Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME® / GENERIC DRUG NAME: Bosulif ® / Bosutinib(SKI-606)
PROTOCOL NO.: 3160A4-2203 (B1871007)
PROTOCOL TITLE: A Phase 1/2 Study of SKI-606 Administered as a Single Agent inJapanese Subjects With Philadelphia Chromosome Positive Leukemias
Study Centers: A total of 22 centers in Japan took part in the study and enrolled subjects.
Study Initiation, Primary Completion and Final Completion Dates:

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Study Initiation Date: 03 December 2007
Primary Completion Date: 05 March 2013
Final Completion Date: 17 June 2015
Phase of Development: Phase 1/2
Study Objectives:
Part 1 (Dose Escalation Component):
Primary Objectives:


Safety confirmation of 600 mg daily or establishment of maximum tolerated dose(MTD) lower than 600 mg, in subjects with chronic phase (CP)imatinib-resistant/refractory or imatinib-intolerant chronic myelogenous leukemia(CML);



Evaluate the overall pharmacokinetic (PK) parameters in this population.

Secondary Objective:

Determine the rate of major cytogenetic response (MCyR) in CP subjects at various
dose levels of bosutinib.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Part 2 (Efficacy Component):
Primary Objective:

Determine the rate of attaining MCyR in subjects entering withimatinib-resistant/refractory or imatinib-intolerant CP CML.

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Secondary Objectives:

Estimate the time to and duration of MCyR in subjects entering withimatinib-resistant/refractory or imatinib-intolerant CP CML;

Estimate the time to and duration of complete hematologic response (CHR) in theimatinib-resistant/refractory or imatinib-intolerant groups;



Estimate MCyR in CP CML subjects entering with imatinib-resistant/refractory or
imatinib-intolerant followed by resistant/refractory or intolerant to dasatinib or
nilotinib;Estimate the time to and duration of MCyR by resistant/refractory or intolerant todasatinib or nilotinib CP CML;

Overall survival (OS) and progression free survival (PFS) rates at 1 and 2 years were
explored;Estimate CHR rate in accelerated or blast phase CML subjects withimatinib-resistant/refractory or intolerant to imatinib;Estimate overall hematologic response (OHR) rate in accelerated or blast phase CML
subjects with imatinib-resistant/refractory or intolerant followed byresistant/refractory or intolerant to dasatinib or nilotinib;Assess the safety of bosutinib during prolonged oral exposure in a leukemic
population;

Determine the population PK parameters of this population.

METHODS
Study Design:This was an open-label, continuous daily dosing, 2-part safety and efficacy study of bosutinibin subjects with Philadelphia Chromosome positive (Ph+) CML.
Part 1: This was designed as a dose-escalation study in imatinib-resistant/refractory or
imatinib-intolerant CP CML subjects, to confirm the safety of bosutinib at dose-levels from
400 mg to 600 mg. As summarized in the Study Flowchart of Part 1 (Table 1), safety
evaluations were conducted at the end of the first 28 days of bosutinib administration.

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Details on dose administration and dose-escalation rules are provided in section study
treatment of this document.
Part 2: After having confirmed the safety of bosutinib 600 mg daily or established the MTD
lower than 600 mg in Part 1, Part 2, an efficacy study of bosutinib 500 mg began. The study
explored the hypotheses that oral daily dosing of bosutinib at 500 mg attained:

MCyR in CP CML subjects with imatinib-resistant/refractory or intolerant to imatinib(second-line: primary cohort);

 CHR in accelerated or blast phase CML subjects with resistant/refractory or intolerant toimatinib (second-line: advanced cohort);
Bone marrow examination and cytogenetics were performed every 3 months for CP CML
subjects. Accelerated or blast phase CML subjects underwent marrow examination every
28 days for the first 3 months and every 3 months thereafter, until the End of the Study.
After discontinuation of bosutinib treatment, survival, progression, and initiation ofother anti-tumor treatment were followed up every 3 months.

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The timing of procedures is described in Table 1 and Table 2.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 1.

Study Flowchart (Part 1)

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Study Procedures

ScreeningaEnd of Treatment(28-42 Days After Last
Dose)

b
Week
1
2
3
4
8
12
q12w
Study Days
–14 to –1
1
7
14
21
28
56
84
168, 252 and 336
Cycle Day
1
7
14
21
28
56
84
84
Study Visit Window
3 3
3
3
3
3
3
c
-----------------------------Continuousdailydosing----------------------------Dose bosutinibd
X
Informed consent
Inclusion/exclusion
X
Medical history/cancer history
Xef
PRBC and platelet transfusion Hx
X
X
X
X
X
X
X
X
X
Chest X-ray
X
X
When clinically indicated
X
g
f
X
X
X
X
Physical examination
X
h
X
X
X
X
Digital ECG
ECHO or MUGAXWhen clinically indicatedWeek 24 onlyX
ECOG performance status
X
X
X
X
X
X
X
Long term follow-up
After bosutinib discontinuation, every 3 months for survival, progression and other anti-tumor Tx
SAEs and AEs (reported from the signing of the ICF)
X
X-----------------------------------------------------------------------i
X-----------------------------------------------------------------------Concomitant treatments
Serum pregnancy test (for women of childbearing potential)
X
As indicated by history/clinical evidence
X
j
X
X
X
X
X
Urinalysis
k
X
X
X
X
X
X
X
X
X
Chemistry
k
X
X
X
X
X
X
X
X
LFTs
l
X
X
X
Creatinine kinase and amylase/lipase
m
f
X
X
X
X
X
X
X
X
X
CBC and differential
X
n
X
X
X
X
X
X
Coagulation testsoo
PCR for Bcr-Abl
X
X
X
X
X
X
p
o
X
X
X
Bone marrow aspirate
X
Cytogenetics, morphology and blast %
X
X
X
X
q
X
X
X
Site response assessmentr
Bcr-Abl sequencing
X
X
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time;
AST = aspartate aminotransferase; Bcr-Abl = fusion transcript or protein resulting from the 9:22 chromosomal translocation responsible for formation of the Philadelphia
chromosome; BUN = blood urea nitrogen; CBC = complete blood count; CHR = complete hematologic response; CK = creatinine kinase; CORE = Computerized Randomizationand Enrollment System; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; Hb = hemoglobin; Ht = hematocrit; ICF = informed
consent form; INR = international normalized ratio; IRB = Institutional Review Board; LDH = lactate dehydrogenase; LFT = liver function test; MUGA = multiple gatedTemplate version 1.6

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Table 1.

Study Flowchart (Part 1)

acquisition scan; NEL = no evidence of leukemia; OAT = oral anticoagulant therapy (such as warfarin); PCR = polymerase chain reaction; PI = principal investigator;
PRBC = packed red blood cells; PT = prothrombin time; QTc = corrected QT; RBC = red blood cell count; SAE = serious adverse event; ULN = upper limit of normal.
a. Screening visit within 14 days before the first dose of bosutinib.
b. Subjects benefiting from bosutinib treatment were eligible for continued treatment beyond 52 weeks with procedures continuing every 12 weeks.
c. The subject had to receive the first dose of bosutinib no more than 2 business days after being enrolled in the CORE system. Day 2 dose was withheld.
d. Signed and dated IRB-approved informed consent before any protocol-specific screening procedures were performed. Procedures performed as standard of care prior to signed
and dated ICF, and within the 14 day screening window could be used for study entry. Bone marrow was excepted.
e. The approximate number and volume of transfusions of both blood and platelets given during the previous 28 days were collected. If the subject was referred to the institution,subject/referring physician recollection was sufficient.
f. Repeated if not performed within 3 days before the first dose of bosutinib.
g. Vital signs (supine blood pressure, heart rate and axillary temperature), height and weight.
h. Triplicate ECGs were performed at Screening, on Day 1 prior to treatment and at hours 1, 2, 3, 4, 6, 8, 24, and 48 postdose, and on Day 8 prior to treatment and at Hour 6
postdose and on Day 15 prior to treatment and at hours 1, 2, 3, 4, 6, 8, and 24 postdose, on Day 21 prior to treatment and at hours 2, 4, 6, and 20-23 postdose and End of
Treatment visit. End of treatment ECG had to occur at least 7 days after the last dose to allow assessment of QTc after clearance of most of the bosutinib from the blood.
Digital ECG recorders were used, and provided by the Sponsor through a third party vendor. An additional set of triplicate ECGs had to be done if a clinically significant
decrease in ejection fraction was detected while on study by ECHO or MUGA. ECG data was sent to an independent central laboratory for a central review.
i. All medications from 28 days before the first dose of bosutinib were collected.
j. Qualitative examination: pH, specific gravity, protein/albumin, glucose/sugar, ketones/acetone, hemoglobin/blood.
k. Blood chemistries included sodium, potassium, chloride, calcium, phosphorus, magnesium, glucose, serum creatinine, and BUN. Uric acid performed until the subject
achieved CHR or NEL.
l. LFTs done as part of a panel that included chemistry and LFTs when possible. LFTs included total protein, albumin, AST, ALT, LDH, ALP, total and direct bilirubin (if total>2.0 × ULN). Amylase and lipase and CK also included at indicated times.
m. Hematology included CBC including a 5-part differential (abnormalities confirmed by manual differentials), platelet count, ANC, RBC, Hb, and Ht. Phase of disease at
screening assignment was based on first day of dosing CBC results. In the case of grade 4 hematologic toxicity, it was recommended that CBC be repeated at least every
2-3 days until recovered to  Grade 2 toxicity.
n. The coagulation tests included PT (expressed as INR), APTT and fibrinogen (if PT/APTT abnormal, screening only). At Screening, test availability documented within
14 days before the first dose of bosutinib if the subject did not take OAT within the past 30 days, and within 3 days before the first dose of bosutinib if the subject took OAT
within the past 30 days.
o. The 4 and 8 week PCRs omitted in situations in which Investigator did not believe the subject was experiencing clinical benefit (ie 90% peripheral blasts).
p. Bone marrow aspirate collected for morphology and cytogenetic analysis. Screening bone marrow obtained any time up to 28 days before the first dose of test article(Day –28). Bone marrow aspirates performed every 12 weeks in Year 1, every 24 weeks in Years 2 and 3, and yearly (q48 weeks) for after Year 4, and as clinically indicated.
Additional bone marrow testing included the sequencing of Bcr-Abl (could be done on peripheral blood if adequate marrow was not available) to determine mutation status. A
marrow sample submitted at any time progression from best response occurred, and for confirmation of progression. This time point could, or could not, coincide withcessation of treatment. (ie, if a subject progressed from complete hematologic response to partial hematologic response, they lost their best response but could not yet
discontinue bosutinib).
q. Site assessments were the PI’s determination of time point responses.
r. Bcr-Abl sequencing done at study end if subject ended for progression. Peripheral blood was acceptable for sequencing if bone marrow was not available.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 2.

Study Flowchart (Part 2)

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Study Procedures
Week
Study Days
Cycle Day
Study Visit Window

Screening1–14 to –1cDose bosutinibdInformed consent
Inclusion/exclusion
Medical history/cancer history
PRBC and platelet transfusion Hx
Chest X-rayg
Physical examinationhDigital ECG
ECHO or MUGAECOG performance status
Long term follow-up

a

1
1

7
7
3

2
14
14
3

3
21
21
3

4
28
28
3

8
56
56
3

12
84
84
3

b

End of Treatment(28-42 Days After
Last Dose)

q12w
168, 252 and 336
843----------------------Continuousdailydosing----------------------X
X
X
e
X
X
X
X
X
X

f

X
X
X
When clinically indicated
X
f
X
X
X
X
h
X
X
X
X
X
X
When clinically indicatedWeek 24 only
X
X
X
X
X
X
X
After bosutinib discontinuation, every 3 months for survival, progression and otheranti-tumor Tx
SAEs and AEs (reported from the signing of the ICF)
X-----------------------------------------------------------------------X
iX-----------------------------------------------------------------------Concomitant treatments
Serum pregnancy test (for women of childbearing potential)
X
As indicated by history/clinical evidence
X
j
X
X
X
X
X
Urinalysis
k
X
X
X
X
X
X
X
X
X
Chemistry
k
X
X
X
X
X
X
X
X
LFTs
l
X
X
X
Creatinine kinase and amylase/lipase
m
f
X
X
X
X
X
X
X
X
X
CBC and differential
X
n
X
X
X
X
X
X
Coagulation testsoo
PCR for Bcr-Abl
X
X
X
X
X
X
p
p
X
X* X*
X
X
Bone marrow aspirate
X
Cytogenetics, morphology and blast %
X
X* X*
X
X
X
q
X* X*
X
X
X
Site response assessmentr
Bcr-Abl sequencing
X
X
 Advanced subjects only (accelerated phase CML/blast phase CML). Bone marrow aspiration was done monthly (3×) on advanced phase subjects until a return to CP wasachieved (whichever came first).
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time;
AST = aspartate aminotransferase; Bcr-Abl = fusion transcript or protein resulting from the 9:22 chromosomal translocation responsible for formation of the Philadelphia

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X

X

X

X
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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

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Table 2.

Study Flowchart (Part 2)

chromosome; BUN = blood urea nitrogen; CBC = complete blood count; CHR = complete hematologic response; CK = creatinine kinase; CML = chronic myelogenous leukemia;
CORE = Computerized Randomization and Enrollment System; CP = chronic phase; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology
Group; Hb = hemoglobin; Ht = hematocrit; ICF = informed consent form; INR = international normalized ratio; IRB = Institutional Review Board; LDH = lactate dehydrogenase;
LFT = liver function test; MUGA = multiple gated acquisition scan; NEL = no evidence of leukemia; OAT = oral anticoagulant therapy (such as warfarin); PCR = polymerase chain
reaction; PRBC = packed red blood cells.
a. Screening visit within 14 days before the first dose of bosutinib.
b. Subjects benefiting from bosutinib treatment were eligible for continued treatment beyond 52 weeks with procedures continuing every 12 weeks performed.
c. The subject received the first dose of bosutinib no more than 2 business days after being enrolled in the CORE system.
d. Signed and dated IRB-approved informed consent before any protocol-specific screening procedures were performed. Procedures performed as standard of care prior to signed
and dated ICF, and within the 14 day screening window could be used for study entry. Bone marrow was excepted.
e. The approximate number and volume of transfusions of both blood and platelets given during the previous 28 days were collected. If the subject was referred to the institution,subject/referring physician recollection was sufficient.
f. Repeated if not performed within 3 days before the first dose of bosutinib.
g. Vital signs (supine blood pressure, heart rate and axillary temperature), height and weight.
h. Triplicate ECGs were performed at Screening, on Day 1 prior to treatment and at Hours 2, 4 and 6 postdose, on Day 14 prior to treatment, on Day 21 prior to treatment and at
Hours 2, 4, 6, and 20-23 postdose, on Day 84 prior to treatment, on Day 168 prior to treatment and on Day 252 prior to treatment and End of Treatment visit for except
exploratory cohort, at Screening, on Day 1 prior to treatment and at hour 4 postdose, on Day 21 prior to treatment, on Day 84 prior to treatment, on Day 168 prior to treatment
and on Day 252 prior to treatment and End of Treatment visit for exploratory cohort. End of treatment ECG occurred at least 7 days after the last dose to allow assessment of
QTc after clearance of most of the bosutinib from the blood. Digital ECG recorders were used, and provided by the Sponsor through a third party vendor. An additional set of
triplicate ECGs done if a clinically significant decrease in ejection fraction was detected while on study by ECHO or MUGA. ECG data was sent to an independent central
laboratory for a central review.
i. All medications from 28 days before the first dose of bosutinib were collected.
j. Qualitative examination: pH, specific gravity, protein/albumin, glucose/sugar, ketones/acetone, hemoglobin/blood.
k. Blood chemistries to include sodium, potassium, chloride, calcium, phosphorus, magnesium, glucose, serum creatinine, and BUN. Uric acid performed until the subject
achieved CHR or NEL.
l. LFTs done as part of a panel that included chemistry and LFTs when possible. LFTs included total protein, albumin, AST, ALT, LDH, ALP, total and direct bilirubin (if total>2.0 × ULN). Amylase and lipase and CK included at indicated times.
m. Hematology included CBC including a 5-part differential (abnormalities confirmed by manual differentials), platelet count, ANC, RBC, Hb, and Ht. Phase of disease at
screening assignment was based on first day of dosing CBC results. In the case of grade 4 hematologic toxicity, it was recommended that CBC be repeated at least every
2-3 days until recovered to  Grade 2 toxicity.
n. The coagulation tests included PT (expressed as INR), APTT and fibrinogen (if PT/APTT abnormal, screening only). At Screening, test availability documented within 14 days
before the first dose of bosutinib if the subject did not take OAT within the past 30 days, and within 3 days before the first dose of bosutinib if the subject took OAT within thepast 30 days.
o. The 4 and 8 week PCRs omitted in situations in which Investigator did not believe the subject was experiencing clinical benefit (ie 90% peripheral blasts).
p. Bone marrow aspirate collected for morphology and cytogenetic analysis. Screening bone marrow obtained any time up to 28 days before the first dose of test article(Day –28). Bone marrow aspirates was performed every 12 weeks in Year 1, every 24 weeks in Years 2 and 3 and yearly.
q. Site Assessments were the PI’s determination of time point responses.
r. Bcr-Abl sequencing done at study end if subject ended for progression. Peripheral blood was acceptable for sequencing if bone marrow was not available.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Number of Subjects (Planned and Analyzed):
Part 1: This was planned to consist of 3 cohorts, with 3 to 6 subjects planned for 400 mg,
500 mg, and 600 mg, respectively. A total of 17 subjects (400 mg: 7 subjects, 500 mg:
7 subjects, 600 mg: 3 subjects) were enrolled and treated with bosutinib.
Part 2: This was planned to consist of 45 subjects, with 25 subjects planned for primarycohort, 10 subjects for advanced cohort and 10 subjects for exploratory cohort. A total of
46 subjects (second-line: 35 subjects consisted of 28 subjects in the primary cohort and7 subjects in the advanced cohort; third-line: 11 subjects) were enrolled and treated withbosutinib 500 mg.

