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

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00261846
• Collaborator: (none)
• Enrollment: 571
• Locations: 111
• Arm: 1
• Actual Duration (Months): 114.6
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an open-label, continuous daily dosing, two-part safety and efficacy study of SKI-606 (bosutinib) in Philadelphia chromosome positive leukemias (Ph+). Part 1 is a dose-escalation study in chronic phase Chronic Myelogenous Leukemia (CML) subjects to establish the maximum tolerated dose (MTD) in this subject population. Part 2 has begun after the completion of Part 1 and after a dose has been established for the compound in chronic phase subjects. Part 2 is a study of the the efficacy of 500mg daily oral SKI-606 (bosutinib) in patients with all phases of Ph+ CML and Ph+ Acute Lymphocytic Leukemia (ALL). The protocol will test the hypotheses that oral daily dosing of bosutinib at 500 mg will attain (1) Major Cytogenetic Response (MCyR) in chronic phase CML patients and (2) Overall Hematological Response (OHR) in advanced leukemia patients. Each phase of the disease will be evaluated as a separate cohort.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia	Drug: Bosutinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 571 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study Of Bosutinib (Ski-606) In Philadelphia Chromosome Positive Leukemias
• Actual Study Start Date: Jan 18, 2006
• Actual Primary Completion Date: Sep 25, 2009
• Actual Study Completion Date: Aug 6, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SKI-606	Drug: Bosutinib; Part 1, starting dose 400 mg oral, daily dosing in the dose-escalation component. Part 2, 500 mg oral, continuous, daily dosing.; Other Names: SKI-606

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicity (DLT) [Part 1 Baseline up to Day 28]

   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).

2. Maximum Tolerated Dose (MTD) [Part 1 Baseline up to Day 28]

   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.

3. Maximum Observed Plasma Concentration (Cmax) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

4. Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

5. Plasma Decay Half-Life (t1/2) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

   Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. NA = not estimable.

6. Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

   AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).

7. Area Under the Concentration-Time Curve (AUC) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

   AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. NA = not estimable.

8. Apparent Oral Clearance (CL/F) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

   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.

9. Apparent Volume of Distribution (Vz/F) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1]

   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.

10. Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15]

    Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.

11. Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15]

    Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.

12. Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15]

    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.

13. Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15]

    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.

14. Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1 [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15]

    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.

15. Accumulation Ratio (R) [0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15]

    R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)

16. Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2 [Week 24]

    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.

Secondary Outcome Measures

1. Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1 [Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52)]

   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.

2. Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1 [Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52)]

   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.

3. Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1 [0 (pre-dose) on Day 1 (Baseline)]

   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.

4. Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1 [6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15]

   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.

5. Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2 [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)]

   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.

6. Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2 [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]

   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.

7. Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2 [Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5]

   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.

8. Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2 [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)]

   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.

9. Duration of Complete Hematologic Response (CHR) - Part 2 [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)]

   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.

10. Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2 [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)]

    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.

11. Cumulative Incidence of Progression/Death - Part 2 [Years 1, 2, 3, 4, and 5 (CP2L only)]

    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.

12. Progression Free Survival (PFS) - Part 2 [Years 1, 2, 3, 4, and 5 (CP2L only)]

    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

13. Kaplan-Meier Estimate of Overall Survival (OS) - Part 2 [Years 1, 2, 3, 4, and 5 (CP2L only)]

    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.

14. Overall Survival (OS) - Part 2 [Years 1, 2, 3, 4, and 5 (CP2L only)]

    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.

15. Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2 [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)]

    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).

16. Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2 [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]

    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.

17. Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Baseline up to follow up visit (30 days after last dose of study treatment)]

    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.

18. Duration of Potentially Clinically Important (PCI) Adverse Events (AEs) [Baseline up to follow-up visit (30 days after last dose of study treatment)]

    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.

19. Percentage of Participants With Change From Baseline in Laboratory Tests Results [Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter]

    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.

20. Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings [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]

    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.

21. Number of Participants With Change From Baseline in Findings of Chest X-ray [Baseline, Week 8, and end of treatment]

    Number of participants whose chest X-ray results changed (worsened or improved) from the Baseline.

22. Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs) [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]

    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.

23. Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) [Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter]

    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.

24. Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs [Screening, Baseline, and end of treatment]

    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).

25. Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values [Post-therapy]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ph+ CML or Ph+ ALL who are primarily refractory to full-dose imatinib (600 mg), have disease progression/relapse while on full-dose imatinib, or are intolerant of any dose of imatinib.

• At least 3 months post stem cell transplantation

• Able to take daily oral capsules/tablets reliably

Exclusion Criteria:

• Subjects with Philadelphia chromosome, and bcr-abl negative CML

• Overt leptomeningeal leukemia

• Subjects without evidence of leukemia in bone marrow (extramedullary disease only)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	HealthONE Presbyterian	Denver	Colorado	United States	80218
3	Rocky Mountain Cancer Centers	Denver	Colorado	United States	80218
4	Georgetown University Hospital	Washington, D.C.	District of Columbia	United States	20007
5	Emory Clinic	Atlanta	Georgia	United States	30322
6	Emory University Hospital	Atlanta	Georgia	United States	30322
7	Winship Cancer Institute	Atlanta	Georgia	United States	30322
8	Oncology Specialists, S.C.	Niles	Illinois	United States	60714
9	Indiana Blood and Marrow Transplantation	Indianapolis	Indiana	United States	46237
10	LSU Health Sciences Center	Shreveport	Louisiana	United States	71103
11	University Of Maryland Medical Center	Baltimore	Maryland	United States	21201
12	University Of Maryland	Baltimore	Maryland	United States	21201
13	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
14	Hudson Valley Hematology and Oncology Associates	Hawthorne	New York	United States	10532
15	Westchester Oncology Hematology Group, P.C.	Hawthorne	New York	United States	10532
16	Westchester Oncology Hematology, Group, P.C.	Hawthorne	New York	United States	10532
17	New York Presbyterian Hospital	New York	New York	United States	10021
18	New York Presbyterian Hospital	New York	New York	United States	10065
19	University of Rochester Cancer Center Pharmacy	Rochester	New York	United States	14642
20	University of Rochester Medical Center Strong Memorial Hospital - James P. Wilmot Cancer Center	Rochester	New York	United States	14642
21	University of Rochester Medical Center	Rochester	New York	United States	14642
22	University of Rochester-James P. Wilmot Cancer Center	Rochester	New York	United States	14642
23	University of Rochester	Rochester	New York	United States	14642
24	Westchester Medical Center	Valhalla	New York	United States	10595
25	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
26	MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
27	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
28	The University of Texas	Houston	Texas	United States	77030
29	Virginia Commonwealth University	Richmond	Virginia	United States	23298-0157
30	Hospital Italiano de la Plata	La Plata	Provincia de Buenos Aires	Argentina	1900
31	Hospital Britanico	Buenos Aires		Argentina	1280
32	Academia Nacional de Medicina-Instituto de Investigaciones Hematologicas	Buenos Aires		Argentina	1425
33	Instituto Medico Especializado Alexander Fleming	Buenos Aires		Argentina	1426
34	Clinica del Sol	Ciudad Autonoma de Buenos Aires		Argentina	C1425DQI
35	Centro Medico S.A.	Corrientes		Argentina	3400
36	Hospital Jose Ramon Vidal	Corrientes		Argentina	3400
37	Hospital universitario austral	Pcia de Buenos Aires		Argentina	B1629ODT
38	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
39	Institute of Medical and Veterinary Science	Adelaide		Australia	SA 5000
40	Department of Clinical Haematology and Bone Marrow Transplantation	Melbourne		Australia	3181
41	Royal Brisbane and Women's Hospital	Queensland		Australia	4029
42	Haematology and Oncology Clinics of Australia	Queensland		Australia	4101
43	Klinikum Kreuzschwestern Wels	Wels		Austria	4600
44	Hospital Brigadeiro da Secretaria de Estado da Saude de Sao Paulo	Jardim Paulista	Sao Paulo/sp - Brazil	Brazil	CEP: 01401-901
45	Centro de Estudos da Disciplina dr Hematologia da Faculdade de Medicine do ABC	Santo Andre	Sp - Brazil	Brazil	CEP 09060-650
46	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo	Sao Paulo	Sp Brazil	Brazil	05403-000
47	Hospital de Clinicas - Universidade Federal do Parana	Curitiba, PR		Brazil	CEP: 80060-900
48	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G1Z2
49	BC Cancer Agency - Cancer Centre for the Southern Interior	Kelowna	British Columbia	Canada	V1Y 5L3
50	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
51	University Health Network Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
52	Sir Mortimer B. Davis, Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
53	Instituto Clinico Oncologico del Sur	Temuco		Chile
54	The First Hospital affiliated to the Medical School of Zhejiang University	Zhejiang	P.r China	China	310003
55	Peking Union Medical College Hospital of Chinese Academy of Medical Sciences	Beijing	P.r. China	China	100730
56	The Department of Hematology, The Chinese PLA General Hospital	Beijing	P.r. China	China	100853
57	The Hematology Hospital of Chinese Academy of Medical Sciences	Tianjin	P.r. China	China	300020
58	The Department of Hematology, Ruijin Hospital Affiliated to School of Medicine of Shanghai Jiaotong	Shanghai		China	200025
59	Hospital Pablo Tobon Uribe	Medellin	Antioquia	Colombia	4459000
60	Fundacion Santa Fe de Bogota	Bogota	Cundinamarca	Colombia
61	Biomedicum Helsinki	Helsinki		Finland	FIN-00029 HUS
62	Universitaet Mainz	Mainz	RP	Germany	55101
63	University Hospital Carl Gustav Carus	Dresden		Germany	01307
64	Universitaetsklinikum Hamburg - Eppendorf	Hamburg		Germany	20246
65	Universitaetsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
66	Universitaetsklinikum Magdeburg A. oe. R.	Magdeburg		Germany	39120
67	III Medizinische Klinik und Poliklinik	Mainz		Germany	55101
68	Klinikum der Johann Gutenberg Universitaet Mainz	Mainz		Germany	55131
69	Universitaet Mainz Iii. Medizinische Klinik Abteilung Fuer Haematologie	Mainz		Germany	D-55101
70	Universitaetsklinikum Mainz	Mainz		Germany
71	III. Medizinische Klinik	Mannheim		Germany	68169
72	Pamela Youde Nethersole Eastern Hosp.	Chai Wan		Hong Kong
73	Queen Mary Hospital	Hong Kong		Hong Kong
74	Fovarosi Onkormanyzat Egyesitett Szent Istvan es Szent Laszlo	Budapest		Hungary	1096
75	Christian Medical College	Vellore	Tamil Nadu	India	632 004
76	University of Bologna	Bologna	Province of Bologna	Italy	40138
77	Azienda Ospedaliero - Universitaria San Luigi Gonzaga	Orbassano	Torino	Italy	10043
78	AOU-S.Orsola-Malpighi - Universita degli Studi di Bologna	Bologna		Italy	40138
79	Azienda Ospedaliera San Gerardo	Monza		Italy	20900
80	The Catholic University of Korea, Seoul St. Mary Hospital	Seoul		Korea, Republic of	137-701
81	Dept. of Hematology	Seoul		Korea, Republic of	138736
82	Hospital Universitario "Dr. Jose Eleuterio Gonzalez"	Nuevo Leon		Mexico	64460
83	Centro Oncologico Estatal ISSEMYM	Toluca Estado de Mexico		Mexico	CP50180
84	VU University Medical Center	Amsterdam		Netherlands	1081 HV
85	University Medical Center Groningen	Groningen		Netherlands	9700 RB
86	UMCG - Pharmacy	Groningen		Netherlands	9713 AP
87	Universitair Medisch Centrum Groningen	Groningen		Netherlands	9713 GZ
88	VUMC	The Netherlands		Netherlands
89	Avd. for blodsykdommer	Trondheim	Norge	Norway	7006
90	Hospital Nacional Edgardo Rebagliati Martins	Lima		Peru	11
91	State Healthcare Institution, Sverdlovsk Regional Clinical Hospital	Ekaterinburg		Russian Federation	620102
92	Kirov Research Institute of Hematology and Blood transfusion of Roszdrav Hematology clinic	Kirov		Russian Federation	610027
93	Hematological Research Centre of RAMS	Moscow		Russian Federation	125167
94	Moscow regional Clinical Research Institute named after M.F Vladimirsky	Moscow		Russian Federation	129110
95	Rostov State Medical University of Roszdrav	Rostov-on Don		Russian Federation	344022
96	Saint Petersburg State Medical University Hematology Department	Saint Petersburg		Russian Federation	197022
97	Singapore General Hospital	Singapore		Singapore	169608
98	University of the Free State	Bloemfontein		South Africa	9301
99	University of Cape Town	Cape Town		South Africa	7925
100	Johannesburg Hospital	Parktown		South Africa	2193
101	Clinical Haematology Unit	Soweto		South Africa	2013
102	Hospital Clinic de Barcelona (Hospital Clinic i Provincial)	Barcelona	Catalonia	Spain	08036
103	Hospital Universitari Clinic de Barcelona	Barcelona	Catalonia	Spain	08036
104	Hospital Universitario La Princesa	Madrid		Spain	28006
105	Hospital Clinico Universitario de Valencia (CHUV)	Valencia		Spain	46010
106	Akademiska University Hospital	Uppsala		Sweden	75185
107	National Taiwan University Hospital - Section of Hematology-Oncology	Taipei 100		Taiwan	10018
108	Northern Centre for Cancer Care - The Newcastle Upon Tyne Hospitals - NHS Foundation Trust	Newcastle Upon Tyne	North East England	United Kingdom	NE7 7DN
109	School of Clinical and Laboratory Sciences	University upon Tyne	North East England	United Kingdom	NE1 7RU
110	Hammersmith Hospital	London		United Kingdom	W12 0HS
111	Clinical Research Facility	Newcastle Upon Tyne, North East England		United Kingdom	NE1 4LP

