Study of Bosutinib in Japanese Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE EFFICACY AND SAFETY OF BOSUTINIB MONOTHERAPY IN JAPANESE ADULT PATIENTS WITH NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03128411

Enrollment

Registered

2017-04-25

Start date

2017-05-15

Completion date

2021-03-04

Last updated

2022-05-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Leukemia, Chronic Myelogenous

Keywords

Leukemia, Chronic Myelogenous

Brief summary

Phase 2, single-arm, open-label trial. Patients will receive bosutinib for the duration of the study.

Detailed description

The study will be open for enrollment until the planned number of approximately 60 Philadelphia Chromosome Positive (Ph+) patients have been registered. All patients will be treated and/or followed for up to approximately 3 years (144 weeks) after registration of the last patient or until study termination. Patients who discontinue study therapy early due to disease progression or intolerance to study medication will continue to be followed yearly for survival for up to approximately 3 years (144 weeks) after registration of the last patient or until study termination.

Interventions

DRUGBosutinib

All patients will receive bosutinib at a starting dose of 400 mg QD.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

* Diagnosis of CP CML of ≤6 months (from initial diagnosis); Diagnosis of CP CML with molecular confirmation by detection of BCR-ABL rearrangement at screening (cytogenetic assessment for Ph is not required for enrollment; however, patients with known Ph- CML prior to registration are not eligible for this study) * Age ≥20 years * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 * Adequate Liver and Renal Function

Exclusion criteria

* Any prior medical treatment for CML, including TKIs, with the exception of hydroxyurea treatment, which is permitted for up to 6 months prior to registration * Any past or current CNS involvement, including leptomeningeal leukemia * Extramedullary disease only * Major surgery or radiotherapy within 14 days prior to registration * History of clinically significant or uncontrolled cardiac disease * Patients with active, uncontrolled bacterial, fungal, or viral infection * Recent or ongoing clinically significant GI disorder * History of another malignancy within 5 years prior to registration * Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on the QT interval * Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations * Participation in other studies involving investigational drug(s) within 30 days or 5 half-lives of investigational product, whichever is longer, prior to registration and/or during study participation * Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or interfere with the interpretation of study results * Investigational site staff members directly involved in the conduct of the study and their family members, or Pfizer employees, including their family members, directly involved in the conduct of the study

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Major Molecular Response (MMR) at Month 12	Month 12	A MMR is defined as less than or equal to (\<=) 0.1 percent (%) BCR-ABL transcripts on the international scale (IS), corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. The MMR value counted only if the response was demonstrated at the 12-month visit; any MMR gained and lost, or never achieved at or before the 12-month visit was considered as non-responder.

