at the time of data cut-off. The primary reason for the treatment
discontinuation was due to AEs (18 patients [30.0%]). The 19 patients who discontinued
study treatment entered into Long-Term Follow-Up Phase, of which 1 patient (1.7%) diedduring Long-Term Follow-Up Phase. A summary of patient disposition is provided inTable 4.

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Table 4.

Summary of Disposition Events - As-Treated Population
Bosutinib(N=60)OverallWithin 12 months

n (%)

n (%)

Subjects Entered:

60 (100.0)

60 (100.0)

Discontinued

19 (31.7)

18 (30.0)

Adverse Event

18 (30.0)

17 (28.3)

Physician Decision

1 (1.7)

1 (1.7)

Number (%) of Subjects

Disposition Phase: TREATMENT

Completed

00

Ongoing

41 (68.3)

42 (70.0)

Subjects Entered:19 (31.7)

18 (30.0)

Discontinued

1 (1.7)0Death

1 (1.7)0

Disposition Phase: LONG-TERM FOLLOW-UP

Completed

00

Ongoing

18 (30.0)

18 (30.0)

Cutoff Date: 12Mar2019

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A total of 36 male patients and 24 female patients were enrolled in the study. The medianage of patients was 55.0 years (range: 20 to 83 years). Nineteen (19) patients (31.7%)
enrolled in the study were 65 years of age. All the patients were Asian (Japanese).
Overall, the distribution of Sokal score was high risk (>1.2), intermediate risk (0.8-1.2), andlow risk (<0.8). The majority of patients had low risk (45.0%) or intermediate risk (43.3%)
Sokal score. The Ph status was positive for all patients. Among them, at Screening, the Ph
status of 1 patient was not reported. However, the status was confirmed as a positive before
the screening period. Most patients (48 patients [80.0%]) had no extramedullary disease;
12 patients (20.0%) had extramedullary disease. The majority of patients (59 patients[98.3%]) had no history of cardiac diseases. The majority of patients (58 patients [96.7%])
had ECOG performance status of 0.

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Efficacy Results:
Primary Efficacy Results:
The details of MMR at 12 months are presented in Table 5. The MMR at 12 months was
55.0% (90% CI: 44.4, 65.6) in the modified as-treated population, demonstrating that the
proportion of patients achieving MMR at 12 months was statistically significantly higher forbosutinib (55.0%; 33/60) compared to the historical control (25%) under H0 with 1-sided
p-value of <0.0001. The primary objective of the protocol was met.

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Table 5.

Summary of Major Molecular Response (MMR) at Month 12 - Modified asTreated Population
Bosutinib(N=60)n (%)

Molecular Response
MMR

33 ( 55.0)

90% CI[44.4, 65.6]

1-sided p-value<.0001

Cutoff Date: 12Mar2019
Note: Percentages are based on the number of subjects. MMR is defined as <= 0.1% BCR-ABL ratio on the international
scale (corresponding to >= 3 log reduction from standardized baseline) with a minimum of 3,000 ABL transcripts assessedby the central laboratory.

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The MMR at 12 months by Sokal risk group was 51.9% (90% CI: 36.0, 67.7),
61.5% (90% CI: 45.8, 77.2) and 42.9% (90% CI: 12.1, 73.6) for low, intermediate and highrisk groups, respectively (Table 6).

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Table 6.

Summary of Major Molecular Response (MMR) at Month 12 by Sokal Risk
Group - Modified as-Treated Population
Bosutinib(N=60)n (%)

Low Risk < 0.8

27

MMR

14 ( 51.9)

90% CI[36.0, 67.7]

Intermediate Risk 0.8-1.2

26

MMR

16 ( 61.5)

90% CI[45.8, 77.2]

High Risk > 1.2

7

MMR

3 ( 42.9)

90% CI[12.1, 73.6]

Cutoff Date: 12Mar2019
Note: Percentages are based on the number of subjects in each group. MMR is defined as <= 0.1% BCR-ABL ratio on theinternational scale (corresponding to >= 3 log reduction from standardized baseline) with a minimum of 3,000 ABLtranscripts assessed by the central laboratory.

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Secondary Efficacy Results:
Major Molecular Response by 12 Months:
The MMR by 12 months was 61.7% (90% CI: 51.3, 72.0) in the modified as-treatedpopulation.
Note: MMR by 18 months was not evaluated in the Core Treatment Phase analysis; the data
for this endpoint were immature as not all patients still on-treatment but without achieving
MMR had reached the Month 18 visit at the time of data cut-off. Therefore, the analysis of
this endpoint is not presented.

