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

Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT03128411
Collaborator
(none)
64
21
1
45.6
3
0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
64 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
May 15, 2017
Actual Primary Completion Date :
Mar 12, 2019
Actual Study Completion Date :
Mar 4, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Bosutinib

Bosutinib monotherapy; All patients will receive bosutinib at a starting dose of 400 mg QD. The dose of bosutinib may be escalated (up to a maximum of 600 mg QD) for unsatisfactory response or reduced for toxicity.

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

Outcome Measures

Primary Outcome Measures

  1. 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 Outcome Measures

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Trough Plasma Concentrations of Bosutinib [Pre-dose on Day 1, Day 28, Day 56, Day 84]

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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).

  23. 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.

  24. 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).

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

Eligibility Criteria

Criteria

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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Fujita Health University Hospital Toyoake-City Aichi Japan 470-1192
2 Toyohashi Municipal Hospital Toyohashi Aichi Japan 441-8570
3 Akita University Hospital Akita City Akita Japan 010-8543
4 Japanese Red Cross Narita Hospital Narita Chiba Japan 286-8523
5 Ehime University Hospital Toon-shi Ehime Japan 791-0295
6 Kobe City Medical Center General Hospital Kobe-city Hyogo Japan 650-0047
7 Ishikawa Prefectural Central Hospital Kanazawa Ishikawa Japan 920-8530
8 Yokohama City University Medical Center Yokohama Kanagawa Japan 232-0024
9 National Hospital Organization Osaka Minami Medical Center Kawachinagano Osaka Japan 586-8521
10 Osaka City University Hospital Osaka-City Osaka Japan 545-8586
11 Kindai University Hospital Osaka-Sayama Osaka Japan 589-8511
12 Hamamatsu University Hospital Hamamatsu Shizuoka Japan 431-3192
13 Juntendo University Hospital Bunkyo-ku Tokyo Japan 113-8431
14 Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital Bunkyo-ku Tokyo Japan 113-8677
15 NTT Medical Center Tokyo Shinagawa-ku Tokyo Japan 141-8625
16 National Hospital Organization Disaster Medical Center Tachikawa Tokyo Japan 190-0014
17 Yamagata University Hospital Yamagata-Shi Yamagata Japan 990-9585
18 Chiba University Hospital Chiba Japan 260-8677
19 National Hospital Organization Kyushu Cancer Center Fukuoka Japan 811-1395
20 Saga University Hospital Saga Japan 849-8501
21 Nippon Medical School Hospital Tokyo Japan 113-8603

Sponsors and Collaborators

  • Pfizer

Investigators

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

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT03128411
Other Study ID Numbers:
  • B1871048
First Posted:
Apr 25, 2017
Last Update Posted:
May 19, 2022
Last Verified:
Apr 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Pfizer
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Bosutinib
Arm/Group Description 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.
Period Title: Treatment Phase
STARTED 60
Received Treatment 60
COMPLETED 36
NOT COMPLETED 24
Period Title: Treatment Phase
STARTED 24
COMPLETED 22
NOT COMPLETED 2

Baseline Characteristics

Arm/Group Title Bosutinib
Arm/Group Description 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.
Overall Participants 60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
53.3
(16.40)
Sex: Female, Male (Count of Participants)
Female
24
40%
Male
36
60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
Not Hispanic or Latino
60
100%
Unknown or Not Reported
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
Asian
60
100%
Native Hawaiian or Other Pacific Islander
0
0%
Black or African American
0
0%
White
0
0%
More than one race
0
0%
Unknown or Not Reported
0
0%

Outcome Measures

1. Primary Outcome
Title Percentage of Participants With Major Molecular Response (MMR) at Month 12
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
55.0
91.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib
Comments 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%.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method z-test, 1-sided
Comments
2. Secondary Outcome
Title Percentage of Participants With Major Molecular Response (MMR) by Month 12
Description 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.
Time Frame Up to Month 12

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
61.7
102.8%
3. Secondary Outcome
Title Percentage of Participants With Major Molecular Response (MMR) by Month 18
Description 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.
Time Frame Up to Month 18

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
66.7
111.2%
4. Secondary Outcome
Title Percentage of Participants With Complete Cytogenetic Response (CCyR) by Month 12
Description 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.
Time Frame Up to Month 12

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
80.0
133.3%
5. Secondary Outcome
Title Probability of Maintaining Major Molecular Response (MMR) at Month 36
Description 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.
Time Frame At Month 36

Outcome Measure Data

Analysis Population Description
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 number of participants evaluable for this outcome measure and who had MMR.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 42
Number (90% Confidence Interval) [Percentage of participants]
100.0
166.7%
6. Secondary Outcome
Title Probability of Maintaining Complete Cytogenetic Response (CCyR) at Month 36
Description 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.
Time Frame At Month 36