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00261846
• Other Study ID Numbers: 3160A4-200; B1871006, 3160A4-200-WW; 2005-004230-40; B1871006
• First Posted: Dec 5, 2005
• Last Update Posted: Jul 27, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Pfizer: Leukemia; tyrosine kinase inhibitor; philadelphia chromosome; Myeloid; Philadelphia Positive
• Additional relevant MeSH terms: Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome

Study Results

Participant Flow

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)
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
Period Title: Period 1: Part 1 (Dose Escalation)
STARTED	0	0	0	195	89	5	38	50	26	79	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

Baseline Characteristics

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
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 Participants	195	89	5	38	50	26	79	64	24	570
Age, Customized (Number) [Number]
<18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 44 years	73 37.4%	22 24.7%	1 20%	5 13.2%	7 14%	10 38.5%	26 32.9%	29 45.3%	6 25%	179 31.4%
Between 45 and 64 years	86 44.1%	40 44.9%	3 60%	23 60.5%	29 58%	14 53.8%	45 57%	25 39.1%	7 29.2%	272 47.7%
>=65 years	36 18.5%	27 30.3%	1 20%	10 26.3%	14 28%	2 7.7%	8 10.1%	10 15.6%	11 45.8%	119 20.9%
Sex: Female, Male (Count of Participants)
Female	82 42.1%	53 59.6%	3 60%	20 52.6%	31 62%	12 46.2%	35 44.3%	22 34.4%	12 50%	270 47.4%
Male	113 57.9%	36 40.4%	2 40%	18 47.4%	19 38%	14 53.8%	44 55.7%	42 65.6%	12 50%	300 52.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicity (DLT)
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Number [participants]	0 0%	0 0%	1 20%

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Number [mg]	NA	NA	NA

3. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) - Part 1
Time Frame	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Mean (Standard Deviation) [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
Time Frame	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Median (Full Range) [hours (hrs)]	4.00	6.00	4.00

5. Primary Outcome

Title	Plasma Decay Half-Life (t1/2) - Part 1
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. NA = not estimable.
Time Frame	0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Outcome Measure Data

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)
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.
Measure Participants	2	3	8
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Mean (Standard Deviation) [ng*hr/mL]	1850 (710)	2060 (483)	2340 (1140)

7. Primary Outcome

Title	Area Under the Concentration-Time Curve (AUC) - Part 1
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

Outcome Measure Data

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)
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.
Measure Participants	2	3	8
Mean (Standard Deviation) [ng*hr/mL]	2530 (1160)	2760 (687)	2420 (457)

8. Primary Outcome

Title	Apparent Oral Clearance (CL/F) - Part 1
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. 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

Outcome Measure Data

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)
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.
Measure Participants	2	3	8
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	8
Mean (Standard Deviation) [liter]	6050 (3550)	6080 (1230)	8540 (3820)

10. Primary Outcome

Title	Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	10
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Median (Full Range) [hrs]	4.05	6.05	6.00

12. Primary Outcome

Title	Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	7
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	9
Mean (Standard Deviation) [ng*hr/mL]	2720 (442)	3650 (425)	3630 (1270)

14. Primary Outcome

Title	Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. 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

Outcome Measure Data

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)
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.
Measure Participants	3	3	9
Mean (Standard Deviation) [L/hr]	150 (23.2)	138 (16.6)	185 (66.2)

15. Primary Outcome

Title	Accumulation Ratio (R)
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

Outcome Measure Data

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)
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.
Measure Participants	3	3	9
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	182
Number (95% Confidence Interval) [percentage of participants]	35.7 18.3%

17. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	3	3	12
Number (95% Confidence Interval) [percentage of participants]	66.7 34.2%	33.3 37.4%	50.0 1000%

18. Secondary Outcome

Title	Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1
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)

Outcome Measure Data

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)
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.
Measure Participants	0	0	0

19. Secondary Outcome

Title	Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1
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)

Outcome Measure Data

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)
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.
Measure Participants	2	3	10
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	1	3	9
Day 1: post-dose (n=1, 1, 9)	-34.66 (NA)	287.52 (NA)	97.79 (283.61)
Day 8: pre-dose (n=1, 1, 9)	562.48 (NA)	170.83 (NA)	3.88 (128.97)
Day 8: post-dose (n=1, 1, 9)	528.62 (NA)	429.79 (NA)	143.57 (289.18)
Day 15: pre-dose (n=1, 2, 7)	177.87 (NA)	-44.64 (8.56)	119.23 (170.91)
Day 15: post-dose (n=1, 3, 7)	-49.85 (NA)	-21.13 (57.91)	138.45 (278.24)

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
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)

Outcome Measure Data

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)
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.
Measure Participants	80	5	36	45	26	182
Number (95% Confidence Interval) [percentage of participants]	61.3 31.4%	40.0 44.9%	38.9 778%	42.2 111.1%	38.5 77%	58.8 226.2%

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
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

Outcome Measure Data

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)
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.
Measure Participants	107	49
Number (95% Confidence Interval) [% probability of retaining MCyR]	67.2	79.8

23. Secondary Outcome

Title	Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2
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

Outcome Measure Data

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)
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.
Measure Participants	107	49
Median (95% Confidence Interval) [weeks]	12.3	12.1

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
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)

Outcome Measure Data

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)
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
Measure Participants	169	76	4	26	37	19	17	7	9	1	2
Number (95% Confidence Interval) [% estimate of maintaining response]	61.5	78.2	50.0	56.5	69.9	61.9	47.1	64.3	NA	NA	100

25. Secondary Outcome

Title	Duration of Complete Hematologic Response (CHR) - Part 2
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)

Outcome Measure Data

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)
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
Measure Participants	169	76	4	26	37	19	17	7	9	1	2
Median (95% Confidence Interval) [weeks]	NA	350.4	NA	NA	295.6	NA	138.0	NA	28.6	40.0	NA

26. Secondary Outcome

Title	Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2
Description	The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response 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)

Outcome Measure Data

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)
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
Measure Participants	169	76	4	26	37	19	17	7	9	1	2
Median (95% Confidence Interval) [weeks]	2.0	1.3	1.6	1.2	1.3	2.4	12.1	12.1	8.0	12.1	10.0