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Diagnosis and Main Criteria for Inclusion and Exclusion:
Subjects with cytogenetic or polymerase chain reaction based diagnosis of CP of Ph+ CML(Part 1), any phase of Ph+ CML (Part 2), whose disease was resistant/refractory to full-dose
imatinib or were intolerant of any dose of imatinib, or whose disease was resistant/refractory
to full-dose imatinib or were intolerant of any dose of imatinib as a first-line treatment andresistant/refractory to full-dose dasatinib or nilotinib, or were intolerant of any dose ofdasatinib or nilotinib. Subjects were also required to have Eastern Cooperative Oncology
Group (ECOG) performance status of 0 or 1 for CP subjects, and 0, 1 or 2 for advanced stage
subjects and to be aged 20 years and <75 years for Part 1 and 20 years for Part 2.
Exclusion Criteria: Subjects with philadelphia chromosome negative chronic myelogenous
leukemia, those who had ongoing requirement for warfarin or other oral anticoagulant
therapy (Part 1), ongoing requirement for hydroxyurea (Part 1), ongoing clinical requirement
for administration of a strong inhibitor or inducer of CYP-3A4 (Part 1) were excluded fromthe study.
Study Treatment:
Bosutinib was orally administered with water and food as a single dose on Day 1 and ascontinuous once-daily dosing from Day 3 (Part 1). The dose on Day 2 was skipped in Part 1
only to provide an appropriate 48 hour PK profile.
Part 1: To confirm the safety of 600 mg daily or to establish the MTD lower than 600 mg,
3 to 6 subjects were to be evaluated for treatment-emergent toxicities at 400 mg, 500 mg, and
600 mg.
Part 2: The starting dose was 500 mg and dose escalation up to 600 mg was allowed for thelack of efficacy.
Subjects in both parts, deemed by the Investigator and the Sponsor to be benefiting from thecompound, were allowed to continue on bosutinib until disease progression, unacceptabletoxicity, or withdrawal of consent occurred.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Efficacy, Pharmacokinetic and Safety Endpoints:
Part 1 (Dose Escalation Component):
Primary Endpoints:

MTD of bosutinib in subjects with CP imatinib-resistant/refractory or
imatinib-intolerant CML, measured as incidence and severity of dose-limiting
toxicities (DLTs) at each dose level (400 mg, 500 mg, and 600 mg);Overall PK parameters in this population.

Secondary Endpoint:

The rate of attaining MCyR in CP subjects at various dose levels of bosutinib.

Pharmacokinetic Endpoints:

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

PK parameters including observed maximum concentration (Cmax), time of maximum
concentration (Tmax), area under the concentration-time curve (AUC), terminal
elimination half-life (t½), apparent oral clearance (CL/F), apparent volume of
distribution (Vz/F) and the accumulation ratio (R) were calculated.

Part 2 (Efficacy Component):
Primary Efficacy Endpoint:

The rate of attaining MCyR in subjects with imatinib-resistant/refractory or
imatinib-intolerant CP CML, who have completed at least 24 weeks of follow-up, or
obtained MCyR prior to 24 weeks.

Secondary Efficacy Endpoints:Time to McyR, duration of McyR, and maintenance rate of MCyR.



The rate of attaining CHR, Time to CHR, and Duration of CHR;



PFS;



Time to treatment failure (TTF);

OS.

Pharmacokinetic Endpoints:


Population PK parameters were estimated in this population.

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Safety Evaluations: The safety variables included incidence and severity of DLTs in Part 1
and adverse events (AEs) at each dose level in Part 1 and in Part 2, changes in laboratory test
results, electrocardiogram, and chest X-ray, concomitant medications used for managementof AEs, and changes in ECOG performance status or physical examination (as summarized inTable 1 and Table 2).
Statistical Methods:

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Analysis Populations: The following 6 analysis populations were analyzed in the study:All-treated population was defined as all enrolled subjects who had received at least
1 dose of bosutinib.



Evaluable populations were defined for cytogenetic, hematologic, and molecularresponses, respectively, as a subset of the all-treated population, ie, all enrolled subjects
who had received at least 1 dose of bosutinib and had an adequate baseline efficacy
assessment for pertinent response.

The per-protocol (PP) population was defined as a subset of the evaluable population, ie,all enrolled subjects who received at least 1 dose of bosutinib, had no major protocol
violation, had an adequate baseline efficacy assessment, and had an adequate
post-baseline efficacy assessment unless the subject had early progression or died.

The safety population was defined as all subjects who had received at least 1 dose ofbosutinib. This population excluded only those subjects who had never received
bosutinib.



The PK concentration population was defined as all enrolled subjects who had received
1 dose of bosutinib and had at least 1 concentration data.

 The PK parameter population was defined as all enrolled subjects who received 1 doseof bosutinib and had at least 1 of the PK parameters of interest.
Efficacy Analysis: The statistical analysis performed for efficacy endpoints was based on the
all-treated, evaluable, and PP populations. The analysis based on the all-treated population
was considered primary. The primary efficacy endpoint was analyzed based on all
3 populations. The secondary efficacy endpoints were analyzed based on the all-treated andevaluable populations, except that TTF, PFS and OS were analyzed based only on the
all-treated population.
Categorical endpoints included the MCyR, CHR, major hematologic response (MHR), OHR,
major molecular response (MMR), and accelerated phase (AP)/ blast phase (BP)transformation rates. The number of subjects with a response were reported. The observed
rate and the exact 2-sided 95% confidence interval (CI) for the rate was also provided.
Time-to-event endpoints included the time to response, duration of response, TTF, PFS, andOS. The number of subjects with each event and censoring were reported. The distributions

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Finalof time-to-event were estimated using the Kaplan-Meier method. The quartile (25%, 50%,
and 75%) time-to-event and the corresponding 2-sided 95% CIs were reported. For the TTF,
PFS, and OS analyses, the rates at Week 48 and at Week 96 and the corresponding 2-sided
95% CIs were also presented.
Safety Analysis: Safety data were tabulated using descriptive statistics and no formal
statistical testing was planned. Safety data was analyzed on the basis of available data insafety population.
Pharmacokinetic Analysis: The PK analyses were based on the PK concentration and PK
parameter populations. Bosutinib plasma concentration profiles were summarized for eachsampling point and each dose group (Part 1 only). The concentration-time curves weredrawn for each subject (Part 1 only). Summaries of bosutinib concentrations and majority of
PK parameters included n, mean, standard deviation, coefficient of variance (CV) %,minimum, median, maximum and geometric mean of data. For certain parameters,
particularly those associated with time observations such as Tmax, total population (n),median, and range (minimum, maximum) were included. The actual times of sample
collection were used in the PK analyses.

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RESULTS
Subject Disposition and Demography:
Subject disposition is summarized in Table 3. In Part 1, 17 subjects were enrolled andtreated with bosutinib. In Part 2, 46 subjects (second-line: 35 subjects, third-line:
11 subjects) were enrolled and treated with bosutinib. Forty-five (45) (86.5%) subjects in the
total second-line subjects and 11 (100%) subjects in the exploratory third-line cohort werelost to follow-up which includes the completion of the study. In the total second-line median
duration of treatment in weeks was 137.14 weeks (range: 1.14 to 372.43 weeks) and median
duration of follow-up in weeks was 149.93 weeks (range: 3.14 to 372.43 weeks). In the
exploratory third-line cohort, the median duration of treatment in weeks was 131.43 weeks(range: 13.00 to 160.14 weeks) and median duration of follow-up in weeks was
131.43 weeks (range: 105.43 to 160.14 weeks).

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 3.

Subject Disposition: All-Treated Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mg
N=3Part 2
Primary
Second-Line
500 mgN=28
2 (7.1)26 (92.9)

Part 2
Total
Advanced Second-Line
Second-Line
N=52
500 mgN=75 (71.4)
7 (13.5)
2 (28.6)
45 (86.5)

Deceased0
0
0
Lost to follow-up
7 (100 )
7 (100 )
3 (100 )Duration of treatment in weeks
N
7
7
3
28
7
Mean
204.98165.45253.10161.53
31.84
Standard deviation
174.03169.71130.05115.05
65.09
Minimum
1.86
1.71
103.001.14
1.14
Maximum
372.43359.86332.29312.00179.00Median270.1488.00
324.00238.00
8.00
Duration of follow-up in weeks
N
7
7
3
28
7
Mean
225.73
195.33254.90190.88
68.53
Standard deviation
150.96145.11130.33
81.01
63.11
Minimum
7.14
3.14
104.43
34.57
17.29
Maximum
372.43362.00332.29312.14179.43
Median270.14112.14328.00238.0025.14
Duration of treatment in weeks is computed as ([date of last dose - date of first dose + 1]/7).
Duration of follow-up in weeks is computed as ([date of last available subject contact - date of first dose + 1]/7).
N = number of subjects.

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Part 2
Exploratory
Third-Line
500 mgN=110
11 (100 )

Total
N=63

7 (11.1)
56 (88.9)

52
155.73134.72
1.14
372.43137.1411
110.9152.80
13.00
160.14131.4363
147.90125.191.14
372.43131.4352
183.39110.343.14
372.43149.9311
131.0620.33
105.43160.14131.4363
174.26102.393.14
372.43132.00Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

The reasons for discontinuation of treatment and discontinuation of study are summarized inTable 4 and Table 5 respectively. The summary of subject populations is presented inTable 6.
Table 4.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Conclusion
StatusReasonan (%)

Reasons for Conclusion of Treatment Phase: Safety Population
Part 1
Part 1
Part 1
Second- Second- SecondLine
Line
Line
400 mg 500 mg 600 mg
N=7
N=7
N=3

Treatment
Part 2
Part 2
Primary Advanced
Second- SecondLine
Line
500 mg
500 mgN=28
N=728 (100 )
7 (100 )
14 (50.0)014 (50.0)0

Total
SecondLine
N=52

Part 2
Exploratory
Third-Line
500 mg
N=11

Total
N=63

Total
7 (100 ) 7 (100 ) 3 (100 )
52 (100 )
11 (100 )63 (100 )Completed
3 (42.9) 3 (42.9) 2 (66.7)
22 (42.3)
7 (63.6)
29 (46.0)
Other:study
3 (42.9) 3 (42.9) 2 (66.7)
22 (42.3)
7 (63.6)
29 (46.0)
completed
Discontinued
4 (57.1) 4 (57.1) 1 (33.3) 14 (50.0)
7 (100 )
30 (57.7)
4 (36.4)
34 (54.0)
Adverse1 (14.3) 1 (14.3)
0
10 (35.7)
2 (28.6)
14 (26.9)
2 (18.2)
16 (25.4)
event
Death
0
0
0
1 (3.6)0
1 (1.9)0
1 (1.6)
Disease1 (14.3) 1 (14.3)
0
1 (3.6)5 (71.4)
8 (15.4)
1 (9.1)9 (14.3)
progression
Investigator 1 (14.3) 1 (14.3)
0
1 (3.6)0
3 (5.8)1 (9.1)4 (6.3)
requestOther
00
1 (33.3)
1 (3.6)02 (3.8)02 (3.2)
Subject
0
1 (14.3)
000
1 (1.9)0
1 (1.6)
requestSymptomatic 1 (14.3)
0000
1 (1.9)0
1 (1.6)deterioration
N = number of subjects; n = number of subjects meeting criteria.
a. Total discontinued is the sum of individual reasons since they are mutually exclusive by subject.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 5.

Reasons for Conclusion of Participation: All-Treated Population

Conclusion
Status Reasonan (%)

Part 1
Secondline
400 mg
N=7Part 1
Secondline
500 mg
N=7Part 1
Secondline
600 mg
N=3Treatment
Part 2
Part 2
Primary Advanced
Second- Secondline
line
500 mg 500 mg
N=28
N=728 (100 ) 7 (100 )
26 (92.9) 2 (28.6)
26 (92.9) 2 (28.6)

Total
Part 2
Second- Exploratory
line
Third-line
N=52
500 mgN=11090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Total
7 (100 ) 7 (100 ) 3 (100 )
52 (100 )
11 (100 )Completed
6 (85.7) 6 (85.7) 3 (100 )
43 (82.7)
10 (90.9)Study
6 (85.7) 6 (85.7) 3 (100 )
43 (82.7)
10 (90.9)
completed
Discontinued
1 (14.3) 1 (14.3)
02 (7.1)5 (71.4) 9 (17.3)
1 (9.1)Death
000
2 (7.1)5 (71.4) 7 (13.5)
0Investigator
0
0
0
0
0
0
1 (9.1)
requestOther
1 (14.3)00001 (1.9)0Subject
0
1 (14.3)
000
1 (1.9)0
requestN = number of subjects; n = number of subjects meeting criteria.
a. Total discontinued is the sum of individual reasons since they are mutually exclusive by subject.

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Total
N=63

63 (100 )53 (84.1)
53 (84.1)
10 (15.9)
7 (11.1)
1 (1.6)
1 (1.6)
1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 6.

Summary of Subject Population: All Consented Subjects

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Population (N)Enrolled subjects
Subjects treated with bosutinib
Analysis populations
All-treated population
Evaluable population
Cytogenetic assessment
Hematologic assessment
Molecular assessment
Per-protocol population
Cytogenetic assessment
Safety population
N = number of subjects.

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Part 1
Second-Line
400 mgPart 1
Second-Line
500 mgPart 1
Second-Line
600 mg3
3

Part 2
Primary
Second-Line
500 mg28
28

Part 2
Advanced
Second-Line
500 mg
7
7

7
7

7
7

7

7

3

28

7

52

11

63

6
7
4

7
7
7

3
3
2

28
28
28

7
7
7

51
52
48

11
11
11

62
63
59

5
7

6
7

3
3

24
28

7
7

45
52

11
11

56
63

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Total
Part 2
Second-Line Exploratory
Third-Line
500 mg
52
11
52
11

Total

63
63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Of the 63 subjects, 24 (38.1%) subjects were female and 39 (61.9%) subjects were male
(Table 7). The median age was 55 years (range: 20 to 78 years).
All 52 second-line subjects had received prior imatinib therapy. In these subjects, thereasons for discontinuation of prior imatinib therapy were imatinib-intolerant in 32 (61.5%)
subjects and imatinib-resistant/refractory in 20 (38.5%) subjects. In the primary cohort,
24 (85.7%) subjects were imatinib-intolerant and 4 (14.3%) subjects wereimatinib-resistant/refractory.

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In the exploratory cohort of third-line subjects, 9 (81.8%) subjects had received priordasatinib therapy and 2 (18.2 %) subjects had received prior nilotinib therapy. The reasonsfor discontinuation of prior dasatinib/nilotinib therapy were dasatinib/nilotinib intolerant in
8 (72.7%) subjects and dasatinib/nilotinib resistant/refractory in 3 (27.3%) subjects.

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Table 7.

Demographic and Baseline Characteristics: All-Treated Population

Characteristic (n, %)090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Part 1
Second-Line
400 mgPart 1
Second-Line
500 mgPart 1
Second-Line
600 mgTreatment
Part 2
Part 2
Primary
Advanced
Second-Line Second-Line
500 mg
500 mgAge (years)
N
7
7
3
28
Mean
42.14
53.57
51.00
53.86
SD
11.14
18.72
23.81
14.59
Minimum
31.00
20.00
24.00
26.00
Maximum
59.00
73.00
69.00
78.00
Median
41.00
62.00
60.00
56.50
Age category<65 years
7 (100)4 (57.1)
2 (66.7)
20 (71.4)
03(42.9)
1(33.3)
8 (28.6)
65 years
Sex
Female3 (42.9)
2 (28.6)
2 (66.7)
12 (42.9)Male
4 (57.1)
5 (71.4)
1 (33.3)
16 (57.1)
RaceJapanese
7 (100)7 (100)3 (100)28 (100)
N = number of subjects; n = number of subjects meeting criteria; SD = standard deviation.

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Total
Second-Line

Part 2
Exploratory
Third-Line
500 mg

Total

7
66.57
8.10
55.00
78.00
66.00

52
53.79
15.49
20.00
78.00
58.00

11
51.18
11.07
34.00
69.00
49.00

63
53.33
14.77
20.00
78.00
55.00

3 (42.9)
4 (57.1)

36 (69.2)
16 (30.8)9 (81.8)
2 (18.2)

45 (71.4)
18 (28.6)

1 (14.3)
6 (85.7)

20 (38.5)
32 (61.5)

4 (36.4)
7 (63.6)

24 (38.1)
39 (61.9)

7 (100)52 (100)

11 (100)

63 (100)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Efficacy and Pharmacokinetic Results:
At 400 mg and at 500 mg bosutinib, 1 of 6 evaluable subjects each had a DLT (liver injury,
Grade 3, and hepatic function abnormal, Grade 4, respectively). No DLTs were reported
among 3 evaluable subjects at 600 mg bosutinib, and thus, safety of bosutinib up to 600 mg
was confirmed (ie, primary endpoint of Part 1 was met).
Therefore, the starting dose of 500 mg bosutinib for Part 2 was assumed appropriate for theJapanese population under study.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Part 1: The percentage of participants with MCyR up to Week 24 is shown in Table 8. The
cumulative MCyR rate up to Week 24 was 42.9% (95% CI: 9.9%, 81.6%),
57.1% (95% CI: 18.4%, 90.1%), and 33.3% (95% CI: 0.8%, 90.6%) in the subjects treatedwith 400 mg, 500 mg, and 600 mg, respectively. The maintained MCyR rate (numerator
includes subjects without baseline response who were in response at Week 24 and subjects
with baseline complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR)
who had a post-baseline response either maintained or improved at Week 24) in the
all treated population is summarized in Table 9.

