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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00261846
Recruitment Status : Completed
First Posted : December 5, 2005
Results First Posted : March 12, 2013
Last Update Posted : July 27, 2017
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Chronic Myeloid Leukemia
Intervention Drug: Bosutinib
Enrollment 571
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 600 mg (Part 1) Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description Single oral dose of bosutinib 400 milligram (mg) on Day 1 and then bosutinib 400 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in chronic phase second-line (CP2L) chronic myelogenous leukemia (CML) Part 2 of the study. Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in advanced phase (AP) CML Part 2 of the study. Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM. Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML. All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I. All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I. Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Period Title: Period 1: Part 1 (Dose Escalation)
Started 3 3 12 0 0 0 0 0 0 0 0 0
Completed 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 3 3 12 0 0 0 0 0 0 0 0 0
Reason Not Completed
Continued in to Part 2             3             3             12             0             0             0             0             0             0             0             0             0
Period Title: Period 2: Part 2 (Efficacy)
Started 0 0 0 195 [1] 89 5 38 50 26 79 [2] 64 24
Completed 0 0 0 60 39 3 16 21 12 30 15 1
Not Completed 0 0 0 135 50 2 22 29 14 49 49 23
Reason Not Completed
Discontinuation of study by sponsor             0             0             0             1             0             0             0             0             1             0             0             0
Withdrawal by Subject             0             0             0             9             8             1             3             3             0             2             0             0
Lost to Follow-up             0             0             0             12             4             0             4             0             1             4             4             0
Other             0             0             0             15             4             0             1             5             4             4             0             0
Death             0             0             0             37             7             1             10             12             3             30             44             22
Extension study             0             0             0             61             27             0             4             9             5             9             1             1
[1]
17 participants from Part 1 (Bosutinib 400mg, 500mg, 600mg cohort) continued in Part 2 of the study.
[2]
1 participant from Part 1 (Bosutinib 600mg cohort) continued in Part 2 of the study.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2) Total
Hide Arm/Group Description Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM. Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML. All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I. All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I. Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL Total of all reporting groups
Overall Number of Baseline Participants 195 89 5 38 50 26 79 64 24 570
Hide Baseline Analysis Population Description
All-treated population - included all enrolled participants who received at least one dose of bosutinib.
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 195 participants 89 participants 5 participants 38 participants 50 participants 26 participants 79 participants 64 participants 24 participants 570 participants
<18 years 0 0 0 0 0 0 0 0 0 0
Between 18 and 44 years 73 22 1 5 7 10 26 29 6 179
Between 45 and 64 years 86 40 3 23 29 14 45 25 7 272
>=65 years 36 27 1 10 14 2 8 10 11 119
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 195 participants 89 participants 5 participants 38 participants 50 participants 26 participants 79 participants 64 participants 24 participants 570 participants
Female
82
  42.1%
53
  59.6%
3
  60.0%
20
  52.6%
31
  62.0%
12
  46.2%
35
  44.3%
22
  34.4%
12
  50.0%
270
  47.4%
Male
113
  57.9%
36
  40.4%
2
  40.0%
18
  47.4%
19
  38.0%
14
  53.8%
44
  55.7%
42
  65.6%
12
  50.0%
300
  52.6%
1.Primary Outcome
Title Number of Participants With Dose Limiting Toxicity (DLT)
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, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).
Time Frame Part 1 Baseline up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Measure Type: Number
Unit of Measure: participants
0 0 1
2.Primary Outcome
Title Maximum Tolerated Dose (MTD)
Hide Description

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. 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, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

NA = not estimable.

Time Frame Part 1 Baseline up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Measure Type: Number
Unit of Measure: mg
NA [1]  NA [1]  NA [1] 
[1]
MTD was not achieved since no more than 1 DLT was observed in any cohort. At the 600mg dose level, 1 DLT and several treatment related grade 2 toxicities were observed, thus, Bosutinib 500 mg was selected as the recommended dose for part 2.
3.Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax) - Part 1
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Mean (Standard Deviation)
Unit of Measure: nanogram per milliliter (ng/mL)
89.3  (50.0) 101.0  (35.6) 120.0  (40.2)
4.Primary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline efficacy assessment.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Median (Full Range)
Unit of Measure: hours (hrs)
4.00
(3.33 to 48.08)
6.00
(6.00 to 6.00)
4.00
(2.17 to 49.33)
5.Primary 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.

NA = not estimable.

Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 2 3 8
Mean (Standard Deviation)
Unit of Measure: hrs
22.91  (3.39) 22.46  (1.73) 22.24  (5.03)
6.Primary Outcome
Title Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1
Hide Description AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
1850  (710) 2060  (483) 2340  (1140)
7.Primary Outcome
Title Area Under the Concentration-Time Curve (AUC) - Part 1
Hide Description

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

NA = not estimable.

Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 2 3 8
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
2530  (1160) 2760  (687) 2420  (457)
8.Primary 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. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

NA = not estimable.

Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 2 3 8
Mean (Standard Deviation)
Unit of Measure: liter per hour (L/hr)
177  (81.3) 189  (47.5) 258  (61.2)
9.Primary 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 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 8
Mean (Standard Deviation)
Unit of Measure: liter
6050  (3550) 6080  (1230) 8540  (3820)
10.Primary Outcome
Title Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1
Hide Description Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 10
Mean (Standard Deviation)
Unit of Measure: ng/mL
146  (20.0) 200  (11.9) 208  (73.3)
11.Primary Outcome
Title Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1
Hide Description Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Median (Full Range)
Unit of Measure: hrs
4.05
(3.08 to 6.08)
6.05
(4.00 to 8.00)
6.00
(2.83 to 11.08)
12.Primary Outcome
Title Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1
Hide Description Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life over 24 hours at steady state (ss), on Day 15 was calculated.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 7
Mean (Standard Deviation)
Unit of Measure: hrs
45.96  (32.30) 21.71  (4.64) 25.87  (24.85)
13.Primary Outcome
Title Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1
Hide Description AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC over 24 hours at steady state (ss), on Day 15 was calculated.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 9
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
2720  (442) 3650  (425) 3630  (1270)
14.Primary Outcome
Title Apparent Oral Clearance at Steady State (CL/F,ss) - 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. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral clearence over 24 hours at steady state (ss), on Day 15 was calculated.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 9
Mean (Standard Deviation)
Unit of Measure: L/hr
150  (23.2) 138  (16.6) 185  (66.2)
15.Primary Outcome
Title Accumulation Ratio (R)
Hide Description R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)
Time Frame 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 9
Mean (Standard Deviation)
Unit of Measure: ratio
3.1  (1.4) 2.8  (0.8) 2.5  (0.9)
16.Primary Outcome
Title Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2
Hide Description CyR is based on the prevalence of Ph+ cells. Major cytogenetic response was categorized as either CCyR or partial CyR (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or less than (<) 1% positive cells from at least 200 cells analyzed from fluorescent in situ hybridization (FISH). PCyR was achieved when 1 to 35% Ph+ cells were present.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Overall Number of Participants Analyzed 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
35.7
(28.8 to 43.1)
17.Secondary Outcome
Title Percentage of Participants With Major Cytogenetic Response (MCyR) - 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% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.
Time Frame Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52)
Hide Outcome Measure Data
Hide Analysis Population Description
Cytogenetic evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline cytogenetic assessment.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 3 3 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
66.7
(9.4 to 99.2)
33.3
(0.8 to 90.6)
50.0
(21.1 to 78.9)
18.Secondary Outcome
Title Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1
Hide Description bcr-Abl is a protein resulting from the transcription of the Philadelphia chromosome following 9:22 chromosomal translocation, and phosphorylation inhibition of which correlates with inhibition of tumor cell growth.
Time Frame Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52)
Hide Outcome Measure Data
Hide Analysis Population Description
Data was not summarized since inadequate data included the issue that molecular transcript analyses could not be performed, because of potential sample quality issues due to time required to transport the specimens from the few investigational sites to the central laboratory.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
19.Secondary Outcome
Title Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1
Hide Description CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the cluster of differentiation 3 (CD3+) (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using fluorescent activated cell sorter (FACS) flow cytometry.
Time Frame 0 (pre-dose) on Day 1 (Baseline)
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 2 3 10
Mean (Standard Deviation)
Unit of Measure: mol/100 cells
457075  (559841.90) 297967.33  (171643.30) 397795.40  (552536.90)
20.Secondary Outcome
Title Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1
Hide Description

CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the CD3+ (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using FACS flow cytometry.

NA = not estimable.

Time Frame 6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' signifies number of participants who were evaluable for this measure. n=number of participants evaluable for this measure at specified time points for each arm group respectively.
Arm/Group Title Bosutinib 400 mg (Part 1) Bosutinib 500 mg (Part 1) Bosutinib 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 continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in AP-CML Part 2 of the study.
Overall Number of Participants Analyzed 1 3 9
Mean (Standard Deviation)
Unit of Measure: percent change
Day 1: post-dose (n=1, 1, 9) -34.66 [1]   (NA) 287.52 [1]   (NA) 97.79  (283.61)
Day 8: pre-dose (n=1, 1, 9) 562.48 [1]   (NA) 170.83 [1]   (NA) 3.88  (128.97)
Day 8: post-dose (n=1, 1, 9) 528.62 [1]   (NA) 429.79 [1]   (NA) 143.57  (289.18)
Day 15: pre-dose (n=1, 2, 7) 177.87 [1]   (NA) -44.64  (8.56) 119.23  (170.91)
Day 15: post-dose (n=1, 3, 7) -49.85 [1]   (NA) -21.13  (57.91) 138.45  (278.24)
[1]
Standard deviation was not estimable since only 1 participant was evaluable.
21.Secondary Outcome
Title Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2
Hide Description CyR is based on the prevalence of Ph+ cells. MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.
Time Frame Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L) or Year 5 (CP2L)
Hide Outcome Measure Data
Hide Analysis Population Description
Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-R (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Overall Number of Participants Analyzed 80 5 36 45 26 182
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
61.3
(49.7 to 71.9)
40.0
(5.3 to 85.3)
38.9
(23.1 to 56.5)
42.2
(27.7 to 57.9)
38.5
(20.2 to 59.4)
58.8
(51.3 to 66.0)
22.Secondary Outcome
Title Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2
Hide Description MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. The Kaplan-Meier probability of retaining an attained/maintained MCyR at Year 5 is reported. Median durations were not reached as of the minimum follow-up. Duration of response in weeks =(date of confirmed loss of first attained response or last valid cytogenetic assessment for those censored - date of first attained response)/7.
Time Frame From first MCyR to loss of MCyR or censoring, assessed every 12 weeks up to 2 years and then every 24 weeks thereafter up to Year 5
Hide Outcome Measure Data
Hide Analysis Population Description
Subgroup of participants from evaluable population who had MCyR.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Overall Number of Participants Analyzed 107 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: % probability of retaining MCyR
67.2
(56.8 to 75.6)
79.8
(63.1 to 89.5)
23.Secondary Outcome
Title Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2
Hide Description

MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. 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 equals (=) (event date minus (-) first dose date plus (+) 1)divided (/)7, where the event date is the non-missing date of the first attained response for responders only.

Time Frame Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5
Hide Outcome Measure Data
Hide Analysis Population Description
Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Overall Number of Participants Analyzed 107 49
Median (95% Confidence Interval)
Unit of Measure: weeks
12.3
(12.1 to 24.0)
12.1
(12.0 to 12.3)
24.Secondary Outcome
Title Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2
Hide Description

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes <5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10^9 per liter (/L) , platelets ≥100×10^9/L & <450×10^9/L, <20% basophils in blood & no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (ADV only & applicable to CP if BM aspirate was performed). 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 attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. The Kaplan-Meier estimate of maintaining CHR at the end of minimum follow-up is presented (CP2L: Year 5; CP3L & ADV: Year 4). NA = not estimable.

NA = not estimable.

Time Frame From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
Hide Outcome Measure Data
Hide Analysis Population Description
Subgroup of participants from evaluable population who had confirmed CHR.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 169 76 4 26 37 19 17 7 9 1 2
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: % estimate of maintaining response
61.5
(52.9 to 69.1)
78.2
(64.4 to 87.1)
50.0
(5.8 to 84.5)
56.5
(30.9 to 75.8)
69.9
(49.7 to 83.3)
61.9
(33.6 to 81.0)
47.1
(20.7 to 69.7)
64.3
(15.1 to 90.2)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
100 [2] 
(NA to 100)
[1]
KM estimate at Year 4 was NA due to insufficient patients and/or follow-up. 95% CIs were NA due to insufficient patients and/or follow-up.
[2]
Lower limit of the 95% CI was NA due to insufficient patients and/or follow-up.
25.Secondary Outcome
Title Duration of Complete Hematologic Response (CHR) - Part 2
Hide Description

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes less than (<)5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10^9 per liter (/L) , platelets <450×10^9/L, platelets ≥100×10^9/L, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed). 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 attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7.