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Complete Cytogenetic Response by 12 Months:
The CCyR by 12 months was 80.0% (90% CI: 71.5, 88.5) in the modified as-treatedpopulation.
Duration of Major Molecular Response:
Data for duration of MMR was not mature at the data cut-off date. Of the 40 (out of
60 patients) that achieved MMR anytime on-treatment in the modified as-treated population,no patients had events at the time of data cut-off (events defined as confirmed loss of MMR,
treatment discontinuation due to disease progression, and deaths that occurred due to diseaseprogression within 28 days after last dose).
Duration of Complete Cytogenetic Response:
Data for duration of CCyR was not mature at the data cut-off date. Of the 48 patients (out of
60 patients) that achieved CCyR anytime on-treatment in the modified as-treated population,no patients had events at the time of the data cut-off (events defined as confirmed loss of
CCyR, treatment discontinuation due to disease progression, and deaths that occurred due todisease progression within 28 days after last dose).
Event-Free Survival:
Data for on-treatment EFS was not mature at the data cut-off date; no on-treatment deaths
were reported. Of 60 patients in the modified as-treated population, 1 patient had events ofinterest (defined as either death, transformation to AP or BP, doubling of WBC without CHR,
loss of CCyR or loss of CHR) and 19 patients (31.7%) had competing risk events (treatment
discontinuation without an EFS event). The cumulative incidence of EFS events at Week 48
was 1.7% (90% CI: 0.2, 6.4) in the modified as-treated population.
Overall Survival:
Data for OS was not mature at the data cut-off date; at this time-point 1 patient had diedduring the study. The Kaplan-Meier estimate of OS at Week 48 was 100.0% (90% CI: 100.0,
100.0) in the modified as-treated population.
Pharmacokinetic Results:
A summary of trough bosutinib plasma concentrations over time is provided in Table 7. The
mean bosutinib concentration averaged over Days 28, 56, and 84 was 82.75 ng/mL (standard
deviation: 47.956 ng/mL) (range: 7.59 to 260 ng/mL). Trough concentrations were stable
over time (Figure 1).
Additional population PK or PK/pharmacodynamic modeling analyses will be conducted andsummarized in a separate population modeling analysis report.
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Table 7.

Summary of Trough Bosutinib Plasma Levels (ng/mL) - PK Analysis Set

Visit

Statistic

Day 1

n

60

Mean (SD)

0.000 (0.0000)

95% CI

0.0, 0.0

Median0.000

Min, Max

0.00, 0.00

n34

Mean (SD)83.564 (64.1056)

95% CI

61.2, 105.9

Median66.500

Min, Max

1.38, 363.00

n

41

Mean (SD)85.963 (46.4095)

95% CI

71.3, 100.6

Median82.600

Min, Max

3.28, 216.00

n

44

Mean (SD)79.659 (41.5369)

95% CI

67.0, 92.3

Median69.100

Min, Max

19.10, 199.00

n

51

Mean (SD)82.748 (47.9555)

95% CI

69.3, 96.2

Median71.200

Min, Max

7.59, 260.00

Day 28

Day 56

Day 84

Average Concentration

Total(N=60)

Cutoff Date: 12Mar2019[1] BLQ - Below Limit of Quantification. Concentrations that are BLQ and reported as less than the Lower Limit of
Quantification (BLQ < LLOQ) will be replaced with zero for Day 1. For Days 28, 56 and 84 values of BLQ (< LLOQ) will
be replaced with LLOQ/2.
[2] Average concentration = mean of Day 28, 56 and 84 trough concentrations

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Figure 1. Box Plot of Trough Bosutinib Plasma
Concentrations (ng/mL) - Pharmacokinetic Analysis Set

Concentrations that were BLQ and reported as less than the LLOQ (BLQ <LLOQ) for Days 28, 56, and 84 were
replaced with LLOQ/2.
Box plot provides median (horizontal line), mean (diamond), outliers (circles) and 25%/75% quartiles withwhiskers to the last points within 1.5 times the interquartile range.
Abbreviations: BLQ=below limit of quantification; LLOQ=lower limit of quantification.

Safety Results:
Study Drug Dosing and Duration:
The summary of exposure to the study drug in as-treated population is provided in Table 8,
and duration of treatment and duration of study is provided in Table 9.
Patients received a median of 419.0 doses (range: 9 to 615 doses) of the study drug; themedian actual dose intensity was 354.73 mg/day (95.3 to 494.1 mg/day). Patients had a
median of 21.0 missed doses (range: 0 to 136). The median dose intensity was lower thanstarting dose (400 mg/day) because many patients needed temporary discontinuation and/or
dose reduction of study drug for the management of AE.
The median duration of study treatment was 15.31 months (range: 0.30 to 21.85 months) andthe median duration on study was 16.56 months (range: 11.07 to 21.85 months).

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Table 8.