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Table 8.

Major Cytogenetic Response Rate up to Week 24: All-Treated Population

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Major Cytogenetic Response
Rate, as:R/E (%)(95% CI)a
Number of subjects with CCyR atBaseline, n (%)bPrimary analysis
Cumulative MCyR up to Week 24
Complete response
Partial response
MCyR at Week 24
Complete response
Partial response
Sensitivity analysis
Cumulative MCyR up to Week 24

Treatment
Part 1
Part 1
Part 1
Part 2
Part 2
Total
Second-Line Second-Line Second-Line
Primary
Advanced Second-Line
400 mg
500 mg
600 mgSecond-Line Second-Line(N=52)
(N=7)
(N=7)
(N=3)
500 mg
500 mg(N=28)
(N=7)
0/7
0/7
1/3 (33.3)
10/28 (35.7)
0/7
11/52 (21.2)

Part 2
Exploratory
Third-Line
500 mg(N=11)
6/11 (54.5)

17/63 (27.0)

3/7 (42.9)(9.9, 81.6)
2/7 (28.6)(3.7, 71.0)
1/7 (14.3)(0.4, 57.9)
3/7 (42.9)(9.9, 81.6)
2/7 (28.6)(3.7, 71.0)
1/7 (14.3)(0.4, 57.9)

2/11 (18.2)(2.3, 51.8)
1/11 (9.1)(0.2, 41.3)
1/11 (9.1)(0.2, 41.3)
2/11 (18.2)(2.3, 51.8)
1/11 (9.1)(0.2, 41.3)
1/11 (9.1)(0.2, 41.3)

23/63 (36.5)(24.7, 49.6)
17/63 (27.0)(16.6, 39.7)
6/63 (9.5)(3.6, 19.6)
20/63 (31.7)(20.6, 44.7)
15/63 (23.8)(14.0, 36.2)
5/63 (7.9)(2.6, 17.6)

4/7 (57.1)(18.4, 90.1)
4/7 (57.1)(18.4, 90.1)
0/7(0.0, 41.0)
3/7 (42.9)(9.9, 81.6)
3/7 (42.9)(9.9, 81.6)
0/7(0.0, 41.0)

1/3 (33.3)(0.8, 90.6)
1/3 (33.3)(0.8, 90.6)
0/3(0.0, 70.8)
1/3 (33.3)(0.8, 90.6)
1/3 (33.3)(0.8, 90.6)
0/3(0.0, 70.8)

10/28 (35.7)(18.6, 55.9)
8/28 (28.6)(13.2, 48.7)
2/28 (7.1)(0.9, 23.5)
10/28 (35.7)(18.6, 55.9)
8/28 (28.6)(13.2, 48.7)
2/28 (7.1)(0.9, 23.5)

3/7 (42.9)(9.9, 81.6)
1/7 (14.3)(0.4, 57.9)
2/7 (28.6)(3.7, 71.0)
1/7 (14.3)(0.4, 57.9)
0/7(0.0, 41.0)
1/7 (14.3)(0.4, 57.9)

21/52 (40.4)(27.0, 54.9)
16/52 (30.8)(18.7, 45.1)
5/52 (9.6)(3.2, 21.0)
18/52 (34.6)(22.0, 49.1)
14/52 (26.9)(15.6, 41.0)
4/52 (7.7)(2.1, 18.5)

Total(N=63)

3/7 (42.9)
4/7 (57.1)
1/2 (50.0)
10/18 (55.6)
3/7 (42.9)
21/41 (51.2)
2/5 (40.0)
23/46 (50.0)(9.9, 81.6)(18.4, 90.1)(1.3, 98.7)(30.8, 78.5)(9.9, 81.6)(35.1, 67.1)(5.3, 85.3)(34.9, 65.1)
Complete response
2/7 (28.6)
4/7 (57.1)
1/2 (50.0)
8/18 (44.4)
1/7 (14.3)
16/41 (39.0)
1/5 (20.0)
17/46 (37.0)(3.7, 71.0)(18.4, 90.1)(1.3, 98.7)(21.5, 69.2)(0.4, 57.9)(24.2, 55.5)(0.5, 71.6)(23.2, 52.5)
Partial response
1/7 (14.3)
0/7
0/2
2/18 (11.1)
2/7 (28.6)
5/41 (12.2)
1/5 (20.0)
6/46 (13.0)(0.4, 57.9)(0.0, 41.0)(0.0, 84.2)(1.4, 34.7)(3.7, 71.0)(4.1, 26.2)(0.5, 71.6)(4.9, 26.3)
MCyR at Week 24
3/7 (42.9)
3/7 (42.9)
1/2 (50.0)
10/18 (55.6)
1/7 (14.3)
18/41 (43.9)
2/5 (40.0)
20/46 (43.5)(9.9, 81.6)(9.9, 81.6)(1.3, 98.7)(30.8, 78.5)(0.4, 57.9)(28.5, 60.3)(5.3, 85.3)(28.9, 58.9)
Complete response
2/7 (28.6)
3/7 (42.9)
1/2 (50.0)
8/18 (44.4)
0/7
14/41 (34.1)
1/5 (20.0)
15/46 (32.6)(3.7, 71.0)(9.9, 81.6)(1.3, 98.7)(21.5, 69.2)(0.0, 41.0)(20.1, 50.6)(0.5, 71.6)(19.5, 48.0)
Partial response
1/7 (14.3)
0/7
0/2
2/18 (11.1)
1/7 (14.3)
4/41 (9.8)
1/5 (20.0)
5/46 (10.9)(0.4, 57.9)(0.0, 41.0)(0.0, 84.2)(1.4, 34.7)(0.4, 57.9)(2.7, 23.1)(0.5, 71.6)(3.6, 23.6)
CCyR = complete cytogenetic response; CI = confidence interval; MCyR = major cytogenetic response (complete + partial); N = number of subjects; n = numberof subjects meeting pre-specified criteria.
a. R - number of responders; E - number of evaluable subjects. Percentages (%) were based on number of evaluable subjects within each treatment group andTemplate version 1.6

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 8.

Major Cytogenetic Response Rate up to Week 24: All-Treated Population

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the corresponding 95% CIs were calculated by the exact method. The best response of post-baseline was selected for each evaluable subject.
b. For primary analysis, subjects with CCyR at Baseline were counted as non-responder and were included in the denominator. For sensitivity analysis, they
were considered as non-evaluable subjects and were excluded from the denominator.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

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Table 9.

Maintained Major Cytogenetic Response Rate: All-Treated Population

Maintained Major Cytogenetic Response Rate,
Treatmentas:Part 1
Part 1
Part 1
Part 2
Part 2
Total
Part 2Total
R/E (%)
Second-Line Second-Line Second-Line Primary
Advanced Second-Line Exploratory (N=63)(95% CI)a
400 mg
500 mg
600 mg Second-Line Second-Line (N=52)
Third-Line
(N=7)
(N=7)
(N=3)
500 mg
500 mg
500 mg(N=28)(N=7)(N=11)
Number of subjects with CCyR at Baseline, n (%)
0/7
0/7
1/3 (33.3) 10/28 (35.7)
0/7
11/52 (21.2) 6/11 (54.5) 17/63 (27.0)
Number of subjects with PCyR at Baseline, n (%)
1/7 (14.3)
3/7 (42.9)
1/3 (33.3) 3/28 (10.7) 1/7 (14.3) 9/52 (17.3) 1/11 (9.1) 10/63 (15.9)
Maintained MCyR at Week 24
3/7 (42.9)
3/7 (42.9)
3/3 (100) 18/28 (64.3) 1/7 (14.3) 28/52 (53.8) 7/11 (63.6) 35/63 (55.6)(9.9, 81.6) (9.9, 81.6) (29.2, 100 ) (44.1, 81.4) (0.4, 57.9) (39.5, 67.8) (30.8, 89.1) (42.5, 68.1)
Complete response
2/7 (28.6)
3/7 (42.9)
2/3 (66.7) 16/28 (57.1)
0/7
23/52 (44.2) 6/11 (54.5) 29/63 (46.0)(3.7, 71.0) (9.9, 81.6) (9.4, 99.2) (37.2, 75.5) (0.0, 41.0) (30.5, 58.7) (23.4, 83.3) (33.4, 59.1)
Partial response
1/7 (14.3)
0/7
1/3 (33.3)
2/28 (7.1)
1/7 (14.3)
5/52 (9.6)
1/11 (9.1) 6/63 (9.5)(0.4, 57.9) (0.0, 41.0) (0.8, 90.6) (0.9, 23.5) (0.4, 57.9) (3.2, 21.0) (0.2, 41.3) (3.6, 19.6)
CCyR = complete cytogenetic response; CI = confidence interval; PCyR = partial cytogenetic response; MCyR = major cytogenetic response(complete + partial);N = number of subjects; n = number of subjects meeting pre-specified criteria.
a. R - number of responders; E - number of evaluable subjects. Percentages (%) were based on number of evaluable subjects within each treatment group andthe corresponding 95% CIs were calculated by the exact method.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Part 2 – Primary Efficacy Endpoint Results: The MCyR results in the evaluable population
were identical to that in the all-treated population as no subjects excluded from the all-treatedpopulation in Part 2. The per-protocol population was also identical to the all-treatedpopulation in the advanced cohort and the exploratory cohort.
In the primary cohort, CCyR was reported in 8 (28.6%) subjects and PCyR was reported in
2 (7.1%) subjects at Week 24. The cumulative MCyR rate up to Week 24 in the all-treatedpopulation was 35.7% (10/28 subjects, 95% CI: 18.6%, 55.9%). The MCyR rate at Week 24
and cumulative MCyR rate through the study were 35.7% and 46.4%, respectively.
Part 2 - Secondary Efficacy Endpoint Results:
Major Cytogenetic Response:In the primary cohort, the time to MCyR in the all-treated population is summarized inTable 10. The median time to MCyR was 12.3 weeks. Note that the first post-baseline
evaluation time point for MCyR was Week 12 in CP subjects.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

The duration of MCyR in the all-treated population is summarized in Table 11. Of the
13 subjects who attained MCyR, 1 subject lost MCyR, therefore, the median duration of
MCyR was not estimable.
The cumulative MCyR rate up to Week 24 in the all-treated population was 18.2%(2/11 subjects, 95% CI: 2.3%, 51.8%) (Table 8).

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 10. Time to Major Cytogenetic Response: All-Treated Population - Responders Only

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Time to MCyR

Number of subjects with MCyR, n (%)
Time to MCyR in weeks (95% CI)
25% quartile

Treatment
Part 1
Part 1
Part 1
Part 2
Part 2
Total
Part 2
Second-Line Second-Line Second-Line
Primary
Advanced Second-Line Exploratory
400 mg
500 mg
600 mgSecond-Line Second-Line(N=52)
Third-Line
(N=7)
(N=7)
(N=3)
500 mg
500 mg
500 mg(N=28)(N=7)(N=11)
4 (57.1)
4 (57.1)
2 (66.7)
13 (46.4)
3 (42.9)26 (50.0)
2 (18.2)

Total(N=63)

28 (44.4)

12.1
7.9
12.1
12.0
4.0
12.0
12.1
12.0
(NE)
(4.3, 12.0)(12.1, 36.4) (11.9, 12.3)(4.0, 12.0) (11.6, 12.1) (12.1, 24.1) (11.6, 12.1)
50% quartile (median)
12.1
11.8
24.3
12.3
5.0
12.1
18.1
12.1
(12.1, 48.3)(4.3, 12.0)(12.1, 36.4)(12.0, 24.1)(4.0, 12.0) (12.0, 12.3) (12.1, 24.1) (12.0, 12.3)
75% quartile
30.2
12.0
36.4
24.1
12.0
24.1
24.1
24.1
(12.1, 48.3) (11.6, 12.0) (12.1, 36.4) (12.3, 36.0)(4.0, 12.0) (12.1, 36.0) (12.1, 24.1) (12.1, 36.0)
CI = confidence interval; MCyR = major cytogenetic response; N = number of subjects; n = number of subjects meeting pre-specified criteria NE = notestimable.

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Table 11. Duration of Major Cytogenetic Response: All-Treated Population - Responders Only

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Duration of MCyR

Number of subjects with MCyR, n (%)
Number of subjects who lost MCyRa
Number of censored subjects
Duration of MCyR in weeks (95% CI)
25% quartile

Treatment
Part 1
Part 1
Part 1
Part 2
Part 2
Total
Part 2
Second-Line Second-Line Second-Line
Primary
Advanced Second-Line Exploratory
400 mg
500 mg
600 mgSecond-Line Second-Line(N=52)
Third-Line
(N=7)
(N=7)
(N=3)
500 mg
500 mg
500 mg(N=28)(N=7)(N=11)
4 (57.1)
4 (57.1)
2 (66.7)
13 (46.4)
3 (42.9)26 (50.0)
2 (18.2)
04 (100 )04 (100 )02 (100 )1 (7.7)
12 (92.3)

NE

NE

NE

NE
( 12.3, NE)NE

2 (66.7)
1 (33.3)

3 (11.5)
23 (88.5)

02 (100 )Total(N=63)

28 (44.4)
3 (10.7)
25 (89.3)

NE
NE
NE
9.1
(9.1, 167.3) (167.3, NE)(167.3, NE)
88.2
50% quartile (median)
NE
NE
NE
NE
NE
NE
(9.1, 167.3)
167.3
75% quartile
NE
NE
NE
NE
NE
NE
NE
(9.1, 167.3)
CI = confidence interval; MCyR = major cytogenetic response; N = number of subjects; n = number of subjects meeting pre-specified criteria NE = not estimable.
a. Percentages (%) were based on number of subjects with MCyR within each treatment group.

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Hematologic Response:
Confirmed complete hematologic response (cCHR) in the all-treated population issummarized in Table 12. In the advanced phase second-line cohort, there were no subjects
who attained cCHR up to Week 24.
The time to cCHR in the all-treated population is summarized in Table 13. The median time
to cCHR was 5.3 weeks in the primary cohort, 84.0 weeks in the advanced cohort, 4.7 weeks
in the total second-line, 2.4 weeks (95% CI: 1.1%, 8.1%) in the third-line CP and 12.4 weeks(95% CI: not estimable [NE]) in the third-line AP/BP.
The duration of cCHR in the all-treated population is summarized in Table 14. Of the
22 subjects with cCHR in the primary cohort, 5 subjects lost cCHR. In the advanced cohort,
1 subject attained cCHR but lost cCHR. Of the 33 subjects with cCHR in the total
second-line, 12 subjects lost cCHR. The median duration of cCHR was not estimable. Of
the 9 subjects with cCHR in the third-line CP, 4 subjects lost cCHR.

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In the exploratory cohort of third-line AP/BP subjects, 1 subject attained cCHR but lost
cCHR. The median duration of cCHR in the third-line CP was NE. The duration of cCHR in
the third-line AP/BP was 36.1 weeks (95%CI: NE).
The major/overall hematologic response results of the third-line AP/BP subject (up to
Week 24) are presented in Table 15.

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Table 12. Complete Hematologic Response Rate: All-Treated Population
Complete Hematologic
Treatment
Response Rate, as:Part 1
Part 1
Part 1
Part 2
Part 2
Total
Part 2
Part 2Total
R/E (%)
Second-Line Second-Line Second-Line
Primary
Advanced
Second-Line Third-Line
Third-Line
N=63(95% CI)a
400 mg
500 mg
600 mgSecond-Line Second-Line(N=52)
CP
AP/BP
(N=7)
(N=7)
(N=3)
500 mg
500 mg
500 mg
500 mg(N=28)(N=7)(N=10)
N=1
Cumulative cCHR
4/7 (57.1)
2/7 (28.6)
2/3 (66.7)
20/28 (71.4)
0/7
28/52 (53.8)
8/10 (80.0)
1/1 (100)
37/63 (58.7)
up to Week 24(18.4, 90.1)(3.7, 71.0)(9.4, 99.2)(51.3, 86.8)(0.0, 41.0)(39.5, 67.8)(44.4, 97.5)(2.5, 100)(45.6, 71.0)
cCHR at Week 24
3/7 (42.9)
2/7 (28.6)
2/3 (66.7)
16/28 (57.1)
0/7
23/52 (44.2)
7/10 (70.0)
1/1 (100)
31/63 (49.2)(9.9, 81.6)(3.7, 71.0)(9.4, 99.2)(37.2, 75.5)(0.0, 41.0)(30.5, 58.7)(34.8, 93.3)(2.5, 100)
(36.4, 62.1)
Subjects who had a CHR at Baseline were included in the denominator, and if the CHR was subsequently confirmed at post-baseline, the subject was counted as
responder and contribute to the numerator.
AP = accelerated phase; BP = blast phase; CP = chronic phase; cCHR = confirmed complete hematologic response; CI = confidence interval; CP = chronic
phase; N = number of subjects.
a. R - number of responders; E - number of evaluable subjects. Percentages (%) were based on number of evaluable subjects within each treatment group andthe corresponding 95% CIs were calculated by the exact method.

