Study Evaluating SKI-606 (Bosutinib) In Japanese Subjects With Philadelphia Chromosome Positive Leukemias

• ClinicalTrials.gov Identifier: NCT00811070
• Recruitment Status: Completed
• First Posted: December 18, 2008
• Results First Posted: June 4, 2014
• Last Update Posted: June 28, 2016
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Myelogenous Leukemia
• Intervention: Drug: SKI-606 (Bosutinib)
• Enrollment: 63

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Advanced Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Period Title: Overall Study
Started	7	7	3	28	7	11
Completed	6	6	3	26	2	10
Not Completed	1	1	0	2	5	1
Reason Not Completed
Death	0	0	0	2	5	0
Other	1	0	0	0	0	0
Withdrawal by Subject	0	1	0	0	0	0
Physician Decision	0	0	0	0	0	1

Baseline Characteristics

Arm/Group Title		Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Advanced Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )	Total
Arm/Group Description		Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Total of all reporting groups
Overall Number of Baseline Participants		7	7	3	28	7	11	63
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	7 participants	7 participants	3 participants	28 participants	7 participants	11 participants	63 participants
< 65 years		7	4	2	20	3	9	45
>= 65 years		0	3	1	8	4	2	18
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	7 participants	3 participants	28 participants	7 participants	11 participants	63 participants
	Female	3 42.9%	2 28.6%	2 66.7%	12 42.9%	1 14.3%	4 36.4%	24 38.1%
	Male	4 57.1%	5 71.4%	1 33.3%	16 57.1%	6 85.7%	7 63.6%	39 61.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1
Description	DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity.
Time Frame	Baseline up to Day 28 (Part 1 )

Outcome Measure Data

Analysis Population Description

Participants enrolled in Part 1 of the study were analyzed for DLT. Two participants (1 each in the 400 mg and 500 mg) who discontinued the treatment by Day 28 due to non-safety reasons were excluded from the analysis.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	6	6	3
Measure Type: Number; Unit of Measure: Participants
	1	1	0

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD) - Part 1
Description	MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT.
Time Frame	Baseline up to Day 28 (Part 1 )

Outcome Measure Data

Analysis Population Description

Participants enrolled in Part 1 of the study were analyzed for DLT. Two participants (1 each in the 400 mg and 500 mg) who discontinued the treatment by Day 28 due to non-safety reasons were excluded from the analysis.

Arm/Group Title	All Treated Participants (Part 1 )
Arm/Group Description:	All participants who received single oral dose of bosutinib 400 mg, 500 mg or 600 mg on Day 1 and then bosutinib 400 mg, 500 mg or 600 mg orally once daily continuously from Day 3 up to Week 4.
Overall Number of Participants Analyzed	15
Measure Type: Number; Unit of Measure: mg
	NA [1]

[1]

MTD was not achieved since no more than 1 DLT was observed in any cohort.

3. Primary Outcome

Title	Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2
Description	Cytogenetic response (CyR) is based on the prevalence of Philadelphia chromosome positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	28
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	35.7; (18.6 to 55.9)

4. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) - Part 1
Description	[Not Specified]
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

n= number of participants analyzed.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Mean (Standard Deviation); Unit of Measure: nanogram per milliliter (ng/mL)
Day 1 (n = 7, 7, 3)	131 (29.7)	128 (23.1)	155 (44.4)
Day 15 (n = 5, 4, 2)	129 (24.4)	226 (49.5)	214 [1] (NA)

[1]

Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.

5. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
Description	[Not Specified]
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

n= number of participants analyzed.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Median (Full Range); Unit of Measure: hour
Day 1 (n = 7, 7, 3)	4.00; (3.97 to 7.90)	3.95; (3.00 to 5.98)	3.98; (3.97 to 4.03)
Day 15 (n = 5, 4, 2)	4.03; (3.92 to 8.00)	3.95; (3.93 to 7.98)	4.00; (3.98 to 4.02)

6. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) - Part 1
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Mean (Standard Deviation); Unit of Measure: hour
	16.82 (2.37)	16.90 (2.47)	17.27 (3.64)

7. Secondary Outcome

Title	Area Under the Concentration-Time Curve (AUC) - Part 1
Description	Area under the plasma concentration time-curve from zero to infinity. AUC on Day 15 was assessed as the steady state AUC.
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

n= number of participants analyzed.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Mean (Standard Deviation); Unit of Measure: nanogram*hour per milliliter (ng•hr/mL)
Day 1 (n = 7, 7, 3)	2474 (482.7)	2720 (560.4)	2760 (625.9)
Day 15 (n = 5, 4, 2)	2235 (220.1)	3690 (962.1)	3371 [1] (NA)

[1]

Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.

8. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) - Part 1
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F on Day 15 was assessed as the steady state CL/F.
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

n= number of participants analyzed.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Mean (Standard Deviation); Unit of Measure: L/hr
Day 1 (n = 7, 7, 3)	167 (34.6)	190 (37.8)	224 (45.7)
Day 15 (n = 5, 4, 2)	180 (17.4)	144 (41.8)	179 [1] (NA)

[1]

Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.

9. Secondary Outcome

Title	Apparent Volume of Distribution (Vz/F) - Part 1
Description	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Mean (Standard Deviation); Unit of Measure: liter
	4035 (879.8)	4570 (713.8)	5707 (2187)

10. Secondary Outcome

Title	Accumulation Ratio (R) - Part 1
Description	R=accumulation ratio (AUCss on Day 15/AUC[0-24] on Day 1)
Time Frame	Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	5	4	2
Mean (Standard Deviation); Unit of Measure: ratio
	1.67 (0.369)	2.16 (0.556)	2.46 [1] (NA)

[1]

Standard deviation was Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.

11. Secondary Outcome

Title	Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2
Description	Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells. The responder for maintained MCyR included 'participants without baseline response who had a response at a specified time' and 'participants with baseline response who had a post-baseline response either maintained or improved at a specified time'.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Advanced Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	28	7	11
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	64.3; (44.1 to 81.4)	14.3; (0.4 to 57.9)	63.6; (30.8 to 89.1)

12. Secondary Outcome

Title	Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1
Description	Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Second-line 400 mg (Part 1 )	Bosutinib Second-line 500 mg (Part 1 )	Bosutinib Second-line 600 mg (Part 1 )
Arm/Group Description:	Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort.	Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred.
Overall Number of Participants Analyzed	7	7	3
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	42.9; (9.9 to 81.6)	57.1; (18.4 to 90.1)	33.3; (0.8 to 90.6)

13. Secondary Outcome

Title	Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2
Description	Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	11
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	18.2; (2.3 to 51.8)

14. Secondary Outcome

Title	Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2
Description	Time to MCyR was the interval from the date of first dose of study medication until the first date of achieving a given response. Time to response in weeks = (event date minus first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last cytogenetic assessment date of a participants.
Time Frame	204 weeks in the second-line participants and 48 weeks in the third-line participants

Outcome Measure Data

Analysis Population Description

Subset of participants who had the response among all treated population

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	13	2
Median (95% Confidence Interval); Unit of Measure: weeks
	12.3; (12.0 to 24.1)	18.1; (12.1 to 24.1)

15. Secondary Outcome

Title	Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2
Description	Duration of MCyR was defined as the interval from the date of the earliest demonstration of a response, until the earliest date of loss of that response. Duration of response in weeks = (date of confirmed loss of first attained response minus date of first attained response)/7 days.
Time Frame	204 weeks in the second-line participants and 48 weeks in the third-line participants

Outcome Measure Data

Analysis Population Description

Subset of participants who had the response among all treated population

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	13	2
Median (95% Confidence Interval); Unit of Measure: weeks
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median and 95% CI was not estimable due to the small number of responders who lost the response.