Summary of Exposure to Study Drug - As-Treated Population
Bosutinib(N=60)

Cumulative Actual Total Dose (mg)n

60

Mean (SD)135876.7 (85103.63)

Median148550.0

Min, Max

3600, 310300

Number of Dosesn

60

Mean (SD)356.5 (208.73)

Median419.0

Min, Max9, 615

Missed Dosesn

60

Mean (SD)34.2 (33.33)

Median21.0

Min, Max0, 136

Actual dose intensity (mg/day) an60

Mean (SD)305.36 (107.037)

Median354.73

Min, Max
Relative dose intensity (%)

95.3, 494.1
b

n

60

Mean (SD)76.34 (26.759)

Median88.68

Min, Max

23.8, 123.5

Cutoff Date: 12Mar2019
aCD: Actual cumulative dose in mg,
LDD: Last dose date of zero or non-zero dose of the study drug, DF: Date of the first non-zero dose of the study drug.
a. Actual dose intensity (mg/day)=aCD/(LDD - DF + 1).
b. Relative dose intensity (%)=100 × (actual dose intensity)/(theoretical dose intensity).

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Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS

Table 9.

Summary of Treatment Duration and Study Duration - As-Treated
Population
Bosutinib(N=60)

Duration of Treatment (Days) an60

Mean (SD)387.6 (200.03)

Median466.0

Min, Max9, 665

Duration of Treatment (Months) an60

Mean (SD)12.734 (6.5713)

Median15.309

Min, Max
Duration of Study (Days)

0.30, 21.85
b

n

60

Mean (SD)499.0 (90.24)

Median504.0

Min, Max

337, 665

Duration of Study (Months) bn60

Mean (SD)16.392 (2.9646)

Median16.557

Min, Max

11.07, 21.85

Cutoff Date: 12Mar2019
Months was calculated as Days/30.44.
a. Duration of therapy was the time from treatment start to last dose of treatment.
b. Duration of study was from the date of first dose of study drug to last known alive date or withdrawn date.

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CLINICAL STUDY REPORT SYNOPSIS
Treatment-Emergent Adverse Events:
A summary of all-causality and treatment-related AEs is presented in Table 10. A total of
60 patients (100.0%) reported at least 1 TEAEs, and 14 patients (23.3%) reported
treatment-emergent SAEs. A total of 568 AEs were reported of which 428 weretreatment-related.
No deaths during bosutinib treatment were reported in the study. A total of 45 patients(75.0%) had Grade 3 or Grade 4 AEs. Thirty-three (33) patients (55.0%) had a dose
reduction, and 42 patients (70.0%) had a temporary discontinuation associated with AEs. A
total of 18 patients (30.0%) discontinued the study drug due to AEs.

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Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS

Table 10. Summary of Treatment-Emergent Adverse Events (All-Causalities andTreatment-Related) - As-Treated Population
Bosutinib(N=60)
All-Causality

Treatment-Related

Number (%) of Subjects:

n (%)

n (%)

Subjects evaluable for adverse events

60

60

Number of adverse events

568

428

Subjects with adverse events60 (100.0)

59 (98.3)

Subjects with medication error events

00

Subjects with serious adverse events

14 (23.3)

12 (20.0)

Subjects with maximum Grade 3 or 4 adverse events

45 (75.0)

45 (75.0)

Subjects with maximum Grade 5 adverse events

00

Subjects with Grade 3 and higher adverse events

45 (75.0)

45 (75.0)

Subjects with adverse events leading to discontinuation of study drug

18 (30.0)

18 (30.0)

Subjects with adverse events leading to dose reduction of study drug

33 (55.0)

32 (53.3)

Subjects with adverse events leading to temporary discontinuation of study drug

42 (70.0)41 (68.3)

Cutoff Date: 12Mar2019
Includes data up to 28 days after the last dose of study drug.
Except for the number of AEs, subjects were counted only once in each row.
Serious AEs - according to the Investigator's assessment.
CTCAE v4.03 applied.

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The all-causality TEAEs that occurred in 10% of patients are presented by SOC andpreferred term in Table 11. The most common TEAEs (≥20%) experienced by patients
receiving bosutinib were diarrhea (86.7%), alanine aminotransferase (ALT) increased(55.0%), aspartate aminotransferase (AST) increased (46.7%), nausea (28.3%),
nasopharyngitis (28.3%), blood alkaline phosphatase increased (26.7%), rash (26.7%), lipase
increased (26.7%), vomiting (25.0%), pyrexia (23.3%) and platelet count decreased (21.7%).
There were gastrointestinal events and liver function related events reported with highfrequency, which were consistent with known bosutinib safety profile.
Treatment-related TEAEs were experienced by 59 patients (98.3%).

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CLINICAL STUDY REPORT SYNOPSIS
The most common treatment-related TEAEs (≥20%) experienced by patients receiving
bosutinib were diarrhea (86.7%), ALT increased (55.0%), AST increased (46.7%), nausea(26.7%), blood alkaline phosphatase increased (26.7%), lipase increased (25.0%) and rash,vomiting, and platelet count decreased (all reported in 21.7% patients).