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Table 13. Time to Complete Hematologic Response : All-Treated Population - Responders Only

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Time to Complete
Hematologic Response

Number of subjects with
cCHR, n (%)

Treatment
Part 1
Part 1
Part 1
Part 2
Part 2
Total
Part 2
Second-Line Second-Line Second-Line
Primary
Advanced Second-Line Third-Line
400 mg
500 mg
600 mgSecond-Line Second-Line(N=52)
CP
(N=7)
(N=7)
(N=3)
500 mg
500 mg
500 mg(N=28)(N=7)(N=10)
4 (57.1)
3 (42.9)
3 (100 )
22 (78.6)
1 (14.3)
33 (63.5)
9 (90.0)

Part 2
Third-Line
AP/BP
500 mg(N=1)
1 (100)

Total
N=63

43
(68.3)

Time to cCHR in weeks (95% CI)
25% quartile
1.1
1.1
1.1
1.1
84.0
1.1
1.1
12.4
1.1
(1.0, 2.1)
(1.1, 43.1)(1.1, 66.1)(1.0, 4.9)
(NE)
(1.1, 2.1)
(1.0, 8.1)
(NE)
(1.1, 2.1)
50% quartile (median)
1.6
11.6
1.1
5.3
84.0
4.7
2.4
12.4
4.7
(1.0, 4.4)
(1.1, 43.1)(1.1, 66.1)(2.0, 11.9)(NE)(2.0, 8.0)
(1.1, 8.1)(NE)
(2.0, 8.1)
75% quartile
3.3
43.1
66.1
12.1
84.0
12.1
8.1
12.4
12.1
(1.1, 4.4)
(1.1, 43.1)(1.1, 66.1)(5.7, 16.0)(NE)(6.1, 35.9)(2.1, 84.1)(NE)(7.9, 23.9)
AP = accelerated phase; BP = blast phase; cCHR = confirmed complete hematologic response; CI = confidence interval; CP = chronic phase; N = number ofsubjects; n = number of subjects meeting pre-specified criteria; NE = not estimable.

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Table 14. Duration of Complete Hematologic Response: All-Treated Population - Responders Only

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Duration of Complete Hematologic
Response

Number of subjects with cCHR, n(%)
a
Number of subjects who lost cCHR
Number of censored subjects
Duration of cCHR in weeks (95% CI)
25% quartile

Treatment
Part 1
Part 1
Part 1
Part 2
Part 2
Total
Part 2
Part 2
Total
Second-Line Second-Line Second-Line Primary
Advanced Second-Line Third-Line Third-Line N=63
400 mg
500 mg
600 mg Second-Line Second-Line (N=52)
CP
AP/BP
(N=7)
(N=7)
(N=3)
500 mg
500 mg
500 mg
500 mg(N=28)(N=7)(N=10)(N=10)
4 (57.1)
3 (42.9)
3 (100 )
22 (78.6)
1 (14.3)
33 (63.5)
9 (90.0)
1 (100)43 (68.3)
2 (50.0)
2 (50.0)

2 (66.7)
1 (33.3)

2 (66.7)
1 (33.3)

5 (22.7)
17 (77.3)

1 (100.0)012 (36.4)
21 (63.6)

4 (44.4)
5 (55.6)

1 (100)017 (39.5)
26 (60.5)

57.0(19.9, NE)

8.1(8.1, NE)

55.1
(55.1, NE)

107.1(52.1, NE)

95.3
(NE)

94.1
(52.1, NE)

28.1(11.4, NE)

36.1
(NE)

55.1
(28.1,
100.9)
NE(96.1, NE)NE

50% quartile (median)

NE
100.9
59.1
NE
95.3
NE
NE
36.1
(19.9, NE)(8.1, NE)
(55.1, NE)(NE)(96.1, NE) (28.1, NE)(NE)
75% quartile
NE
NE
NE
NE
95.3
NE
NE
36.1
(94.1, NE)(8.1, NE)
(55.1, NE)(NE)
36.6, NE)(NE)
AP = accelerated phase; BP = blast phase; cCHR = confirmed complete hematologic response; CI = confidence interval; CP = chronic phase; N = number ofsubjects; n = number of subjects meeting pre-specified criteria ; NE = not estimable.
a.
Percentages (%) were based on number of subjects with CHR within each treatment group.

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Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 15. Major/Overall Hematologic Response Rate: All-treated
Population - Accelerated/Blast Phase CML Subjects Only
Treatment
Part 2 Third-line AP/BP
500 mg (N=1)
Cumulative cMHR up to Week 24
1/1 (100 )(2.5, 100)cMHR at Week 24
1/1 (100 )(2.5, 100)
Cumulative cOHR up to Week 24
1/1 (100 )(2.5, 100)cOHR at Week 24
1/1 (100 )(2.5, 100)
Confirmed MHR/OHR rate. Subjects who had a MHR/OHR at Baseline were included in the denominator, andif the MHR/OHR was subsequently confirmed at post-baseline, the subject was counted as responder andcontribute to the numerator.
AP = accelerated phase; BP = blast phase; cMHR = confirmed major hematologic response; cOHR = confirmed
overall hematologic response CI = confidence interval; MHR = major hematologic response; N = number ofsubjects; OHR = overall hematologic response.
a. R - number of responders; E - number of evaluable subjects. Percentages (%) were based on number of
evaluable subjects within each treatment group and the corresponding 95% CIs were calculated by the exact
method.

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Major/Overall Hematologic Response Rate,
R/E (%) (95% CI)aTime to Treatment Failure: The TTF was assessed as the secondary endpoint in all 3 cohorts
and results are presented in Table 16.
In the primary cohort, treatment failure was reported in 14 (50%) subjects. The estimatedprobability of no treatment failure was 57.1% at Week 144. The median TTF was
253.9 weeks. In the advanced cohort, treatment failure was reported in 7 (100%) subjects.
The estimated probability of no treatment failure was 14.3% at Week 144. The median TTF
was 10.0 weeks.
In the total second-line, treatment failure was reported in 30 (57.7%) subjects. The median
TTF was 139.7 weeks (95%CI: 39.7, NE). The estimated probability of no treatment failure
was 50.0% at Week 144. In the exploratory third-line cohort, treatment failure was reported
in 4 (36.4%) subjects. The estimated probability of no treatment failure was 63.6% at
Week 144 (approximately 3 years).

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Table 16. Time to Treatment Failure: All-Treated Population

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TTF

Number of subjects withtreatment failure, n (%)
Number of censored subjects,n (%)
TTF in weeks (95% CI)
25% quartile

Part 1
Second-Line
400 mg(N=7)

Part 1
Second-Line
500 mg(N=7)

Part 1
Second-Line
600 mg(N=3)

4 (57.1)

4 (57.1)

1 (33.3)

3 (42.9)

3 (42.9)

2 (66.7)

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mg(N=28)(N=7)
14 (50.0)
7 (100 )
14 (50.0)0

Total
Second-Line(N=52)
30 (57.7)

Part 2
Exploratory
Third-Line
500 mg(N=11)
4 (36.4)

Total(N=63)

34 (54.0)

22 (42.3)

7 (63.6)

29 (46.0)

3.3
3.3
103.1
29.9
2.6
19.1
77.4
22.0
(2.1, NE)
(3.0, NE)(103.1, NE)(16.1, 166.6)(1.1, 13.0)(4.6, 39.7)(14.1, NE)(10.0,76.0)
50% quartile (median)
270.1
88.1
NE
253.9
10.0
139.7
NE
179.1
(3.3, NE)
(3.3, NE)(103.1, NE)(76.0, NE)(2.6, 22.3)(39.7, NE)(77.4, NE)(76.0, NE)
75% quartile
NE
NE
NE
NE
22.3
NE
NE
NE
(68.3, NE)(34.6, NE)(103.1, NE)(253.9, NE)(4.6, 179.1)
TTF ratea at Week 48, %
71.4
57.1
100
67.9
14.3
61.5
81.8
65.1
(38.0, 100)
(20.5, 93.8)(100, 100)
(50.6, 85.2)(0.0, 40.2)(48.3, 74.8)(59.0, 100)
(53.3, 76.9)
TTF ratea at Week 96, %
57.1
42.9
100
60.7
14.3
53.8
72.7
57.1
(20.5, 93.8)(6.2, 79.5)(100, 100)(42.6, 78.8)(0.0, 40.2)(40.3, 67.4)(46.4, 99.0) (44.9, 69.4)
TTF rate at Week 144, %
57.1
42.9
66.7
57.1
14.3
50.0
63.6
52.4
(20.5, 93.8)(6.2, 79.5)(13.3, 100)
(38.8, 75.5)(0.0, 40.2)(36.4, 63.6)(35.2, 92.1) (40.0, 64.7)
TTF rate at Week 192, %
57.1
42.9
66.7
53.6
NE
46.2
NE
48.4
(20.5, 93.8)(6.2, 79.5)(13.3, 100)(35.1, 72.0)(32.6, 59.7)(35.8, 60.9)
TTF rate at Week 240, %
57.1
42.9
66.7
53.6
NE
46.2
NE
48.4
(20.5, 93.8)(6.2, 79.5)(13.3, 100)(35.1, 72.0)(32.6, 59.7)(35.8, 60.9)
TTF rate at Week 288, %
42.9
42.9
66.7
45.9
NE
39.9
NE
41.8
(6.2, 79.5)(6.2, 79.5)(13.3, 100)(24.9, 67.0)(25.7, 54.2)(28.1, 55.6)
TTF rate at Week 336, %
42.9
42.9
NE
NE
NE
39.9
NE
41.8
(6.2, 79.5)(6.2, 79.5)(25.7, 54.2)(28.1, 55.6)
CI = confidence interval; N = number of subjects; n = number of subjects meeting pre-specified criteria; NE = not estimable; TTF = time to treatment failure.
a. TTF rate indicates the probability of no treatment failure.

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Progression Free Survival: The PFS was assessed as a secondary endpoint in all cohorts.
The PFS in the all-treated population is summarized in Table 17.
In the primary cohort, disease progression or death was reported in 1 (3.6%) subject. The
estimated PFS rate was 94.4% at Week 144. The median time to PFS was NE. In theadvanced cohort, disease progression or death was reported in 6 (85.7%) subjects. The
estimated PFS rate was 21.4% at Week 144. The median time to PFS was 13.0 weeks.
In the total second-line, PFS events were reported in 9 (17.3%) subjects. The estimated PFS
rate was 81.8% (95% CI: 70.1%, 93.5%) at Week 144. The median PFS was NE.

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In the exploratory cohort of third-line, PFS events were reported in 1 subject (9.1%). The
estimated PFS rate was 88.9% (95% CI: 68.4%, 100%) at Week 144. The median PFS wasNE.

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Table 17. Progression-Free Survival: All-Treated Population

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PFS

Number of subjects with
progression or who died, n(%)
Number of censored subjects,n (%)
PFS in weeks (95% CI)
25% quartile
50% quartile (median)
75% quartile

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mg(N=28)(N=7)
1 (3.6)6 (85.7)

Part 1
Second-Line
400 mg(N=7)

Part 1
Second-Line
500 mg(N=7)

Part 1
Second-Line
600 mg(N=3)

1 (14.3)

1 (14.3)

06 (85.7)

6 (85.7)

3 (100 )27 (96.4)

NE(2.1, NE)NENE
(88.1, NE)NE(88.1, NE)
NE

NE

NE

NE

NE

NE

NE

NE

PFS rate at Week 48, %Total
Second-Line(N=52)
9 (17.3)

Part 2
Exploratory
Third-Line
500 mg(N=11)
1 (9.1)

Total(N=63)

10 (15.9)

1 (14.3)

43 (82.7)

10 (90.9)

53 (84.1)

2.6(1.1, 24.0)
13.0(2.6, 179.1)
24.0(4.6, 179.1)
21.4(0.0, 56.3)
21.4(0.0, 56.3)
21.4(0.0, 56.3)
NENE(88.1, NE)NENE( 77.4, NE)NENE( 95.1, NE)
NE

NE

NE

NE

85.7
100
100
100
87.6
100
89.8
(59.8, 100)
(100, 100)
(100, 100)
(100, 100)
(78.3, 96.9)(100, 100)(82.0, 97.6)
PFS rate at Week 96, %
85.7
75.0
100
94.4
81.8
88.9
82.9
(59.8, 100)(32.6, 100)
(100, 100)
(83.9, 100)
(70.1, 93.5)(68.4, 100)(72.6, 93.3)
PFS rate at Week 144, %
85.7
75.0
100
94.4
81.8
88.9
82.9
(59.8, 100)(32.6, 100)
(100, 100)
(83.9, 100)
(70.1, 93.5)(68.4, 100)(72.6, 93.3)
PFS rate at Week 192, %
85.7
75.0
100
94.4
78.5
NE
79.6
(59.8, 100)(32.6, 100)
(100, 100)
(83.9, 100)(65.6, 91.4)(67.8, 91.4)
PFS rate at Week 240, %
85.7
75.0
100
94.4
NE
78.5
NE
79.6
(59.8, 100)(32.6, 100)
(100, 100)
(83.9, 100)(65.6, 91.4)(67.8, 91.4)
PFS rate at Week 288, %
85.7
75.0
100
94.4
NE
78.5
NE
79.6
(59.8, 100)(32.6, 100)
(100, 100)
(83.9, 100)(65.6, 91.4)(67.8, 91.4)
PFS rate at Week 336, %
85.7
75.0
NE
NE
NE
78.5
NE
79.6
(59.8, 100)(32.6, 100)(65.6, 91.4)(67.8, 91.4)
The determination of disease progression was based on the Investigator's assessment.
CI = confidence interval; N = number of subjects; n = number of subjects meeting pre-specified criteria; NE = not estimable; PFS = progression free survival.

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Overall Survival: OS was assessed as a secondary endpoint in all cohorts. The OS in the
all-treated population is summarized in Table 18. In the primary cohort, death was reported
in 2 (7.1%) subject. The estimated OS rate was 96.4% at Week 144. In the advanced cohort,death was reported in 5 (71.4%) subjects. The estimated OS rate was 28.6% at Week 144. In
the total second-line, death was reported in 7 (13.5%) subjects. The estimated OS rate was
87.6% (95% CI: 78.3%, 96.9%) at Week 144.

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There was no death in the exploratory cohort of third-line subjects. The estimated OS rate at
Week 144 was 100%.

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Table 18. Overall Survival: All-Treated Population

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OS

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mg(N=28)(N=7)
2 (7.1)5 (71.4)
26 (92.9)
2 (28.6)

Part 1
Second-Line
400 mg(N=7)

Part 1
Second-Line
500 mg(N=7)

Part 1
Second-Line
600 mg(N=3)

Number of deaths, n (%)
Number of censoredsubjects, n (%)
OS in weeks (95% CI)
25% quartile0
7 (100 )07 (100 )03 (100 )

NE

NE

NE

NE
(253.9, NE)

21.4(17.3, 106.0)

NE(253.9, NE)NE

50% quartile (Median)

NE

NE

NE

NE

NE

NE

75% quartile

NE

NE

NE

NE

25.1
(21.4, NE)NE(23.7, NE)
42.9(6.2, 79.5)
42.9(6.2, 79.5)
28.6(0.0, 62.0)
NENE(253.9,
NE)
NE

NE

NE

NE

OS rate at Week 48, %Total
Second-Line(N=52)
7 (13.5)
45 (86.5)

Part 2
Exploratory
Third-Line
500 mg(N=11)0
11 (100 )

100
100
100
96.4
90.0
100
(100, 100)
(100, 100)
(100, 100)
(89.6, 100)
(81.7, 98.3)(100, 100)
OS rate at Week 96, %
100
100
100
96.4
90.0
100
(100, 100)
(100, 100)
(100, 100)
(89.6, 100)
(81.7, 98.3)(100, 100)
OS rate at Week 144, %
100
100
100
96.4
87.6
100
(100, 100)
(100, 100)
(100, 100)
(89.6, 100)
(78.3, 96.9)(100, 100)
OS rate at Week 192, %
100
100
100
96.4
87.6
NE
(100, 100)
(100, 100)
(100, 100)
(89.6, 100)
(78.3, 96.9)
OS rate at Week 240, %
100
100
100
96.4
NE
87.6
NE
(100, 100)
(100, 100)
(100, 100)
(89.6, 100)
(78.3, 96.9)
OS rate at Week 288, %
100
100
100
82.7
NE
82.2
NE
(100, 100)
(100, 100)
(100, 100)(57.0, 100)
(68.6, 95.7)
OS rate at Week 336, %
100
100
NE
NE
NE
82.2
NE
(100, 100)
(100, 100)
(68.6, 95.7)
CI = confidence interval; N = number of subjects; n = number of subjects meeting pre-specified criteria; NE = not estimable; OS = overall survival.