NA = not estimable.

Time Frame From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
Hide Outcome Measure Data
Hide Analysis Population Description
Subgroup of participants from evaluable population who had confirmed CHR.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 169 76 4 26 37 19 17 7 9 1 2
Median (95% Confidence Interval)
Unit of Measure: weeks
NA [1] 
(297.7 to NA)
350.4 [2] 
(350.4 to NA)
NA [3] 
(9.6 to NA)
NA [3] 
(38.3 to NA)
295.6 [2] 
(289.0 to NA)
NA [3] 
(56.0 to NA)
138.0 [2] 
(24.0 to NA)
NA [3] 
(102.0 to NA)
28.6 [2] 
(20.1 to NA)
40.0 [4] 
(NA to NA)
NA [5] 
(NA to NA)
[1]
KM estimate at Year 5 was NA due to insufficient patients and/or follow-up. The upper limit of 95% CI was NA due to insufficient patients and/or follow-up.
[2]
The upper limit of 95% CI was NA due to insufficient patients and/or follow-up.
[3]
KM estimate at Year 4 was NA due to insufficient patients and/or follow-up. The upper limit of 95% CI was NA due to insufficient patients and/or follow-up.
[4]
95% CIs were NA due to insufficient patients and/or follow-up.
[5]
KM estimate at Year 4 was NA due to insufficient patients and/or follow-up. 95% CIs were NA due to insufficient patients and/or follow-up.
26.Secondary Outcome
Title Time to Achieve Complete Hematologic Response (CHR) for Responders Only - 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 for responders only.
Time Frame Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
Hide Outcome Measure Data
Hide Analysis Population Description
Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment - responders only.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 169 76 4 26 37 19 17 7 9 1 2
Median (95% Confidence Interval)
Unit of Measure: weeks
2.0
(1.1 to 2.1)
1.3
(1.1 to 2.1)
1.6
(1.1 to 2.1)
1.2
(1.1 to 3.0)
1.3
(1.1 to 2.3)
2.4
(1.1 to 3.3)
12.1
(8.1 to 24.0)
12.1
(4.3 to 72.0)
8.0
(4.0 to 13.0)
12.1 [1] 
(NA to NA)
10.0
(4.0 to 13.0)
[1]
95% CIs were NA due to insufficient patients and/or follow-up.
27.Secondary Outcome
Title Cumulative Incidence of Progression/Death - Part 2
Hide Description

The cumulative incidence of on-treatment progression or death adjusting for the competing risk of treatment discontinuation without the event. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4. 95% confidence intervals were calculated using Gray’s method.

NA = not estimable. One year = 12 months.

Time Frame Years 1, 2, 3, 4, and 5 (CP2L only)
Hide Outcome Measure Data
Hide Analysis Population Description
All-treated population included all enrolled participants who received at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 49 30 36 28 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Year 1
10.8
(7.2 to 16.1)
4.5
(1.7 to 11.7)
20.0
(3.5 to 100.0)
23.7
(13.4 to 41.9)
12.0
(5.7 to 25.4)
23.1
(11.4 to 46.6)
28.6
(18.4 to 44.5)
20.0
(9.8 to 40.9)
47.2
(33.4 to 66.7)
71.4
(56.5 to 90.3)
58.3
(41.6 to 81.8)
Year 2
19.0
(14.2 to 25.4)
6.7
(3.1 to 14.6)
40.0
(13.7 to 100.0)
23.7
(13.4 to 41.9)
14.0
(7.0 to 27.8)
30.8
(17.3 to 54.8)
42.9
(31.0 to 59.2)
23.3
(12.2 to 44.6)
50.0
(36.1 to 69.3)
71.4
(56.5 to 90.3)
58.3
(41.6 to 81.8)
Year 3
22.1
(16.9 to 28.7)
9.0
(4.6 to 17.4)
40.0
(13.7 to 100.0)
23.7
(13.4 to 41.9)
16.0
(8.5 to 30.2)
34.6
(20.4 to 58.7)
44.9
(32.9 to 61.2)
26.7
(14.7 to 48.3)
50.0
(36.1 to 69.3)
75.0
(60.6 to 92.9)
58.3
(41.6 to 81.8)
Year 4
22.6
(17.4 to 29.3)
9.0
(4.6 to 17.4)
40.0
(13.7 to 100.0)
23.7
(13.4 to 41.9)
16.0
(8.5 to 30.2)
34.6
(20.4 to 58.7)
44.9
(32.9 to 61.2)
26.7
(14.7 to 48.3)
50.0
(36.1 to 69.3)
75.0
(60.6 to 92.9)
58.3
(41.6 to 81.8)
Year 5
23.1
(17.9 to 29.8)
10.1
(5.4 to 18.8)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
In Part 2 subjects in CP3L and ADV treatment groups were only evaluated up to Year 4.
28.Secondary Outcome
Title Progression Free Survival (PFS) - Part 2
Hide Description

PFS was based on Kaplan-Meier method. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4.

NA = not estimable. One year = 12 months

Time Frame Years 1, 2, 3, 4, and 5 (CP2L only)
Hide Outcome Measure Data
Hide Analysis Population Description
All-treated population included all enrolled participants who received at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 49 30 36 28 24
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
81.5 [2] 
(81.5 to NA)
NA [3] 
(0.9 to NA)
NA [3] 
(11.1 to NA)
NA [3] 
(68.5 to NA)
NA [3] 
(14.1 to NA)
20.4 [2] 
(11.8 to NA)
35.4 [2] 
(14.6 to NA)
7.9
(4.0 to 10.1)
1.8
(0.9 to 5.5)
1.5
(0.7 to 3.8)
[1]
KM estimate at Year 5 was NA due to insufficient patients and/or follow-up. 95% CIs were NA due to insufficient patients and/or follow-up.
[2]
Upper limit of 95% CI was NA due to insufficient patients and/or follow-up.
[3]
KM estimate at Year 4 was NA due to insufficient patients and/or follow-up. Upper limit of 95% CI was NA due to insufficient patients and/or follow-up.
29.Secondary Outcome
Title Kaplan-Meier Estimate of Overall Survival (OS) - 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 or date of last contact for those censored.

NA = not estimable. One year = 12 months.

