Primary Outcomes

Measure: Rate of complete molecular response (CMR) after treatment with dasatinib

Time: at 12 months

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Secondary Outcomes

Measure: Dasatinib of dose intensity

Time: at 12 months

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Measure: Expansions rate of large granular lymphocyte

Time: at 12 months

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Measure: Progression free survival

Time: at 12 months

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Measure: Number of Participants with Adverse Events

Time: at 12 months

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Primary Outcomes

Measure: To confirm the patterns of resistance including point mutations which are newly expressed during the nilotinib treatment

Time: 5 years

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Secondary Outcomes

Measure: To analyze and evaluate the overall survival and disease free survival in the nilotinib treatment according to progression of the disease and types of point mutations

Time: 5 years

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Primary Outcomes

Description: Major Molecular Response, is defined as a 3-log reduction in BCR-ABL transcripts from the standardized baseline, which represents 100% on the international scale, so a 3-log reduction is fixed at 0.1% for MMR; N/A = not applicable. 95% CI is Clopper-Pearson(Exact) two-sided 95% confidence intervals. P-value is based on Cochran-Mantel-Haenszel (CMH) test stratified by Sokal score(high, intermediate, low, and unknown) and time between 3 month molecular analysis and randomization (<=4 weeks vs >4 weeks). Month 12 is calculated fro

Measure: Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment

Time: At 12 months after Day 1 initiation of 1st line treatment with imatinib or imatinib at any dose, after less than optimal response to first-line imatinib.

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Secondary Outcomes

Description: Time to MMR is how fast patients achieve optimal response. It is the time between randomization date and first date that MMR criteria are satisfied.

Measure: Median Time to Major Molecular Response (MMR)

Time: Up to 10 years

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Description: Time to MR^4.5 is how fast patients achieve a deeper response. It is the time between randomization date and first date that MR^4.5 criteria are satisfied.

Measure: Time to Molecular Response (MR)^4.5

Time: Up to 10 years

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Description: PFS is how long patients are likely to live without progression of their disease. It is the time from randomization date to progression date or death date, whichever occurs first.

Measure: Progression Free Survival (PFS)

Time: Up to 10 years

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Description: OS is how long patients are likely to remain alive. It is the time from randomization date to death date.

Measure: Overall Survival (OS)

Time: Up to 10 years

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Primary Outcomes

Measure: The overall probability of maintenance of complete molecular remission at 12 months after stopping dasatinib.

Time: at 12 months

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Secondary Outcomes

Measure: Rate of complete molecular remission that will be sustained after dasatinib rechallenge.

Time: at 12 months

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Primary Outcomes

Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.

Measure: Percentage of Participants with Major Cytogenetic Response (MCyR) by Week 52 in Chronic Phase Second-line Population and Chronic Phase Third-line Population of Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients.

Time: Week 52

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Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.

Measure: Percentage of Participants with Major Cytogenetic Response (MCyR) by Week 52 in Chronic Phase Fourth-line and later-line Population of Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients.

Time: Week 52

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Description: OHR includes Complete Hematological Response (CHR) or return to chronic phase (RCP).

Measure: Percentage of Participants with Overall Hematologic Response (OHR) by Week 52 in Advanced Leukemia Population patients.

Time: Week 52

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Secondary Outcomes

Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.

Measure: Estimate cumulative probability of Percentage of Participants with Major Cytogenetic Response in Chronic Phase and Advanced Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

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Description: OHR includes Complete Hematological Response (CHR) or return to chronic phase (RCP).

Measure: Estimate cumulative probability of Percentage of Participants with Overall Hematologic Response in the Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient population by number of lines of prior therapy.

Time: Week 52

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Measure: Characterize distribution of best response (molecular, cytogenetic, or hematologic) in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

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Measure: Estimating probability of Percentage of Participants with Major Cytogenetic Response at 3, 6, 12, 18, and 24 months in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Month 3, 6, 12, 18, and 24

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Measure: Estimating the probability of confirmed Overall Hematologic Response at 3, 6, 9, 12, 18, and 24 months in the Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Month 3, 6, 9, 12, 18, and 24

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Measure: Estimating the probability of cumulative confirmed Complete Hematologic Response in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

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Measure: Estimating the probability of cumulative major molecular response in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

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Primary Outcomes

Description: is to be evaluated by using a combination of criteria. Molecular remissions will be defined by standard criteria for BCR-ABL1 and IGH qRT-PCR. Flow cytometric assessment of MRD will be defined by standard flow cytometry criteria

Measure: Clinical response

Time: 2 years

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Secondary Outcomes

Description: Molecular remission status will be defined by undetectable BCR-ABL1 transcripts and/or IGH clonal gene rearrangement in bone marrow aspirate (BMA) examination as determined by qRT-PCR in CLIA laboratory.