Template version 1.6

Page 34

Total(N=63)

7 (11.1)
56 (88.9)

91.8(84.9, 98.7)
91.8(84.9, 98.7)
89.9(82.2, 97.6)
89.9(82.2, 97.6)
89.9(82.2, 97.6)
84.3(71.4, 97.1)
84.3(71.4, 97.1)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Part 1 - Primary Pharmacokinetics Endpoints Results: PK analysis (Part 1) was conducted asof the interim data release on 13 July 2011. Plasma samples were available fornon-compartmental analysis from 17 subjects receiving oral bosutinib doses of 400 mg,
500 mg, and 600 mg from Part 1. The plasma concentrations from 1 subject on Day 8 and1 subject on Day 15 were excluded from the summary of concentrations and the plasma
concentrations from 5 subjects on Day 15 were not obtained due to temporarily dose
discontinuations. These subjects were excluded from PK analysis. Individual and mean
plasma concentrations time of bosutinib after single ascending oral doses of bosutinib,
once-daily ascending oral doses of bosutinib on Day 8, or once-daily ascending oral doses ofbosutinib on Day 15.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

The PK analyses indicated that after single or multiple doses of 400 mg, 500 mg, or 600 mg
of bosutinib, absorption was relatively slow, with a median Tmax of approximately 4 hours.
PK results for bosutinib are summarized after single oral doses of 400 mg, 500 mg, and
600 mg on Day 1 in Table 19 and for bosutinib 400 mg, 500 mg, and 600 mg after once-daily
dosing on Day 15 are presented in Table 20. On Day 1, following single doses of bosutinib
400 mg, 500 mg, and 600 mg, the mean Cmax of bosutinib were 131 ng/mL (CV =23%),
128 ng/mL (CV =18%), and 155 ng/mL (CV =29%), respectively. The corresponding steadystate mean Cmax on Day 15 were 129 ng/mL (CV =19%), 226 ng/mL (CV =22%), and
214 ng/mL (CV was not calculated) for the 400 mg, 500 mg, and 600 mg, respectively. Aftera single oral dose of bosutinib on Day 1, mean AUC were 2474 ng•h/mL (CV =20%),2720 ng•h/mL (CV =21%) and 2760 ng•h/mL (CV =23%) after the 400 mg, 500 mg, and
600 mg, respectively. The corresponding steady state mean AUC (AUCss) were2235 ng•h/mL (CV =10%), 3690 ng•h/mL (CV =26%), and 3371 ng•h/mL (CV was not
calculated), respectively. Multiple dose exposure was 1.67 to 2.46-fold higher than single
dose exposure (mean accumulation ratio, R = AUCss on Day 15/area under theconcentration-time curve from 0 to 24 hours [AUC24] on Day 1) at doses of 400 mg, 500 mg,
and 600 mg.
Vz/F was large with mean values ranged from 4035 L to 5707 L, and the CV was 16% to38%. CL/F ranged from 167 L/h to 224 L/h (CV =20% to 21%). Mean t½ after a single doseon Day 1 was 17 hours. These values should be taken with caution because the blood
samples were collected for 48 hours and t½, Vz/F and CL/F results are likely to change if
assessed for blood samples collected over a longer period.
After a single dose and multiple oral daily doses, bosutinib exposure generally increased withincreasing dose. However, Cmax and AUC at the 500 mg, and 600 mg doses were not well
separated. This was likely due to high variability and small number of subjects.

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Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 19. Pharmacokinetic Parameters of Bosutinib After Once - Daily Ascending
Oral Doses of Bosutinib to Subjects With Leukemia on Day 1
Parameters(Mean  SD)
N

Bosutinib 400 mg

Bosutinib 500 mg

Bosutinib 600 mg

7
73
13129.7
12823.1
15544.4
Tmax (h)a4.00 (3.97-7.90)
3.95 (3.00-5.98)
3.98 (3.97-4.03)
t½ (h)
16.822.37
16.902.47
17.273.64
AUC24 (ng•h/mL)
1503309.7
1617262.0
1692563.7
AUCt (ng•h/mL)
2091406.1
2283429.9
2347651.7
AUC (ng•h/mL)
2474482.7
2720560.4
2760625.9
CL/F (L/h)
16734.6
19037.8
22445.7
Vz/F (L)4035879.8
4570713.8
57072187
AUC24 = area under the concentration-time curve from 0 to 24 hours; AUCt = area under the concentration-time
curve to the last observable concentration at time t; AUC = area under the concentration-time curve from 0 to
infinite time; CL/F = apparent oral dose clearance; Cmax= maximum concentration; N = total population;
SD = standard deviation; Tmax = time of maximum concentration; t½ = terminal elimination half-life;
Vz/F = apparent volume of distribution.
a. Median (minimum - maximum).

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Cmax (ng/mL)

Table 20. Pharmacokinetic Parameters of Bosutinib After Once - Daily Ascending
Oral Doses of Bosutinib to Subjects With Leukemia on Day 15
Parameters(Mean  SD)
N

Bosutinib 400 mg

Bosutinib 500 mg

Bosutinib 600 mg

5
4
2
214
12924.4
22649.5
Tmax (h)a4.03 (3.92 - 8.00)
3.95 (3.93 - 7.98)
4.00 (3.98 - 4.02)
AUCss (ng•h/mL)
3371
2235220.1
3690962.1
CLss/F (L/h)
17918017.4
14441.8
R
2.46
1.670.369
2.160.556
AUC24 = area under the concentration time curve from 0 to 24 hours; AUCss = area under theconcentration-time curve within the dosage interval at steady state; CLss/F = apparent oral dose clearance at
steady state; Cmax= maximum concentration; R = accumulation ratio (AUCss on Day 15/AUC24 on Day 1);
SD = standard deviation; Tmax = time of maximum concentration.
a. Median (minimum - maximum).
Cmax (ng/mL)

Safety Results:
Part 1 – Primary Endpoint Results:
Dose-Limiting Toxicity: The occurrence of DLT was assessed during the first 28 days oftreatment. Subjects had to take at least 18 of 27 planned doses (66%, omitting a dose on
Day 2) to be evaluable.
In Part 1, 1 of 6 evaluable subjects had a DLT (liver injury, Grade 3) at 400 mg, and 1 of 6
evaluable subjects had a DLT (hepatic function abnormal, Grade 4) at 500 mg both wereconsidered related to study treatment. No DLTs were reported among 3 evaluable subjects at
600 mg. Thus, safety of bosutinib up to 600 mg was confirmed and bosutinib 500 mg as thestarting dose for part 2 of a previous open-label, continuous daily dosing, two-part safety andTemplate version 1.6

Page 36

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Finalefficacy study (A Phase 1/2 Study of SKI-606 in Philadelphia Chromosome Positive
Leukemias [NCT00261846]) was assumed to be appropriate in Japanese subjects as thestarting dose for Part 2.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Serious Adverse Events: Table 21 provides the incidence of all-causality serious adverse
events (SAEs) by system organ class and preferred term. SAEs were reported in 21 (33.3%)
subjects in total; 19 (36.5%) subjects in the total second-line subjects and 2 (18.2%) subjects
in the third-line subjects. The treatment-related SAEs were reported in 14 (26.9%) subjects inthe total second-line subjects as presented in Table 22. No drug related SAEs were reported
in the third-line subjects.

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Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 21. Number (%) of Subjects Reporting Serious Adverse Events : Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Any adverse event
Blood and lymphatic systemdisorders
Thrombocytopenia
Cardiac disorders
Acute myocardial infarction
Eye disorders
Cataract
Macular fibrosis
Macular hole
Gastrointestinal disorders
Diarrhoea
Vomiting
General disorders andadministration site conditions
Fatigue
Hepatobiliary disorders
Hepatic function abnormal
Liver injury
Infections and infestations
Diverticulitis
Enterocolitis infectious
Gastroenteritis
Pertussis
Pneumonia pneumococcal
Urinary tract infection
Injury, poisoning and procedural
complications
Spinal compression fracture

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=710 (35.7)
3 (42.9)

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=32 (28.6)

3 (42.9)

1 (33.3)

0

0

0

0

1 (14.3)

1 (1.9)0

1 (1.6)

0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0

0
0
0
2 (7.1)1 (3.6)
1 (3.6)
1 (3.6)
1 (3.6)
1 (3.6)
1 (3.6)

1 (14.3)
0
0
0
0
0
0
0
0
0

1 (1.9)00
2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)0
1 (9.1)1 (9.1)1 (9.1)1 (9.1)00
000

1 (1.6)
1 (1.6)
1 (1.6)3 (4.8)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)000

1 (3.6)0

1 (1.9)0

1 (1.6)0
1 (14.3)
0
1 (14.3)
1 (14.3)000001 (14.3)

0
1 (14.3)
1 (14.3)
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0

1 (3.6)000
4 (14.3)
1 (3.6)
1 (3.6)
1 (3.6)
1 (3.6)
1 (3.6)
0

0
0
0
0
0
0
0
0
0
0
0

1 (1.9)2 (3.8)1 (1.9)1 (1.9)5 (9.6)
1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)00001 (9.1)00
1 (9.1)000

1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)6 (9.5)
1 (1.6)
1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)00

1 (33.3)

00

1 (1.9)0

1 (1.6)00

1 (33.3)

00

1 (1.9)0

1 (1.6)

Page 38

Total
Part 2
Second-line Exploratory
N=52
Third-line
500 mgN=11
19 (36.5)
2 (18.2)

Total
N=63

21 (33.3)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 21. Number (%) of Subjects Reporting Serious Adverse Events : Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Musculoskeletal and connective
tissue disorders
Osteonecrosis
Neoplasms benign, malignant
and unspecified (including cysts
and polyps)
Bladder cancer
Bladder neoplasm
Blast cell crisis
Nervous system disorders
Cerebral haemorrhage
Posterior reversible
encephalopathy syndrome
Psychiatric disorders
Completed suicide
Renal and urinary disorders
Renal impairment
Respiratory, thoracic andmediastinal disorders
Alveolitis allergic
Dyspnoea
Pleural effusion
Pleurisy
Skin and subcutaneous tissue
disorders
Drug eruption
Rash

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=71 (3.6)0Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mg
N=3

0

0

0

0

0

0

1 (3.6)0

1 (1.9)0

1 (1.6)000

1 (3.6)

1 (14.3)2 (3.8)02 (3.2)

0
0
0
0
0

0
0
0
0
0

0
0
0
0
0

1 (3.6)
1 (3.6)02 (7.1)1 (3.6)00
1 (14.3)
00

1 (1.9)1 (1.9)1 (1.9)2 (3.8)1 (1.9)00
0
00

1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)
1 (1.6)000

1 (3.6)0

1 (1.9)0

1 (1.6)

0
0
0
0

0
0
0
0

0
0
0
0

0
0
1 (3.6)
1 (3.6)

1 (14.3)
1 (14.3)
00

1 (1.9)1 (1.9)1 (1.9)1 (1.9)0000

1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)0

2 (28.6)

02 (7.1)1 (14.3)

5 (9.6)0

5 (7.9)00001 (14.3)
0
1 (14.3)
0

0
0
0
0

0
1 (3.6)0
1 (3.6)00
1 (14.3)0

1 (1.9)1 (1.9)2 (3.8)1 (1.9)0000

1 (1.6)
1 (1.6)2 (3.2)
1 (1.6)000

2 (7.1)0

2 (3.8)02 (3.2)

0
0

0
0

0
0

1 (3.6)
1 (3.6)00

1 (1.9)1 (1.9)00

1 (1.6)
1 (1.6)

Page 39

Total
Part 2
Second-line Exploratory
N=52
Third-line
500 mgN=11
1 (1.9)
0

Total
N=63

1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 21. Number (%) of Subjects Reporting Serious Adverse Events : Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Treatment
Part 2
Part 2
Total
Part 2
Total
Primary
Advanced
Second-line Exploratory
N=63
Second-line
Second-line
N=52
Third-line
500 mg
500 mg
500 mg
N=28
N=7
N=11
Classifications of serious adverse events are based on the Medical Dictionary for Regulatory Activities.
N = number of subjects.
a. Totals for the number of subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may have reported 2 different
adverse events within the higher level category.

Template version 1.6

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mg
N=3Page 40

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 22. Number (%) of Subjects Reporting Drug Related Serious Adverse Events : Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Any adverse event
Blood and lymphatic systemdisorders
Thrombocytopenia
Gastrointestinal disorders
Diarrhoea
Vomiting
General disorders andadministration site conditions
Fatigue
Hepatobiliary disorders
Hepatic function abnormal
Liver injury
Infections and infestations
Pertussis
Musculoskeletal and connective
tissue disorders
Osteonecrosis
Neoplasms benign, malignant
and unspecified (including cysts
and polyps)
Bladder cancer
Bladder neoplasm
Nervous system disorders
Cerebral haemorrhage
Posterior reversible
encephalopathy syndrome
Renal and urinary disorders
Renal impairment

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line Second-line
500 mg
500 mgN=28
N=78 (28.6)
2 (28.6)
0
1 (14.3)

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=3

1 (14.3)03 (42.9)
0

0
0

0
0
0
0
0

0
0
0
0
0

0
0
0
0
0

0
1 (3.6)
1 (3.6)
1 (3.6)
1 (3.6)0
1 (14.3)
0
1 (14.3)
00001 (14.3)
1 (14.3)
0
0
0
0

0
0
0
0
0
0
0

0
0

0
0

0
0
0
0
0
0
0

14 (26.9)
1 (1.9)Part 2
Exploratory
Third-line
500 mgN=1100

14 (22.2)
1 (1.6)

1 (14.3)00001 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)00
0
00

1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)

1 (3.6)000
1 (3.6)
1 (3.6)
1 (3.6)

0
0
0
0
0
0
0

1 (1.9)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)

0
0
0
0
0
0
0

1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)00

1 (3.6)
1 (3.6)00

1 (1.9)1 (1.9)00

1 (1.6)
1 (1.6)

0
0
0
0
0

0
0
0
0
0

1 (3.6)
1 (3.6)2 (7.1)1 (3.6)
1 (3.6)00
0
00

1 (1.9)1 (1.9)2 (3.8)1 (1.9)1 (1.9)00
0
00

1 (1.6)
1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)00

00

1 (3.6)
1 (3.6)00

1 (1.9)1 (1.9)00

1 (1.6)
1 (1.6)

Page 41

Total
Second-line
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 22. Number (%) of Subjects Reporting Drug Related Serious Adverse Events : Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mg
N=3Treatment
Part 2
Part 2
Primary
Advanced
Second-line Second-line
500 mg
500 mgN=28
N=70
1 (14.3)

Total
Second-line
N=52

Part 2
Exploratory
Third-line
500 mg
N=11
0

Total
N=63

Respiratory, thoracic and0
2 (28.6)03 (5.8)3 (4.8)
mediastinal disorders
Alveolitis allergic0
1 (14.3)
000
1 (1.9)0
1 (1.6)
Pleural effusion0
1 (14.3)
00
1 (14.3)2 (3.8)02 (3.2)Skin and subcutaneous tissue
000
2 (7.1)0
2 (3.8)02 (3.2)
disorders
Drug eruption000
1 (3.6)0
1 (1.9)0
1 (1.6)Rash
000
1 (3.6)0
1 (1.9)0
1 (1.6)Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities.
N = number of subjects.
a. Totals for the number of subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may have reported 2 different
adverse events within the higher level category.

Template version 1.6

Page 42

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Adverse Events: Table 23 and Table 24 provide the incidence of all-causality andtreatment-related, treatment-emergent AEs by system organ class and preferred term in 5%subjects in any of the cohorts.

Template version 1.6

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Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Any adverse event
Blood and lymphatic systemdisordersAnaemia
Eosinophilia
Iron deficiency anaemia
Leukopenia
Lymphopenia
Neutropenia
Thrombocytopenia
Cardiac disorders
Acute myocardial infarction
Pericardial effusion
Ventricular extrasystoles
Congenital, familial and genetic
disorders
Hydrocele
Ear and labyrinth disorders
Deafness
VertigoEye disorders
Cataract
Conjunctival haemorrhage
Conjunctival hyperaemia
Conjunctivitis allergic
Dry eyeOcular hyperaemia
Papilloedema
Vision blurredTemplate version 1.6

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=3

7 (100)4 (57.1)

7 (100)4 (57.1)

3 (100)2 (66.7)

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=728 (100)
7 (100)17 (60.7)
4 (57.1)

1 (14.3)
00
1 (14.3)
2 (28.6)
2 (28.6)
2 (28.6)000001 (14.3)002 (28.6)
2 (28.6)
2 (28.6)
3 (42.9)
2 (28.6)
0
1 (14.3)
1 (14.3)
1 (14.3)00002 (66.7)
1 (33.3)
1 (33.3)00000

7 (25.0)
3 (10.7)
3 (10.7)
5 (17.9)
11 (39.3)
4 (14.3)
8 (28.6)
4 (14.3)03 (10.7)0002 (28.6)
02 (28.6)
2 (28.6)
00
1 (14.3)
0
1 (14.3)
0001 (14.3)0002 (28.6)
1 (14.3)
1 (14.3)
0001 (14.3)
0
1 (14.3)

0
0
0
0
0
0
0
0
0
0
0
0
0

0
2 (7.1)00
10 (35.7)
2 (7.1)1 (3.6)02 (7.1)1 (3.6)0
0
0

Page 44

Total
Second-line
N=52
52 (100)
31 (59.6)

Part 2
Exploratory
Third-line
500 mgN=11
11 (100)
6 (54.5)

Total
N=63

63 (100)
37 (58.7)

4 (57.1)
00
3 (42.9)
2 (28.6)
3 (42.9)
3 (42.9)0000013 (25.0)
3 (5.8)3 (5.8)11 (21.2)
19 (36.5)
12 (23.1)
17 (32.7)
6 (11.5)
04 (7.7)
1 (1.9)1 (1.9)0
1 (9.1)0
2 (18.2)
5 (45.5)
2 (18.2)
2 (18.2)
1 (9.1)1 (9.1)000

13 (20.6)
4 (6.3)3 (4.8)13 (20.6)
24 (38.1)
14 (22.2)
19 (30.2)
7 (11.1)
1 (1.6)4 (6.3)
1 (1.6)
1 (1.6)0
1 (14.3)
1 (14.3)03 (42.9)
0
1 (14.3)
1 (14.3)
0001 (14.3)0

1 (1.9)5 (9.6)
1 (1.9)2 (3.8)17 (32.7)
3 (5.8)3 (5.8)2 (3.8)2 (3.8)2 (3.8)1 (1.9)1 (1.9)1 (1.9)00001 (9.1)1 (9.1)
0
0
0
0
0
0
0

1 (1.6)5 (7.9)1 (1.6)2 (3.2)18 (28.6)
4 (6.3)3 (4.8)2 (3.2)2 (3.2)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Gastrointestinal disorders
Abdominal discomfort
Abdominal distension
Abdominal pain
Abdominal pain upper
Anal fissure
Cheilitis
Chronic gastritis
Constipation
Dental caries
Diarrhoea
Dry mouth
Dyspepsia
Enterocolitis
Gastric polyps
Gastritis
Gastritis erosive
Gastrooesophageal reflux
diseaseGingival swelling
Haemorrhoids
Leukoplakia oral
NauseaOesophagitis
Pancreatitis
Pancreatitis acute
Periodontal disease
Proctalgia
Stomatitis