Secondary

Measure	Time frame	Description
Percentage of Participants With Major Molecular Response (MMR) by Month 18	Up to Month 18	A MMR is defined as less than or equal to (\<=) 0.1 percent (%) BCR-ABL transcripts on the international scale (IS), corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. The MMR value counted only if the response was demonstrated at or before the 18-month visit.
Percentage of Participants With Complete Cytogenetic Response (CCyR) by Month 12	Up to Month 12	CCyR is based on the prevalence of Philadelphia chromosome positive metaphases among cells in metaphase on a bone marrow sample. CCyR was defined as absence of detectable Philadelphia chromosome positive cells. CCyR was achieved when there were 0 Philadelphia chromosome positive metaphases among at least 20 metaphases from a bone marrow sample or when MMR was achieved if no bone marrow analysis was performed. The CCyR value was counted only if the response was demonstrated at or before the 12-month visit.
Probability of Maintaining Major Molecular Response (MMR) at Month 36	At Month 36	Duration of MMR: time from first date of MMR until first date of confirmed loss of MMR, treatment discontinuation due to progressive disease (PD), or death due to PD within 28 days after last dose or censoring. PD: progression to Accelerated phase (AP) or to Blast Phase (BP). AP: 15-29% blasts in blood or marrow, or\>30% blasts plus promyelocytes in blood or marrow with blasts \<30%; ≥20% basophils in blood. BP: ≥30% Blasts in blood or bone marrow, extramedullary blast proliferation, other than in spleen. Kaplan-Meier analysis was used.
Probability of Maintaining Complete Cytogenetic Response (CCyR) at Month 36	At Month 36	Duration of CCyR, from first date of CCyR to confirmed loss of CCyR, treatment discontinuation due to PD, death due to PD within 28 days after last dose or censoring. Confirmed loss: at least 1 Ph+ metaphase confirmed by a second determination \>=4 weeks later or unconfirmed loss followed by treatment discontinuation due to suboptimal response. PD: progression to AP or to BP. Kaplan-Meier analysis was used.
Cumulative Incidence of Event Free Survival (EFS) at Month 36	Up to Month 36	EFS: time from 1st dose until 1st occurrence of 1 of the following events or censoring: 1)death from any cause 2)transformation to AP or BP 3)loss of complete hematologic response (CHR) 4)loss of CCyR 5)participants not achieving CHR: doubling of WBCs \>= 1 month apart with 2nd value \>20\10\^9/L and maintained in subsequent assessments for \>=2 weeks. Loss of CHR: appearance of any of the following confirmed by 2nd determination\>=4 weeks later (unless associated with CML-related treatment discontinuation): WBC count: \>20.0\10\^9/L, platelet count: \>=600\*10\^9/L, appearance of palpable spleen/other extra medullary involvement, appearance of 5% myelocytes or blasts or promyelocytes in peripheral blood. Loss of CCyR:\>= one Ph+ metaphase confirmed by 2nd determination \>=4 weeks later(unless associated with CML-related treatment discontinuation). Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without event.
Probability of Overall Survival (OS) at Month 36	Up to Month 36	Overall survival was defined as the time from first dose of study drug to death due to any cause or censoring. Kaplan-Meier analysis was used for determination of probability of overall survival.
Trough Plasma Concentrations of Bosutinib	Pre-dose on Day 1, Day 28, Day 56, Day 84	—
Summary and Analysis of Trough Bosutinib Plasma Concentration by Major Molecular Response (MMR) Response	Pre-dose on Day 28, Day 56 and Day 84	Trough bosutinib plasma concentration is reported classified on basis of participants with MMR response as Yes and No at specified time points. A MMR is defined as less than or equal to (\<=) 0.1 percent (%) BCR-ABL transcripts on the international scale (IS), corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory.
Summary and Analysis of Trough Bosutinib Plasma Concentration by CCyR Response	Pre-dose on Day 28, Day 56 and Day 84	Trough bosutinib plasma concentration is reported classified on basis of participants with CCyR Response as Yes and No at specified time points. CCyR is based on the prevalence of Philadelphia chromosome positive metaphases among cells in metaphase on a bone marrow sample. CCyR was defined as absence of detectable Philadelphia chromosome positive cells. CCyR was achieved when there were 0 Philadelphia chromosome positive metaphases among at least 20 metaphases from a bone marrow sample or when MMR was achieved if no bone marrow analysis was performed.