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CLINICAL STUDY REPORT SYNOPSIS

Table 11. Summary of Treatment-Emergent Adverse Events in at Least 10% of Subjects by MedDRA System Organ Classand Preferred Term in Decreasing Frequency Order (All-Causalities and Treatment-Related) - As-Treated
Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)
All-Causality

Treatment-Related

Number (%) of Subjects:
by System Organ Classand Preferred Term

n (%)

n (%)

With Any Adverse Event

60 (100.0)

59 (98.3)

GASTROINTESTINAL DISORDERS

52 (86.7)

52 (86.7)

Diarrhoea

52 (86.7)

52 (86.7)

Nausea17 (28.3)

16 (26.7)

Vomiting

15 (25.0)

13 (21.7)

Constipation

7 (11.7)5 (8.3)

Abdominal pain upper

6 (10.0)

5 (8.3)INVESTIGATIONS

51 (85.0)

49 (81.7)

Alanine aminotransferase increased

33 (55.0)

33 (55.0)

Aspartate aminotransferase increased

28 (46.7)

28 (46.7)

Blood alkaline phosphatase increased

16 (26.7)

16 (26.7)

Lipase increased

16 (26.7)

15 (25.0)

Platelet count decreased

13 (21.7)

13 (21.7)

Gamma-glutamyltransferase increased

11 (18.3)

11 (18.3)

Amylase increased

9 (15.0)

9 (15.0)

Lymphocyte count decreased

7 (11.7)

7 (11.7)

Neutrophil count decreased

7 (11.7)

7 (11.7)

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CLINICAL STUDY REPORT SYNOPSIS
Table 11. Summary of Treatment-Emergent Adverse Events in at Least 10% of Subjects by MedDRA System Organ Classand Preferred Term in Decreasing Frequency Order (All-Causalities and Treatment-Related) - As-Treated
Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)
All-Causality

Treatment-Related

Number (%) of Subjects:
by System Organ Classand Preferred Term

n (%)

n (%)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

42 (70.0)39 (65.0)

16 (26.7)

13 (21.7)

Rash
Rash maculo-papular

8 (13.3)

8 (13.3)

39 (65.0)

8 (13.3)

Nasopharyngitis

17 (28.3)

2 (3.3)Upper respiratory tract infection

6 (10.0)

1 (1.7)19 (31.7)

19 (31.7)

10 (16.7)

10 (16.7)

17 (28.3)

11 (18.3)

14 (23.3)

8 (13.3)

15 (25.0)

9 (15.0)

7 (11.7)

1 (1.7)12 (20.0)

11 (18.3)

7 (11.7)

6 (10.0)

7 (11.7)5 (8.3)7 (11.7)5 (8.3)

INFECTIONS AND INFESTATIONSBLOOD AND LYMPHATIC SYSTEM DISORDERS
Anaemia
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Pyrexia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Back pain
HEPATOBILIARY DISORDERS
Liver disorder
NERVOUS SYSTEM DISORDERS
Headache

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Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Table 11. Summary of Treatment-Emergent Adverse Events in at Least 10% of Subjects by MedDRA System Organ Classand Preferred Term in Decreasing Frequency Order (All-Causalities and Treatment-Related) - As-Treated
Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

Number (%) of Subjects:
by System Organ Classand Preferred Term

Cutoff Date: 12Mar2019
Includes data up to 28 days after the last dose of study drug.
Subjects were counted only once per event.
MedDRA v21.1 coding dictionary applied.

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All-Causality

Treatment-Related

n (%)

n (%)

Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Grade 3 and Higher Treatment-Emergent Adverse Events:
A summary of incidence of all-causality and treatment-related Grade 3 TEAEs inat least 5% of patients is provided in Table 12.
There were no Grade 5 TEAEs reported in the study. Grade 3 TEAEs were experienced by
45 patients (75.0%) in the study, of which Grade 3 events were reported in 34 patients(56.7%) and Grade 4 events were reported in 11 patients (18.3%).
The most common Grade 3 TEAEs (≥10%) experienced by patients receiving bosutinib
were ALT increased (33.3%), AST increased (18.3%), diarrhea (15.0%) and lipase increased(15.0%). Out of the reported Grade 3 TEAEs, the majority of the TEAEs were considered
to be treatment-related.