Template version 1.6

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=3

7 (100)1 (14.3)
0
1 (14.3)
1 (14.3)00003 (42.9)
7 (100)00001 (14.3)
00

7 (100)0
1 (14.3)
0
1 (14.3)
1 (14.3)002 (28.6)
2 (28.6)
7 (100)0
1 (14.3)000003 (100)02 (66.7)
1 (33.3)
0
0
0
0
0
0
3 (100)1 (33.3)
0
0
0
0
0
0

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=727 (96.4)
7 (100)2 (7.1)0
3 (10.7)
1 (14.3)
00
5 (17.9)
00
1 (14.3)
002 (7.1)0
3 (10.7)
2 (28.6)
4 (14.3)
026 (92.9)
7 (100)1 (3.6)0
1 (3.6)
1 (14.3)
2 (7.1)1 (14.3)
2 (7.1)0
6 (21.4)
02 (7.1)0
2 (7.1)0

1 (14.3)
0
1 (14.3)
2 (28.6)
1 (14.3)
00
1 (14.3)
0
1 (14.3)0003 (42.9)
0
1 (14.3)0003 (42.9)0001 (33.3)000001 (33.3)

02 (7.1)0
12 (42.9)000
2 (7.1)3 (10.7)
5 (17.9)

Page 450001 (14.3)
00001 (14.3)
1 (14.3)

Total
Second-line
N=52
51 (98.1)
3 (5.8)7 (13.5)
2 (3.8)7 (13.5)
2 (3.8)02 (3.8)7 (13.5)
9 (17.3)
50 (96.2)
2 (3.8)3 (5.8)3 (5.8)2 (3.8)7 (13.5)
2 (3.8)2 (3.8)

Part 2
Exploratory
Third-line
500 mgN=11
11 (100)
00
1 (9.1)2 (18.2)
01 (9.1)00
2 (18.2)
10 (90.9)
02 (18.2)
0
0
0
0
0

Total
N=63

62 (98.4)
3 (4.8)7 (11.1)
3 (4.8)9 (14.3)2 (3.2)
1 (1.6)2 (3.2)7 (11.1)
11 (17.5)
60 (95.2)
2 (3.2)5 (7.9)3 (4.8)2 (3.2)7 (11.1)
2 (3.2)2 (3.2)

1 (1.9)2 (3.8)1 (1.9)19 (36.5)
1 (1.9)1 (1.9)0
3 (5.8)4 (7.7)
11 (21.2)0005 (45.5)
00
1 (9.1)00
1 (9.1)1 (1.6)2 (3.2)
1 (1.6)24 (38.1)
1 (1.6)
1 (1.6)
1 (1.6)3 (4.8)4 (6.3)12 (19.0)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Toothache
Vomiting
General disorders andadministration site conditions
Chest discomfort
ChillsFatigue
Injection site reaction
MalaiseOedema peripheral
Peripheral swelling
Pyrexia
Hepatobiliary disorders
Hepatic function abnormal
Hepatotoxicity
Liver disorder
Liver injury
Immune system disorders
Seasonal allergy
Infections and infestations
Bronchitis
Carbuncle
Cellulitis
Conjunctivitis
Cystitis
Diarrhoea infectiousEnterocolitis bacterialEnterocolitis infectiousEnterocolitis viral

Template version 1.6

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=30
1 (14.3)
4 (57.1)

1 (14.3)
2 (28.6)
3 (42.9)

03 (100)3 (100)Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=71 (3.6)0
14 (50.0)
3 (42.9)
14 (50.0)
2 (28.6)

00
1 (14.3)
0
1 (14.3)
0
1 (14.3)
1 (14.3)
2 (28.6)
0
1 (14.3)
0
1 (14.3)
00
5 (71.4)
1 (14.3)
0
1 (14.3)
00
1 (14.3)
0
1 (14.3)
0001 (14.3)
1 (14.3)0002 (28.6)
2 (28.6)
2 (28.6)00000
6 (85.7)
1 (14.3)
1 (14.3)
0
0
0
0
0
0
1 (14.3)

2 (66.7)
1 (33.3)
1 (33.3)00001 (33.3)
2 (66.7)
2 (66.7)0001 (33.3)
1 (33.3)
3 (100)00001 (33.3)
0
1 (33.3)0000
4 (14.3)
02 (7.1)2 (7.1)0
7 (25.0)
6 (21.4)
4 (14.3)0
1 (3.6)02 (7.1)1 (3.6)23 (82.1)
2 (7.1)00
2 (7.1)2 (7.1)00
1 (3.6)
0

Page 46

1 (14.3)
0
0
0
0
0
0
1 (14.3)
0
0
0
0
0
0
0
2 (28.6)
0001 (14.3)
0
0
0
0
0

Total
Second-line
N=52
2 (3.8)23 (44.2)
26 (50.0)

Part 2
Exploratory
Third-line
500 mgN=110
1 (9.1)
3 (27.3)

Total
N=63

2 (3.2)24 (38.1)
29 (46.0)

3 (5.8)1 (1.9)7 (13.5)
1 (1.9)3 (5.8)2 (3.8)1 (1.9)12 (23.1)
12 (23.1)
8 (15.4)
1 (1.9)1 (1.9)1 (1.9)3 (5.8)2 (3.8)39 (75.0)
4 (7.7)
1 (1.9)1 (1.9)3 (5.8)3 (5.8)1 (1.9)1 (1.9)2 (3.8)1 (1.9)0
1 (9.1)1 (9.1)0
1 (9.1)000
3 (27.3)
2 (18.2)
01 (9.1)000
9 (81.8)000
1 (9.1)1 (9.1)0000

3 (4.8)2 (3.2)8 (12.7)
1 (1.6)4 (6.3)2 (3.2)
1 (1.6)12 (19.0)
15 (23.8)
10 (15.9)
1 (1.6)2 (3.2)
1 (1.6)3 (4.8)2 (3.2)48 (76.2)
4 (6.3)
1 (1.6)
1 (1.6)4 (6.3)4 (6.3)
1 (1.6)
1 (1.6)2 (3.2)
1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Epididymitis
Folliculitis
Gastroenteritis
Gastroenteritis viral
Gingivitis
Herpes zoster
Influenza
Nasopharyngitis
Otitis media
Periodontitis
Pharyngitis
Pulpitis dental
Respiratory tract infection
Skin infection
Tinea versicolour
Tonsillitis
Upper respiratory tract
infection
Urinary tract infection
Injury, poisoning and procedural
complications
Allergic transfusion reaction
Arthropod sting
Contusion
Foot fracture
Ligament injury
Meniscus injury
Post-traumatic neck
syndrome

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=7002 (7.1)0
5 (17.9)000
1 (3.6)
1 (14.3)
2 (7.1)0
3 (10.7)
018 (64.3)
000
3 (10.7)
03 (10.7)
1 (14.3)
0
0
0
0
0
0
0
0
0
0
0
0

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=30
1 (14.3)
1 (14.3)
0
1 (14.3)
0
1 (14.3)
4 (57.1)
00
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
00
1 (14.3)

1 (14.3)
0
1 (14.3)
1 (14.3)
2 (28.6)
1 (14.3)
1 (14.3)
5 (71.4)
0001 (14.3)
0
0
0
0
0

0
0
1 (33.3)
0
1 (33.3)00
3 (100.0)
0
0
0
0
0
0
1 (33.3)
1 (33.3)
0

1 (14.3)
2 (28.6)0002 (66.7)

1 (3.6)7 (25.0)00
1 (14.3)
0
1 (14.3)
1 (14.3)
0

0
0
0
0
0
0
0

0
0
0
2 (66.7)00001 (3.6)2 (7.1)0
0
0
0Page 47

Total
Second-line
N=52
1 (1.9)3 (5.8)8 (15.4)
1 (1.9)6 (11.5)
3 (5.8)5 (9.6)30 (57.7)
03 (5.8)5 (9.6)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)Part 2
Exploratory
Third-line
500 mgN=111 (9.1)0
1 (9.1)0
1 (9.1)0
0
6 (54.5)
1 (9.1)
0
0
0
0
0
0
0
1 (9.1)

Total
N=63

2 (3.2)3 (4.8)9 (14.3)
1 (1.6)
7 (11.1)
3 (4.8)5 (7.9)36 (57.1)
1 (1.6)3 (4.8)5 (7.9)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)0
1 (14.3)2 (3.8)12 (23.1)

0
2 (18.2)

2 (3.2)14 (22.2)

1 (14.3)
0
0
0
0
0
0

1 (1.9)1 (1.9)3 (5.8)2 (3.8)1 (1.9)1 (1.9)00
1 (9.1)0000
1 (9.1)1 (1.6)2 (3.2)3 (4.8)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Rib fracture
Spinal compression fracture
Tendon injury
Thermal burn
Investigations
Alanine aminotransferase
increased
Amylase decreased
Amylase increased
Aspartate aminotransferase
increased
Blood albumin decreased
Blood albumin increased
Blood alkaline phosphataseincreased
Blood bilirubin increased
Blood calcium decreased
Blood calcium increased
Blood chloride decreased
Blood cholinesterase
decreased
Blood creatine phosphokinase
decreased
Blood creatine phosphokinase
increased
Blood creatinine increased
Blood fibrinogen increased
Blood lactate dehydrogenase
increased

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mg
N=28
N=7
0
0
0
0
0
0
0
0
23 (82.1)
4 (57.1)
13 (46.4)
0Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=300
1 (14.3)
05 (71.4)
3 (42.9)0000
6 (85.7)
4 (57.1)

1 (33.3)
1 (33.3)
0
1 (33.3)
2 (66.7)0004 (57.1)

1 (14.3)02 (28.6)

1 (33.3)000
5 (17.9)9 (32.1)0001 (14.3)
1 (14.3)
2 (28.6)

1 (33.3)
0
0

0
0
0
0
0

0
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)0

1 (1.9)1 (1.9)1 (1.9)1 (1.9)40 (76.9)
20 (38.5)

Part 2
Exploratory
Third-line
500 mgN=110000
7 (63.6)
4 (36.4)

1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)47 (74.6)
24 (38.1)

0
1 (14.3)02 (3.8)6 (11.5)
15 (28.8)

01 (9.1)
4 (36.4)

2 (3.2)7 (11.1)
19 (30.2)

2 (7.1)0
7 (25.0)000

4 (7.7)
1 (1.9)9 (17.3)

00
2 (18.2)

4 (6.3)
1 (1.6)
11 (17.5)

0
1 (33.3)000

1 (3.6)
0
0
0
0

0
0
0
0
0

1 (1.9)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (9.1)0000

2 (3.2)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)

2 (28.6)

1 (33.3)

00

3 (5.8)0

3 (4.8)

1 (14.3)

1 (14.3)

0

4 (14.3)0

6 (11.5)

2 (18.2)

8 (12.7)

1 (14.3)
0
1 (14.3)

2 (28.6)
1 (14.3)
02 (66.7)
0
1 (33.3)

2 (7.1)0
2 (7.1)1 (14.3)
00

8 (15.4)
1 (1.9)4 (7.7)00
2 (18.2)

8 (12.7)
1 (1.6)6 (9.5)

Page 48

Total
Second-line
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Blood potassium decreased
Blood potassium increased
Blood sodium decreased
Blood urea increased
Blood uric acid increased
Blood urine present
C-reactive protein increased
Electrocardiogram QT
prolonged
Gamma-glutamyltransferase
increased
Glucose urine present
Haemoglobin decreased
International normalised ratio
decreased
International normalised ratio
increased
Lipase increased
Liver function test abnormal
Lymphocyte count decreased
Neutrophil count decreased
Platelet count decreased
Protein total decreased
Protein urine present
Prothrombin time prolonged
Prothrombin time shortened
Renal function test abnormal
Specific gravity urine
abnormal

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=700
1 (3.6)000
2 (7.1)
0
0
0
0
0
0
0
0
0

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mg
N=3

0
0
0
0
0
0
0
0

1 (14.3)02 (28.6)
00
1 (14.3)
1 (14.3)
0

1 (33.3)
0
1 (33.3)
00
1 (33.3)
00

1 (14.3)

2 (28.6)0

6 (21.4)

1 (14.3)0003 (42.9)00
1 (33.3)
1 (33.3)

0

1 (14.3)

0
0
0
0
0
0
0
0
0
0
0

2 (28.6)
0
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
00
1 (14.3)2 (3.8)1 (1.9)3 (5.8)2 (3.8)02 (3.8)1 (1.9)0Part 2
Exploratory
Third-line
500 mgN=110
1 (9.1)00
1 (9.1)00
1 (9.1)2 (3.2)2 (3.2)3 (4.8)2 (3.2)
1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)0

9 (17.3)

1 (9.1)10 (15.9)

02 (7.1)0000

1 (1.9)6 (11.5)
1 (1.9)000

1 (1.6)6 (9.5)
1 (1.6)000

1 (1.9)0

1 (1.6)00
0
00
1 (33.3)
00
1 (33.3)
008 (28.6)
1 (3.6)0
1 (3.6)2 (7.1)
0
0
0
0
0
0

1 (14.3)
0
0
0
0
0
0
0
0
1 (14.3)
0

11 (21.2)
1 (1.9)1 (1.9)2 (3.8)3 (5.8)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)4 (36.4)
1 (9.1)0
1 (9.1)
0
0
0
0
0
0
0

15 (23.8)
2 (3.2)
1 (1.6)3 (4.8)3 (4.8)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)

Page 49

Total
Second-line
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Weight decreased
Weight increased
White blood cell countdecreased
White blood cell countincreased
Metabolism and nutrition
disorders
Decreased appetite
Dehydration
Gout
Hyperglycaemia
Hyperkalaemia
Hyperlipidaemia
Hypertriglyceridaemia
Hyperuricaemia
Hypoalbuminaemia
Hypocalcaemia
Hypokalaemia
Hypophosphataemia
Musculoskeletal and connective
tissue disorders
Arthralgia
Arthritis
Back pain
Intervertebral disc protrusion
Muscle spasms
Muscular weakness
Musculoskeletal pain

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=76 (21.4)
2 (28.6)
1 (3.6)0
1 (3.6)0Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=300
1 (14.3)

00
1 (14.3)

1 (33.3)00001 (33.3)

04 (57.1)

6 (85.7)

1 (33.3)

1 (14.3)002 (28.6)00001 (14.3)
1 (14.3)02 (28.6)
3 (42.9)

3 (42.9)
0
1 (14.3)
0
0
0
0
0
0
1 (14.3)03 (42.9)
2 (28.6)

1 (14.3)
0
1 (14.3)
0001 (14.3)

0001 (14.3)000

9 (17.3)
1 (1.9)3 (5.8)

Part 2
Exploratory
Third-line
500 mgN=110
1 (9.1)1 (9.1)9 (14.3)2 (3.2)4 (6.3)0

1 (1.9)0

1 (1.6)16 (57.1)

4 (57.1)

31 (59.6)

1 (9.1)32 (50.8)

1 (33.3)
00
1 (33.3)
0
0
0
0
0
0
0
0
1 (33.3)

6 (21.4)
1 (3.6)0
1 (3.6)
1 (3.6)4 (14.3)00002 (7.1)7 (25.0)9 (32.1)

3 (42.9)
1 (14.3)
00
1 (14.3)
0
1 (14.3)
1 (14.3)
0001 (14.3)
1 (14.3)

14 (26.9)
2 (3.8)1 (1.9)4 (7.7)2 (3.8)4 (7.7)
1 (1.9)1 (1.9)1 (1.9)2 (3.8)2 (3.8)13 (25.0)
16 (30.8)

1 (9.1)
0
0
0
0
0
0
0
0
0
0
0
4 (36.4)

15 (23.8)
2 (3.2)
1 (1.6)4 (6.3)2 (3.2)4 (6.3)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)2 (3.2)13 (20.6)
20 (31.7)

0
0
0
0
0
0
0

1 (3.6)
1 (3.6)
1 (3.6)2 (7.1)2 (7.1)3 (10.7)
0

1 (14.3)
0
0
0
0
0
0

3 (5.8)1 (1.9)2 (3.8)3 (5.8)2 (3.8)3 (5.8)1 (1.9)2 (18.2)
1 (9.1)1 (9.1)000
1 (9.1)5 (7.9)2 (3.2)3 (4.8)3 (4.8)2 (3.2)3 (4.8)2 (3.2)

Page 50

Total
Second-line
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Musculoskeletal stiffness
Myalgia
Pain in extremity
Plantar fasciitis
Rheumatoid arthritis
Neoplasms benign, malignant andunspecified (including cysts andpolyps)Blast cell crisis
Ear neoplasm
Nervous system disorders
Depressed level ofconsciousness
Dizziness
Dysgeusia
HeadacheHypoaesthesia
Intercostal neuralgia
Neuropathy peripheral
Paraesthesia
Peripheral sensory neuropathy
Sensory disturbanceSomnolence
Psychiatric disorders
Confusional state
Insomnia
Renal and urinary disorders
Haematuria
Pollakiuria

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=70
1 (14.3)
1 (3.6)
0
0
0
0
0
0
0
4 (14.3)
1 (14.3)

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=300
1 (14.3)
1 (14.3)
00001 (14.3)
0
0
0

0
0
0
0
1 (33.3)
1 (33.3)

00
1 (14.3)0002 (28.6)
00
1 (33.3)
2 (66.7)000
9 (32.1)0001 (14.3)
0
1 (14.3)
0
0
0
0
0
0
0
0
1 (14.3)
00001 (14.3)
1 (14.3)
0
0
0
0
0
0
1 (14.3)
0
1 (14.3)0001 (33.3)
0
1 (33.3)0001 (33.3)
1 (33.3)
1 (33.3)
0
1 (33.3)
1 (33.3)00001 (3.6)
1 (3.6)
1 (3.6)0
1 (3.6)
1 (3.6)000
1 (3.6)4 (14.3)03 (10.7)
7 (25.0)
2 (7.1)1 (3.6)