27. Secondary Outcome

Title	Cumulative Incidence of Progression/Death - Part 2
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)

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	49	30	36	28	24
Year 1	10.8 5.5%	4.5 5.1%	20.0 400%	23.7 62.4%	12.0 24%	23.1 88.8%	28.6 36.2%	20.0 31.3%	47.2 196.7%	71.4 12.5%	58.3 NaN
Year 2	19.0 9.7%	6.7 7.5%	40.0 800%	23.7 62.4%	14.0 28%	30.8 118.5%	42.9 54.3%	23.3 36.4%	50.0 208.3%	71.4 12.5%	58.3 NaN
Year 3	22.1 11.3%	9.0 10.1%	40.0 800%	23.7 62.4%	16.0 32%	34.6 133.1%	44.9 56.8%	26.7 41.7%	50.0 208.3%	75.0 13.2%	58.3 NaN
Year 4	22.6 11.6%	9.0 10.1%	40.0 800%	23.7 62.4%	16.0 32%	34.6 133.1%	44.9 56.8%	26.7 41.7%	50.0 208.3%	75.0 13.2%	58.3 NaN
Year 5	23.1 11.8%	10.1 11.3%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN

28. Secondary Outcome

Title	Progression Free Survival (PFS) - Part 2
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)

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	49	30	36	28	24
Median (95% Confidence Interval) [Months]	NA	81.5	NA	NA	NA	NA	20.4	35.4	7.9	1.8	1.5

29. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival (OS) - Part 2
Description	OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death 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)

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	49	30	36	28	24
Year 1	96.3 49.4%	98.9 111.1%	100 2000%	85.8 225.8%	91.8 183.6%	96.2 370%	81.3 102.9%	72.9 113.9%	44.3 184.6%	39.3 6.9%	16.7 NaN
Year 2	88.2 45.2%	97.7 109.8%	80.0 1600%	79.7 209.7%	83.3 166.6%	92.3 355%	72.7 92%	59.0 92.2%	41.3 172.1%	25.0 4.4%	8.3 NaN
Year 3	84.1 43.1%	93.0 104.5%	80.0 1600%	66.1 173.9%	83.3 166.6%	86.5 332.7%	70.1 88.7%	45.1 70.5%	41.3 172.1%	16.7 2.9%	8.3 NaN
Year 4	81.5 41.8%	93.0 104.5%	80.0 1600%	66.1 173.9%	79.3 158.6%	86.5 332.7%	65.7 83.2%	45.1 70.5%	20.7 86.3%	16.7 2.9%	8.3 NaN
Year 5	80.6 41.3%	88.4 99.3%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN

30. Secondary Outcome

Title	Overall Survival (OS) - Part 2
Description	OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death 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)

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	49	30	36	28	24
Median (95% Confidence Interval) [Months]	NA	81.5	NA	NA	NA	NA	NA	33.4	11.2	8.9	3.6

31. Secondary Outcome

Title	Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2
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)

Outcome Measure Data

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)
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
Measure Participants	194	89	5	38	49	25	43	29	34	26	22
Number (95% Confidence Interval) [percentage of participants]	87.1 44.7%	85.4 96%	80.0 1600%	68.4 180%	75.5 151%	76.0 292.3%	39.5 50%	24.1 37.7%	26.5 110.4%	3.8 0.7%	9.1 NaN

32. Secondary Outcome

Title	Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2
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

Outcome Measure Data

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)
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
Measure Participants	43	29	34	26	22
Number (95% Confidence Interval) [percentage of participants]	67.4 34.6%	41.4 46.5%	38.2 764%	15.4 40.5%	9.1 18.2%

33. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
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)

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	49	30	36	28	24
AEs	99.5 51%	100.0 112.4%	100.0 2000%	100.0 263.2%	100.0 200%	100.0 384.6%	100.0 126.6%	100.0 156.3%	97.2 405%	100.0 17.5%	95.8 NaN
SAEs	41.5 21.3%	38.2 42.9%	20.0 400%	39.5 103.9%	38.0 76%	19.2 73.8%	49.0 62%	63.3 98.9%	55.6 231.7%	60.7 10.6%	70.8 NaN

34. Secondary Outcome

Title	Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)
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)

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	79	64	24
Anaemia	14.0	36.0	38.0	19.0	13.0	61.0	12.5	4.0	7.0
ALT	29.0	15.0	NA	21.5	8.0	21.0	21.5	7.5	3.0
AST	29.0	13.5	NA	18.0	8.5	15.0	14.0	2.0	5.0
Diarrhoea	1.0	2.0	2.0	2.0	2.0	1.0	2.0	2.0	3.0
Effusion	18.5	29.0	79.5	20.0	28.0	20.0	21.0	58.0	5.0
Infection	10.0	9.5	11.5	8.0	9.0	8.0	9.0	9.5	9.0
Nausea	2.0	4.0	4.0	2.0	14.0	2.0	6.0	6.5	9.0
Neutropenia	23.0	15.0	23.0	14.5	21.0	26.0	8.0	5.0	6.5
Oedema	29.0	81.5	4.0	1.0	12.5	28.0	88.5	11.0	5.0
Rash	15.0	13.0	17.0	12.0	19.0	12.5	13.0	7.5	12.0
Renal events	27.0	190.0	1167.0	162.0	11.0	56.5	26.0	9.0	12.0
Thrombocytopenia	22.0	15.0	38.5	15.0	15.0	21.5	11.5	5.0	9.0
Vomiting	1.0	1.0	NA	1.0	2.0	7.0	1.0	1.0	1.5
Cardiac events	11.0	6.0	NA	7.5	22.0	1.0	14.0	3.0	1.5
Vascular events	3.5	6.0	NA	10.5	1.5	10.0	2.0	1.0	1.0
Hypertension	16.0	1.0	NA	7.0	1.0	NA	5.0	NA	2.0
Gastrointestinal events	1.0	2.0	2.0	2.0	2.0	2.0	2.0	3.0	4.0
Haemorrhage	10.0	16.0	23.0	4.0	27.5	7.5	6.0	4.0	3.5
Hypersensitivity	9.0	8.0	NA	7.0	6.0	5.0	1.0	NA	NA
Liver	29.0	16.0	8.0	25.5	9.0	21.0	16.0	8.0	5.0
Myelosuppression	22.0	18.0	28.0	15.0	15.0	27.0	11.5	5.0	7.0

35. Secondary Outcome

Title	Percentage of Participants With Change From Baseline in Laboratory Tests Results
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

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	79	64	24
Hemoglobin: shift from Normal to Grade 3	0.5 0.3%	1.1 1.2%	0.0 0%	0.0 0%	0.0 0%	3.8 14.6%	5.1 6.5%	1.6 2.5%	0.0 0%
Hemoglobin: shift from Normal to Grade 4	1.0 0.5%	0.0 0%	0.0 0%	0.0 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 1.8%	10.1 11.3%	0.0 0%	2.6 6.8%	0.0 0%	0.0 0%	7.6 9.6%	6.3 9.8%	8.3 34.6%
Hemoglobin: shift from Grade 1 to Grade 4	1.5 0.8%	0.0 0%	0.0 0%	0.0 0%	4.0 8%	0.0 0%	1.3 1.6%	3.1 4.8%	0.0 0%
Hemoglobin: shift from Grade 2 to Grade 3	3.1 1.6%	6.7 7.5%	0.0 0%	7.9 20.8%	0.0 0%	0.0 0%	10.1 12.8%	15.6 24.4%	16.7 69.6%
Hemoglobin: shift from Grade 2 to Grade 4	2.1 1.1%	1.1 1.2%	0.0 0%	0.0 0%	4.0 8%	0.0 0%	2.5 3.2%	4.7 7.3%	4.2 17.5%
Hemoglobin: shift from Grade 3 to Grade 4	0.5 0.3%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	5.1 6.5%	4.7 7.3%	0.0 0%
Absolute neutrophils (ANC): Normal to Grade 3	7.2 3.7%	9.0 10.1%	0.0 0%	5.3 13.9%	4.0 8%	11.5 44.2%	10.1 12.8%	3.1 4.8%	0.0 0%
ANC: shift from Normal to Grade 4	2.1 1.1%	3.4 3.8%	20.0 400%	7.9 20.8%	4.0 8%	3.8 14.6%	2.5 3.2%	3.1 4.8%	0.0 0%
ANC: shift from Grade 1 to Grade 3	0.0 0%	2.2 2.5%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	2.5 3.2%	7.8 12.2%	12.5 52.1%
ANC: shift from Grade 1 to Grade 4	0.5 0.3%	0.0 0%	0.0 0%	2.6 6.8%	2.0 4%	0.0 0%	1.3 1.6%	20.3 31.7%	4.2 17.5%
ANC: shift from Grade 2 to Grade 3	1.0 0.5%	3.4 3.8%	0.0 0%	2.6 6.8%	2.0 4%	0.0 0%	3.8 4.8%	0.0 0%	0.0 0%
ANC: shift from Grade 2 to Grade 4	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	1.3 1.6%	3.1 4.8%	8.3 34.6%
ANC: shift from Grade 3 to Grade 4	0.0 0%	1.1 1.2%	0.0 0%	0.0 0%	2.0 4%	0.0 0%	0.0 0%	4.7 7.3%	8.3 34.6%
Platelet count: shift from Normal to Grade 3	13.3 6.8%	13.5 15.2%	0.0 0%	15.8 41.6%	12.0 24%	7.7 29.6%	11.4 14.4%	4.7 7.3%	4.2 17.5%
Platelet count: shift from Normal to Grade 4	3.6 1.8%	7.9 8.9%	0.0 0%	0.0 0%	8.0 16%	15.4 59.2%	7.6 9.6%	1.6 2.5%	0.0 0%
Platelet count: shift from Grade 1 to Grade 3	3.6 1.8%	5.6 6.3%	0.0 0%	2.6 6.8%	2.0 4%	3.8 14.6%	5.1 6.5%	3.1 4.8%	4.2 17.5%
Platelet count: shift from Grade 1 to Grade 4	1.5 0.8%	1.1 1.2%	0.0 0%	2.6 6.8%	4.0 8%	0.0 0%	6.3 8%	6.3 9.8%	0.0 0%
Platelet count: shift from Grade 2 to Grade 3	0.5 0.3%	2.2 2.5%	20.0 400%	0.0 0%	2.0 4%	0.0 0%	3.8 4.8%	4.7 7.3%	0.0 0%
Platelet count: shift from Grade 2 to Grade 4	0.5 0.3%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	1.3 1.6%	4.7 7.3%	0.0 0%
Platelet count: shift from Grade 3 to Grade 4	1.0 0.5%	0.0 0%	0.0 0%	0.0 0%	2.0 4%	0.0 0%	5.1 6.5%	10.9 17%	29.2 121.7%
ALT: shift from Normal to Grade 3	8.7 4.5%	12.4 13.9%	0.0 0%	0.0 0%	10.0 20%	15.4 59.2%	5.1 6.5%	1.6 2.5%	0.0 0%
ALT: shift from Grade 1 to Grade 3	1.0 0.5%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	3.8 4.8%	0.0 0%	0.0 0%
AST: shift from Normal to Grade 3	4.1 2.1%	7.9 8.9%	0.0 0%	0.0 0%	0.0 0%	7.7 29.6%	2.5 3.2%	1.6 2.5%	0.0 0%
AST: shift from Normal to Grade 4	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	3.8 14.6%	0.0 0%	0.0 0%	0.0 0%
AST: shift from Grade 1 to Grade 3	0.0 0%	0.0 0%	0.0 0%	0.0 0%	2.0 4%	0.0 0%	2.5 3.2%	0.0 0%	0.0 0%
ALP: shift from Normal to Grade 3	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	1.3 1.6%	0.0 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 0%	0.0 0%	0.0 0%	1.6 2.5%	0.0 0%
Total bilirubin: shift from Normal to Grade 3	0.0 0%	0.0 0%	0.0 0%	0.0 0%	2.0 4%	0.0 0%	0.0 0%	6.3 9.8%	4.2 17.5%
ALT: shift from Normal to Grade 4	0.0 0%	2.2 2.5%	0.0 0%	0.0 0%	0.0 0%	3.8 14.6%	0.0 0%	0.0 0%	0.0 0%
Total bilirubin: shift from Grade 2 to Grade 3	0.0 0%	0.0 0%	0.0 0%	0.0 0%	2.0 4%	0.0 0%	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
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