Summary of Trough Bosutinib Plasma Concentration by Total Bilirubin	Pre-dose on Day 28, Day 56 and Day 84	Trough bosutinib plasma concentration is reported classified on basis of total bilirubin level range at baseline. Level range 1: \<=7.7 micromole per liter (micromol/L), level rage 2: \>7.7 and \<= 10.3 micromol/L, level range 3: \>10.3 and \<=12.85 micromol/L and level range 4: \>12.85 micromol/L.
Summary of Trough Bosutinib Plasma Concentration by Creatinine Clearance	Pre-dose on Day 28, Day 56 and Day 84	Trough bosutinib plasma concentration is reported classified on basis of different ranges of creatinine clearance at baseline. Level range 1: \<=71.479 milliliter per minute (mL/min), level rage 2: \>71.479 and \<=100.936 mL/min, level range 3: \>100.936 and \<=129.355 mL/min) and level range 4: \>129.355 mL/min.
Summary of Trough Bosutinib Plasma Concentration by Aspartate Aminotransferase	Pre-dose on Day 28, Day 56 and Day 84	Trough bosutinib plasma concentration is reported classified on basis of different ranges of aspartate aminotransferase at baseline. Level range 1: \<=22 units per liter (U/L), level rage 2: \>22 and \<=26 U/L, level range 3: \>26 and \<=33 U/L and level range 4: \>33 U/L.
Summary of Trough Bosutinib Plasma Concentration by Alanine Aminotransferase	Pre-dose on Day 28, Day 56 and Day 84	Trough bosutinib plasma concentration is reported classified on basis of different ranges of alanine aminotransferase at baseline. Level range 1: \<=17.5 U/L, level rage 2: \>17.5 and \<=25 U/L, level range 3: \>25 and \<=32 U/L and level range 4: \>32 U/L.
Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Diarrhea	Pre-dose on Day 28, Day 56 and Day 84 for trough bosutinib plasma concentration up to 12 March 2019; maximum of 22 months, approximately, for the adverse event of interest	Trough bosutinib plasma concentration is reported classified on basis of presence/ or absence of grade 1 diarrhea as Yes and No at specified time points. As per national cancer institute common terminology criteria (NCI-CTCAE) version 4.03, Grade 1: increase of \<4 stools per day over baseline.
Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Nausea	Pre-dose on Day 28, Day 56 and Day 84 for trough bosutinib plasma concentration up to 12 March 2019; maximum of 22 months, approximately, for the adverse event of interest	Trough bosutinib plasma concentration is reported classified on basis of presence/ or absence of grade 1 Nausea as Yes and No at specified time points. As per NCI-CTCAE version 4.03, Grade 1: loss of appetite without alteration in eating habits.
Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Vomiting	Pre-dose on Day 28, Day 56 and Day 84 for trough bosutinib plasma concentration up to 12 March 2019; maximum of 22 months, approximately, for the adverse event of interest	Trough bosutinib plasma concentration is reported classified on basis of presence/ or absence of grade 1 vomiting as Yes and No at specified time points. As per NCI-CTCAE version 4.03, Grade 1: 1 - 2 episodes (separated by 5 minutes) in 24 hours.
Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Thrombocytopenia	Pre-dose on Day 28, Day 56 and Day 84 for trough bosutinib plasma concentration up to 12 March 2019; maximum of 22 months, approximately, for the adverse event of interest	Trough bosutinib plasma concentration is reported classified on basis of presence/ or absence of grade 1 thrombocytopenia as Yes and No at specified time points. As per NCI-CTCAE version 4.03, Grade 1: platelet count decreased: 75.0 - 50.0\*10\^9/L.
Percentage of Participants With Major Molecular Response (MMR) by Month 12	Up to Month 12	A MMR is defined as less than or equal to (\<=) 0.1 percent (%) BCR-ABL transcripts on the international scale (IS), corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. The MMR value counted only if the response was demonstrated at or before the 12-month visit.