16. Secondary Outcome

Title	Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2
Description	CHR response was considered to be achieved if participants met all of the following criteria: White Blood Cells =< institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes <5% in blood, absolute neutrophil count >=1.0*10^9 per liter (/L), platelets >=100 but <450*10^9/L, <20% basophils in blood and no extramedulary involvement (including hepato- or splenomegaly), =<5% BM blasts.
Time Frame	Baseline up to Week 192

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Advanced Second-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	7
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	14.3; (0.4 to 57.9)

17. Secondary Outcome

Title	Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2
Description	The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last assessment date of a participant.
Time Frame	Baseline up to Week 192

Outcome Measure Data

Analysis Population Description

Subset of participants who had the response among all treated population.

Arm/Group Title	Bosutinib Advanced Second-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	1
Median (95% Confidence Interval); Unit of Measure: weeks
	84.0 [1]; (NA to NA)

[1]

Only 1 participant was analyzed, therefore, 95% CI was not calculated

18. Secondary Outcome

Title	Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2
Description	The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of first attained response - date of first attained response)/7.
Time Frame	Baseline up to Week 192

Outcome Measure Data

Analysis Population Description

Subset of participants who had the response among all treated population

Arm/Group Title	Bosutinib Advanced Second-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	1
Median (95% Confidence Interval); Unit of Measure: weeks
	95.3 [1]; (NA to NA)

[1]

Only 1 participant was analyzed, therefore, 95% CI was not calculated

19. Secondary Outcome

Title	Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
Description	OHR included CHR, no evidence of leukemia (NEL), minor hematologic response (MiHR) or return to chronic phase (RCP), participants had to meet at least 1 of this criterion. Criteria for RCP: disappearance of features defining AP/BP, but still in CP and persistence of clonal evolution. Criteria for MiHR: <15% blasts in blood and bone marrow, <30% blasts+promyelocytes in blood and bone marrow, <20% basophils in blood, no extramedullary disease other than liver/spleen. Criteria for CHR and NEL: <20% basophils in blood, no extramedullary involvement including liver/spleen, no peripheral blasts or promyelocytes, myelocytes + metamyelocytes <5% in blood, <5% (NEL) and <=5% (CHR) marrow blasts, 0.5*10^9 <= Absolute neutrophil count (ANC) <1.0*10^9/L (NEL) and ANC>=1.0*10^9/L (CHR), 20*10^9 <=platelets<100 *10^9/L (NEL) and platelets>=100 but <450x10^9/L (CHR), white blood cells <=institutional upper limit of the normal range.
Time Frame	Baseline up to Week 192

Outcome Measure Data

Analysis Population Description

Subset of the third-line cohort who was in accelerated or blast phase

Arm/Group Title	Bosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase (AP/BP) third-line imatinib resistant/intolerant followed by dasatinib or nilotinib resistant/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	1
Measure Type: Number; Unit of Measure: percentage of participants
	100

20. Secondary Outcome

Title	Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
Description	The time to OHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last assessment date of a participant.
Time Frame	Baseline up to Week 192

Outcome Measure Data

Analysis Population Description

Subset of participants who had the response among all treated population and who was in accelerated or blast phase in the third-line cohort

Arm/Group Title	Bosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase (AP/BP) third-line imatinib resistant/intolerant followed by dasatinib or nilotinib resistant/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	1
Median (95% Confidence Interval); Unit of Measure: weeks
	12.4 [1]; (NA to NA)

[1]

Only 1 participant was analyzed, therefore, 95% CI was not calculated

21. Secondary Outcome

Title	Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
Description	The duration of OHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of first attained response - date of first attained response)/7.
Time Frame	Baseline up to Week 192

Outcome Measure Data

Analysis Population Description

Subset of participants who had the response among all treated population and who was in accelerated or blast phase in the third-line cohort

Arm/Group Title	Bosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase (AP/BP) third-line imatinib resistant/intolerant followed by dasatinib or nilotinib resistant/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	1
Median (95% Confidence Interval); Unit of Measure: weeks
	36.1 [1]; (NA to NA)

[1]

Only 1 participant was analyzed, therefore, 95% CI was not calculated.