Outcome Measure Data

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)
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
Measure Participants	195	89	5	37	50	26	78	62	23
Number [Percentage of participants]	32.3 16.6%	23.6 26.5%	20.0 400%	24.3 63.9%	22.0 44%	23.1 88.8%	39.7 50.3%	59.7 93.3%	34.8 145%

37. Secondary Outcome

Title	Number of Participants With Change From Baseline in Findings of Chest X-ray
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

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	79	64	24
Worsened From Baseline	35 17.9%	18 20.2%	1 20%	6 15.8%	18 36%	3 11.5%	16 20.3%	10 15.6%	3 12.5%
Improved From Baseline	15 7.7%	7 7.9%	0 0%	4 10.5%	1 2%	3 11.5%	6 7.6%	11 17.2%	1 4.2%
Total	50 25.6%	25 28.1%	1 20%	10 26.3%	19 38%	6 23.1%	22 27.8%	21 32.8%	4 16.7%

38. Secondary Outcome

Title	Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)
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

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	79	64	24
ALT	7 3.6%	3 3.4%	0 0%	0 0%	0 0%	1 3.8%	1 1.3%	0 0%	0 0%
AST	5 2.6%	3 3.4%	0 0%	2 5.3%	3 6%	4 15.4%	2 2.5%	0 0%	0 0%
Anemia	6 3.1%	8 9%	2 40%	2 5.3%	2 4%	1 3.8%	6 7.6%	1 1.6%	1 4.2%
Cardiac events	13 6.7%	4 4.5%	0 0%	2 5.3%	6 12%	0 0%	7 8.9%	2 3.1%	1 4.2%
Gastrointestinal toxicity - Diarrhoea	120 61.5%	46 51.7%	2 40%	22 57.9%	26 52%	14 53.8%	44 55.7%	22 34.4%	10 41.7%
Effusion	11 5.6%	5 5.6%	1 20%	3 7.9%	9 18%	1 3.8%	9 11.4%	2 3.1%	0 0%
Haemorrhage	12 6.2%	3 3.4%	0 0%	1 2.6%	0 0%	1 3.8%	4 5.1%	6 9.4%	3 12.5%
Hypertension	15 7.7%	4 4.5%	0 0%	2 5.3%	4 8%	1 3.8%	7 8.9%	2 3.1%	2 8.3%
Hypersensitivity reactions	5 2.6%	2 2.2%	0 0%	4 10.5%	2 4%	2 7.7%	1 1.3%	1 1.6%	0 0%
Infection	92 47.2%	39 43.8%	4 80%	11 28.9%	18 36%	10 38.5%	37 46.8%	30 46.9%	7 29.2%
Hepatic events	10 5.1%	5 5.6%	0 0%	0 0%	0 0%	2 7.7%	3 3.8%	3 4.7%	0 0%
Gastrointestinal toxicity - Nausea	33 16.9%	25 28.1%	1 20%	11 28.9%	10 20%	8 30.8%	19 24.1%	23 35.9%	7 29.2%
Neutropenia	2 1%	5 5.6%	1 20%	5 13.2%	1 2%	1 3.8%	6 7.6%	5 7.8%	2 8.3%
Rash	44 22.6%	37 41.6%	2 40%	8 21.1%	16 32%	3 11.5%	20 25.3%	9 14.1%	2 8.3%
Oedema	13 6.7%	9 10.1%	1 20%	3 7.9%	3 6%	0 0%	7 8.9%	7 10.9%	3 12.5%
Renal	2 1%	2 2.2%	0 0%	0 0%	1 2%	0 0%	4 5.1%	3 4.7%	0 0%
Thrombocytopenia	4 2.1%	2 2.2%	3 60%	10 26.3%	19 38%	13 50%	3 3.8%	3 4.7%	0 0%
Vascular events	6 3.1%	3 3.4%	0 0%	0 0%	3 6%	0 0%	2 2.5%	1 1.6%	0 0%
Gastrointestinal toxicity - Vomiting	25 12.8%	9 10.1%	0 0%	5 13.2%	7 14%	4 15.4%	17 21.5%	14 21.9%	4 16.7%

39. Secondary Outcome

Title	Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
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

Outcome Measure Data

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)
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
Measure Participants	195	89	5	38	50	26	49	30	36	28	24
Baseline: Grade 0; maximum on-therapy: Grade 0	92 47.2%	36 40.4%	2 40%	21 55.3%	20 40%	19 73.1%	17 21.5%	9 14.1%	9 37.5%	2 0.4%	2 NaN
Baseline: Grade 0; maximum on-therapy: Grade 1	50 25.6%	25 28.1%	0 0%	5 13.2%	8 16%	5 19.2%	11 13.9%	5 7.8%	47 195.8%	2 0.4%	4 NaN
Baseline: Grade 0; maximum on-therapy: Grade 2	3 1.5%	3 3.4%	0 0%	0 0%	1 2%	0 0%	0 0%	1 1.6%	0 0%	1 0.2%	2 NaN
Baseline: Grade 0; maximum on-therapy: Grade 3	4 2.1%	2 2.2%	0 0%	1 2.6%	1 2%	0 0%	1 1.3%	0 0%	0 0%	0 0%	0 NaN
Baseline: Grade 0; maximum on-therapy: Grade 4	2 1%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 NaN
Baseline: Grade 1; maximum on-therapy: Grade 0	0 0%	0 0%	0 0%	2 5.3%	0 0%	0 0%	0 0%	1 1.6%	3 12.5%	1 0.2%	1 NaN
Baseline: Grade 1; maximum on-therapy: Grade 1	32 16.4%	13 14.6%	2 40%	7 18.4%	13 26%	2 7.7%	14 17.7%	7 10.9%	7 29.2%	5 0.9%	3 NaN
Baseline: Grade 1; maximum on-therapy: Grade 2	10 5.1%	6 6.7%	1 20%	1 2.6%	5 10%	0 0%	2 2.5%	5 7.8%	0 0%	6 1.1%	3 NaN
Baseline: Grade 1; maximum on-therapy: Grade 3	0 0%	2 2.2%	0 0%	0 0%	0 0%	0 0%	2 2.5%	0 0%	0 0%	3 0.5%	0 NaN
Baseline: Grade 1; maximum on-therapy: Grade 4	2 1%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.6%	1 4.2%	0 0%	0 NaN
Baseline: Grade 2; maximum on-therapy: Grade 0	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.2%	0 0%	0 NaN
Baseline: Grade 2; maximum on-therapy: Grade 1	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.3%	0 0%	0 0%	1 0.2%	0 NaN
Baseline: Grade 2; maximum on-therapy: Grade 2	0 0%	1 1.1%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	6 25%	1 0.2%	4 NaN
Baseline: Grade 2; maximum on-therapy: Grade 3	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.6%	2 8.3%	1 0.2%	0 NaN
Baseline: Grade 2; maximum on-therapy: Grade 4	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.2%	1 NaN
Baseline: Missing	0 0%	1 1.1%	0 0%	0 0%	1 2%	0 0%	0 0%	0 0%	0 0%	0 0%	0 NaN
Baseline: Grade 0; maximum on-therapy: Missing	0 0%	0 0%	0 0%	1 2.6%	1 2%	0 0%	0 0%	0 0%	0 0%	1 0.2%	1 NaN
Baseline: Grade 1; maximum on-therapy: Missing	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 0.5%	3 NaN

40. Secondary Outcome

Title	Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs
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