Number of Participants With Laboratory Abnormalities, Chemistry: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or 4	From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)	Laboratory parameters include: Alanine aminotransferase (ALT) increased: Grade 3: \>5.0-20.0\upper limit of normal (ULN),Grade 4:\>20.0\ULN, Alkaline phosphatase (ALP) increased: Grade 3: \>5.0 - 20.0 x ULN, Grade 4: \>20.0 x ULN, Aspartate aminotransferase (AST) increased: Grade 3: \>5.0 - 20.0 \ULN, Grade 4: \>20.0\ULN. Blood bilirubin increased:Grade 3:\>3.0 - 10.0\ULN,Grade 4: \>10.0\ULN, creatine phosphokinase (CPK) increased: Grade 3: \>5\ULN-10\ULN, Grade 4: \>10\ULN, Hyperglycemia: Grade 3: \>250-500 milligrams/deciliter (mg/dL), Grade 4: \>500 mg/dL. Hypermagnesemia: Grade 3: \>3.0-8.0 mg/dL, Grade 4: \>8.0 mg/dL, Hypokalemia: Grade 3: \<3.0-2.5 millimoles/ liter (mmol/L), Grade 4:\<2.5 mmol/L); Hyponatremia: Grade 3: \<130-120 mmol/L, Grade 4: \<120 mmol/L. Hypophosphatemia: Grade 3: \<2.0-1.0 mg/dL, Grade 4: \<1.0 mg/dL. Lipase increased: Grade 3:\>2.0-5.0\ULN, Grade 4: \>5.0\ULN. Serum amylase increased: Grade 3: \>2.0 - 5.0\ULN, Grade 4: \>5.0\* ULN.
Number of Participants With Laboratory Abnormalities, Hematology: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or 4	From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)	Laboratory parameters include: Anemia: Grade 3: hemoglobin (Hgb) \<8.0 g/dL, Grade 4: Life-threatening consequences; urgent intervention indicated, Lymphocyte count decreased: Grade 3: \<500 - 200/millimeter(mm)\^3, Grade 4: \<200/mm\^3, Neutrophil count decreased: Grade 3: \<1000 - 500/mm\^3, Grade 4: \<500/mm\^3, Platelet count decreased: Grade 3: \<50.0 - 25.0\10\^9 /L, Grade 4: \<25.0\10\^9 /L. White blood cell decreased: Grade 3: \<2.0 - 1.0\10\^9 /L, Grade 4: \<1.0\10\^9 /L. Only those rows in which at least 1 participant had data were reported.
Number of Participants With Laboratory Abnormalities, Coagulation: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3	From first dose and up to 12 March 2019; maximum of 22 months, approximately	Coagulation parameters include: APTT prolonged (Grade 3: \>2.5\ULN and hemorrhage), and INR increased (Grade 3 \>2.5\ULN).
Number of Participants With Clinically Significant Vital Signs Findings	From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)	Vital signs included: body weight Increase \>= 10% change from baseline and Decrease \>= 10% change from baseline, systolic blood pressure in millimeters of mercury (mmHg): \<80 mmHg and \>210 mmHg, diastolic blood pressure in mmHg: \<40 mmHg and \>130 mmHg, heart rate in beats per minute (bpm): \<40 bpm and \>150 bpm, temperature in degree Celsius (C): \<32 and \>40 degree C.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings	From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)	ECG parameters included: QTc corrected by Bazett's (QTcB) interval: \>500 msec (milliseconds), QTc corrected by Fridericia's (QTcF) interval: \>500 msec and \>450 msec (men) or \>470 msec (women).
Number of Participants Assessed for Left Ventricular Ejection Fraction	At end of treatment for patients who discontinued treatment post initial dose (up to 12 March 2019)	Interpretation categories included: a) normal, b) abnormal, not clinically significant and c) abnormal, clinically significant.
Percentage of Participants With Major Molecular Response (MMR) at Months 3, 6, 9 and 18	Month 3, 6, 9 and 18	A MMR is defined as less than or equal to (\<=) 0.1 percent (%) BCR-ABL transcripts on the international scale (IS), corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. The MMR value counted only if the response was demonstrated at the designated visit; any MMR gained and lost, or never achieved at or before the designated visit was considered as non-responder.
Percentage of Participants With Molecular Response 1 (MR1) at Month 3	Month 3	MR1 is defined as \<= 10% BCR-ABL with a minimum of 3,000 ABL transcripts assessed by the central laboratory.
Percentage of Participants With Molecular Response 2 (MR2) at Month 6	Month 6	MR2 is defined as \<= 1% BCR-ABL with a minimum of 3,000 ABL transcripts assessed by the central laboratory.
Percentage of Participants With Molecular Response 4.0 (MR4.0) and Molecular Response 4.5 (MR4.5) at Months 3, 6, 9 and 12	Months 3, 6, 9 and 12	MR4.0 defined as either: detectable disease with \<= 0.01% BCR-ABL with a minimum of 9,800 ABL transcripts assessed by the central laboratory, or undetectable disease in cDNA with a minimum of 9,800 ABL transcripts assessed by the central laboratory. MR4.5 defined as either: detectable disease with \<= 0.0032% BCR-ABL with a minimum of 30,990 ABL transcripts assessed by the central laboratory or undetectable disease in cDNA with a minimum of 30,990 ABL transcripts assessed by the central laboratory. The MMR value counted only if the response was demonstrated at the designated visit; any MMR gained and lost, or never achieved at or before the designated visit was considered as non-responder.