Outcome Measure Data

Analysis Population Description
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 number of participants evaluable for this outcome measure and who had CCyR.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 48
Number (90% Confidence Interval) [Percentage of participants]
100.0
166.7%
7. Secondary Outcome
Title Cumulative Incidence of Event Free Survival (EFS) at Month 36
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
1.7
2.8%
8. Secondary Outcome
Title Probability of Overall Survival (OS) at Month 36
Description 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.
Time Frame Up to Month 36

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
96.7
161.2%
9. Secondary Outcome
Title Trough Plasma Concentrations of Bosutinib
Description
Time Frame Pre-dose on Day 1, Day 28, Day 56, Day 84

Outcome Measure Data

Analysis Population Description
The PK population will be defined as any patient in the safety population of patients who had at least 1 concentration of bosutinib on-treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Day 1
0.000
(0.000)
Day 28
83.564
(64.1056)
Day 56
85.963
(46.4095)
Day 84
79.659
(41.5369)
10. Secondary Outcome
Title Summary and Analysis of Trough Bosutinib Plasma Concentration by Major Molecular Response (MMR) Response
Description 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.
Time Frame Pre-dose on Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against Yes and No categories respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Yes: Day 28
94.943
(71.9332)
No: Day 28
59.770
(35.4568)
Yes: Day 56
88.196
(48.9671)
No: Day 56
82.092
(42.9741)
Yes: Day 84
81.339
(41.5443)
No: Day 84
75.654
(42.9290)
11. Secondary Outcome
Title Summary and Analysis of Trough Bosutinib Plasma Concentration by CCyR Response
Description 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.
Time Frame Pre-dose on Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against Yes and No categories respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Yes: Day 28
87.006
(64.1820)
No: Day 28
28.490
(38.3393)
Yes: Day 56
90.550
(45.4543)
No: Day 56
52.936
(43.6721)
Yes: Day 84
79.429
(40.1538)
No: Day 84
82.800
(69.5117)
12. Secondary Outcome
Title Summary of Trough Bosutinib Plasma Concentration by Total Bilirubin
Description 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.
Time Frame Pre-dose on Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against each categories/levels respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Day 28: (<=7.7 micromol/L)
61.833
(18.0632)
Day 28: (>7.7 and <=10.3 micromol/L)
96.867
(87.7756)
Day 28: (>10.3 and <=12.85 micromol/L)
76.963
(59.0962)
Day 28: (>12.85 micromol/L)
84.599
(54.3057)
Day 56: (<=7.7 micromol/L)
60.044
(22.6753)
Day 56: (>7.7 and <=10.3 micromol/L)
81.246
(44.3985)
Day 56: (>10.3 and <=12.85 micromol/L)
91.940
(49.9495)
Day 56: (>12.85 micromol/L)
107.025
(53.5192)
Day 84: (<=7.7 micromol/L)
50.775
(19.4910)
Day 84: (>7.7 and <=10.3 micromol/L)
75.478
(34.0806)
Day 84: (>10.3 and <=12.85 micromol/L)
98.133
(56.5691)
Day 84: (>12.85 micromol/L)
95.950
(46.2820)
13. Secondary Outcome
Title Summary of Trough Bosutinib Plasma Concentration by Creatinine Clearance
Description 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.
Time Frame Pre-dose on Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against each categories/levels respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Day 28: (<=71.479 mL/min)
75.039
(63.7599)
Day 28: (>71.479 and <=10 0.936 mL/min)
84.114
(49.0390)
Day 28: (>100.936 and <=1 29.355 mL/min)
100.100
(97.8388)
Day 28: (>129.355 mL/min)
72.610
(26.2392)
Day 56:(<=71.479 mL/min)
93.056
(56.2220)
Day 56:(>71.479 and <=10 0.936 mL/min)
92.764
(47.9905)
Day 56: (>100.936 and <=1 29.355 mL/min)
95.580
(58.4145)
Day 56: (>129.355 mL/min)
72.200
(32.9961)
Day 84: (<=71.479 mL/min)
92.540
(49.2182)
Day 84:(>71.479 and <=10 0.936 mL/min)
90.590
(45.9533)
Day 84:(>100.936 and <=1 29.355 mL/min)
69.100
(41.0767)
Day 84: (>129.355 mL/min)
70.277
(30.6643)
14. Secondary Outcome
Title Summary of Trough Bosutinib Plasma Concentration by Aspartate Aminotransferase
Description 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.
Time Frame Pre-dose on Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against each categories/levels respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Day 28: (<=22 U/L)
65.771
(26.3239)
Day 28: (>22 and <=26 U/L)
140.617
(120.1651)
Day 28: (>26 and <=33 U/L)
66.056
(37.4551)
Day 28: (>33 U/L)
82.711
(47.9527)
Day 56: (<=22 U/L)
82.117
(51.0937)
Day 56: (>22 and <=26 U/L)
76.050
(43.6907)
Day 56: (>26 and <=33 U/L)
93.607
(44.5087)
Day 56: (>33 U/L)
89.711
(50.6123)
Day 84: (<=22 U/L)
54.550
(23.4932)
Day 84: (>22 and <=26 U/L)
81.325
(55.3891)
Day 84: (>26 and <=33 U/L)
85.886
(39.3348)
Day 84: (>33 U/L)
92.208
(41.4203)
15. Secondary Outcome
Title Summary of Trough Bosutinib Plasma Concentration by Alanine Aminotransferase
Description 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.
Time Frame Pre-dose on Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against each categories/levels respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Day 28: (<=17.5 U/L)
49.111
(24.6077)
Day 28: (>17.5 and <=25 U/L)
98.882
(131.3382)
Day 28: (>25 and <=32 U/L)
94.175
(44.7227)
Day 28: (>32 U/L)
86.000
(39.7021)
Day 56: (<=17.5 U/L)
66.878
(33.4154)
Day 56: (>17.5 and <=25 U/L)
82.317
(69.6971)
Day 56: (>25 and <= 32 U/L)
104.350
(47.3634)
Day 56: (>32 U/L)
85.354
(40.1619)
Day 84: (<=17.5 U/L)
65.011
(43.4694)
Day 84: (>17.5 and <=25 U/L)
73.511
(43.4070)
Day 84: (>25 and <=32 U/L)
92.254
(49.1564)
Day 84: (>32 U/L)
81.462
(29.7583)
16. Secondary Outcome
Title Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Diarrhea
Description 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.
Time Frame 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