Outcome Measure Data

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)
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
Measure Participants	188	81	5	35	46	25	75	56	20
SBP >210 mmHg	1.1 0.6%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Weight increase 10%	16.0 8.2%	6.3 7.1%	20.0 400%	12.1 31.8%	6.5 13%	16.0 61.5%	11.0 13.9%	7.5 11.7%	6.3 26.3%
Weight decrease 10%	21.9 11.2%	16.3 18.3%	0 0%	6.1 16.1%	15.2 30.4%	0 0%	23.3 29.5%	9.4 14.7%	0 0%
SBP <80 mmHg	0 0%	0 0%	0 0%	0 0%	0 0%	4.0 15.4%	0 0%	0 0%	0 0%
Temperature <32C	0 0%	0 0%	0 0%	0 0%	0 0%	4.0 15.4%	0 0%	0 0%	0 0%
Pulse <40bpm	0 0%	1.4 1.6%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Resp >50 breaths/min	0 0%	0 0%	0 0%	0 0%	0 0%	5.0 19.2%	0 0%	0 0%	0 0%
Resp <10 breaths/min	0 0%	0 0%	0 0%	0 0%	2.4 4.8%	0 0%	0 0%	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
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

Outcome Measure Data

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)
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
Measure Participants	24	16	1	2	11	4	8	3	0
Pulse <40 bpm	4.2 2.2%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
SBP >210 mmHg	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	12.5 15.8%	0 0%
Weight increase 10%	4.2 2.2%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	33.3 52%
Weight decrease 10%	12.5 6.4%	6.7 7.5%	0 0%	0 0%	9.1 18.2%	0 0%	16.7 21.1%	0 0%