Cumulative Incidence of Major Molecular Response (MMR) at Month 36	At Month 36	Percentage of participants with MMR at Month 36. Cumulative incidence of MMR was measured from first dose to the first date of response. Documented participants who did not have an MMR response were censored at the last molecular assessment. A MMR is defined as \<=0.1% BCR-ABL transcripts on the international scale, corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.
Cumulative Incidence of Molecular Response 4.0 (MR4.0) at Month 36	At Month 36	Percentage of participants with MR4.0 at month 36. Cumulative incidence of MR4.0, was measured from first dose to the first date of MR 4.0. Documented participants who did not have an MR4.0 response were censored at the last molecular assessment. MR4.0 defined as either 1) detectable disease with \<=0.01% BCR-ABL IS or 2) undetectable disease in cDNA with a minimum number of 9800 ABL transcripts specified by the central laboratory. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.
Cumulative Incidence of Molecular Response 4.5 (MR4.5) at Month 36	At Month 36	Percentage of participants with MR4.5 at Month 36. Cumulative incidence of MR 4.5 was measured from first dose to the first date of MR 4.5. Documented participants who did not have an MR4.5 response were censored at the last molecular assessment. MR 4.5 defined as either 1) detectable disease with \<=0.0032% BCR-ABL IS or 2) undetectable disease in cDNA with a minimum number of 30990 ABL transcripts specified by the central laboratory in the same volume of cDNA used to test for BCR-ABL. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.
Cumulative Incidence of Complete Cytogenetic Response (CCyR) at Month 36	At Month 36	Percentage of participants with CCyR at Month 36. Cumulative incidence of CCyR, was measured from first dose to the first date of CCyR. Documented participants who did not have a CCyR response were censored at the last cytogenetic assessment. CCyR was defined as absence of detectable Philadelphia chromosome positive cells. CCyR was achieved when there were 0 Philadelphia chromosome positive metaphases among at least 20 metaphases from a bone marrow sample or when MMR was achieved if no bone marrow analysis was performed. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.
Percentage of Participants With Cumulative Complete Haematological Response (CHR)	Up to Month 36	CHR is based on peripheral blood assessment: WBC \<=10\10\^9/L, basophils \<5% in blood, no myelocytes, promyelocytes, myeloblasts in the blood differential, platelet count \<450\ 10\^9/L, spleen non-palpable. In the absence of extramedullary disease info, it was assumed that spleen was non-palpable. If CHR could not be assessed due to one or more missing components of CHR and participant had a MMR or a CCyR and all assessed components of CHR were within appropriate limits, then CHR was imputed using CCyR or MMR. CHR must be of at least 4 weeks in duration and confirmed by 2 assessments at least 4 weeks apart.
Cumulative Incidence of Transformation to Accelerated Phase (AP) and Blast Phase (BP) at Month 36	At Month 36	Percentage of participants with transformation to AP and BP at Month 36. Transformation to AP or to BP CML defined as the time from first dose to the first date of transformation to accelerated phase or to blast phase CML. Documented participants who did not progress to AP or BP were censored at the last hematologic assessment. The transformation to AP or to BP was counted while participants were on treatment up to 28 days after last dose. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.
Number of Participants With BCR-ABL Mutation at Treatment Discontinuation	Maximum up to 44 months of treatment	Mutation analysis was performed in case of either lack of response, suboptimal response or loss of response, or at the End of Treatment/Withdrawal visit.
Number of Participants With Treatment-Emergent Adverse Events (AEs): National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or Higher	From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. The severity was graded by NCI CTCAE v.4.03. Grade 1 was mild AE. Grade 2 was moderate AE. Grade 3 was severe AE. Grade 4 was life-threatening consequences and urgent intervention indicated AE. Grade 5 was death related to AE. Number of participants with Grade 3 or higher AEs are reported.