Time Frame Years 1, 2, 3, 4, and 5 (CP2L only)
Hide Outcome Measure Data
Hide Analysis Population Description
All-treated population included all enrolled participants who received at least 1 dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 49 30 36 28 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Year 1
96.3
(92.5 to 98.2)
98.9
(92.1 to 99.8)
100
(100 to 100)
85.8
(69.2 to 93.8)
91.8
(79.7 to 96.6)
96.2
(75.7 to 99.4)
81.3
(67.2 to 89.8)
72.9
(53.0 to 85.4)
44.3
(27.4 to 59.9)
39.3
(21.7 to 56.5)
16.7
(5.2 to 33.7)
Year 2
88.2
(82.7 to 92.1)
97.7
(91.0 to 99.4)
80.0
(20.4 to 96.9)
79.7
(62.0 to 89.8)
83.3
(69.3 to 91.3)
92.3
(72.6 to 98.0)
72.7
(57.6 to 83.1)
59.0
(39.2 to 74.3)
41.3
(24.9 to 57.0)
25.0
(11.1 to 41.8)
8.3
(1.4 to 23.3)
Year 3
84.1
(77.8 to 88.7)
93.0
(83.9 to 97.1)
80.0
(20.4 to 96.9)
66.1
(44.5 to 80.9)
83.3
(69.3 to 91.3)
86.5
(62.9 to 95.6)
70.1
(54.7 to 81.1)
45.1
(25.4 to 63.0)
41.3
(24.9 to 57.0)
16.7
(5.6 to 32.9)
8.3
(1.4 to 23.3)
Year 4
81.5
(74.7 to 86.6)
93.0
(83.9 to 97.1)
80.0
(20.4 to 96.9)
66.1
(44.5 to 80.9)
79.3
(63.1 to 89.0)
86.5
(62.9 to 95.6)
65.7
(48.6 to 78.3)
45.1
(25.4 to 63.0)
20.7
(2.0 to 53.2)
16.7
(5.6 to 32.9)
8.3
(1.4 to 23.3)
Year 5
80.6
(73.6 to 85.9)
88.4
(76.6 to 94.5)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
In Part 2 subjects in CP3L and ADV treatment groups were only evaluated up to Year 4.
30.Secondary Outcome
Title Overall Survival (OS) - 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 or date of last contact for those censored.

NA = not estimable. One year = 12 months.

Time Frame Years 1, 2, 3, 4, and 5 (CP2L only)
Hide Outcome Measure Data
Hide Analysis Population Description
All-treated population included all enrolled participants who received at least 1 dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 49 30 36 28 24
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
81.5 [2] 
(81.5 to NA)
NA [3] 
(21.0 to NA)
NA [3] 
(34.4 to NA)
NA [3] 
(68.5 to NA)
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
33.4 [2] 
(14.6 to NA)
11.2 [2] 
(9.4 to NA)
8.9
(4.1 to 17.4)
3.6
(1.3 to 7.6)
[1]
KM estimate at Year 5 was NA due to insufficient patients and/or follow-up. 95% CIs were NA due to insufficient patients and/or follow-up.
[2]
The upper 95% CI was NA due to insufficient patients and/or follow-up.
[3]
KM estimate at Year 4 was NA due to insufficient patients and/or follow-up. The upper 95% CI was NA due to insufficient patients and/or follow-up.
[4]
KM estimate at Year 4 was NA due to insufficient patients and/or follow-up. 95% CIs were NA due to insufficient patients and/or follow-up.
31.Secondary Outcome
Title Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2
Hide Description Hematologic response: if participants met all of the following criteria of CHR: 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/L , platelets <450×10^9/L, platelets ≥100×10^9/L, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed).
Time Frame Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
Hide Outcome Measure Data
Hide Analysis Population Description
Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 194 89 5 38 49 25 43 29 34 26 22
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
87.1
(81.6 to 91.5)
85.4
(76.3 to 92.0)
80.0
(28.4 to 99.5)
68.4
(51.3 to 82.5)
75.5
(61.1 to 86.7)
76.0
(54.9 to 90.6)
39.5
(25.0 to 55.6)
24.1
(10.3 to 43.5)
26.5
(12.9 to 44.4)
3.8
(0.1 to 19.6)
9.1
(1.1 to 29.2)
32.Secondary Outcome
Title Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2
Hide Description OHR included CHR, no evidence of leukemia (≤5% bone marrow blasts, no peripheral blood blasts or promyelocytes, <5% myelocytes + metamyelocytes in blood, white blood cells ≤ institutional upper limit of normal, 450x10^9/L > platelets > 20x10^9/L, absolute neutrophil count ≥0.5x10^9/L, <20% basophils in blood, no extramedullary involvement [including liver or spleen]), minor hematologic response (acute lymphoblastic leukemia [ALL] patients only, defined as <15% blasts in marrow & blood, <30% blasts + promyelocytes in marrow & blood, <20% basophils in peripheral blood & no extramedullary disease other than spleen & liver) or return to chronic phase (AP/BP participants, defined as <15% blasts in both peripheral blood &bone marrow, <30% blasts + promyelocytes in both peripheral blood & bone marrow, <20% basophils in both peripheral blood & bone marrow, no extramedullary Involvement other than liver or spleen). Participants had to meet at least 1 criterion.
Time Frame Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment.
Arm/Group Title Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 43 29 34 26 22
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
67.4
(51.5 to 80.9)
41.4
(23.5 to 61.1)
38.2
(22.2 to 56.4)
15.4
(4.4 to 34.9)
9.1
(1.1 to 29.2)
33.Secondary Outcome
Title Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time Frame Baseline up to follow up visit (30 days after last dose of study treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 49 30 36 28 24
Measure Type: Number
Unit of Measure: percentage of participants
AEs 99.5 100.0 100.0 100.0 100.0 100.0 100.0 100.0 97.2 100.0 95.8
SAEs 41.5 38.2 20.0 39.5 38.0 19.2 49.0 63.3 55.6 60.7 70.8
34.Secondary Outcome
Title Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)
Hide Description

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. The event did not necessarily have a causal relationship with the treatment. PCI AEs included anemia, alanine aminotranferase (ALT), aspartate aminotransferase (AST), cardiac, diarrhea, edema, effusion, gastrointestinal, hemorrhage, hypersensitivity, hypertension, infection, liver, myelosuppression, nausea, neutropenia, rash, renal, thrombocytopenia, vomiting, and vascular events. Duration of AE was calculated as (stop date minus start date) plus 1 for non-missing and non-partial dates.

NA = not estimable.