Adverse Events

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)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/195 (41.5%)		34/89 (38.2%)		1/5 (20%)		15/38 (39.5%)		19/50 (38%)		5/26 (19.2%)		43/79 (54.4%)		37/64 (57.8%)		17/24 (70.8%)
Blood and lymphatic system disorders
Thrombocytopenia	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		3/79 (3.8%)		0/64 (0%)		1/24 (4.2%)
Anaemia	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		5/79 (6.3%)		1/64 (1.6%)		0/24 (0%)
Febrile neutropenia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		3/64 (4.7%)		4/24 (16.7%)
Leukocytosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		2/64 (3.1%)		2/24 (8.3%)
Neutropenia	0/195 (0%)		0/89 (0%)		1/5 (20%)		3/38 (7.9%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		1/24 (4.2%)
Granulocytopenia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Leukopenia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Pancytopenia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Splenomegaly	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Leukostasis syndrome	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Cardiac disorders
Atrial fibrillation	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		2/50 (4%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Acute myocardial infarction	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Cardiac failure	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Cardiac failure congestive	3/195 (1.5%)		2/89 (2.2%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Coronary artery disease	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Myocardial infarction	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Pericardial effusion	2/195 (1%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		2/50 (4%)		0/26 (0%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Pericarditis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Angina pectoris	1/195 (0.5%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Angina unstable	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Arrhythmia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Left ventricular dysfunction	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Pericardial haemorrhage	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Tachycardia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Bradycardia	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cardiorenal syndrome	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Coronary artery stenosis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Extrasystoles	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Palpitations	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pleuropericarditis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Ventricular fibrillation	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cardiac arrest	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cardiac disorder	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Congenital, familial and genetic disorders
Cytogenetic abnormality	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Eye disorders
Diplopia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Glaucoma	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Cataract	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Visual acuity reduced	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Vitreous haemorrhage	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Gastrointestinal disorders
Diarrhoea	4/195 (2.1%)		3/89 (3.4%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		2/24 (8.3%)
Nausea	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		5/64 (7.8%)		1/24 (4.2%)
Gastrointestinal haemorrhage	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		2/64 (3.1%)		1/24 (4.2%)
Vomiting	0/195 (0%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		4/64 (6.3%)		1/24 (4.2%)
Abdominal pain	2/195 (1%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		3/79 (3.8%)		1/64 (1.6%)		0/24 (0%)
Inguinal hernia	0/195 (0%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pancreatitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Rectal haemorrhage	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Abdominal pain upper	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Gastritis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Haematochezia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Intestinal obstruction	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Toothache	0/195 (0%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Abdominal adhesions	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Abdominal distension	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Colitis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Colitis ischaemic	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Colitis ulcerative	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Dental caries	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Duodenal ulcer haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Dysphagia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Epigastric discomfort	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Food poisoning	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Gastritis erosive	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Ileus	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Lower gastrointestinal haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Melaena	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pancreatitis acute	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Proctocolitis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Retroperitoneal haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Abdominal pain lower	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Gastrooesophageal reflux disease	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Haemorrhoids	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Intestinal haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Intestinal ischaemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Large intestinal stenosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
General disorders
Pyrexia	5/195 (2.6%)		2/89 (2.2%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		4/79 (5.1%)		5/64 (7.8%)		1/24 (4.2%)
Chest pain	2/195 (1%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		3/79 (3.8%)		1/64 (1.6%)		0/24 (0%)
General physical health deterioration	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		3/64 (4.7%)		2/24 (8.3%)
Asthenia	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Disease progression	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		4/79 (5.1%)		3/64 (4.7%)		1/24 (4.2%)
Chills	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Multi-organ failure	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Oedema	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Pain	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		2/64 (3.1%)		0/24 (0%)
Adverse drug reaction	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Local swelling	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Malaise	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Mucosal inflammation	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Oedema peripheral	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Submandibular mass	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Adhesion	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Death	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Hepatobiliary disorders
Cholecystitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Cholecystitis acute	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Cholelithiasis	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hepatic function abnormal	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Bile duct stone	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Gallbladder disorder	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Perforation bile duct	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Immune system disorders
Drug hypersensitivity	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Hypersensitivity	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Infections and infestations
Pneumonia	6/195 (3.1%)		5/89 (5.6%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		9/79 (11.4%)		5/64 (7.8%)		3/24 (12.5%)
Sepsis	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		4/79 (5.1%)		1/64 (1.6%)		1/24 (4.2%)
Urinary tract infection	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Bacteraemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		2/64 (3.1%)		1/24 (4.2%)
Septic shock	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Upper respiratory tract infection	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Bronchitis	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cellulitis	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Gastroenteritis viral	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Lung infection	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Sinusitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Abscess limb	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Appendicitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Appendicitis perforated	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Brain abscess	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Bronchopneumonia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Clostridium difficile colitis	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cystitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Enterococcal sepsis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Erysipelas	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Escherichia bacteraemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Escherichia sepsis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Febrile infection	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Fungal infection	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Gastroenteritis	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Gingival abscess	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Influenza	1/195 (0.5%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Kidney infection	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Meningitis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Orchitis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Pharyngitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pneumonia bacterial	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pneumonia fungal	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pneumonia necrotising	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pseudomembranous colitis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pseudomonal sepsis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Pyelonephritis acute	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Staphylococcal bacteraemia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Staphylococcal sepsis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Tooth abscess	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Tooth infection	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Urinary tract infection bacterial	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Infection	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Atypical pneunomia	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Device related infection	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Diverticulitis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Infectious colitis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Infectious pleural effusion	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Perirectal abscess	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Post procedure infection	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pulmonary mycosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Injury, poisoning and procedural complications
Abdominal injury	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cervical vertebral fracture	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Clavicle fracture	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Gastrointestinal stoma complication	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Humerus fracture	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Overdose	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Post procedural haematuria	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Post procedural swelling	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Rib fracture	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Road traffic accident	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Seroma	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Subdural haematoma	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Subdural haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Tooth fracture	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Transfusion reaction	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Upper limb fracture	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Wound haematoma	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Contusion	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Facial bone fracture	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Failure to anastomose	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Injury	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Muscle injury	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Procedural haemorrhage	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Vascular pseudoaneurysm	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Investigations
Platelet count decreased	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		2/79 (2.5%)		0/64 (0%)		2/24 (8.3%)
Alanine aminotransferase increased	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Aspartate aminotransferase increased	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Blood bilirubin increased	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Blood creatine phosphokinase increased	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Blood glucose increased	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Blood pressure increased	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Haemoglobin decreased	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hepatic enzyme increased	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Liver function test abnormal	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Weight decreased	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Blood creatinine increased	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Intraocular pressure increased	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Metabolism and nutrition disorders
Dehydration	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		1/24 (4.2%)