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Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS

Table 12. Summary of Treatment-Emergent Adverse Events of Grade 3 and Higher in at Least 5% of Subjects by MedDRA
System Organ Class and Preferred Term in Decreasing Frequency Order (All-Causalities and Treatment-Related)- As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)
All-Causality

Treatment-Related

Number (%) of Subjects:
by System Organ Classand Preferred Term

n (%)

n (%)

With Any Adverse Event

45 (75.0)

45 (75.0)

INVESTIGATIONS

35 (58.3)

33 (55.0)

Alanine aminotransferase increased

20 (33.3)

20 (33.3)

Aspartate aminotransferase increased

11 (18.3)

11 (18.3)

Lipase increased

9 (15.0)

8 (13.3)

Neutrophil count decreased

5 (8.3)5 (8.3)Lymphocyte count decreased

4 (6.7)4 (6.7)

Gamma-glutamyltransferase increased

3 (5.0)3 (5.0)

Platelet count decreased

3 (5.0)3 (5.0)9 (15.0)

9 (15.0)

9 (15.0)

9 (15.0)

7 (11.7)

7 (11.7)

4 (6.7)4 (6.7)7 (11.7)

7 (11.7)5 (8.3)5 (8.3)

GASTROINTESTINAL DISORDERS
Diarrhoea
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Lymphopenia
HEPATOBILIARY DISORDERS
Liver disorder

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Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Table 12. Summary of Treatment-Emergent Adverse Events of Grade 3 and Higher in at Least 5% of Subjects by MedDRA
System Organ Class and Preferred Term in Decreasing Frequency Order (All-Causalities and Treatment-Related)- As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

Number (%) of Subjects:
by System Organ Classand Preferred Term

Cutoff Date: 12Mar2019
Includes data up to 28 days after the last dose of study drug.
Subjects were only counted once per event.
MedDRA v21.1 coding dictionary and CTCAE version 4.03 applied.

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All-Causality

Treatment-Related

n (%)

n (%)

Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Permanent Discontinuations due to Adverse Events:
The details of AEs leading to study drug discontinuations are provided in Table 13. A totalof 18 patients (30.0%) experienced AEs leading to discontinuation of study drug. The mostcommon AEs leading to discontinuation of study drug (≥5% of patients) were
ALT increased (10.0%) and AST increased (8.3%). All the events leading to permanent
discontinuation were considered to be treatment-related.

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Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS

Table 13. Summary of Treatment-Emergent Adverse Events Leading to Treatment Discontinuations (All-Causalities andTreatment-Related) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)
All-Causality

Treatment-Related

Number (%) of Subjects:
by System Organ Classand Preferred Term

n (%)

n (%)

With Any Adverse Event

18 (30.0)

18 (30.0)

BLOOD AND LYMPHATIC SYSTEM DISORDERS

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

HEPATOBILIARY DISORDERS

Thrombocytopenia

2 (3.3)2 (3.3)Drug-induced liver injury

1 (1.7)

1 (1.7)

Liver disorder

1 (1.7)

1 (1.7)

INFECTIONS AND INFESTATIONS

1 (1.7)

1 (1.7)

Pneumonia

1 (1.7)

1 (1.7)INVESTIGATIONS

10 (16.7)

10 (16.7)

Alanine aminotransferase increased

6 (10.0)

6 (10.0)

Aspartate aminotransferase increased

5 (8.3)5 (8.3)

Lipase increased

2 (3.3)2 (3.3)Hepatic enzyme increased

1 (1.7)

1 (1.7)

Neutrophil count decreased

1 (1.7)

1 (1.7)

Pancreatic enzymes increased

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)4 (6.7)4 (6.7)RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Pleural effusion
SKIN AND SUBCUTANEOUS TISSUE DISORDERS

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS
Table 13. Summary of Treatment-Emergent Adverse Events Leading to Treatment Discontinuations (All-Causalities andTreatment-Related) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)
All-Causality

Treatment-Related

n (%)

n (%)

Drug eruption

2 (3.3)2 (3.3)

Erythema multiforme

2 (3.3)2 (3.3)

Number (%) of Subjects:
by System Organ Classand Preferred Term

Cutoff Date: 12Mar2019
Includes data up to 28 days after the last dose of study drug.
Subjects were counted only once per event.
MedDRA v21.1 coding dictionary applied.

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CLINICAL STUDY REPORT SYNOPSIS
Dose Reductions or Temporary Discontinuations due to Adverse Events:
A total of 42 patients (70.0%) temporarily discontinued the study drug due to AEs. The mostcommon AEs leading to temporary discontinuation of study drug (≥5% of patients) were
ALT increased (28.3%), AST increased (16.7%), liver disorder (10.0%), diarrhea (10.0%),
lymphocyte count decreased (5.0%), and neutrophil count decreased (5.0%).
A total of 33 patients (55.0%) had their dose reduced due to AEs. The most common AEs
leading to dose reduction of the study drug (≥5% of patients) were ALT increased (21.7%),
AST increased (13.3%), lipase increased (8.3%), and neutrophil count decreased (5.0%).
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events:
Deaths:There was 1 death reported after the SAE reporting period (ie, after the last dose of study
drug + 28 days) among patients who participated in this study. The reason of the death was
disease progression, and was not related to the study drug.
Other Serious Adverse Events:
A summary of the incidence of all-causality and treatment-related SAEs by SOC, preferredterm and maximum Common Terminology Criteria for Adverse Events are provided inTable 14.
The incidence of SAEs was reported in 14 patients (23.3%), of which SAEs reported in
12 patients (20.0%) were considered to be treatment-related. The SAE of diabetic
retinopathy reported in 1 patient and the SAEs of wound infection and ankle fracture reported
in another patient were not considered to be treatment-related.
The most frequently reported treatment-emergent SAEs (≥2 patients) were diarrhea, liver
disorder and dehydration (all reported as 3.3%).