Page 51

Total
Second-line
N=52
1 (1.9)1 (1.9)2 (3.8)1 (1.9)1 (1.9)6 (11.5)

Part 2
Exploratory
Third-line
500 mgN=110
1 (9.1)1 (9.1)
0
0
0

Total
N=63

1 (1.6)2 (3.2)3 (4.8)1 (1.6)
1 (1.6)6 (9.5)

1 (14.3)
0
1 (14.3)
1 (14.3)

1 (1.9)1 (1.9)15 (28.8)
1 (1.9)00
5 (45.5)0

1 (1.6)
1 (1.6)20 (31.7)
1 (1.6)

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

2 (3.8)1 (1.9)4 (7.7)
1 (1.9)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)6 (11.5)
1 (1.9)4 (7.7)8 (15.4)
2 (3.8)1 (1.9)1 (9.1)1 (9.1)1 (9.1)00
1 (9.1)000
1 (9.1)000
2 (18.2)
01 (9.1)3 (4.8)2 (3.2)5 (7.9)1 (1.6)2 (3.2)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)6 (9.5)
1 (1.6)4 (6.3)10 (15.9)
2 (3.2)2 (3.2)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Renal impairment
Urogenital haemorrhage
Reproductive system and breast
disorders
Benign prostatic hyperplasia
Pelvic pain
Respiratory, thoracic andmediastinal disorders
Alveolitis allergic
CoughDyspnoea
Epistaxis
Haemoptysis
Hyperventilation
Nasal congestion
Nasal dryness
Oropharyngeal pain
Pleural effusion
Pleurisy
Productive coughRhinorrhoea
Upper respiratory tract
inflammation
Skin and subcutaneous tissue
disorders
Acne
Alopecia
Drug eruption
Dry skin

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=73 (10.7)000
1 (3.6)0Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mgN=30
1 (14.3)
1 (14.3)

0
0
0

0
0
0

0
1 (14.3)
2 (28.6)

00
4 (57.1)

00
1 (33.3)

00
9 (32.1)0
1 (14.3)
0
0
0
0
0
0
0
0
0
1 (14.3)
1 (14.3)
1 (14.3)

1 (14.3)
1 (14.3)
0
1 (14.3)
0
1 (14.3)0002 (28.6)
1 (14.3)
0
0
0

0
0
0
0
0
0
1 (33.3)
0
1 (33.3)00000

6 (85.7)

6 (85.7)

1 (14.3)
00
1 (14.3)

0001 (14.3)

3 (5.8)1 (1.9)2 (3.8)

Part 2
Exploratory
Third-line
500 mgN=110
1 (9.1)1 (9.1)3 (4.8)2 (3.2)3 (4.8)002 (28.6)0
1 (1.9)18 (34.6)

1 (9.1)0
3 (27.3)

1 (1.6)
1 (1.6)21 (33.3)

00
2 (7.1)00
000
2 (7.1)4 (14.3)
1 (3.6)00
4 (14.3)

00001 (14.3)
00
1 (14.3)
0
1 (14.3)00001 (1.9)2 (3.8)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)1 (1.9)3 (5.8)7 (13.5)
2 (3.8)1 (1.9)1 (1.9)5 (9.6)

0
0
0
0
0
0
0
0
1 (9.1)2 (18.2)00001 (1.6)2 (3.2)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)4 (6.3)9 (14.3)2 (3.2)
1 (1.6)
1 (1.6)5 (7.9)3 (100 )

25 (89.3)

3 (42.9)

43 (82.7)

7 (63.6)

50 (79.4)

00003 (10.7)2 (7.1)2 (7.1)1 (3.6)000
1 (14.3)

4 (7.7)2 (3.8)2 (3.8)4 (7.7)000
1 (9.1)4 (6.3)2 (3.2)2 (3.2)5 (7.9)Page 52

Total
Second-line
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 23. Number (%) of Subjects Reporting Treatment-Emergent Adverse Events (5% Subjects in Any of the Cohorts):
Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Part 1
Second-line
400 mg
N=7Part 1
Second-line
500 mg
N=7Part 1
Second-line
600 mg
N=3Treatment
Part 2
Part 2
Primary
Advanced
Second-line
Second-line
500 mg
500 mgN=28
N=73 (10.7)
03 (10.7)
01 (3.6)00
0
00
1 (3.6)0
1 (3.6)
0
0
0

Total
Second-line
N=52

Part 2
Exploratory
Third-line
500 mgN=11001 (9.1)1 (9.1)1 (9.1)1 (9.1)
0
0

Total
N=63

Eczema1 (14.3)
2 (28.6)0
6 (11.5)
6 (9.5)
Eczema asteatotic
00
1 (33.3)
4 (7.7)4 (6.3)
Erythema0
1 (14.3)02 (3.8)3 (4.8)Erythema nodosum0000
1 (1.6)
Generalised erythema0000
1 (1.6)Hyperkeratosis
000
1 (1.9)2 (3.2)
Leukoderma
1 (14.3)
1 (14.3)03 (5.8)3 (4.8)Night sweats
1 (14.3)
00
1 (1.9)1 (1.6)
Palmar-plantar00001 (14.3)
1 (1.9)0
1 (1.6)erythrodysaesthesia syndrome
Photosensitivity reaction
1 (14.3)00001 (1.9)2 (18.2)
3 (4.8)Pigmentation disorder
000
2 (7.1)0
2 (3.8)1 (9.1)3 (4.8)Pruritus
1 (14.3)
1 (14.3)
0
4 (14.3)0
6 (11.5)
2 (18.2)
8 (12.7)Rash
3 (42.9)
6 (85.7)
3 (100 )16 (57.1)
3 (42.9)31 (59.6)
5 (45.5)
36 (57.1)
Seborrhoeic dermatitis
1 (14.3)
00
4 (14.3)
05 (9.6)0
5 (7.9)Urticaria
3 (42.9)
1 (14.3)000
4 (7.7)04 (6.3)
Xeroderma
1 (14.3)00001 (1.9)0
1 (1.6)
Vascular disorders
1 (14.3)
1 (14.3)
1 (33.3)
6 (21.4)
09 (17.3)
09 (14.3)
Haemorrhage00
1 (33.3)
00
1 (1.9)0
1 (1.6)Hypertension
1 (14.3)
1 (14.3)
0
4 (14.3)0
6 (11.5)0
6 (9.5)Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).
Non SAE and SAE results are not separated out.
N = number of subjects, SAE = serious adverse events.
a. Totals for the number of subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may have reported 2 different
adverse events within the higher level category.

Template version 1.6

Page 53

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Any adverse event
Blood and lymphatic systemdisordersAnaemia
Eosinophilia
Leukopenia
Lymphopenia
Neutropenia
Thrombocytopenia
Cardiac disorders
Pericardial effusion
Ventricular extrasystoles
Ear and labyrinth disorders
Deafness
VertigoEye disorders
Conjunctival haemorrhage
Conjunctival hyperaemia
Dry eyePapilloedema
Gastrointestinal disorders
Abdominal discomfort
Abdominal distension
Abdominal pain
Abdominal pain upper
Anal fissure
Cheilitis
Chronic gastritis
Constipation

Template version 1.6

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mgN=3

7 (100)3 (42.9)

7 (100)4 (57.1)

3 (100)2 (66.7)

1 (14.3)
0
1 (14.3)02 (28.6)
2 (28.6)
0001 (14.3)
0
1 (14.3)
1 (14.3)
00
1 (14.3)07 (100)1 (14.3)
0
1 (14.3)000001 (14.3)02 (28.6)
2 (28.6)
2 (28.6)
3 (42.9)
2 (28.6)
1 (14.3)
1 (14.3)
0
0
0
0
0
0
0
0
7 (100)0
1 (14.3)
0
1 (14.3)
1 (14.3)
00
1 (14.3)0002 (66.7)
1 (33.3)
1 (33.3)
0
0
0
0
0
0
0
0
0
0
0
3 (100)0
1 (33.3)
1 (33.3)00
0
00Page 54

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mgN=28
N=728 (100)
7 (100)14 (50.0)
4 (57.1)
7 (25.0)
3 (10.7)
5 (17.9)
8 (28.6)
4 (14.3)
8 (28.6)
4 (14.3)
3 (10.7)
01 (3.6)00
4 (14.3)
1 (3.6)0
1 (3.6)026 (92.9)
1 (3.6)00
5 (17.9)002 (7.1)1 (3.6)4 (57.1)
03 (42.9)
2 (28.6)
3 (42.9)
3 (42.9)0001 (14.3)
1 (14.3)03 (42.9)
1 (14.3)
1 (14.3)
0
1 (14.3)
7 (100)0
1 (14.3)000002 (28.6)

Total
SecondLine
N=52
52 (100)
27 (51.9)

Part 2
Exploratory
Third-Line
500 mgN=11
11 (100)
6 (54.5)

Total
N=63

63 (100)
33 (52.4)

13 (25.0)
3 (5.8)11 (21.2)
14 (26.9)
12 (23.1)
17 (32.7)
6 (11.5)
4 (7.7)
1 (1.9)3 (5.8)1 (1.9)1 (1.9)8 (15.4)
2 (3.8)1 (1.9)2 (3.8)1 (1.9)50 (96.2)
2 (3.8)3 (5.8)2 (3.8)6 (11.5)
1 (1.9)02 (3.8)4 (7.7)0
1 (9.1)2 (18.2)
5 (45.5)
2 (18.2)
2 (18.2)
0
0
0
0
0
0
0
0
0
0
0
11 (100)
00
1 (9.1)2 (18.2)
01 (9.1)00

13 (20.6)
4 (6.3)
13 (20.6)
19 (30.2)
14 (22.2)
19 (30.2)
6 (9.5)4 (6.3)
1 (1.6)3 (4.8)1 (1.6)
1 (1.6)8 (12.7)
2 (3.2)
1 (1.6)2 (3.2)
1 (1.6)61 (96.8)
2 (3.2)3 (4.8)3 (4.8)8 (12.7)
1 (1.6)
1 (1.6)2 (3.2)4 (6.3)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Diarrhoea
Dry mouth
Dyspepsia
Gastritis
Gastrooesophageal reflux
diseaseGingival swelling
Leukoplakia oral
NauseaOesophagitis
Pancreatitis
Pancreatitis acute
Proctalgia
Stomatitis
Toothache
Vomiting
General disorders andadministration site conditions
Chest discomfort
ChillsFatigue
Malaise
Peripheral swelling
Pyrexia
Hepatobiliary disorders
Hepatic function abnormal
Hepatotoxicity
Liver disorder
Liver injury

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mgN=28
N=725 (89.3)
7 (100)1 (3.6)0
1 (3.6)
1 (14.3)
6 (21.4)
02 (7.1)0Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mgN=3

7 (100)00
00

7 (100)0
1 (14.3)00

3 (100)1 (33.3)
0001 (14.3)
1 (14.3)
2 (28.6)
1 (14.3)000001 (14.3)
4 (57.1)002 (28.6)
0
1 (14.3)003 (42.9)
1 (14.3)
2 (28.6)
3 (42.9)00
1 (33.3)00001 (33.3)
02 (66.7)
3 (100)0012 (42.9)000
2 (7.1)4 (14.3)
014 (50.0)
9 (32.1)

00
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
2 (28.6)
0
1 (14.3)
0
1 (14.3)

00
1 (14.3)002 (28.6)
2 (28.6)
2 (28.6)0002 (66.7)
0
1 (33.3)
00
1 (33.3)
2 (66.7)
2 (66.7)000003 (10.7)
1 (3.6)0
5 (17.9)
4 (14.3)
3 (10.7)
01 (3.6)
0

Page 55

Total
SecondLine
N=52
49 (94.2)
2 (3.8)3 (5.8)6 (11.5)
2 (3.8)

Part 2
Exploratory
Third-Line
500 mgN=11
10 (90.9)
01 (9.1)
0
0

Total
N=63

59 (93.7)
2 (3.2)4 (6.3)6 (9.5)2 (3.2)00
1 (14.3)
0001 (14.3)
1 (14.3)03 (42.9)
2 (28.6)

1 (1.9)1 (1.9)18 (34.6)
1 (1.9)1 (1.9)0
3 (5.8)9 (17.3)
1 (1.9)22 (42.3)
21 (40.4)

005 (45.5)
00
1 (9.1)0
1 (9.1)0
1 (9.1)
3 (27.3)

1 (1.6)
1 (1.6)23 (36.5)
1 (1.6)
1 (1.6)
1 (1.6)3 (4.8)10 (15.9)
1 (1.6)23 (36.5)
24 (38.1)

1 (14.3)
00001 (14.3)000003 (5.8)0
6 (11.5)
2 (3.8)1 (1.9)10 (19.2)
10 (19.2)
7 (13.5)
1 (1.9)1 (1.9)1 (1.9)0
1 (9.1)1 (9.1)1 (9.1)00
3 (27.3)
2 (18.2)
01 (9.1)0

3 (4.8)1 (1.6)
7 (11.1)
3 (4.8)1 (1.6)10 (15.9)
13 (20.6)
9 (14.3)
1 (1.6)2 (3.2)
1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Infections and infestations
Bronchitis
Cellulitis
Conjunctivitis
Cystitis
Folliculitis
Gastroenteritis
Gingivitis
Herpes zoster
Influenza
Nasopharyngitis
Periodontitis
Tinea versicolour
Upper respiratory tract
infection
Investigations
Alanine aminotransferase
increased
Amylase decreased
Amylase increased
Aspartate aminotransferase
increased
Blood albumin decreased
Blood albumin increased
Blood alkaline phosphataseincreased
Blood bilirubin increased
Blood calcium decreased
Blood calcium increased

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mgN=28
N=713 (46.4)
2 (28.6)2 (7.1)0000
1 (14.3)
1 (3.6)02 (7.1)0
3 (10.7)
01 (3.6)
1 (14.3)00
1 (3.6)0
9 (32.1)02 (7.1)00000Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mgN=33 (42.9)
1 (14.3)
1 (14.3)
00
1 (14.3)00002 (28.6)
00
1 (14.3)

5 (71.4)
1 (14.3)
00001 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
3 (42.9)0001 (33.3)
0
0
0
0
0
0
0
0
0
0
0
1 (33.3)
05 (71.4)
3 (42.9)

6 (85.7)
4 (57.1)

2 (66.7)
022 (78.6)
13 (46.4)

00
4 (57.1)

1 (14.3)02 (28.6)

1 (33.3)
0
0

0
0
0

1 (14.3)
1 (14.3)
2 (28.6)00001 (14.3)
1 (14.3)

24 (46.2)
4 (7.7)
1 (1.9)1 (1.9)1 (1.9)3 (5.8)4 (7.7)3 (5.8)1 (1.9)2 (3.8)14 (26.9)
2 (3.8)1 (1.9)1 (1.9)Part 2
Exploratory
Third-Line
500 mgN=11
3 (27.3)
000
1 (9.1)00
0
00
2 (18.2)
00027 (42.9)
4 (6.3)
1 (1.6)
1 (1.6)2 (3.2)3 (4.8)4 (6.3)3 (4.8)1 (1.6)2 (3.2)16 (25.4)
2 (3.2)
1 (1.6)
1 (1.6)4 (57.1)
039 (75.0)
20 (38.5)

6 (54.5)
4 (36.4)

45 (71.4)
24 (38.1)

0
5 (17.9)9 (32.1)0
1 (14.3)02 (3.8)6 (11.5)
15 (28.8)

01 (9.1)
4 (36.4)

2 (3.2)7 (11.1)
19 (30.2)

1 (33.3)00

1 (3.6)0
7 (25.0)000

3 (5.8)1 (1.9)9 (17.3)

00
2 (18.2)

3 (4.8)1 (1.6)
11 (17.5)

0
1 (33.3)0

1 (3.6)00

0
00

1 (1.9)2 (3.8)1 (1.9)1 (9.1)00

2 (3.2)2 (3.2)
1 (1.6)

Page 56

Total
SecondLine
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Blood chloride decreased
Blood cholinesterase
decreased
Blood creatine
phosphokinase decreased
Blood creatine
phosphokinase increased
Blood creatinine increased
Blood fibrinogen increased
Blood lactate
dehydrogenase increased
Blood potassium decreased
Blood sodium decreased
Blood urea increased
Blood urine presentElectrocardiogram QT
prolonged
Gamma-glutamyltransferase
increased
Glucose urine present
Haemoglobin decreased
International normalised
ratio decreased
International normalised
ratio increased
Lipase increased
Liver function test abnormal
Lymphocyte countdecreased

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mg
N=28
N=7
0
0
0
0

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mgN=300

1 (14.3)
1 (14.3)0002 (28.6)

1 (33.3)

0

1 (14.3)

00

1 (14.3)
0
1 (14.3)

2 (28.6)
1 (14.3)
0

0
0
0
0
0

1 (1.9)1 (1.9)Part 2
Exploratory
Third-Line
500 mgN=1100

1 (1.6)
1 (1.6)0

3 (5.8)0

3 (4.8)

3 (10.7)

04 (7.7)2 (18.2)

6 (9.5)2 (66.7)
0
1 (33.3)

2 (7.1)0
2 (7.1)1 (14.3)
00

8 (15.4)
1 (1.9)4 (7.7)00
2 (18.2)

8 (12.7)
1 (1.6)6 (9.5)

1 (14.3)
2 (28.6)
0
1 (14.3)
0

1 (33.3)
1 (33.3)
000002 (7.1)
0
0

0
0
0
0
0

2 (3.8)3 (5.8)2 (3.8)1 (1.9)00
000
1 (9.1)2 (3.2)3 (4.8)2 (3.2)
1 (1.6)
1 (1.6)0

2 (28.6)03 (10.7)05 (9.6)1 (9.1)6 (9.5)