22. Secondary Outcome

Title	Time to Treatment Failure (TTF) Rate - Part 2
Description	TTF was the interval from the date of first dose of bosutinib until the earlier date of progression or death (any cause), withdrawal from treatment owing to an AE, subject refusal, or loss to follow-up (censored at the last contact date), or further anti-tumor therapy before documented progression (whichever occurred first). TTF rate indicates the probability of no treatment failure. Percent of participants with no treatment failure were estimated.
Time Frame	Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Advanced Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	28	7	11
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Week 48	67.9; (50.6 to 85.2)	14.3; (0.0 to 40.2)	81.8; (59.0 to 100)
Week 96	60.7; (42.6 to 78.8)	14.3; (0.0 to 40.2)	72.7; (46.4 to 99.0)
Week 144	57.1; (38.8 to 75.5)	14.3; (0.0 to 40.2)	63.6; (35.2 to 92.1)
Week 192	53.6; (35.1 to 72.0)	NA [1]; (NA to NA)	NA [2]; (NA to NA)
Week 240	53.6; (35.1 to 72.0)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
Week 288	45.9; (24.9 to 67.0)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
Week 336	NA [4]; (NA to NA)	NA [3]; (NA to NA)	NA [3]; (NA to NA)

[1]

TTF rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 179.

[2]

TTF rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 160.

[3]

Data was not collected as participants were only assessed up to Week 192.

[4]

TTF rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 312.

23. Secondary Outcome

Title	Progression-free Survival (PFS) Rate - Part 2
Description	PFS was based on Kaplan-Meier estimates. PFS was defined as time in weeks from start of study treatment to treatment discontinuation due to disease progression as assessed by the investigator. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from death case report forms (CRFs). Percent of participants with PFS were estimated.
Time Frame	Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Advanced Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	28	7	11
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Week 48	100; (100 to 100)	21.4; (0.0 to 56.3)	100; (100 to 100)
Week 96	94.4; (83.9 to 100)	21.4; (0.0 to 56.3)	88.9; (68.4 to 100)
Week 144	94.4; (83.9 to 100)	21.4; (0.0 to 56.3)	88.9; (68.4 to 100)
Week 192	94.4; (83.9 to 100)	NA [1]; (NA to NA)	NA [2]; (NA to NA)
Week 240	94.4; (83.9 to 100)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
Week 288	94.4; (83.9 to 100)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
Week 336	NA [4]; (NA to NA)	NA [3]; (NA to NA)	NA [3]; (NA to NA)

[1]

PFS rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 179.

[2]

PFS rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 160.

[3]

Data was not collected as participants were only assessed up to Week 192.

[4]

PFS rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 312.

24. Secondary Outcome

Title	Overall Survival (OS) Rate - Part 2
Description	OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death, censored at the participant's last contact date. Percent of participants with OS were estimated.
Time Frame	Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants

Outcome Measure Data

Analysis Population Description

All treated population was defined as all participants who received at least 1 dose of bosutinib.

Arm/Group Title	Bosutinib Primary Second-line 500 mg (Part 2 )	Bosutinib Advanced Second-line 500 mg (Part 2 )	Bosutinib Exploratory Third-line 500 mg (Part 2 )
Arm/Group Description:	Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.	Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.
Overall Number of Participants Analyzed	28	7	11
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Week 48	96.4; (89.6 to 100)	42.9; (6.2 to 79.5)	100; (100 to 100)
Week 96	96.4; (89.6 to 100)	42.9; (6.2 to 79.5)	100; (100 to 100)
Week 144	96.4; (89.6 to 100)	28.6; (0.0 to 62.0)	100; (100 to 100)
Week 192	96.4; (89.6 to 100)	NA [1]; (NA to NA)	NA [2]; (NA to NA)
Week 240	96.4; (89.6 to 100)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
Week 288	82.7; (57.0 to 100)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
Week 336	NA [4]; (NA to NA)	NA [3]; (NA to NA)	NA [3]; (NA to NA)

[1]

OS rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 179.