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against Yes and No categories respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Yes: Day 28
85.585
(69.4219)
No: Day 28
74.133
(31.1208)
Yes: Day 56
86.086
(46.9140)
No: Day 56
85.080
(47.7414)
Yes: Day 84
85.219
(41.7195)
No: Day 84
50.271
(26.8976)
17. Secondary Outcome
Title Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Nausea
Description 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.
Time Frame 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

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against Yes and No categories respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Yes: Day 28
90.998
(72.5190)
No: Day 28
81.971
(63.5134)
Yes: Day 56
111.482
(54.9565)
No: Day 56
76.606
(39.8971)
Yes: Day 84
91.867
(57.5206)
No: Day 84
76.520
(36.7957)
18. Secondary Outcome
Title Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Vomiting
Description 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.
Time Frame 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

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against Yes and No categories respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Yes: Day 28
58.826
(29.1613)
No: Day 28
89.977
(69.3702)
Yes: Day 56
87.135
(53.5627)
No: Day 56
85.533
(44.5062)
Yes: Day 84
90.030
(32.1444)
No: Day 84
76.609
(43.8653)
19. Secondary Outcome
Title Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Thrombocytopenia
Description 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.
Time Frame 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

Outcome Measure Data

Analysis Population Description
PK population included of all enrolled participants, who received at least 1 dose of study treatment and had at least 1 concentration of bosutinib on-treatment. For Day 28, 56, 84: total number of participants analyzed for each time point were sum of "number analyzed" against Yes and No categories respectively.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Yes: Day 28
80.167
(46.6352)
No: Day 28
83.893
(66.1379)
Yes: Day 56
87.700
(35.9669)
No: Day 56
85.722
(48.0957)
Yes: Day 84
75.067
(33.1815)
No: Day 84
79.995
(42.4024)
20. Secondary Outcome
Title 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
Description 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.
Time Frame From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)

Outcome Measure Data

Analysis Population Description
As-treated population included all enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Count of Participants [Participants]
49
81.7%
21. Secondary Outcome
Title Number of Participants With Laboratory Abnormalities, Chemistry: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or 4
Description 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.
Time Frame From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)

Outcome Measure Data

Analysis Population Description
As-treated population included all enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
ALT increased
30
50%
ALP increased
1
1.7%
AST increased
16
26.7%
Blood bilirubin increased
1
1.7%
CPK increased
3
5%
Hyperglycemia
2
3.3%
Hypermagnesemia
1
1.7%
Hypokalemia
2
3.3%
Hyponatremia
3
5%
Hypophosphatemia
3
5%
Lipase increased
14
23.3%
Serum amylase increased
1
1.7%
Creatinine increased
0
0%
Hypercalcemia
0
0%
Hyperkalemia
0
0%
Hypernatremia
0
0%
Hypoalbuminemia
0
0%
Hypocalcemia
0
0%
Hypoglycemia
0
0%
Hypomagnesemia
0
0%
22. Secondary Outcome
Title Number of Participants With Laboratory Abnormalities, Hematology: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or 4
Description 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.
Time Frame From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)