Time Frame Baseline up to follow-up visit (30 days after last dose of study treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 79 64 24
Median (Full Range)
Unit of Measure: days
Anaemia
14.0
(1 to 1373)
36.0
(2 to 688)
38.0
(38 to 38)
19.0
(1 to 284)
13.0
(6 to 271)
61.0
(6 to 335)
12.5
(1 to 502)
4.0
(1 to 52)
7.0
(1 to 20)
ALT
29.0
(1 to 775)
15.0
(1 to 344)
NA [1] 
(NA to NA)
21.5
(7 to 236)
8.0
(5 to 87)
21.0
(4 to 42)
21.5
(7 to 252)
7.5
(1 to 41)
3.0
(1 to 5)
AST
29.0
(1 to 803)
13.5
(1 to 330)
NA [1] 
(NA to NA)
18.0
(14 to 22)
8.5
(8 to 22)
15.0
(8 to 21)
14.0
(1 to 188)
2.0
(2 to 2)
5.0
(5 to 5)
Diarrhoea
1.0
(1 to 2174)
2.0
(1 to 1121)
2.0
(1 to 59)
2.0
(1 to 189)
2.0
(1 to 413)
1.0
(1 to 289)
2.0
(1 to 910)
2.0
(1 to 211)
3.0
(1 to 500)
Effusion
18.5
(1 to 1428)
29.0
(5 to 657)
79.5
(14 to 421)
20.0
(7 to 842)
28.0
(1 to 907)
20.0
(5 to 258)
21.0
(4 to 1536)
58.0
(11 to 101)
5.0
(4 to 25)
Infection
10.0
(1 to 1026)
9.5
(1 to 546)
11.5
(1 to 46)
8.0
(1 to 85)
9.0
(2 to 366)
8.0
(1 to 183)
9.0
(1 to 281)
9.5
(1 to 78)
9.0
(1 to 39)
Nausea
2.0
(1 to 972)
4.0
(1 to 446)
4.0
(1 to 7)
2.0
(1 to 168)
14.0
(1 to 713)
2.0
(1 to 42)
6.0
(1 to 247)
6.5
(1 to 274)
9.0
(1 to 31)
Neutropenia
23.0
(1 to 506)
15.0
(1 to 337)
23.0
(13 to 70)
14.5
(4 to 81)
21.0
(3 to 504)
26.0
(7 to 92)
8.0
(1 to 252)
5.0
(1 to 52)
6.5
(5 to 8)
Oedema
29.0
(1 to 1416)
81.5
(1 to 1807)
4.0
(1 to 52)
1.0
(1 to 455)
12.5
(2 to 774)
28.0
(3 to 316)
88.5
(2 to 670)
11.0
(1 to 214)
5.0
(1 to 8)
Rash
15.0
(1 to 1622)
13.0
(1 to 965)
17.0
(7 to 52)
12.0
(1 to 348)
19.0
(1 to 1612)
12.5
(1 to 150)
13.0
(1 to 428)
7.5
(1 to 218)
12.0
(1 to 33)
Renal events
27.0
(1 to 831)
190.0
(7 to 903)
1167.0
(1167 to 1167)
162.0
(21 to 299)
11.0
(1 to 203)
56.5
(29 to 84)
26.0
(3 to 1403)
9.0
(1 to 27)
12.0
(12 to 12)
Thrombocytopenia
22.0
(1 to 1762)
15.0
(1 to 1541)
38.5
(14 to 120)
15.0
(1 to 336)
15.0
(2 to 420)
21.5
(6 to 350)
11.5
(1 to 889)
5.0
(1 to 176)
9.0
(3 to 43)
Vomiting
1.0
(1 to 165)
1.0
(1 to 36)
NA [1] 
(NA to NA)
1.0
(1 to 141)
2.0
(1 to 59)
7.0
(1 to 39)
1.0
(1 to 128)
1.0
(1 to 41)
1.5
(1 to 9)
Cardiac events
11.0
(1 to 1428)
6.0
(1 to 657)
NA [1] 
(NA to NA)
7.5
(1 to 842)
22.0
(1 to 907)
1.0
(1 to 1)
14.0
(1 to 1536)
3.0
(1 to 19)
1.5
(1 to 2)
Vascular events
3.5
(1 to 277)
6.0
(1 to 59)
NA [1] 
(NA to NA)
10.5
(3 to 18)
1.5
(1 to 266)
10.0
(10 to 10)
2.0
(1 to 22)
1.0
(1 to 14)
1.0
(1 to 19)
Hypertension
16.0
(1 to 1343)
1.0
(1 to 1659)
NA [1] 
(NA to NA)
7.0
(7 to 7)
1.0
(1 to 418)
NA [1] 
(NA to NA)
5.0
(1 to 204)
NA [1] 
(NA to NA)
2.0
(2 to 2)
Gastrointestinal events
1.0
(1 to 2174)
2.0
(1 to 1121)
2.0
(1 to 59)
2.0
(1 to 189)
2.0
(1 to 713)
2.0
(1 to 289)
2.0
(1 to 910)
3.0
(1 to 274)
4.0
(1 to 500)
Haemorrhage
10.0
(1 to 862)
16.0
(1 to 131)
23.0
(23 to 23)
4.0
(1 to 11)
27.5
(1 to 190)
7.5
(1 to 58)
6.0
(1 to 147)
4.0
(1 to 28)
3.5
(1 to 21)
Hypersensitivity
9.0
(6 to 38)
8.0
(7 to 9)
NA [1] 
(NA to NA)
7.0
(1 to 28)
6.0
(1 to 15)
5.0
(1 to 9)
1.0
(1 to 1)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
Liver
29.0
(1 to 803)
16.0
(1 to 344)
8.0
(8 to 8)
25.5
(7 to 236)
9.0
(5 to 136)
21.0
(3 to 82)
16.0
(1 to 252)
8.0
(1 to 441)
5.0
(1 to 9)
Myelosuppression
22.0
(1 to 1762)
18.0
(1 to 1541)
28.0
(13 to 120)
15.0
(1 to 336)
15.0
(2 to 504)
27.0
(6 to 769)
11.5
(1 to 889)
5.0
(1 to 376)
7.0
(1 to 43)
[1]
No events therefore duration not available.
35.Secondary Outcome
Title Percentage of Participants With Change From Baseline in Laboratory Tests Results
Hide Description Laboratory assessments included urinalysis, complete blood count (CBC), prothrombin time/partial prothromboplastin time (PT/PPT), international normalized ratio (INR), blood chemistry and serum pregnancy test (β-HCG). Parameters of special interest included liver function tests and those related to myelosuppression. Potentially clinically important (PCI) laboratory values were defined as National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher. Maximum CTCAE grade, and only participants who shifted to Grade 3/4 on-treatment, are reported.
Time Frame Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 79 64 24
Measure Type: Number
Unit of Measure: Percentage of Participants
Hemoglobin: shift from Normal to Grade 3 0.5 1.1 0.0 0.0 0.0 3.8 5.1 1.6 0.0
Hemoglobin: shift from Normal to Grade 4 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Hemoglobin: shift from Grade 1 to Grade 3 3.6 10.1 0.0 2.6 0.0 0.0 7.6 6.3 8.3
Hemoglobin: shift from Grade 1 to Grade 4 1.5 0.0 0.0 0.0 4.0 0.0 1.3 3.1 0.0
Hemoglobin: shift from Grade 2 to Grade 3 3.1 6.7 0.0 7.9 0.0 0.0 10.1 15.6 16.7
Hemoglobin: shift from Grade 2 to Grade 4 2.1 1.1 0.0 0.0 4.0 0.0 2.5 4.7 4.2
Hemoglobin: shift from Grade 3 to Grade 4 0.5 0.0 0.0 0.0 0.0 0.0 5.1 4.7 0.0