Failure to thrive	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		3/64 (4.7%)		0/24 (0%)
Acidosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Decreased appetite	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Gout	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hyperglycaemia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Hypoglycaemia	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Hypophosphataemia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Fluid retention	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Hypovolaemia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/195 (0%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		2/50 (4%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Arthralgia	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Bone pain	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Osteoarthritis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Pain in extremity	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Bone cyst	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Groin pain	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Intervertebral disc protrusion	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Myalgia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Myositis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Neck pain	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Osteochondrosis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Spinal column stenosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Spinal osteoarthritis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Synovitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Foot deformity	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Lumbar spinal stenosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Osteonecrosis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Rotator cuff syndrome	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Blast cell crisis	2/195 (1%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Blast crisis in myelogenous leukaemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		2/64 (3.1%)		0/24 (0%)
Basal cell carcinoma	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Squamous cell carcinoma	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Chloroma	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Chronic myelomonocytic leukaemia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Colon cancer	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Colon cancer metastatic	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Gastric cancer	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Keratoacanthoma	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Leukaemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Lung adenocarcinoma	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Melanocytic naevus	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Neoplasm skin	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Non-small cell lung cancer	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Prostate cancer	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Squamous cell carcinoma of skin	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Thyroid neoplasm	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Uterine Leiomyoma	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Bowen's disease	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Angiomyolipoma	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Anogenital warts	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Central nervous system leukaemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Chronic myeloid leukaemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Laryngeal neoplasm	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Neoplasm prostate	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Paraproteinaemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Nervous system disorders
Headache	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		4/79 (5.1%)		2/64 (3.1%)		2/24 (8.3%)
Subarachnoid haemorrhage	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Cerebral haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		1/24 (4.2%)
Hemiparesis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Syncope	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Carotid arteriosclerosis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cerebral infarction	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Cerebrovascular accident	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Dizziness	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Encephalitis post varicella	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Epilepsy	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Intraventricular haemorrhage	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Loss of consciousness	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Monoparesis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Paraesthesia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Partial seizures	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Speech disorder	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cerebellar infarction	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Encephalopathy	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Ischaemic stroke	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Nervous system disorder	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		2/64 (3.1%)		0/24 (0%)
Parkinson's disease	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Radiculitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Trigeminal neuralgia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Psychiatric disorders
Confusional state	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Completed suicide	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Hallucination, visual	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Mental status change	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Renal and urinary disorders
Renal failure	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Acute prerenal failure	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Calculus bladder	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cystitis haemorrhagic	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Haematuria	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Nephrolithiasis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Renal impairment	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Tubulointerstitial nephritis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Acute kidney injury	4/195 (2.1%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		2/64 (3.1%)		0/24 (0%)
Chronic kidney disease	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Prerenal failure	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Renal disorder	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Urinary retention	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Reproductive system and breast disorders
Breast hyperplasia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Cervical dysplasia	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Dysfunctional uterine bleeding	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pelvic pain	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Vaginal haemorrhage	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Menorrhagia	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	8/195 (4.1%)		4/89 (4.5%)		0/5 (0%)		3/38 (7.9%)		3/50 (6%)		1/26 (3.8%)		5/79 (6.3%)		2/64 (3.1%)		1/24 (4.2%)
Dyspnoea	5/195 (2.6%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		2/50 (4%)		0/26 (0%)		4/79 (5.1%)		1/64 (1.6%)		0/24 (0%)
Pneumonitis	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Respiratory failure	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		2/64 (3.1%)		2/24 (8.3%)
Asthma	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Acute respiratory failure	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Chronic obstructive pulmonary disease	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Dyspnoea exertional	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Lung infiltration	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Organising pneumonia	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Pleurisy	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Pleuritic pain	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pneumonia aspiration	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pulmonary embolism	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pulmonary fibrosis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Pulmonary oedema	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Haemoptysis	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Lung disorder	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Skin and subcutaneous tissue disorders
Rash	2/195 (1%)		6/89 (6.7%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Urticaria	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Angioedema	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Circumoral oedema	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Dermatitis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Erythema multiforme	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Skin lesion	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Rash generalised	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Social circumstances
Pregnancy of partner	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Surgical and medical procedures
Allogenic bone marrow transplantation therapy	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Knee anthroplasty	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Vascular disorders
Hypertension	2/195 (1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hypotension	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Aortic stenosis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Venous thrombosis	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Necrosis ischaemic	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Peripheral arterial occlusive disease	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	194/195 (99.5%)		89/89 (100%)		5/5 (100%)		38/38 (100%)		50/50 (100%)		26/26 (100%)		79/79 (100%)		62/64 (96.9%)		23/24 (95.8%)
Blood and lymphatic system disorders
Thrombocytopenia	61/195 (31.3%)		32/89 (36%)		3/5 (60%)		9/38 (23.7%)		18/50 (36%)		12/26 (46.2%)		35/79 (44.3%)		18/64 (28.1%)		5/24 (20.8%)
Anaemia	45/195 (23.1%)		24/89 (27%)		2/5 (40%)		7/38 (18.4%)		7/50 (14%)		6/26 (23.1%)		33/79 (41.8%)		19/64 (29.7%)		10/24 (41.7%)
Neutropenia	26/195 (13.3%)		13/89 (14.6%)		1/5 (20%)		8/38 (21.1%)		6/50 (12%)		7/26 (26.9%)		12/79 (15.2%)		16/64 (25%)		2/24 (8.3%)
Leukopenia	19/195 (9.7%)		8/89 (9%)		0/5 (0%)		4/38 (10.5%)		1/50 (2%)		0/26 (0%)		7/79 (8.9%)		9/64 (14.1%)		2/24 (8.3%)
Leukocytosis	7/195 (3.6%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		2/50 (4%)		0/26 (0%)		4/79 (5.1%)		4/64 (6.3%)		2/24 (8.3%)
Cardiac disorders
Pericardial effusion	3/195 (1.5%)		2/89 (2.2%)		1/5 (20%)		1/38 (2.6%)		4/50 (8%)		0/26 (0%)		4/79 (5.1%)		1/64 (1.6%)		0/24 (0%)
Mitral valve incompetence	1/195 (0.5%)		1/89 (1.1%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Tachycardia	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		4/64 (6.3%)		0/24 (0%)
Ear and labyrinth disorders
Ear pain	3/195 (1.5%)		2/89 (2.2%)		0/5 (0%)		2/38 (5.3%)		1/50 (2%)		1/26 (3.8%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Eye disorders
Eye oedema	1/195 (0.5%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Scleral haemorrhage	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Visual acuity reduced	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		2/38 (5.3%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Gastrointestinal disorders
Diarrhoea	166/195 (85.1%)		76/89 (85.4%)		5/5 (100%)		30/38 (78.9%)		42/50 (84%)		22/26 (84.6%)		67/79 (84.8%)		41/64 (64.1%)		15/24 (62.5%)
Nausea	85/195 (43.6%)		46/89 (51.7%)		2/5 (40%)		20/38 (52.6%)		23/50 (46%)		12/26 (46.2%)		36/79 (45.6%)		30/64 (46.9%)		12/24 (50%)
Vomiting	73/195 (37.4%)		32/89 (36%)		0/5 (0%)		14/38 (36.8%)		24/50 (48%)		7/26 (26.9%)		35/79 (44.3%)		26/64 (40.6%)		11/24 (45.8%)
Abdominal pain	50/195 (25.6%)		24/89 (27%)		0/5 (0%)		8/38 (21.1%)		12/50 (24%)		8/26 (30.8%)		19/79 (24.1%)		11/64 (17.2%)		3/24 (12.5%)
Abdominal pain upper	41/195 (21%)		17/89 (19.1%)		0/5 (0%)		8/38 (21.1%)		9/50 (18%)		4/26 (15.4%)		9/79 (11.4%)		7/64 (10.9%)		0/24 (0%)
Constipation	22/195 (11.3%)		17/89 (19.1%)		2/5 (40%)		2/38 (5.3%)		7/50 (14%)		3/26 (11.5%)		14/79 (17.7%)		9/64 (14.1%)		4/24 (16.7%)
Dyspepsia	21/195 (10.8%)		7/89 (7.9%)		0/5 (0%)		7/38 (18.4%)		4/50 (8%)		1/26 (3.8%)		9/79 (11.4%)		1/64 (1.6%)		1/24 (4.2%)
Abdominal distension	17/195 (8.7%)		8/89 (9%)		0/5 (0%)		2/38 (5.3%)		4/50 (8%)		3/26 (11.5%)		1/79 (1.3%)		4/64 (6.3%)		0/24 (0%)
Flatulence	4/195 (2.1%)		6/89 (6.7%)		0/5 (0%)		3/38 (7.9%)		3/50 (6%)		1/26 (3.8%)		2/79 (2.5%)		2/64 (3.1%)		0/24 (0%)
Abdominal discomfort	8/195 (4.1%)		9/89 (10.1%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		4/79 (5.1%)		1/64 (1.6%)		2/24 (8.3%)
Toothache	12/195 (6.2%)		6/89 (6.7%)		1/5 (20%)		2/38 (5.3%)		2/50 (4%)		0/26 (0%)		3/79 (3.8%)		0/64 (0%)		0/24 (0%)
Aphthous stomatitis	2/195 (1%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Gastrointestinal sounds abnormal	0/195 (0%)		0/89 (0%)		1/5 (20%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Gingival bleeding	5/195 (2.6%)		1/89 (1.1%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		1/64 (1.6%)		1/24 (4.2%)
Gingival pain	2/195 (1%)		2/89 (2.2%)		1/5 (20%)		2/38 (5.3%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Haemorrhoids	7/195 (3.6%)		2/89 (2.2%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		3/26 (11.5%)		4/79 (5.1%)		2/64 (3.1%)		1/24 (4.2%)
Mouth ulceration	6/195 (3.1%)		3/89 (3.4%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		2/26 (7.7%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Stomatitis	2/195 (1%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		1/26 (3.8%)		2/79 (2.5%)		2/64 (3.1%)		2/24 (8.3%)
Tongue oedema	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
General disorders
Pyrexia	58/195 (29.7%)		17/89 (19.1%)		1/5 (20%)		5/38 (13.2%)		7/50 (14%)		3/26 (11.5%)		28/79 (35.4%)		22/64 (34.4%)		10/24 (41.7%)
Fatigue	49/195 (25.1%)		24/89 (27%)		3/5 (60%)		8/38 (21.1%)		12/50 (24%)		2/26 (7.7%)		17/79 (21.5%)		13/64 (20.3%)		5/24 (20.8%)
Asthenia	25/195 (12.8%)		16/89 (18%)		2/5 (40%)		2/38 (5.3%)		1/50 (2%)		4/26 (15.4%)		11/79 (13.9%)		3/64 (4.7%)		5/24 (20.8%)
Oedema peripheral	17/195 (8.7%)		11/89 (12.4%)		1/5 (20%)		1/38 (2.6%)		4/50 (8%)		4/26 (15.4%)		6/79 (7.6%)		7/64 (10.9%)		5/24 (20.8%)
Pain	16/195 (8.2%)		5/89 (5.6%)		2/5 (40%)		2/38 (5.3%)		2/50 (4%)		1/26 (3.8%)		6/79 (7.6%)		3/64 (4.7%)		2/24 (8.3%)