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CLINICAL STUDY REPORT SYNOPSIS

Table 14. Summary of Serious Adverse Events by MedDRA System Organ Class, Preferred Term and Maximum CTCAE
Grade (All-Causalities and Treatment-Related) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Treatment-Related

Number (%) of Subjects:
by System Organ Classand Preferred Term

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

With Any Adverse Event

14 (23.3)

14 (23.3)

12 (20.0)

12 (20.0)

EYE DISORDERS

1 (1.7)

1 (1.7)00

1 (1.7)

1 (1.7)00

2 (3.3)2 (3.3)2 (3.3)2 (3.3)

Diarrhoea

2 (3.3)2 (3.3)2 (3.3)2 (3.3)

Vomiting

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Diabetic retinopathy
GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Pyrexia
HEPATOBILIARY DISORDERS

3 (5.0)3 (5.0)3 (5.0)3 (5.0)Liver disorder

2 (3.3)2 (3.3)2 (3.3)2 (3.3)Drug-induced liver injury

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)4 (6.7)3 (5.0)3 (5.0)3 (5.0)Gastroenteritis

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Pneumonia

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Pyelonephritis

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Sepsis1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Wound infection

1 (1.7)000

1 (1.7)

1 (1.7)00

INFECTIONS AND INFESTATIONSINJURY, POISONING AND PROCEDURAL COMPLICATIONSCCIPage 33

Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Table 14. Summary of Serious Adverse Events by MedDRA System Organ Class, Preferred Term and Maximum CTCAE
Grade (All-Causalities and Treatment-Related) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Number (%) of Subjects:
by System Organ Classand Preferred Term

Treatment-Related

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

Ankle fracture

1 (1.7)

1 (1.7)00

INVESTIGATIONS

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Alanine aminotransferase increased

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Aspartate aminotransferase increased

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)2 (3.3)2 (3.3)2 (3.3)2 (3.3)2 (3.3)2 (3.3)2 (3.3)2 (3.3)

1 (1.7)0

1 (1.7)0

1 (1.7)0

1 (1.7)0

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)2 (3.3)2 (3.3)2 (3.3)2 (3.3)

Drug eruption

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Erythema multiforme

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)METABOLISM AND NUTRITION DISORDERS
Dehydration
RENAL AND URINARY DISORDERS
Acute kidney injury
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Pleural effusion
SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Cutoff Date: 12Mar2019
Includes data up to 28 days after the last dose of study drug.
Subjects were counted only once per event.
MedDRA v21.1 coding dictionary and CTCAE v4.03 applied.

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CLINICAL STUDY REPORT SYNOPSIS
Other Significant Adverse Events:
The summary of all treatment-emergent adverse event of special interest (AESI) categories,
all-causalities and treatment-related are provided in Table 15. These events included cardiac,edema, effusion, gastrointestinal, hemorrhage, hypertension, infection, myelosuppression,liver-related, rash, vascular, and renal AEs. No hypersensitivity AESIs were reported in the
study.

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CLINICAL STUDY REPORT SYNOPSIS

Table 15. Summary of Treatment-Emergent Adverse Events of Special Interest Categories (All-Causalities and TreatmentRelated) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Treatment-Related

Number (%) of Subjects:
by AESIs Categories
and Preferred Term

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

With Any Adverse Event

60 (100.0)

41 (68.3)

59 (98.3)

41 (68.3)

3 (5.0)03 (5.0)03 (5.0)03 (5.0)03 (5.0)02 (3.3)0Face oedema

1 (1.7)0

1 (1.7)0

Oedema1 (1.7)0

1 (1.7)0

Weight increased

1 (1.7)000

5 (8.3)

1 (1.7)5 (8.3)

1 (1.7)

Pleural effusion

4 (6.7)

1 (1.7)4 (6.7)

1 (1.7)

Pericardial effusion

3 (5.0)03 (5.0)

0

GASTROINTESTINALCARDIAC
Pericardial effusion
EDEMA

EFFUSION

52 (86.7)

9 (15.0)52 (86.7)

9 (15.0)

Diarrhoea

52 (86.7)

9 (15.0)52 (86.7)

9 (15.0)

Nausea17 (28.3)

0

16 (26.7)

0Vomiting

15 (25.0)

1 (1.7)13 (21.7)

1 (1.7)HEMORRHAGE

5 (8.3)0

1 (1.7)0Contusion

1 (1.7)000Epistaxis

1 (1.7)0

1 (1.7)0

Haemorrhoidal haemorrhage

1 (1.7)

