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

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

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

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

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

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

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)

Duration of Complete Hematologic Response (CHR) - Part 2

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)

Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2

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)

Cumulative Incidence of Progression/Death - Part 2

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)

Progression Free Survival (PFS) - Part 2

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)

Kaplan-Meier Estimate of Overall Survival (OS) - Part 2

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)

Overall Survival (OS) - Part 2

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)

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

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)

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

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

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

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)

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

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)

Percentage of Participants With Change From Baseline in Laboratory Tests Results

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

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

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

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

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

Time frame: Baseline, Week 8, and end of treatment

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

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

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

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

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

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

Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values

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