[2]

OS rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 160.

[3]

Data was not collected as participants were only assessed up to Week 192.

[4]

OS rate and 95% CI was not calculated as all participants were discontinued the follow up by Week 312.

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Arm/Group Title	Total Second-line	Exploratory Third-line	Total Population
Arm/Group Description	All participants who received bosutinib orally once daily in second-line chronic myelogenous leukemia (CML), who were imatinib resistant/refractory/intolerant.	All participants who received bosutinib 500 mg orally once daily in third-line chronic myelogenous leukemia (CML), participants were with imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant.	Total participants who were second-line or third-line chronic myelogenous leukemia (CML).
All-Cause Mortality
	Total Second-line	Exploratory Third-line	Total Population
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Total Second-line	Exploratory Third-line	Total Population
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	19/52 (36.54%)	2/11 (18.18%)	21/63 (33.33%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Cardiac disorders
Acute myocardial infarction † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Eye disorders
Cataract † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Macular fibrosis † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Macular hole † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Gastrointestinal disorders
Diarrhoea † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Vomiting † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
General disorders
Fatigue † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Hepatobiliary disorders
Hepatic function abnormal † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Liver injury † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Infections and infestations
Enterocolitis infectious † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Gastroenteritis † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Pertussis † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Pneumonia pneumococcal † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Urinary tract infection † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Diverticulitis † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Injury, poisoning and procedural complications
Spinal compression fracture † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Musculoskeletal and connective tissue disorders
Osteonecrosis † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Bladder neoplasm † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Blast cell crisis † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Nervous system disorders
Posterior reversible encephalopathy syndrome † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Cerebral haemorrhage † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Psychiatric disorders
Completed suicide † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Renal and urinary disorders
Renal impairment † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion † 1	2/52 (3.85%)	0/11 (0.00%)	2/63 (3.17%)
Pleurisy † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Alveolitis allergic † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Dyspnoea † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Skin and subcutaneous tissue disorders
Drug eruption † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
Rash † 1	1/52 (1.92%)	0/11 (0.00%)	1/63 (1.59%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Total Second-line	Exploratory Third-line	Total Population
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	52/52 (100.00%)	11/11 (100.00%)	63/63 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	13/52 (25.00%)	0/11 (0.00%)	13/63 (20.63%)
Eosinophilia † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Leukopenia † 1	11/52 (21.15%)	2/11 (18.18%)	13/63 (20.63%)
Lymphopenia † 1	19/52 (36.54%)	5/11 (45.45%)	24/63 (38.10%)
Neutropenia † 1	12/52 (23.08%)	2/11 (18.18%)	14/63 (22.22%)
Thrombocytopenia † 1	16/52 (30.77%)	2/11 (18.18%)	18/63 (28.57%)
Iron deficiency anaemia † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Cardiac disorders
Pericardial effusion † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Eye disorders
