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

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

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

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

Population: 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.

Time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Population: Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

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

Population: Safety population included all participants who received at least 1 dose of study medication

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

Population: Safety population included all participants who received at least 1 dose of study medication.

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

Population: Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.

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

Population: 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.

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

Population: 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.

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

Population: Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

Time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Population: Evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline efficacy assessment.

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)

Population: All-treated population included all enrolled participants who received at least one dose of study medication.

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)

Population: Subgroup of participants from evaluable population who had confirmed CHR.

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)

Population: Safety population included all participants who receive at least one dose of study medication.

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)

Population: Subgroup of participants from evaluable population who had confirmed CHR.

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)

Population: All-treated population included all enrolled participants who received at least 1 dose of study medication.

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

Population: Subgroup of participants from evaluable population who had MCyR.

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

Population: Safety population included all participants who receive at least one dose of study medication.

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

Population: Safety population included all participants who receive at least one dose of study medication.

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

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

Population: Safety population included all participants who received at lease one dose of study medication.

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)

Population: All-treated population included all enrolled participants who received at least 1 dose of study medication.

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

Population: Safety population included all participants who receive at least one dose of study medication.

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

Population: 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.

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

Population: 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.

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)

Population: Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment.

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)

Population: Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.

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)

Population: Cytogenetic evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline cytogenetic assessment.

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

Population: 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.

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

Population: Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment.

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)

Population: Safety population included all participants who receive at least one dose of study medication.

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

Population: 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.

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)

Population: 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.

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)

Population: 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.

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)

Population: All-treated population included all enrolled participants who received at least one dose of study medication.

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)

Population: 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.

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

Population: Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.