Countries

Japan

Participant flow

Participants by arm

Arm	Count
Bosutinib Participants with newly diagnosed CP CML received bosutinib treatment, orally at a dose of 400 mg QD. In treatment phase, participants received bosutinib once daily for up to 12 months, which was extended further to at least additional 24 months (total of at least 36 months) or until end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. If participants discontinued the treatment phase only then they entered the long-term follow-up phase up to approximately 3 years after registration of the last participant, or until study termination, whichever comes first.	60
Total	60

Arm

Count

Bosutinib

Participants with newly diagnosed CP CML received bosutinib treatment, orally at a dose of 400 mg QD. In treatment phase, participants received bosutinib once daily for up to 12 months, which was extended further to at least additional 24 months (total of at least 36 months) or until end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. If participants discontinued the treatment phase only then they entered the long-term follow-up phase up to approximately 3 years after registration of the last participant, or until study termination, whichever comes first.

Total

Withdrawals & dropouts

Period	Reason	FG000
Long Term Follow-up Phase	Death	2
Treatment Phase	Adverse Event	21
Treatment Phase	Other	2
Treatment Phase	Physician Decision	1

Baseline characteristics

Characteristic	Bosutinib
Age, Continuous	53.3 years STANDARD_DEVIATION 16.4
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	60 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	60 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	0 Participants
Sex: Female, Male Female	24 Participants
Sex: Female, Male Male	36 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	2 / 60
other Total, other adverse events	60 / 60
serious Total, serious adverse events	14 / 60

Outcome results

Primary

Percentage of Participants With Major Molecular Response (MMR) at Month 12

A MMR is defined as less than or equal to (\<=) 0.1 percent (%) BCR-ABL transcripts on the international scale (IS), corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. The MMR value counted only if the response was demonstrated at the 12-month visit; any MMR gained and lost, or never achieved at or before the 12-month visit was considered as non-responder.

Time frame: Month 12

Arm	Measure	Value (NUMBER)
Bosutinib	Percentage of Participants With Major Molecular Response (MMR) at Month 12	55.0 Percentage of participants

Comparison: With a sample size of 60 participants, study was powered at \>82% to test null hypothesis: true MMR rate at 12 months (48 weeks) is 25% versus alternative hypothesis: true MMR rate is 40% with one-sided alpha of 5%.p-value: <0.0001z-test, 1-sided

Secondary

Cumulative Incidence of Complete Cytogenetic Response (CCyR) at Month 36

Percentage of participants with CCyR at Month 36. Cumulative incidence of CCyR, was measured from first dose to the first date of CCyR. Documented participants who did not have a CCyR response were censored at the last cytogenetic assessment. CCyR was defined as absence of detectable Philadelphia chromosome positive cells. CCyR was achieved when there were 0 Philadelphia chromosome positive metaphases among at least 20 metaphases from a bone marrow sample or when MMR was achieved if no bone marrow analysis was performed. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.

Time frame: At Month 36

Arm	Measure	Value (NUMBER)
Bosutinib	Cumulative Incidence of Complete Cytogenetic Response (CCyR) at Month 36	80.0 Percentage of participants

Secondary

Cumulative Incidence of Event Free Survival (EFS) at Month 36

EFS: time from 1st dose until 1st occurrence of 1 of the following events or censoring: 1)death from any cause 2)transformation to AP or BP 3)loss of complete hematologic response (CHR) 4)loss of CCyR 5)participants not achieving CHR: doubling of WBCs \>= 1 month apart with 2nd value \>20\*10\^9/L and maintained in subsequent assessments for \>=2 weeks. Loss of CHR: appearance of any of the following confirmed by 2nd determination\>=4 weeks later (unless associated with CML-related treatment discontinuation): WBC count: \>20.0\*10\^9/L, platelet count: \>=600\*10\^9/L, appearance of palpable spleen/other extra medullary involvement, appearance of 5% myelocytes or blasts or promyelocytes in peripheral blood. Loss of CCyR:\>= one Ph+ metaphase confirmed by 2nd determination \>=4 weeks later(unless associated with CML-related treatment discontinuation). Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without event.

Time frame: Up to Month 36

Arm	Measure	Value (NUMBER)
Bosutinib	Cumulative Incidence of Event Free Survival (EFS) at Month 36	1.7 Percentage of participants

Secondary

Cumulative Incidence of Major Molecular Response (MMR) at Month 36

Percentage of participants with MMR at Month 36. Cumulative incidence of MMR was measured from first dose to the first date of response. Documented participants who did not have an MMR response were censored at the last molecular assessment. A MMR is defined as \<=0.1% BCR-ABL transcripts on the international scale, corresponding to a \>=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.