Conjunctival haemorrhage † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Cataract † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Gastrointestinal disorders
Abdominal discomfort † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Abdominal distension † 1	7/52 (13.46%)	0/11 (0.00%)	7/63 (11.11%)
Abdominal pain † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Abdominal pain upper † 1	7/52 (13.46%)	2/11 (18.18%)	9/63 (14.29%)
Cheilitis † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Constipation † 1	7/52 (13.46%)	0/11 (0.00%)	7/63 (11.11%)
Dental caries † 1	9/52 (17.31%)	2/11 (18.18%)	11/63 (17.46%)
Diarrhoea † 1	50/52 (96.15%)	10/11 (90.91%)	60/63 (95.24%)
Dyspepsia † 1	3/52 (5.77%)	2/11 (18.18%)	5/63 (7.94%)
Gastritis † 1	7/52 (13.46%)	0/11 (0.00%)	7/63 (11.11%)
Nausea † 1	19/52 (36.54%)	5/11 (45.45%)	24/63 (38.10%)
Proctalgia † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Stomatitis † 1	11/52 (21.15%)	1/11 (9.09%)	12/63 (19.05%)
Vomiting † 1	22/52 (42.31%)	1/11 (9.09%)	23/63 (36.51%)
Enterocolitis † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Pancreatitis acute † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Periodontal disease † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
General disorders
Chest discomfort † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Chills † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Fatigue † 1	7/52 (13.46%)	1/11 (9.09%)	8/63 (12.70%)
Malaise † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Pyrexia † 1	12/52 (23.08%)	0/11 (0.00%)	12/63 (19.05%)
Hepatobiliary disorders
Hepatic function abnormal † 1	7/52 (13.46%)	2/11 (18.18%)	9/63 (14.29%)
Liver disorder † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Infections and infestations
Bronchitis † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Cystitis † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Folliculitis † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Gastroenteritis † 1	8/52 (15.38%)	0/11 (0.00%)	8/63 (12.70%)
Gingivitis † 1	6/52 (11.54%)	1/11 (9.09%)	7/63 (11.11%)
Influenza † 1	5/52 (9.62%)	0/11 (0.00%)	5/63 (7.94%)
Nasopharyngitis † 1	30/52 (57.69%)	6/11 (54.55%)	36/63 (57.14%)
Otitis media † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Periodontitis † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Pharyngitis † 1	5/52 (9.62%)	0/11 (0.00%)	5/63 (7.94%)
Conjunctivitis † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Epididymitis † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Herpes zoster † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Upper respiratory tract infection † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Injury, poisoning and procedural complications
Arthropod sting † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Post-traumatic neck syndrome † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Contusion † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Investigations
Alanine aminotransferase increased † 1	20/52 (38.46%)	4/11 (36.36%)	24/63 (38.10%)
Amylase increased † 1	6/52 (11.54%)	1/11 (9.09%)	7/63 (11.11%)
Aspartate aminotransferase increased † 1	15/52 (28.85%)	4/11 (36.36%)	19/63 (30.16%)
Blood albumin decreased † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Blood alkaline phosphatase increased † 1	9/52 (17.31%)	2/11 (18.18%)	11/63 (17.46%)
Blood bilirubin increased † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Blood creatine phosphokinase decreased † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Blood creatine phosphokinase increased † 1	6/52 (11.54%)	2/11 (18.18%)	8/63 (12.70%)
Blood creatinine increased † 1	8/52 (15.38%)	0/11 (0.00%)	8/63 (12.70%)
Blood lactate dehydrogenase increased † 1	4/52 (7.69%)	2/11 (18.18%)	6/63 (9.52%)
Blood sodium decreased † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Electrocardiogram QT prolonged † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Gamma-glutamyltransferase increased † 1	9/52 (17.31%)	1/11 (9.09%)	10/63 (15.87%)
Haemoglobin decreased † 1	6/52 (11.54%)	0/11 (0.00%)	6/63 (9.52%)
Lipase increased † 1	11/52 (21.15%)	4/11 (36.36%)	15/63 (23.81%)
Liver function test abnormal † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Neutrophil count decreased † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Platelet count decreased † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Weight decreased † 1	9/52 (17.31%)	0/11 (0.00%)	9/63 (14.29%)