0

0

0

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS
Table 15. Summary of Treatment-Emergent Adverse Events of Special Interest Categories (All-Causalities and TreatmentRelated) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Number (%) of Subjects:
by AESIs Categories
and Preferred Term

Treatment-Related

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

Metrorrhagia

1 (1.7)000Petechiae

1 (1.7)0

1 (1.7)0

Retinal haemorrhage

1 (1.7)0

0

0

HYPERTENSION

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)Hypertension

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

INFECTION

39 (65.0)

4 (6.7)8 (13.3)

4 (6.7)

Nasopharyngitis

17 (28.3)

02 (3.3)0Upper respiratory tract infection

6 (10.0)0

1 (1.7)0Influenza

5 (8.3)0

0

0Gastroenteritis

4 (6.7)

1 (1.7)

1 (1.7)

1 (1.7)

Cystitis

3 (5.0)0

1 (1.7)0

Bronchitis

2 (3.3)0

1 (1.7)0Tinea pedis

2 (3.3)0

1 (1.7)0Angular cheilitis

1 (1.7)0

0

0Conjunctivitis

1 (1.7)000

Eye infection

1 (1.7)000Herpes simplex

1 (1.7)000

Infectious colitis

1 (1.7)000Lung infection

1 (1.7)0

1 (1.7)0Onychomycosis

1 (1.7)

0

0

0

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CLINICAL STUDY REPORT SYNOPSIS
Table 15. Summary of Treatment-Emergent Adverse Events of Special Interest Categories (All-Causalities and TreatmentRelated) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Number (%) of Subjects:
by AESIs Categories
and Preferred Term

Treatment-Related

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

Otitis externa

1 (1.7)000Paronychia

1 (1.7)00

0

Pneumonia

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Pyelonephritis

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Rhinolaryngitis

1 (1.7)0

00

Sepsis1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)Sinusitis

1 (1.7)000Urethritis

1 (1.7)000Urinary tract infection

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Wound infection

1 (1.7)000LIVER-RELATED

48 (80.0)29 (48.3)

47 (78.3)

29 (48.3)

Alanine aminotransferase increased

33 (55.0)

20 (33.3)

33 (55.0)

20 (33.3)

Aspartate aminotransferase increased

28 (46.7)

11 (18.3)

28 (46.7)

11 (18.3)

Blood alkaline phosphatase increased

16 (26.7)

0

16 (26.7)

0Liver disorder

7 (11.7)5 (8.3)6 (10.0)

5 (8.3)

Ascites2 (3.3)0

2 (3.3)0Blood bilirubin increased

2 (3.3)

1 (1.7)2 (3.3)

1 (1.7)

Hepatic function abnormal

2 (3.3)0

2 (3.3)0Transaminases increased

2 (3.3)

1 (1.7)2 (3.3)

1 (1.7)

Bilirubin conjugated increased

1 (1.7)0

1 (1.7)0

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Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Table 15. Summary of Treatment-Emergent Adverse Events of Special Interest Categories (All-Causalities and TreatmentRelated) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Number (%) of Subjects:
by AESIs Categories
and Preferred Term

Treatment-Related

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

Drug-induced liver injury

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Hepatic enzyme increased

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

Hepatobiliary disease

1 (1.7)0

1 (1.7)0

Liver function test abnormal

1 (1.7)0

1 (1.7)0

Liver injury

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)

MYELOSUPPRESSION

27 (45.0)

16 (26.7)

27 (45.0)

16 (26.7)

Platelet count decreased

13 (21.7)

3 (5.0)13 (21.7)

3 (5.0)Anaemia

10 (16.7)

0

10 (16.7)

0

Lymphocyte count decreased

7 (11.7)

4 (6.7)7 (11.7)

4 (6.7)

Neutrophil count decreased

7 (11.7)5 (8.3)7 (11.7)5 (8.3)

Thrombocytopenia

5 (8.3)2 (3.3)5 (8.3)2 (3.3)

White blood cell count decreased

5 (8.3)

1 (1.7)5 (8.3)

1 (1.7)Lymphopenia

4 (6.7)4 (6.7)4 (6.7)4 (6.7)

Neutropenia

3 (5.0)2 (3.3)3 (5.0)2 (3.3)

Leukopenia

1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)RASH

33 (55.0)

3 (5.0)29 (48.3)

3 (5.0)Rash

16 (26.7)

1 (1.7)13 (21.7)

1 (1.7)

Rash maculo-papular

8 (13.3)

1 (1.7)8 (13.3)

1 (1.7)

Dermatitis acneiform

4 (6.7)04 (6.7)0Eczema asteatotic

4 (6.7)0

1 (1.7)0

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Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Table 15. Summary of Treatment-Emergent Adverse Events of Special Interest Categories (All-Causalities and TreatmentRelated) - As-Treated Population
Number of Subjects Evaluable for AEs