Measure: Complete Molecular Remission (CMR) rate

Time: 2 years

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Primary Outcomes

Measure: Number of patients who are in major molecular response (MMR)

Time: One year treatment

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Secondary Outcomes

Measure: Number of patients who obtain molecular response

Time: At 6 and 12 months from treatment start

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Measure: Number of patients discontinuing treatment for failure, adverse events or other reasons

Time: At 12 and 36 months

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Measure: Number of Adverse Events (AEs)

Time: At 36 months

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Measure: Number of patients alive

Time: At 36 months

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Measure: Number of patients on treatment at 200, 300 and 400 mg or more daily

Time: At 6, 12 and 36 months

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Measure: Number and type of BCR-ABL1 mutations

Time: At 36 months

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Measure: Patient reported quality of life

Time: At 3, 6, and 12 months

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Primary Outcomes

Description: To compare the MMR rate of ABL001 versus bosutinib

Measure: Major Molecular Response (MMR) rate

Time: at 24 weeks

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Secondary Outcomes

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Major Molecular Response (MMR) rate

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib. Cytogenic response will include Complete, Partial, Major, Minor, Minimal and no response.

Measure: Complete Cytogenetic response rate

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to MMR

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Duration of MMR

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to CCyR

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Duration of CCyR

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to treatment failure

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Progression free survival

Time: 96 weeks after the last patient received the first study dose

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Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Overall survival

Time: 96 weeks after the last patient received the first study dose

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Description: To characterize the PK of ABL001 in the CML-CP population

Measure: Trough plasma concentrations

Time: 96 weeks after the last patient received the first study dose

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Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: Cmax,

Time: 96 weeks after the last patient received the first study dose

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Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: Tmax

Time: 96 weeks after the last patient received the first study dose

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Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: AUC0-12h

Time: 96 weeks after the last patient received the first study dose

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Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: CL/F

Time: 96 weeks after the last patient received the first study dose

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Primary Outcomes

Description: calculation of the incidence rate of grade 2 to 4 GI toxicity with and without regard to causality

Measure: Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities)

Time: within the first 6 months of treatment

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Secondary Outcomes

Description: Apart from grade 2 to 4 GI toxicity, the occurrence of toxicity will be analyzed in general. This regards all grade toxicity, 2 to 4 grade and 3 to 4 grade toxicity (NCI CTCAE v4.0).

Measure: overall Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities)

Time: at month 6, 12 and 24

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Description: Rating of CCyR, MMR, MR4 and MR4.5 after bone marrow aspiration and biopsy

Measure: Molecular response mesured by efficacy parametern

Time: at month 3, 6, 12, 18 and 24

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Description: The EORTC QLQ-CML30 will be scored according to the respective user's guides.

Measure: Patient-reported outcome measures (QoL)

Time: at month 3 and 6

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Description: Progression will be assessed according to the visit schedule at any visit.

Measure: Progression-free survival (PFS)

Time: at month 3, 6, 9, 12, 15, 18, 21 and 24

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Description: Survival will be assessed according to the visit schedule at any visit.

Measure: Overall Survival (OS)

Time: at month 3, 6, 9, 12, 15, 18, 21 and 24

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Description: The rate and type of mutations will be described. The rate will be given as percentage of patients developing mutations.

Measure: The rate of emerging mutations during Bosutinib treatment

Time: at month 3, 6, 9, 12, 15, 18, 21 and 24

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Other Outcomes

Description: Ankle Brachial Index (ABI) will be prospectively evaluated followed by analysis of various biomarkers for vascular damage

Measure: Vascular biology substudy: analysis of clinical and laboratory vascular and metabolic risk factors

Time: baseline, at months 6, 12 and 24

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Description: It is planned to analyze PK parameters sequentially by taking serum from PB and subsequent HPLC-MS/MS technology. Pharmacodynamics in different compartments will be analyzed by means of flow-cytometry of PB and BM samples.

