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Trial record 1 of 1 for:    NCT00811070
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Study Evaluating SKI-606 (Bosutinib) In Japanese Subjects With Philadelphia Chromosome Positive Leukemias

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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:
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
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 )
Hide 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
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
Hide 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
Hide 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%
1.Primary Outcome
Title Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1
Hide 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 )
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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 )
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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 )
Hide 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.
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
Hide 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   --/--   --/--   --/-- 
Show Serious Adverse Events Hide 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
Show Other (Not Including Serious) Adverse Events Hide 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
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
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00811070     History of Changes
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