White blood cell count decreased † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Blood potassium increased † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Blood uric acid increased † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Weight increased † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Metabolism and nutrition disorders
Decreased appetite † 1	14/52 (26.92%)	1/11 (9.09%)	15/63 (23.81%)
Hyperglycaemia † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Hyperlipidaemia † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Hypophosphataemia † 1	13/52 (25.00%)	0/11 (0.00%)	13/63 (20.63%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/52 (5.77%)	2/11 (18.18%)	5/63 (7.94%)
Intervertebral disc protrusion † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Muscular weakness † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Musculoskeletal pain † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Myalgia † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Arthritis † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Back pain † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Pain in extremity † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Nervous system disorders
Dizziness † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Headache † 1	4/52 (7.69%)	1/11 (9.09%)	5/63 (7.94%)
Somnolence † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Dysgeusia † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Neuropathy peripheral † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Psychiatric disorders
Insomnia † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Renal and urinary disorders
Renal impairment † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Urogenital haemorrhage † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Pollakiuria † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain † 1	3/52 (5.77%)	1/11 (9.09%)	4/63 (6.35%)
Pleural effusion † 1	6/52 (11.54%)	2/11 (18.18%)	8/63 (12.70%)
Upper respiratory tract inflammation † 1	5/52 (9.62%)	0/11 (0.00%)	5/63 (7.94%)
Skin and subcutaneous tissue disorders
Acne † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Dry skin † 1	4/52 (7.69%)	1/11 (9.09%)	5/63 (7.94%)
Eczema † 1	6/52 (11.54%)	0/11 (0.00%)	6/63 (9.52%)
Erythema † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Generalised erythema † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Hyperkeratosis † 1	1/52 (1.92%)	1/11 (9.09%)	2/63 (3.17%)
Leukoderma † 1	3/52 (5.77%)	0/11 (0.00%)	3/63 (4.76%)
Photosensitivity reaction † 1	1/52 (1.92%)	2/11 (18.18%)	3/63 (4.76%)
Pruritus † 1	6/52 (11.54%)	2/11 (18.18%)	8/63 (12.70%)
Rash † 1	31/52 (59.62%)	5/11 (45.45%)	36/63 (57.14%)
Seborrhoeic dermatitis † 1	5/52 (9.62%)	0/11 (0.00%)	5/63 (7.94%)
Urticaria † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Eczema asteatotic † 1	4/52 (7.69%)	0/11 (0.00%)	4/63 (6.35%)
Erythema nodosum † 1	0/52 (0.00%)	1/11 (9.09%)	1/63 (1.59%)
Pigmentation disorder † 1	2/52 (3.85%)	1/11 (9.09%)	3/63 (4.76%)
Vascular disorders
Hypertension † 1	6/52 (11.54%)	0/11 (0.00%)	6/63 (9.52%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Takahashi N, Cortes JE, Sakaida E, Ishizawa K, Ono T, Doki N, Matsumura I, Garcia-Gutierrez V, Rosti G, Ono C, Ohkura M, Tanetsugu Y, Viqueira A, Brummendorf TH. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis. Int J Hematol. 2022 Jun;115(6):838-851. doi: 10.1007/s12185-022-03314-y. Epub 2022 Mar 2.

Takahashi N, Nakaseko C, Kobayashi Y, Miyamura K, Ono C, Koide Y, Fujii Y, Ohnishi K. Long-term treatment with bosutinib in a phase 1/2 study in Japanese chronic myeloid leukemia patients resistant/intolerant to prior tyrosine kinase inhibitor treatment. Int J Hematol. 2017 Sep;106(3):398-410. doi: 10.1007/s12185-017-2239-8. Epub 2017 Apr 13.

Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, Yamamoto K, Miyamura K, Taniwaki M, Okada M, Kawaguchi T, Shibata A, Fujii Y, Ono C, Ohnishi K. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol. 2015 Feb;101(2):154-64. doi: 10.1007/s12185-014-1722-8. Epub 2014 Dec 25.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00811070
• Other Study ID Numbers: 3160A4-2203; B1871007 ( Other Identifier: Alias Study Number )
• First Submitted: December 17, 2008
• First Posted: December 18, 2008
• Results First Submitted: March 3, 2014
• Results First Posted: June 4, 2014
• Last Update Posted: June 28, 2016