Absolute neutrophils (ANC): Normal to Grade 3 7.2 9.0 0.0 5.3 4.0 11.5 10.1 3.1 0.0
ANC: shift from Normal to Grade 4 2.1 3.4 20.0 7.9 4.0 3.8 2.5 3.1 0.0
ANC: shift from Grade 1 to Grade 3 0.0 2.2 0.0 0.0 0.0 0.0 2.5 7.8 12.5
ANC: shift from Grade 1 to Grade 4 0.5 0.0 0.0 2.6 2.0 0.0 1.3 20.3 4.2
ANC: shift from Grade 2 to Grade 3 1.0 3.4 0.0 2.6 2.0 0.0 3.8 0.0 0.0
ANC: shift from Grade 2 to Grade 4 0.0 0.0 0.0 0.0 0.0 0.0 1.3 3.1 8.3
ANC: shift from Grade 3 to Grade 4 0.0 1.1 0.0 0.0 2.0 0.0 0.0 4.7 8.3
Platelet count: shift from Normal to Grade 3 13.3 13.5 0.0 15.8 12.0 7.7 11.4 4.7 4.2
Platelet count: shift from Normal to Grade 4 3.6 7.9 0.0 0.0 8.0 15.4 7.6 1.6 0.0
Platelet count: shift from Grade 1 to Grade 3 3.6 5.6 0.0 2.6 2.0 3.8 5.1 3.1 4.2
Platelet count: shift from Grade 1 to Grade 4 1.5 1.1 0.0 2.6 4.0 0.0 6.3 6.3 0.0
Platelet count: shift from Grade 2 to Grade 3 0.5 2.2 20.0 0.0 2.0 0.0 3.8 4.7 0.0
Platelet count: shift from Grade 2 to Grade 4 0.5 0.0 0.0 0.0 0.0 0.0 1.3 4.7 0.0
Platelet count: shift from Grade 3 to Grade 4 1.0 0.0 0.0 0.0 2.0 0.0 5.1 10.9 29.2
ALT: shift from Normal to Grade 3 8.7 12.4 0.0 0.0 10.0 15.4 5.1 1.6 0.0
ALT: shift from Grade 1 to Grade 3 1.0 0.0 0.0 0.0 0.0 0.0 3.8 0.0 0.0
AST: shift from Normal to Grade 3 4.1 7.9 0.0 0.0 0.0 7.7 2.5 1.6 0.0
AST: shift from Normal to Grade 4 0.0 0.0 0.0 0.0 0.0 3.8 0.0 0.0 0.0
AST: shift from Grade 1 to Grade 3 0.0 0.0 0.0 0.0 2.0 0.0 2.5 0.0 0.0
ALP: shift from Normal to Grade 3 0.0 0.0 0.0 0.0 0.0 0.0 1.3 0.0 0.0
ALP: shift from Grade 1 to Grade 3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.6 0.0
Total bilirubin: shift from Normal to Grade 3 0.0 0.0 0.0 0.0 2.0 0.0 0.0 6.3 4.2
ALT: shift from Normal to Grade 4 0.0 2.2 0.0 0.0 0.0 3.8 0.0 0.0 0.0
Total bilirubin: shift from Grade 2 to Grade 3 0.0 0.0 0.0 0.0 2.0 0.0 0.0 0.0 0.0
36.Secondary Outcome
Title Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings
Hide Description Criteria for PCI changes in ECG (12-lead) were defined as: no sinus rhythm; PR interval >=220 msec and increase of >=20 msec; QRS interval >=120 msec; QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett formula (QTcB) >500 msec or increase of >60 msec; heart rate <=45 beats per minute (bpm) or >=120 bpm or decrease/increase of >=15 bpm.
Time Frame Baseline, 0 (pre-dose), 2, 4, 6 hours on Day 1, 0 (pre-dose), 2, 4, 6, 20-23 hours on Day 21, and end of treatment visit
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication. 'N' (Number of Participants Analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 37 50 26 78 62 23
Measure Type: Number
Unit of Measure: Percentage of participants
32.3 23.6 20.0 24.3 22.0 23.1 39.7 59.7 34.8
37.Secondary Outcome
Title Number of Participants With Change From Baseline in Findings of Chest X-ray
Hide Description Number of participants whose chest X-ray results changed (worsened or improved) from the Baseline.
Time Frame Baseline, Week 8, and end of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at lease one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 79 64 24
Measure Type: Number
Unit of Measure: participants
Worsened From Baseline 35 18 1 6 18 3 16 10 3
Improved From Baseline 15 7 0 4 1 3 6 11 1
Total 50 25 1 10 19 6 22 21 4
38.Secondary Outcome
Title Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)
Hide Description Number of participants taking any non-study medications which were administered from Study Day 1 to 30 days after last dose of study treatment as a management of an AE are reported.
Time Frame Baseline and Weeks 1, 2, 3, 4, 8, 12, then every 12 weeks thereafter until end of treatment, for a mean duration of 28 months
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 79 64 24
Measure Type: Number
Unit of Measure: participants
ALT 7 3 0 0 0 1 1 0 0
AST 5 3 0 2 3 4 2 0 0
Anemia 6 8 2 2 2 1 6 1 1
Cardiac events 13 4 0 2 6 0 7 2 1
Gastrointestinal toxicity - Diarrhoea 120 46 2 22 26 14 44 22 10
Effusion 11 5 1 3 9 1 9 2 0
Haemorrhage 12 3 0 1 0 1 4 6 3
Hypertension 15 4 0 2 4 1 7 2 2
Hypersensitivity reactions 5 2 0 4 2 2 1 1 0
Infection 92 39 4 11 18 10 37 30 7
Hepatic events 10 5 0 0 0 2 3 3 0
Gastrointestinal toxicity - Nausea 33 25 1 11 10 8 19 23 7
Neutropenia 2 5 1 5 1 1 6 5 2
Rash 44 37 2 8 16 3 20 9 2
Oedema 13 9 1 3 3 0 7 7 3
Renal 2 2 0 0 1 0 4 3 0
Thrombocytopenia 4 2 3 10 19 13 3 3 0
Vascular events 6 3 0 0 3 0 2 1 0
Gastrointestinal toxicity - Vomiting 25 9 0 5 7 4 17 14 4
39.Secondary Outcome
Title Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
Hide Description ECOG-PS measured on-therapy (time between first dose and last dose date with a 30-day lag) assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work;2=ambulatory (>50% of waking hrs), capable of all self care, unable to carry out any work activities;3=capable of only limited self care, confined to bed/chair >50% of waking hrs;4=completely disabled, cannot carry on any self care, totally confined to bed/chair;5=dead.