Bosutinib(N=60)

CTCAE Grade

All-Causality

Number (%) of Subjects:
by AESIs Categories
and Preferred Term

Treatment-Related

All Gradesn (%)

Grade≥ 3n (%)

All Gradesn (%)

Grade≥ 3n (%)

Eczema3 (5.0)02 (3.3)0Rash generalised

2 (3.3)0

2 (3.3)0Rash papular

2 (3.3)0

2 (3.3)0

Dermatitis contact

1 (1.7)0

00Erythema1 (1.7)

1 (1.7)

1 (1.7)

1 (1.7)RENAL

4 (6.7)04 (6.7)0Acute kidney injury

2 (3.3)0

2 (3.3)0Blood creatinine increased

1 (1.7)0

1 (1.7)0

Renal impairment

1 (1.7)0

1 (1.7)0

1 (1.7)000

1 (1.7)0

0

0

VASCULAR
Peripheral coldness
Cutoff Date: 12Mar2019
Includes data up to 28 days after the last dose of study drug.
MedDRA v21.1 coding dictionary and CTCAE v4.03 applied.

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Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
An analysis of AESI did not identify any new safety signals. Within the categories of AESIs(cardiac, edema, effusion, gastrointestinal, hemorrhage, hypertension, infection, liver-related,
myelosuppression, rash, renal, and vascular), the most frequent Grade 3 events wereliver-related, myelosuppression, gastrointestinal, infection and rash AESIs, which wasconsistent with the known safety profile of bosutinib. The overall incidence of cardiac,hemorrhage, effusion, vascular, hypertension, and renal AESIs was low (<9%).
For the gastrointestinal AESIs, including the most frequently reported event of diarrhea(86.7%), the median time to first event was 1.0 days (range: 1 to 271 days), and there wereno patients who permanently discontinued due to the gastrointestinal AESIs. For theliver-related AESIs, the most common AESIs were ALT increased (33 patients [55.0%]),AST increased (28 patients [46.7%]), blood alkaline phosphatase increased (16 patients[26.7%]) and liver disorder (7 patients [11.7%]). The median time to first event was
15.0 days (range: 1 to 169 days). A total of 10 patients (16.7%) were permanently
discontinued due to liver-related AESIs. Among those patients with liver-related AESIs,
58.3% of patients had their study drug dose temporarily stopped in response to liver-related
AESIs; of which most patients were successfully rechallenged with study drug and there
were no cases of Hy’s law or permanent liver injury observed in the study. Vascular andcardiac AEs were reported infrequently (1.7% and 5.0%, respectively). Vascular event
search criteria included coronary artery disorders, arteriosclerosis, stenosis, vascularinsufficiency and necrosis, embolism and thrombosis. The only reported vascular AE wasperipheral coldness. Cardiac event search criteria included cardiac arrhythmias, heart
failures, pericardial disorders, and QT prolongation. The only reported cardiac AE waspericardial effusion.
Renal AESIs were reported in 6.7% of patients and all the events were considered to betreatment-related. The renal AESIs were resolved in 3 out of 4 patients and no permanent
discontinuation was reported due to renal AESIs. Effusion AESIs (pleural effusion andpericardial effusion) were reported in 8.3% of patients. Edema AESIs were reported in 5.0%of patients. There was 1 AESI of hypertension (Grade 3) that was reported in the study andno events of hypersensitivity AESIs were reported.
The most frequently reported blood chemistry related laboratory abnormalities were ALT
increased, AST increased, alkaline phosphatase increased, creatinine increased, andhypoalbuminemia and hypocalcemia. The most frequently reported hematological laboratory
abnormalities were lymphocyte count decreased, hemoglobin decreased (anemia) and platelet
count decreased.
Overall, there were no clinically significant findings in ECGs/vital signs and left ventricularejection fraction.

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Final Clinical Study Report
Protocol B1871048

CLINICAL STUDY REPORT SYNOPSIS
Conclusions:
In Japanese patients with newly diagnosed Ph+ CP CML, bosutinib showed favorable
efficacy similar to Study AV001, which demonstrated the superior efficacy of bosutinib
400 mg QD to imatinib 400 mg QD, one of the standard therapies, therefore it is suggested
that bosutinib offers clinically meaningful benefit for Japanese patients with newly diagnosed
Ph+ CP CML.
Bosutinib had a generally acceptable profile in Japanese patients with newly diagnosed
Ph+ CP CML. The safety profile of bosutinib was consistent with the known safety profile
of bosutinib and no new safety signals were identified.
In conclusion, the benefit-risk balance of bosutinib at a starting dose of 400 mg QD in
Japanese patients with newly diagnosed Ph+ CP CML is considered favorable. Bosutinib
can be an important effective treatment option for Japanese patients with newly diagnosed
Ph+ CP CML.

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