1 (14.3)0003 (42.9)00
1 (33.3)
1 (33.3)

02 (7.1)0000

1 (1.9)6 (11.5)
1 (1.9)000

1 (1.6)6 (9.5)
1 (1.6)0

1 (14.3)

000

1 (1.9)0

1 (1.6)000

2 (28.6)
0
1 (14.3)000

7 (25.0)
1 (3.6)0

1 (14.3)
00

10 (19.2)
1 (1.9)1 (1.9)4 (36.4)
1 (9.1)0

14 (22.2)
2 (3.2)
1 (1.6)

Page 57

Total
SecondLine
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Neutrophil count decreased
Platelet count decreased
Protein total decreased
Protein urine present
Prothrombin time prolonged
Prothrombin time shortened
Renal function test
abnormalSpecific gravity urine
abnormal
Weight decreased
White blood cell countdecreased
Metabolism and nutrition
disorders
Decreased appetite
Dehydration
Hyperglycaemia
Hypertriglyceridaemia
Hyperuricaemia
Hypoalbuminaemia
Hypocalcaemia
Hypophosphataemia
Musculoskeletal and connective
tissue disorders
Arthralgia
Back pain
Myalgia
Rheumatoid arthritis

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mgN=28
N=71 (3.6)02 (7.1)
0
0
0
0
0
0
0
0
0
0
1 (14.3)

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mg
N=3

0
0
0
0
0
0
0

1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)00001 (33.3)
00
1 (33.3)
00

1 (14.3)

0001 (14.3)

0
1 (14.3)

1 (33.3)03 (42.9)

6 (85.7)

1 (14.3)
00001 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
0
1 (14.3)00

2 (3.8)3 (5.8)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)Part 2
Exploratory
Third-Line
500 mgN=111 (9.1)
0
0
0
0
0
0

3 (4.8)3 (4.8)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)0

1 (1.9)0

1 (1.6)6 (21.4)
1 (3.6)

1 (14.3)
08 (15.4)
3 (5.8)0
1 (9.1)8 (12.7)
4 (6.3)

1 (33.3)

13 (46.4)

3 (42.9)26 (50.0)

1 (9.1)27 (42.9)

3 (42.9)000001 (14.3)
3 (42.9)01 (33.3)
0
1 (33.3)000001 (33.3)

5 (17.9)
1 (3.6)00
0
00
7 (25.0)
6 (21.4)

3 (42.9)
1 (14.3)
0
1 (14.3)
1 (14.3)
00
1 (14.3)
013 (25.0)
2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)2 (3.8)12 (23.1)
8 (15.4)

1 (9.1)
0
0
0
0
0
0
0
2 (18.2)

14 (22.2)
2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)
12 (19.0)
10 (15.9)

0
0
0
0

0
0
0
1 (33.3)0
1 (3.6)
1 (3.6)
0

0
0
0
0

0
2 (3.8)1 (1.9)1 (1.9)1 (9.1)0
1 (9.1)0

1 (1.6)2 (3.2)2 (3.2)
1 (1.6)

Page 58

Total
SecondLine
N=52

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Neoplasms benign, malignant
and unspecified (including cysts
and polyps)
Ear neoplasm
Nervous system disorders
Dizziness
Dysgeusia
HeadacheHypoaesthesia
Neuropathy peripheral
Paraesthesia
Peripheral sensory
neuropathy
Sensory disturbanceSomnolence
Psychiatric disorders
Insomnia
Renal and urinary disorders
Haematuria
Renal impairment
Urogenital haemorrhage
Respiratory, thoracic andmediastinal disorders
Alveolitis allergic
Cough
Epistaxis
Haemoptysis
Nasal congestion
Oropharyngeal pain

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mgN=28
N=71 (3.6)0Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mgN=3001 (33.3)

0
0
0
0
0
0
0
0
0

0
2 (28.6)
00
1 (14.3)
1 (14.3)0001 (33.3)
2 (66.7)
00
1 (33.3)
00
1 (33.3)
1 (33.3)0
6 (21.4)
01 (3.6)
1 (3.6)0
1 (3.6)
0
0

0
0
0
0
1 (14.3)
00
1 (14.3)
1 (14.3)

00
1 (14.3)
1 (14.3)00004 (57.1)

1 (33.3)
0
0
0
0
0
0
0
1 (33.3)

0
1 (14.3)
00001 (14.3)
1 (14.3)
1 (14.3)
0
0
0

0
0
0
0
1 (33.3)
1 (33.3)

Page 59

Total
SecondLine
N=52
2 (3.8)

Part 2
Exploratory
Third-Line
500 mg
N=11
0

Total
N=63

2 (3.2)

0
0
0
0
0
0
0
0
0

1 (1.9)10 (19.2)
0
1 (1.9)3 (5.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)05 (45.5)
1 (9.1)1 (9.1)1 (9.1)0
1 (9.1)00

1 (1.6)15 (23.8)
1 (1.6)2 (3.2)4 (6.3)
1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)0
1 (3.6)2 (7.1)1 (3.6)5 (17.9)2 (7.1)3 (10.7)
05 (17.9)

0
0
0
0
0
0
0
0
2 (28.6)

1 (1.9)1 (1.9)3 (5.8)2 (3.8)6 (11.5)
2 (3.8)3 (5.8)1 (1.9)13 (25.0)0
1 (9.1)00
1 (9.1)00
1 (9.1)
3 (27.3)

1 (1.6)2 (3.2)3 (4.8)2 (3.2)7 (11.1)
2 (3.2)3 (4.8)2 (3.2)16 (25.4)

0
0
0
0
0
0

0
0
0
1 (14.3)
00

1 (1.9)2 (3.8)1 (1.9)1 (1.9)1 (1.9)1 (1.9)00
000
1 (9.1)1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Pleural effusion
Pleurisy
Productive coughRhinorrhoea
Skin and subcutaneous tissue
disorders
Acne
Alopecia
Drug eruption
Dry skinEczemaEczema asteatotic
Erythema
Erythema nodosum
Generalised erythemaHyperkeratosis
Leukoderma
Night sweats
Palmar-plantar
erythrodysaesthesia syndrome
Photosensitivity reaction
Pigmentation disorder
Pruritus
Rash
Seborrhoeic dermatitis
Urticaria
Xeroderma
Vascular disorders
Haemorrhage

Template version 1.6

Treatment
Part 2
Part 2
Primary
Advanced
Second-Line
Second-Line
500 mg
500 mgN=28
N=74 (14.3)
1 (14.3)
0
0
0
0
0
0
24 (85.7)
3 (42.9)

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mgN=300
1 (14.3)
1 (14.3)
4 (57.1)

2 (28.6)
1 (14.3)
00
5 (71.4)00003 (100)1 (14.3)
00
1 (14.3)
1 (14.3)000001 (14.3)
1 (14.3)000001 (14.3)
0
1 (14.3)
0001 (14.3)
0
0

0
0
0
0
0
1 (33.3)
0
0
0
0
0
0
0

3 (10.7)2 (7.1)2 (7.1)0
2 (7.1)1 (3.6)
1 (3.6)00
1 (3.6)
1 (3.6)00

1 (14.3)
0
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
1 (14.3)
0001 (14.3)
4 (57.1)0001 (14.3)00003 (100 )000
1 (33.3)
1 (33.3)

02 (7.1)4 (14.3)
16 (57.1)
4 (14.3)00
3 (10.7)
0Page 60

Total
SecondLine
N=52
7 (13.5)
1 (1.9)1 (1.9)1 (1.9)39 (75.0)

Part 2
Exploratory
Third-Line
500 mgN=11
2 (18.2)000
6 (54.5)

Total
N=63

9 (14.3)
1 (1.6)
1 (1.6)
1 (1.6)45 (71.4)

000
1 (14.3)
0
0
0
0
0
0
0
0
1 (14.3)

4 (7.7)2 (3.8)2 (3.8)2 (3.8)4 (7.7)2 (3.8)2 (3.8)00
1 (1.9)3 (5.8)1 (1.9)1 (1.9)000
1 (9.1)000
1 (9.1)1 (9.1)1 (9.1)000

4 (6.3)2 (3.2)2 (3.2)3 (4.8)4 (6.3)2 (3.2)2 (3.2)
1 (1.6)
1 (1.6)2 (3.2)3 (4.8)1 (1.6)
1 (1.6)000
2 (28.6)
00000

1 (1.9)2 (3.8)6 (11.5)
26 (50.0)
5 (9.6)
1 (1.9)1 (1.9)6 (11.5)
1 (1.9)2 (18.2)00
4 (36.4)00000

3 (4.8)2 (3.2)6 (9.5)30 (47.6)
5 (7.9)1 (1.6)
1 (1.6)6 (9.5)
1 (1.6)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 24. Number (%) of Subjects Reporting Drug Related Treatment-Emergent Adverse Events (5% Subjects in Any of
the Cohorts): Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Treatment
Part 2
Part 2
Total
Part 2
Total
Primary
Advanced
SecondExploratory
N=63
Second-Line
Second-LineLine
Third-Line
500 mg
500 mgN=52
500 mg
N=28
N=7
N=11
Hypertension
1 (14.3)
1 (14.3)
02 (7.1)0
4 (7.7)04 (6.3)
Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).
Non SAE and SAE results are not separated out.
N = number of subjects; SAE = serious adverse events.
a. Totals for the number of subjects at a higher level are not necessarily the sum of those at the lower levels since a subject might report 2 different adverse
events within the higher level category.

Template version 1.6

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mg
N=3Page 61Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Permanent Discontinuations due to Adverse Events: AEs leading to permanent
discontinuation are summarized in Table 25.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

AEs leading to treatment discontinuation were reported in 18 (28.6%) subjects in total;
16 (30.8%) subjects in the total second-line subjects and 2 (18.2%) subjects in the third-line
subjects. In total, the most common AEs leading to treatment discontinuation(incidence 3%) were aspartate aminotransferase increased (6.3%), hepatic function
abnormal (4.8%), alanine aminotransferase increased (4.8%) and thrombocytopenia (3.2%).

Template version 1.6

Page 62

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 25. Number (%) of Subjects Reporting Adverse Events Leading to Permanent Discontinuation: Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

System Organ Classa
Preferred Term

Any adverse event
Blood and lymphatic systemdisorders
Thrombocytopenia
Hepatobiliary disorders
Hepatic function abnormal
Liver injury
Investigations
Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Lipase increased
Liver function test abnormal
Platelet count decreased
Neoplasms benign, malignant andunspecified (including cysts andpolyps)Bladder cancer
Blast cell crisis
Nervous system disorders
Cerebral haemorrhage
Posterior reversible
encephalopathy syndrome
Skin and subcutaneous tissue
disordersRash

Template version 1.6

Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mg
N=3Part 2
Advanced
Second-Line
500 mgN=73 (42.9)

Total
Second-Line
N=52

0

Part 2
Primary
Second-Line
500 mgN=28
11 (39.3)

16 (30.8)

Part 2
Exploratory
Third-Line
500 mgN=11
2 (18.2)

1 (14.3)

1 (14.3)

0

0

0

0

2 (28.6)

2 (3.8)0

18(28.6)
2 (3.2)0
1 (14.3)
0
1 (14.3)
0001 (14.3)
1 (14.3)
0
0
0

0
0
0
0
0
0

0
1 (3.6)
1 (3.6)0
6 (21.4)
3 (10.7)

2 (28.6)000002 (3.8)3 (5.8)2 (3.8)1 (1.9)6 (11.5)
3 (5.8)0
1 (9.1)1 (9.1)0
1 (9.1)0

2 (3.2)4 (6.3)3 (4.8)1(1.6)
7 (11.1)
3 (4.8)000

4 (14.3)

04 (7.7)04 (6.3)

0
0
0
0

0
0
0
0

0
0
0
0

1 (3.6)0
1 (3.6)
1 (3.6)000
1 (14.3)

1 (1.9)0
1 (1.9)2 (3.8)0
1 (9.1)00

1 (1.6)
1 (1.6)
1 (1.6)2 (3.2)

0
0
0
0
0

0
0
0
0
0

0
0
0
0
0

1 (3.6)02 (7.1)1 (3.6)
1 (3.6)0
1 (14.3)
000

1 (1.9)1 (1.9)2 (3.8)1 (1.9)1 (1.9)00
0
00

1 (1.6)
1 (1.6)2 (3.2)
1 (1.6)
1 (1.6)000

1 (3.6)0

1 (1.9)0

1 (1.6)000

1 (3.6)0

1 (1.9)0

1 (1.6)

Page 63

Total
N=63

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 25. Number (%) of Subjects Reporting Adverse Events Leading to Permanent Discontinuation: Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Classifications of adverse events were based on MedDRA.
MedDRA = Medical Dictionary for Regulatory Activities; N = number of subjects.
a. Totals for the number of subjects at a higher level were not necessarily the sum of those at the lower levels since a subject may have reported 2 different
adverse events within the higher level category.

Template version 1.6

Page 64

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Temporary Discontinuations due to Adverse Events: AEs leading to dose delays werereported in 53 (84.1%) subjects in total; 44 (84.6%) subjects in the total second-line subjects
and 9 (81.8%) subjects in the third-line exploratory cohort. In total, the most common AEs
leading to dose delays (incidence 10%) were rash (23.8%), alanine aminotransferase
increased (19.0%), thrombocytopenia (15.9%), lipase increased (15.9%), diarrhea (12.7%),
neutropenia (11.1%) and aspartate aminotransferase increased (11.1%).

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Death: A summary of deaths is provided in Table 26. Overall 7 subjects died, of these,
1 subject who received bosutinib 500 mg in the primary second-line died within 30 days ofthe last dose. The reason for death was an AE related to bosutinib (cerebral haemorrhage).
Six (6) second-line subjects died after 30 days from the last dose. The reasons for death were
AE unrelated to bosutinib in 3 subjects (pneumonia occurring 86 days after the last dose,
pulmonary aspergillosis occurring 103 days after the last dose, and suicide occurring 686
days after the last dose) and disease progression in 3 subjects.

Template version 1.6

Page 65

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Table 26. Summary of Deaths: Safety Population

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

Deaths (n, %)Part 1
Second-Line
400 mg
N=7Part 1
Second-Line
500 mg
N=7Part 1
Second-Line
600 mg
N=3

Number of all deaths000
Number of deaths within 30 days of last
0
0
0
dose
Number of deaths after 30 days from0
0
0last dose
Reason for deatha
000Adverse event unrelated to test000
articleAdverse event related to test article000Disease progression000Cause-specific death rate
Number of deaths due to disease000progression
N = total number of subjects; n= number of subjects meeting pre-specified criteria.
a. Percentages were based on number of subjects who died in each group.

Template version 1.6

Page 66

Part 2
Primary
Second-Line
500 mgN=28
2 (7.1)1 (3.6)

Part 2
Advanced
Second-Line
500 mgN=75 (71.4)
0

Total
Second-line
N=52
7 (13.5)
1 (1.9)Part 2
Exploratory
Third-Line
500 mgN=11001 (3.6)

Total
N=63

7 (11.1)
1 (1.6)5 (71.4)

6 (11.5)0

6 (9.5)

2 (100)0

5 (100 )
3 (60.0)

7 (100 )
3 (42.9)

00

7 (100)3 (42.9)

1 (50)
1 (50)

2 (40.0)

1 (14.3)
3 (42.9)

0

1 (14.3)
3 (42.9)

1 (3.6)

2 (28.6)

3 (5.8)0

3 (4.8)

Public Disclosure Synopsis
Protocol 3160A4-2203 (B1871007) – 11 October 2016 – Final

Clinical Laboratory Evaluation: A total of 53 subjects (84.1%) experienced Grade 3 or 4
abnormality in laboratory test results. The most common Grade 3 or 4 hematology test
abnormalities (incidence 20%) were lymphocytes (33.3%), neutrophils (27.0%), andplatelet count (23.8%). The most common Grade 3 or 4 blood chemistry test abnormalities(incidence 20%) were uric acid (31.7%), alanine aminotransferase (27.0%), and lipase(24.2%). There were no abnormalities that met the criteria for potential Hy’s Law cases.
Vital Signs, Electrocardiogram, Physical Findings, and Other Observations Related to Safety:
Fourteen (14) subjects (23.0%) had a potentially clinically important (PCI) value in vital
signs or body weight. Of which, 13 subjects (21.7%) were found to have PCI value of 10%change of body weight, in addition 1 (1.7%) subject had a heart rate value of <40 beats/min.
No PCI values were reported in other vital signs (supine blood pressure and axillarytemperature). An increase of QT interval by >0-30 msec was reported in 3 subjects in the
400 mg cohort, 10 subjects in the primary cohort and 7 subjects in the exploratory third-line
cohort. An increase of QT interval by >30 msec was reported in 2 subjects in the exploratory
third-line cohort. A total of 6 (12.2%) subjects experienced Grade 1 or 2 left ventricularejection fraction abnormalities.

090177e189cb706d\Approved\Approved On: 17-Oct-2016 00:06

CONCLUSIONS:The safety of bosutinib up to 600 mg was confirmed in Part 1 of the study and bosutinib
500 mg as the starting dose for part 2 of a previous open-label, continuous daily dosing,two-part safety and efficacy study (A Phase 1/2 Study of SKI-606 in Philadelphia
Chromosome Positive Leukemias [NCT00261846]) was assumed to be appropriate inJapanese subjects as the starting dose for Part 2 of the study.
Overall, bosutinib given at 500 mg demonstrated efficacy in Japanese second-line CML
subjects. A CCyR was observed in a third-line CML subject. Bosutinib demonstrated an
acceptable safety profile at an oral daily dose of 500 mg in Japanese subjects with Ph+ CML.

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