Time Frame Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg, AP-CML IM R/I (Part 2) Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, BP-CML IM R/I (Part 2) Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with AP IM R/I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with AP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with BP IM R/I CML ; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with BP Multi-TKI: IM, D and/or NI R/I CML.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 195 89 5 38 50 26 49 30 36 28 24
Measure Type: Number
Unit of Measure: participants
Baseline: Grade 0; maximum on-therapy: Grade 0 92 36 2 21 20 19 17 9 9 2 2
Baseline: Grade 0; maximum on-therapy: Grade 1 50 25 0 5 8 5 11 5 47 2 4
Baseline: Grade 0; maximum on-therapy: Grade 2 3 3 0 0 1 0 0 1 0 1 2
Baseline: Grade 0; maximum on-therapy: Grade 3 4 2 0 1 1 0 1 0 0 0 0
Baseline: Grade 0; maximum on-therapy: Grade 4 2 0 0 0 0 0 0 0 0 0 0
Baseline: Grade 1; maximum on-therapy: Grade 0 0 0 0 2 0 0 0 1 3 1 1
Baseline: Grade 1; maximum on-therapy: Grade 1 32 13 2 7 13 2 14 7 7 5 3
Baseline: Grade 1; maximum on-therapy: Grade 2 10 6 1 1 5 0 2 5 0 6 3
Baseline: Grade 1; maximum on-therapy: Grade 3 0 2 0 0 0 0 2 0 0 3 0
Baseline: Grade 1; maximum on-therapy: Grade 4 2 0 0 0 0 0 0 1 1 0 0
Baseline: Grade 2; maximum on-therapy: Grade 0 0 0 0 0 0 0 0 0 1 0 0
Baseline: Grade 2; maximum on-therapy: Grade 1 0 0 0 0 0 0 1 0 0 1 0
Baseline: Grade 2; maximum on-therapy: Grade 2 0 1 0 0 0 0 0 0 6 1 4
Baseline: Grade 2; maximum on-therapy: Grade 3 0 0 0 0 0 0 0 1 2 1 0
Baseline: Grade 2; maximum on-therapy: Grade 4 0 0 0 0 0 0 0 0 0 1 1
Baseline: Missing 0 1 0 0 1 0 0 0 0 0 0
Baseline: Grade 0; maximum on-therapy: Missing 0 0 0 1 1 0 0 0 0 1 1
Baseline: Grade 1; maximum on-therapy: Missing 0 0 0 0 0 0 0 0 0 3 3
40.Secondary Outcome
Title Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs
Hide Description Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of <40 beats per min and value >150 beats per min, systolic blood pressure (SBP) of <80 or >210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, respiratory rate (Resp) of <10 or >50 breaths/min and criteria for PCI change in physical examination: >=10% increase or decrease of body weight in kilogram (kg).
Time Frame Screening, Baseline, and end of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 188 81 5 35 46 25 75 56 20
Measure Type: Number
Unit of Measure: percentage of participants
SBP >210 mmHg 1.1 0 0 0 0 0 0 0 0
Weight increase 10% 16.0 6.3 20.0 12.1 6.5 16.0 11.0 7.5 6.3
Weight decrease 10% 21.9 16.3 0 6.1 15.2 0 23.3 9.4 0
SBP <80 mmHg 0 0 0 0 0 4.0 0 0 0
Temperature <32C 0 0 0 0 0 4.0 0 0 0
Pulse <40bpm 0 1.4 0 0 0 0 0 0 0
Resp >50 breaths/min 0 0 0 0 0 5.0 0 0 0
Resp <10 breaths/min 0 0 0 0 2.4 0 0 0 0
41.Secondary Outcome
Title Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values
Hide Description Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of <40 beats per min and value >150 beats per min, SBP of <80 or >210 mmHg, DBP of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, Resp of <10 or >50 breaths/min and criteria for PCI change in physical examination: >=10% increase or decrease of body weight in kg. No Ph+ ALL participants were analyzed post-therapy (N=0). Part 1 safety data were originally presented in 2011 and are included as cumulative data in the Part 2 final safety results.
Time Frame Post-therapy
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who receive at least one dose of study medication. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure. PLEASE NOTE: Results were not applicable for Arms in Part 1 since all participants in Part 1 entered Part 2 and continued the study treatment.
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description:
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Overall Number of Participants Analyzed 24 16 1 2 11 4 8 3 0
Measure Type: Number
Unit of Measure: percentage of participants
Pulse <40 bpm 4.2 0 0 0 0 0 0 0
SBP >210 mmHg 0 0 0 0 0 0 12.5 0
Weight increase 10% 4.2 0 0 0 0 0 0 33.3
Weight decrease 10% 12.5 6.7 0 0 9.1 0 16.7 0
Time Frame Adverse events (AEs) and serious AEs were assessed from informed consent through and including 30 days after last administration of study treatment or at the End of Treatment Visit, whichever comes last.
Adverse Event Reporting Description An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study. Part 1 safety data were originally presented in 2011 and are included as cumulative data in the Part 2 final safety results.
 