Time frame: At Month 36

Arm	Measure	Value (NUMBER)
Bosutinib	Cumulative Incidence of Major Molecular Response (MMR) at Month 36	70.0 Percentage of participants

Secondary

Cumulative Incidence of Molecular Response 4.0 (MR4.0) at Month 36

Percentage of participants with MR4.0 at month 36. Cumulative incidence of MR4.0, was measured from first dose to the first date of MR 4.0. Documented participants who did not have an MR4.0 response were censored at the last molecular assessment. MR4.0 defined as either 1) detectable disease with \<=0.01% BCR-ABL IS or 2) undetectable disease in cDNA with a minimum number of 9800 ABL transcripts specified by the central laboratory. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.

Time frame: At Month 36

Arm	Measure	Value (NUMBER)
Bosutinib	Cumulative Incidence of Molecular Response 4.0 (MR4.0) at Month 36	50.0 Percentage of participants

Secondary

Cumulative Incidence of Molecular Response 4.5 (MR4.5) at Month 36

Percentage of participants with MR4.5 at Month 36. Cumulative incidence of MR 4.5 was measured from first dose to the first date of MR 4.5. Documented participants who did not have an MR4.5 response were censored at the last molecular assessment. MR 4.5 defined as either 1) detectable disease with \<=0.0032% BCR-ABL IS or 2) undetectable disease in cDNA with a minimum number of 30990 ABL transcripts specified by the central laboratory in the same volume of cDNA used to test for BCR-ABL. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.

Time frame: At Month 36

Arm	Measure	Value (NUMBER)
Bosutinib	Cumulative Incidence of Molecular Response 4.5 (MR4.5) at Month 36	46.7 Percentage of participants

Secondary

Cumulative Incidence of Transformation to Accelerated Phase (AP) and Blast Phase (BP) at Month 36

Percentage of participants with transformation to AP and BP at Month 36. Transformation to AP or to BP CML defined as the time from first dose to the first date of transformation to accelerated phase or to blast phase CML. Documented participants who did not progress to AP or BP were censored at the last hematologic assessment. The transformation to AP or to BP was counted while participants were on treatment up to 28 days after last dose. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event.

Time frame: At Month 36

Arm	Measure	Value (NUMBER)
Bosutinib	Cumulative Incidence of Transformation to Accelerated Phase (AP) and Blast Phase (BP) at Month 36	NA Percentage of participants

Secondary

Number of Participants Assessed for Left Ventricular Ejection Fraction

Interpretation categories included: a) normal, b) abnormal, not clinically significant and c) abnormal, clinically significant.

Time frame: At end of treatment for patients who discontinued treatment post initial dose (up to 12 March 2019)

Population: As-treated population included all enrolled participants who received at least 1 dose of study treatment. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Bosutinib	Number of Participants Assessed for Left Ventricular Ejection Fraction	Normal	15 Participants
Bosutinib	Number of Participants Assessed for Left Ventricular Ejection Fraction	Abnormal, not clinically significant	3 Participants
Bosutinib	Number of Participants Assessed for Left Ventricular Ejection Fraction	Abnormal, Clinically Significant	0 Participants

Secondary

Number of Participants With BCR-ABL Mutation at Treatment Discontinuation

Mutation analysis was performed in case of either lack of response, suboptimal response or loss of response, or at the End of Treatment/Withdrawal visit.

Time frame: Maximum up to 44 months of treatment

Population: The modified as-treated population included all enrolled participants with Philadelphia chromosome positive CP CML harboring b2a2 and/or b3a2 transcripts who received at least 1 dose of study treatment. Here, ''Overall Number of Participants Analyzed'' signifies participants with mutation testing.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Bosutinib	Number of Participants With BCR-ABL Mutation at Treatment Discontinuation	0 Participants

Secondary

Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings

ECG parameters included: QTc corrected by Bazett's (QTcB) interval: \>500 msec (milliseconds), QTc corrected by Fridericia's (QTcF) interval: \>500 msec and \>450 msec (men) or \>470 msec (women).

Time frame: From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)