Chest pain	13/195 (6.7%)		7/89 (7.9%)		1/5 (20%)		1/38 (2.6%)		2/50 (4%)		0/26 (0%)		6/79 (7.6%)		3/64 (4.7%)		2/24 (8.3%)
Oedema	9/195 (4.6%)		4/89 (4.5%)		0/5 (0%)		2/38 (5.3%)		2/50 (4%)		0/26 (0%)		5/79 (6.3%)		2/64 (3.1%)		2/24 (8.3%)
Chills	13/195 (6.7%)		5/89 (5.6%)		0/5 (0%)		0/38 (0%)		3/50 (6%)		0/26 (0%)		3/79 (3.8%)		2/64 (3.1%)		3/24 (12.5%)
Chest discomfort	1/195 (0.5%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		2/50 (4%)		1/26 (3.8%)		4/79 (5.1%)		1/64 (1.6%)		0/24 (0%)
Face oedema	4/195 (2.1%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		1/79 (1.3%)		0/64 (0%)		1/24 (4.2%)
Influenza like illness	6/195 (3.1%)		5/89 (5.6%)		1/5 (20%)		1/38 (2.6%)		3/50 (6%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Temperature intolerance	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	4/195 (2.1%)		1/89 (1.1%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		2/79 (2.5%)		5/64 (7.8%)		1/24 (4.2%)
Immune system disorders
Drug hypersensitivity	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		3/38 (7.9%)		1/50 (2%)		1/26 (3.8%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Infections and infestations
Nasopharyngitis	25/195 (12.8%)		13/89 (14.6%)		1/5 (20%)		3/38 (7.9%)		5/50 (10%)		4/26 (15.4%)		7/79 (8.9%)		1/64 (1.6%)		0/24 (0%)
Upper respiratory tract infection	19/195 (9.7%)		9/89 (10.1%)		2/5 (40%)		3/38 (7.9%)		7/50 (14%)		0/26 (0%)		8/79 (10.1%)		2/64 (3.1%)		0/24 (0%)
Influenza	21/195 (10.8%)		6/89 (6.7%)		1/5 (20%)		4/38 (10.5%)		4/50 (8%)		3/26 (11.5%)		5/79 (6.3%)		0/64 (0%)		1/24 (4.2%)
Urinary tract infection	20/195 (10.3%)		8/89 (9%)		1/5 (20%)		1/38 (2.6%)		2/50 (4%)		2/26 (7.7%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Bronchitis	13/195 (6.7%)		3/89 (3.4%)		1/5 (20%)		1/38 (2.6%)		2/50 (4%)		1/26 (3.8%)		6/79 (7.6%)		0/64 (0%)		0/24 (0%)
Sinusitis	7/195 (3.6%)		3/89 (3.4%)		1/5 (20%)		2/38 (5.3%)		4/50 (8%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Gastrointestinal infection	0/195 (0%)		0/89 (0%)		0/5 (0%)		2/38 (5.3%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Gingivitis	4/195 (2.1%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		1/64 (1.6%)		0/24 (0%)
Lower respiratory tract infection	1/195 (0.5%)		1/89 (1.1%)		1/5 (20%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Oral candidiasis	1/195 (0.5%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		4/79 (5.1%)		2/64 (3.1%)		0/24 (0%)
Oral herpes	3/195 (1.5%)		3/89 (3.4%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		1/26 (3.8%)		6/79 (7.6%)		1/64 (1.6%)		0/24 (0%)
Pharyngitis	6/195 (3.1%)		5/89 (5.6%)		1/5 (20%)		2/38 (5.3%)		0/50 (0%)		1/26 (3.8%)		1/79 (1.3%)		1/64 (1.6%)		0/24 (0%)
Pneumonia	2/195 (1%)		2/89 (2.2%)		0/5 (0%)		1/38 (2.6%)		3/50 (6%)		1/26 (3.8%)		2/79 (2.5%)		4/64 (6.3%)		1/24 (4.2%)
Respiratory tract infection viral	4/195 (2.1%)		3/89 (3.4%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		3/26 (11.5%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Wound infection	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Injury, poisoning and procedural complications
Contusion	1/195 (0.5%)		7/89 (7.9%)		0/5 (0%)		0/38 (0%)		2/50 (4%)		0/26 (0%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Procedural pain	5/195 (2.6%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		2/50 (4%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Investigations
Alanine aminotransferase increased	42/195 (21.5%)		21/89 (23.6%)		1/5 (20%)		6/38 (15.8%)		6/50 (12%)		5/26 (19.2%)		11/79 (13.9%)		4/64 (6.3%)		2/24 (8.3%)
Platelet count decreased	16/195 (8.2%)		11/89 (12.4%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		2/26 (7.7%)		5/79 (6.3%)		4/64 (6.3%)		2/24 (8.3%)
Weight decreased	27/195 (13.8%)		8/89 (9%)		0/5 (0%)		0/38 (0%)		7/50 (14%)		0/26 (0%)		6/79 (7.6%)		3/64 (4.7%)		0/24 (0%)
Blood creatinine increased	18/195 (9.2%)		8/89 (9%)		1/5 (20%)		4/38 (10.5%)		6/50 (12%)		4/26 (15.4%)		6/79 (7.6%)		3/64 (4.7%)		0/24 (0%)
Lipase increased	17/195 (8.7%)		9/89 (10.1%)		0/5 (0%)		3/38 (7.9%)		2/50 (4%)		2/26 (7.7%)		6/79 (7.6%)		3/64 (4.7%)		0/24 (0%)
Blood alkaline phosphatase increased	6/195 (3.1%)		3/89 (3.4%)		0/5 (0%)		3/38 (7.9%)		0/50 (0%)		3/26 (11.5%)		5/79 (6.3%)		3/64 (4.7%)		1/24 (4.2%)
Amylase increased	12/195 (6.2%)		3/89 (3.4%)		0/5 (0%)		2/38 (5.3%)		1/50 (2%)		3/26 (11.5%)		1/79 (1.3%)		3/64 (4.7%)		0/24 (0%)
Aspartate aminotransferase increased	38/195 (19.5%)		18/89 (20.2%)		0/5 (0%)		2/38 (5.3%)		3/50 (6%)		4/26 (15.4%)		12/79 (15.2%)		4/64 (6.3%)		1/24 (4.2%)
Blood creatine phosphokinase increased	14/195 (7.2%)		1/89 (1.1%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		1/26 (3.8%)		3/79 (3.8%)		0/64 (0%)		0/24 (0%)
Haemoglobin decreased	6/195 (3.1%)		10/89 (11.2%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		3/26 (11.5%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Weight increased	12/195 (6.2%)		3/89 (3.4%)		0/5 (0%)		3/38 (7.9%)		1/50 (2%)		0/26 (0%)		2/79 (2.5%)		3/64 (4.7%)		0/24 (0%)
White blood cell count decreased	6/195 (3.1%)		9/89 (10.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		3/79 (3.8%)		4/64 (6.3%)		1/24 (4.2%)
Blood urea increased	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		2/38 (5.3%)		2/50 (4%)		0/26 (0%)		2/79 (2.5%)		1/64 (1.6%)		0/24 (0%)
Blood uric acid increased	11/195 (5.6%)		1/89 (1.1%)		0/5 (0%)		2/38 (5.3%)		2/50 (4%)		0/26 (0%)		4/79 (5.1%)		0/64 (0%)		1/24 (4.2%)
Gamma-glutamyltransferase increased	4/195 (2.1%)		2/89 (2.2%)		0/5 (0%)		3/38 (7.9%)		0/50 (0%)		1/26 (3.8%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Globulins decreased	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Haematocrit decreased	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		1/26 (3.8%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Neutrophil count decreased	3/195 (1.5%)		5/89 (5.6%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		3/79 (3.8%)		1/64 (1.6%)		2/24 (8.3%)
White blood cells urine positive	3/195 (1.5%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Metabolism and nutrition disorders
Decreased appetite	29/195 (14.9%)		12/89 (13.5%)		1/5 (20%)		3/38 (7.9%)		7/50 (14%)		4/26 (15.4%)		7/79 (8.9%)		12/64 (18.8%)		1/24 (4.2%)
Hypokalaemia	10/195 (5.1%)		5/89 (5.6%)		0/5 (0%)		0/38 (0%)		3/50 (6%)		2/26 (7.7%)		2/79 (2.5%)		6/64 (9.4%)		2/24 (8.3%)
Hypophosphataemia	12/195 (6.2%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		1/26 (3.8%)		5/79 (6.3%)		3/64 (4.7%)		2/24 (8.3%)
Hyperuricaemia	6/195 (3.1%)		6/89 (6.7%)		1/5 (20%)		1/38 (2.6%)		5/50 (10%)		0/26 (0%)		3/79 (3.8%)		2/64 (3.1%)		0/24 (0%)
Hypocalcaemia	8/195 (4.1%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		2/79 (2.5%)		5/64 (7.8%)		1/24 (4.2%)
Hyperglycaemia	8/195 (4.1%)		2/89 (2.2%)		0/5 (0%)		2/38 (5.3%)		1/50 (2%)		2/26 (7.7%)		4/79 (5.1%)		1/64 (1.6%)		2/24 (8.3%)
Hyperkalaemia	6/195 (3.1%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		4/26 (15.4%)		4/79 (5.1%)		3/64 (4.7%)		0/24 (0%)
Hypernatraemia	0/195 (0%)		0/89 (0%)		0/5 (0%)		2/38 (5.3%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hypoglycaemia	2/195 (1%)		1/89 (1.1%)		1/5 (20%)		2/38 (5.3%)		0/50 (0%)		1/26 (3.8%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Hypomagnesaemia	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		2/79 (2.5%)		4/64 (6.3%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	31/195 (15.9%)		17/89 (19.1%)		0/5 (0%)		5/38 (13.2%)		10/50 (20%)		6/26 (23.1%)		12/79 (15.2%)		8/64 (12.5%)		3/24 (12.5%)
Back pain	22/195 (11.3%)		16/89 (18%)		1/5 (20%)		5/38 (13.2%)		5/50 (10%)		3/26 (11.5%)		8/79 (10.1%)		4/64 (6.3%)		4/24 (16.7%)
Pain in extremity	27/195 (13.8%)		4/89 (4.5%)		0/5 (0%)		2/38 (5.3%)		5/50 (10%)		3/26 (11.5%)		9/79 (11.4%)		6/64 (9.4%)		3/24 (12.5%)
Myalgia	16/195 (8.2%)		7/89 (7.9%)		0/5 (0%)		3/38 (7.9%)		1/50 (2%)		1/26 (3.8%)		7/79 (8.9%)		6/64 (9.4%)		2/24 (8.3%)
Bone pain	11/195 (5.6%)		3/89 (3.4%)		0/5 (0%)		3/38 (7.9%)		5/50 (10%)		1/26 (3.8%)		1/79 (1.3%)		7/64 (10.9%)		3/24 (12.5%)
Musculoskeletal pain	8/195 (4.1%)		3/89 (3.4%)		0/5 (0%)		5/38 (13.2%)		3/50 (6%)		2/26 (7.7%)		5/79 (6.3%)		3/64 (4.7%)		1/24 (4.2%)
Muscle spasms	7/195 (3.6%)		7/89 (7.9%)		0/5 (0%)		2/38 (5.3%)		5/50 (10%)		1/26 (3.8%)		4/79 (5.1%)		1/64 (1.6%)		2/24 (8.3%)
Groin pain	1/195 (0.5%)		0/89 (0%)		0/5 (0%)		2/38 (5.3%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		1/24 (4.2%)
Joint swelling	1/195 (0.5%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		1/64 (1.6%)		1/24 (4.2%)
Musculoskeletal chest pain	2/195 (1%)		1/89 (1.1%)		0/5 (0%)		2/38 (5.3%)		1/50 (2%)		0/26 (0%)		3/79 (3.8%)		1/64 (1.6%)		1/24 (4.2%)
Musculoskeletal stiffness	0/195 (0%)		1/89 (1.1%)		1/5 (20%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Neck pain	4/195 (2.1%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		2/26 (7.7%)		1/79 (1.3%)		4/64 (6.3%)		0/24 (0%)
Nervous system disorders
Headache	35/195 (17.9%)		18/89 (20.2%)		1/5 (20%)		7/38 (18.4%)		15/50 (30%)		8/26 (30.8%)		12/79 (15.2%)		13/64 (20.3%)		6/24 (25%)
Dizziness	16/195 (8.2%)		9/89 (10.1%)		2/5 (40%)		5/38 (13.2%)		8/50 (16%)		3/26 (11.5%)		11/79 (13.9%)		7/64 (10.9%)		2/24 (8.3%)
Hypoaesthesia	11/195 (5.6%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		1/26 (3.8%)		3/79 (3.8%)		2/64 (3.1%)		1/24 (4.2%)
Paraesthesia	11/195 (5.6%)		3/89 (3.4%)		1/5 (20%)		0/38 (0%)		3/50 (6%)		0/26 (0%)		2/79 (2.5%)		1/64 (1.6%)		0/24 (0%)
Dysgeusia	3/195 (1.5%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		1/26 (3.8%)		2/79 (2.5%)		1/64 (1.6%)		1/24 (4.2%)
Neuropathy peripheral	3/195 (1.5%)		1/89 (1.1%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		3/79 (3.8%)		1/64 (1.6%)		1/24 (4.2%)
Sensory disturbance	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Somnolence	4/195 (2.1%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		2/26 (7.7%)		2/79 (2.5%)		1/64 (1.6%)		0/24 (0%)
Syncope	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		2/24 (8.3%)
Psychiatric disorders
Insomnia	6/195 (3.1%)		3/89 (3.4%)		3/5 (60%)		1/38 (2.6%)		5/50 (10%)		1/26 (3.8%)		8/79 (10.1%)		5/64 (7.8%)		2/24 (8.3%)
Anxiety	8/195 (4.1%)		7/89 (7.9%)		0/5 (0%)		1/38 (2.6%)		2/50 (4%)		1/26 (3.8%)		8/79 (10.1%)		3/64 (4.7%)		0/24 (0%)
Depression	9/195 (4.6%)		4/89 (4.5%)		1/5 (20%)		0/38 (0%)		3/50 (6%)		2/26 (7.7%)		2/79 (2.5%)		5/64 (7.8%)		0/24 (0%)
Renal and urinary disorders
Dysuria	6/195 (3.1%)		4/89 (4.5%)		0/5 (0%)		3/38 (7.9%)		0/50 (0%)		2/26 (7.7%)		1/79 (1.3%)		2/64 (3.1%)		1/24 (4.2%)
Pollakiuria	2/195 (1%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Renal failure	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		1/38 (2.6%)		1/50 (2%)		0/26 (0%)		5/79 (6.3%)		1/64 (1.6%)		1/24 (4.2%)
Urinary retention	1/195 (0.5%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	46/195 (23.6%)		19/89 (21.3%)		2/5 (40%)		7/38 (18.4%)		12/50 (24%)		4/26 (15.4%)		24/79 (30.4%)		8/64 (12.5%)		1/24 (4.2%)
Dyspnoea	23/195 (11.8%)		9/89 (10.1%)		1/5 (20%)		2/38 (5.3%)		9/50 (18%)		1/26 (3.8%)		14/79 (17.7%)		12/64 (18.8%)		4/24 (16.7%)
Oropharyngeal pain	25/195 (12.8%)		10/89 (11.2%)		1/5 (20%)		2/38 (5.3%)		3/50 (6%)		2/26 (7.7%)		8/79 (10.1%)		3/64 (4.7%)		2/24 (8.3%)
Pleural effusion	18/195 (9.2%)		7/89 (7.9%)		1/5 (20%)		3/38 (7.9%)		13/50 (26%)		1/26 (3.8%)		8/79 (10.1%)		2/64 (3.1%)		2/24 (8.3%)
Dyspnoea exertional	7/195 (3.6%)		1/89 (1.1%)		1/5 (20%)		1/38 (2.6%)		5/50 (10%)		0/26 (0%)		3/79 (3.8%)		1/64 (1.6%)		0/24 (0%)
Epistaxis	3/195 (1.5%)		1/89 (1.1%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		2/26 (7.7%)		3/79 (3.8%)		3/64 (4.7%)		2/24 (8.3%)
Atelectasis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		2/24 (8.3%)
Nasal congestion	0/195 (0%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		3/50 (6%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		0/24 (0%)
Productive cough	4/195 (2.1%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		5/50 (10%)		0/26 (0%)		0/79 (0%)		2/64 (3.1%)		0/24 (0%)
Pulmonary hilum mass	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Pulmonary mass	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		1/38 (2.6%)		3/50 (6%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Rales	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		2/24 (8.3%)
Rhinorrhoea	4/195 (2.1%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		2/64 (3.1%)		1/24 (4.2%)
Skin and subcutaneous tissue disorders
Rash	63/195 (32.3%)		36/89 (40.4%)		2/5 (40%)		10/38 (26.3%)		18/50 (36%)		3/26 (11.5%)		27/79 (34.2%)		20/64 (31.3%)		4/24 (16.7%)
Pruritus	18/195 (9.2%)		9/89 (10.1%)		0/5 (0%)		9/38 (23.7%)		8/50 (16%)		3/26 (11.5%)		6/79 (7.6%)		4/64 (6.3%)		0/24 (0%)
Dry skin	16/195 (8.2%)		4/89 (4.5%)		0/5 (0%)		1/38 (2.6%)		4/50 (8%)		3/26 (11.5%)		3/79 (3.8%)		1/64 (1.6%)		0/24 (0%)
Skin lesion	10/195 (5.1%)		4/89 (4.5%)		0/5 (0%)		2/38 (5.3%)		2/50 (4%)		2/26 (7.7%)		4/79 (5.1%)		1/64 (1.6%)		0/24 (0%)
Alopecia	11/195 (5.6%)		3/89 (3.4%)		1/5 (20%)		0/38 (0%)		3/50 (6%)		0/26 (0%)		1/79 (1.3%)		2/64 (3.1%)		0/24 (0%)
Night sweats	2/195 (1%)		1/89 (1.1%)		0/5 (0%)		2/38 (5.3%)		3/50 (6%)		1/26 (3.8%)		2/79 (2.5%)		0/64 (0%)		0/24 (0%)
Angioedema	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Dermatitis	4/195 (2.1%)		0/89 (0%)		0/5 (0%)		2/38 (5.3%)		0/50 (0%)		1/26 (3.8%)		2/79 (2.5%)		1/64 (1.6%)		0/24 (0%)
Ecchymosis	0/195 (0%)		1/89 (1.1%)		0/5 (0%)		0/38 (0%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Erythema	5/195 (2.6%)		7/89 (7.9%)		0/5 (0%)		1/38 (2.6%)		2/50 (4%)		2/26 (7.7%)		4/79 (5.1%)		1/64 (1.6%)		0/24 (0%)
Hyperhidrosis	3/195 (1.5%)		3/89 (3.4%)		0/5 (0%)		1/38 (2.6%)		3/50 (6%)		1/26 (3.8%)		2/79 (2.5%)		3/64 (4.7%)		0/24 (0%)
Nail disorder	0/195 (0%)		0/89 (0%)		0/5 (0%)		1/38 (2.6%)		0/50 (0%)		2/26 (7.7%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Petechiae	3/195 (1.5%)		0/89 (0%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		3/64 (4.7%)		3/24 (12.5%)
Skin burning sensation	2/195 (1%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Skin depigmentation	0/195 (0%)		0/89 (0%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Swelling face	1/195 (0.5%)		1/89 (1.1%)		1/5 (20%)		1/38 (2.6%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Vascular disorders
Hypertension	17/195 (8.7%)		6/89 (6.7%)		0/5 (0%)		2/38 (5.3%)		5/50 (10%)		1/26 (3.8%)		6/79 (7.6%)		2/64 (3.1%)		2/24 (8.3%)
Flushing	1/195 (0.5%)		2/89 (2.2%)		1/5 (20%)		0/38 (0%)		0/50 (0%)		0/26 (0%)		0/79 (0%)		0/64 (0%)		0/24 (0%)
Haematoma	3/195 (1.5%)		2/89 (2.2%)		0/5 (0%)		0/38 (0%)		1/50 (2%)		0/26 (0%)		1/79 (1.3%)		0/64 (0%)		3/24 (12.5%)

Limitations/Caveats

Analyses of progression free survival and overall survival was based on all-treated population, instead of evaluable population which was the primary efficacy population as per planned analyses.

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Certain Agreements

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

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