Arm/Group Title Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Hide Arm/Group Description Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM. Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML. Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML. All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I. All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I. Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
All-Cause Mortality
Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) AP-CML Total (Part 2) BP-CML Total (Part 2) Bosutinib 500 mg, Ph+ ALL (Part 2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   81/195 (41.54%)   34/89 (38.20%)   1/5 (20.00%)   15/38 (39.47%)   19/50 (38.00%)   5/26 (19.23%)   43/79 (54.43%)   37/64 (57.81%)   17/24 (70.83%) 
Blood and lymphatic system disorders                   
Thrombocytopenia * 1  3/195 (1.54%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  3/79 (3.80%)  0/64 (0.00%)  1/24 (4.17%) 
Anaemia * 1  3/195 (1.54%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  5/79 (6.33%)  1/64 (1.56%)  0/24 (0.00%) 
Febrile neutropenia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  3/64 (4.69%)  4/24 (16.67%) 
Leukocytosis * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  2/64 (3.13%)  2/24 (8.33%) 
Neutropenia * 1  0/195 (0.00%)  0/89 (0.00%)  1/5 (20.00%)  3/38 (7.89%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  1/24 (4.17%) 
Granulocytopenia * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Leukopenia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  1/24 (4.17%) 
Pancytopenia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  1/24 (4.17%) 
Splenomegaly * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Leukostasis syndrome * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Cardiac disorders                   
Atrial fibrillation * 1  3/195 (1.54%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  2/50 (4.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Acute myocardial infarction * 1  2/195 (1.03%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  1/79 (1.27%)  1/64 (1.56%)  0/24 (0.00%) 
Cardiac failure * 1  3/195 (1.54%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Cardiac failure congestive * 1  3/195 (1.54%)  2/89 (2.25%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Coronary artery disease * 1  1/195 (0.51%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Myocardial infarction * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  1/50 (2.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Pericardial effusion * 1  2/195 (1.03%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  2/50 (4.00%)  0/26 (0.00%)  2/79 (2.53%)  0/64 (0.00%)  0/24 (0.00%) 
Pericarditis * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Angina pectoris * 1  1/195 (0.51%)  2/89 (2.25%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Angina unstable * 1  2/195 (1.03%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Arrhythmia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Left ventricular dysfunction * 1  2/195 (1.03%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Pericardial haemorrhage * 1  2/195 (1.03%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Tachycardia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  2/79 (2.53%)  0/64 (0.00%)  0/24 (0.00%) 
Bradycardia * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Cardiorenal syndrome * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Coronary artery stenosis * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Extrasystoles * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Palpitations * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Pleuropericarditis * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Ventricular fibrillation * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Cardiac arrest * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Cardiac disorder * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Congenital, familial and genetic disorders                   
Cytogenetic abnormality * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  1/26 (3.85%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Eye disorders                   
Diplopia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Glaucoma * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Cataract * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Visual acuity reduced * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Vitreous haemorrhage * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Gastrointestinal disorders                   
Diarrhoea * 1  4/195 (2.05%)  3/89 (3.37%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  1/64 (1.56%)  2/24 (8.33%) 
Nausea * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  5/64 (7.81%)  1/24 (4.17%) 
Gastrointestinal haemorrhage * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  2/64 (3.13%)  1/24 (4.17%) 
Vomiting * 1  0/195 (0.00%)  2/89 (2.25%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  4/64 (6.25%)  1/24 (4.17%) 
Abdominal pain * 1  2/195 (1.03%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  3/79 (3.80%)  1/64 (1.56%)  0/24 (0.00%) 
Inguinal hernia * 1  0/195 (0.00%)  2/89 (2.25%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Pancreatitis * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Rectal haemorrhage * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  1/26 (3.85%)  0/79 (0.00%)  0/64 (0.00%)  1/24 (4.17%) 
Abdominal pain upper * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Gastritis * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Haematochezia * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Intestinal obstruction * 1  1/195 (0.51%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Toothache * 1  0/195 (0.00%)  2/89 (2.25%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Abdominal adhesions * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Abdominal distension * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Colitis * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  1/26 (3.85%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Colitis ischaemic * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Colitis ulcerative * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  1/26 (3.85%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Dental caries * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Duodenal ulcer haemorrhage * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Dysphagia * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Epigastric discomfort * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Food poisoning * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Gastritis erosive * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Ileus * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Lower gastrointestinal haemorrhage * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Melaena * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Pancreatitis acute * 1  1/195 (0.51%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Proctocolitis * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  1/26 (3.85%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Retroperitoneal haemorrhage * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Abdominal pain lower * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  0/64 (0.00%)  0/24 (0.00%) 
Gastrooesophageal reflux disease * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Haemorrhoids * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Intestinal haemorrhage * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Intestinal ischaemia * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Large intestinal stenosis * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
General disorders                   
Pyrexia * 1  5/195 (2.56%)  2/89 (2.25%)  0/5 (0.00%)  1/38 (2.63%)  1/50 (2.00%)  0/26 (0.00%)  4/79 (5.06%)  5/64 (7.81%)  1/24 (4.17%) 
Chest pain * 1  2/195 (1.03%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  3/79 (3.80%)  1/64 (1.56%)  0/24 (0.00%) 
General physical health deterioration * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  1/79 (1.27%)  3/64 (4.69%)  2/24 (8.33%) 
Asthenia * 1  3/195 (1.54%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Disease progression * 1  3/195 (1.54%)  0/89 (0.00%)  0/5 (0.00%)  1/38 (2.63%)  0/50 (0.00%)  0/26 (0.00%)  4/79 (5.06%)  3/64 (4.69%)  1/24 (4.17%) 
Chills * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  1/24 (4.17%) 
Multi-organ failure * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  2/79 (2.53%)  0/64 (0.00%)  0/24 (0.00%) 
Oedema * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  1/50 (2.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  1/24 (4.17%) 
Pain * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  2/64 (3.13%)  0/24 (0.00%) 
Adverse drug reaction * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Local swelling * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Malaise * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  1/24 (4.17%) 
Mucosal inflammation * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Oedema peripheral * 1  0/195 (0.00%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  1/64 (1.56%)  0/24 (0.00%) 
Submandibular mass * 1  0/195 (0.00%)  1/89 (1.12%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64 (0.00%)  0/24 (0.00%) 
Adhesion * 1  1/195 (0.51%)  0/89 (0.00%)  0/5 (0.00%)  0/38 (0.00%)  0/50 (0.00%)  0/26 (0.00%)  0/79 (0.00%)  0/64