Measure: Pharmacokinetic (PK), pharmacodynamic (PD) substudy

Time: at day 1, months 1, 2, 3, 12, 18, 24

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Description: Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response under Bosutinib

Measure: Telomere substudy

Time: at months 1, 2, 3, 12 and 24

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Description: Documentation of subclone evolution or elimination during Bosutinib treatment

Measure: Ultra-deep next-generation sequencing (UD-NGS)

Time: at months 1, 2, 3, 12 and 24

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Description: Documentation of patient´s comorbidity profile using 3 different comorbidity scales

Measure: Assessment of patients comorbidities and correlation to individual patient´s adverse side effect profile substudy

Time: through study completion, an average of 2 years

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Description: Investigation the role of the 5-HT pathway in directing bosutinib induced diarrhea by assessment of 5-HT and certain cytokine levels and genetic analysis including SNP and GWAS

Measure: Transport mechanisms of Bosutinib and mechanisms of diarrhea substudy

Time: every 14 days month 1-3

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Primary Outcomes

Description: Data from Phase 1; Dose-limiting toxicities determined as adverse events occurring in the first cycle (28 days) of treatment, which are attributable to bosutinib. Assessment will be done according the following DLT definition: Non-hematologic AEs: grade ≥3 toxicities, except those that have not been optimally treated; any grade ≥2 toxicity requiring discontinuation/interruption for ≥7 days during the first 28 days of treatment; clinically significant laboratory abnormalities grade ≥3 or lasting ≥7 days despite optimal treatment Hematologic AEs: grade 4 neutropenia or thrombocytopenia lasting ≥7 days (not explained by persistent leukemia).

Measure: 1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.

Time: First 28 days of treatment (first cycle)

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Description: Data from Phase 1; Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time postdose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days); unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 1; Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib:Time to Cmax (Tmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 1; Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.

Measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 1; Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 1; Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Measure: PK parameters of bosutinib: Apparent clearance (CL/F).

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 2; AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).

Measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy (pooled across ND and R/I CML patients and by line of therapy).

Time: AE's will be collected from signing informed consent continuously during the study until 28 days after last dose (on average, 2 years).

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Description: Data from Phase 2; subset of newly diagnosed patients. Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 & and before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 2; subset of newly diagnosed patients. Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.]

Measure: PK parameters of bosutinib:Time to Cmax (Tmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 2; subset of newly diagnosed patients. Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.

Measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 2; subset of newly diagnosed patients. Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase 2; subset of newly diagnosed patients. Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Measure: PK parameters of bosutinib: Apparent clearance (CL/F).

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase1 and Phase 2. Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Data from Phase1 and Phase 2. Volume of distribution are calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Measure: Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Phase 2

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days); for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Description: Data from Phase1 and Phase 2. Clearance is calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations

Measure: Population PK parameters of bosutinib including clearance based on combined PK data from Phase 1 and Phase 2

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

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Secondary Outcomes

Description: Data from Phase 1. AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).]

Measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;

Time: From signing informed consent, continuously during the study until 28 days after last dose (on average 2 years).

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Description: Data from Phase 1. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6

Measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table

Time: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. Kamofsky or Lansky performance score is collected to evaluate performance status.

Measure: ECG abnormalities: QT interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.

Measure: ECG abnormalities: RR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.

Measure: ECG abnormalities: PR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.

Measure: ECG abnormalities: QRS duration

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 1. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status

Measure: Performance status abnormalities

Time: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)

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Description: Data from Phase 1. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).]

Measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Time: Hematologic response:Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).

Measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Time: Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).]

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Description: Time to response is defined as the time period from start of treatment with bosutinib to first response, unconfirmed for molecular and cytogenetic and confirmed for hematologic. Patients without events are censored at the last molecular, cytogenetic, or hematologic assessment where response could be assessed for the respective endpoint

Measure: Time to the respective responses by line of therapy

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 2. Duration of response is defined is defined as the time period from the date of the earliest demonstration of a response until the earliest date of confirmed loss of that response.

Measure: Duration of the respective responses by line of therapy

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 2. EFS is defined as the interval from the date of first dose of bosutinib until the earlier date of EFS events. Patients without the event will be censored at the last evaluation date.

Measure: Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2).

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 2. OS or survival time is defined as the interval from the date of first dose of bosutinib until the date of death due to any cause. Patients without the event will be censored at the last evaluation date

Measure: Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 2. Pooled across ND and R/I CML and by line of therapy. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test and contraception will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6

Measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table

Time: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: QT interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: RR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: PR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: QRS duration

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

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Description: Data from Phase 2. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status.

Measure: Performance status abnormalities

Time: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)

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Other Outcomes

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).

Measure: Parameters of bone metabolism and growth: linear growth

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone age

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys),

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys)

Time: [Time Frame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 1. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. ON a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'

Measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 1. A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.

Measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age.

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).

Measure: Parameters of bone metabolism and growth: linear growth

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone age

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys)

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

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Description: Data from Phase 2. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. On a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'

Measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale.

Time: Through study completion, a maximum of around 10 years

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Description: Data from Phase 2 A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.

Measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age.

Time: Through study completion, a maximum of around 10 years

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