Outcome Measure Data

Analysis Population Description
As-treated population included all enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Anemia
4
6.7%
Lymphocyte count decreased
14
23.3%
Neutrophil count decreased
9
15%
Platelet count decreased
6
10%
White blood cell decreased
2
3.3%
23. Secondary Outcome
Title Number of Participants With Laboratory Abnormalities, Coagulation: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3
Description Coagulation parameters include: APTT prolonged (Grade 3: >2.5*ULN and hemorrhage), and INR increased (Grade 3 >2.5*ULN).
Time Frame From first dose and up to 12 March 2019; maximum of 22 months, approximately

Outcome Measure Data

Analysis Population Description
As-treated population included all enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Activated partial thromboplastin time
0
0%
INR increased
0
0%
24. Secondary Outcome
Title Number of Participants With Clinically Significant Vital Signs Findings
Description 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.
Time Frame From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)

Outcome Measure Data

Analysis Population Description
As-treated population included all enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Body weight: Increase >= 10% change from baseline
12
20%
Body weight: Decrease >= 10% change from baseline
2
3.3%
Systolic blood pressure: <80 mmHg
0
0%
Systolic blood pressure: >210 mmHg
0
0%
Diastolic blood pressure: <40 mmHg
1
1.7%
Diastolic blood pressure: >130 mmHg
0
0%
Heart rate: <40 bpm
0
0%
Heart rate: >150 bpm
0
0%
Temperature: <32 C
0
0%
Temperature: >40 C
1
1.7%
25. Secondary Outcome
Title Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
Description 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)

Outcome Measure Data

Analysis Population Description
As-treated population included all enrolled participants who received at least 1 dose of study treatment.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
QTcB interval: >500 msec
0
0%
QTcF interval: >500 msec
0
0%
QTcF interval: >450 msec (Men) or >470 msec (Women)
1
1.7%
26. Secondary Outcome
Title Number of Participants Assessed for Left Ventricular Ejection Fraction
Description 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)

Outcome Measure Data

Analysis Population Description
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/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 18
Normal
15
25%
Abnormal, not clinically significant
3
5%
Abnormal, Clinically Significant
0
0%
27. Secondary Outcome
Title Percentage of Participants With Major Molecular Response (MMR) at Months 3, 6, 9 and 18
Description 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.
Time Frame Month 3, 6, 9 and 18

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Month 3
10.0
16.7%
Month 6
50.0
83.3%
Month 9
53.3
88.8%
Month 18
61.7
102.8%
28. Secondary Outcome
Title Percentage of Participants With Molecular Response 1 (MR1) at Month 3
Description MR1 is defined as <= 10% BCR-ABL with a minimum of 3,000 ABL transcripts assessed by the central laboratory.
Time Frame Month 3

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
80.0
133.3%
29. Secondary Outcome
Title Percentage of Participants With Molecular Response 2 (MR2) at Month 6
Description MR2 is defined as <= 1% BCR-ABL with a minimum of 3,000 ABL transcripts assessed by the central laboratory.
Time Frame Month 6

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
66.7
111.2%
30. Secondary Outcome
Title Percentage of Participants With Molecular Response 4.0 (MR4.0) and Molecular Response 4.5 (MR4.5) at Months 3, 6, 9 and 12
Description 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.
Time Frame Months 3, 6, 9 and 12

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
MR4.0: Month 3
0
0%
MR4.0: Month 6
18.3
30.5%
MR4.0: Month 9
25.0
41.7%
MR4.0: Month 12
31.7
52.8%
MR4.5: Month 3
0
0%
MR4.5: Month 6
8.3
13.8%
MR4.5: Month 9
16.7
27.8%
MR4.5: Month 12
21.7
36.2%
31. Secondary Outcome
Title Cumulative Incidence of Major Molecular Response (MMR) at Month 36
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
70.0
116.7%
32. Secondary Outcome
Title Cumulative Incidence of Molecular Response 4.0 (MR4.0) at Month 36
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
50.0
83.3%
33. Secondary Outcome
Title Cumulative Incidence of Molecular Response 4.5 (MR4.5) at Month 36
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
46.7
77.8%
34. Secondary Outcome
Title Cumulative Incidence of Complete Cytogenetic Response (CCyR) at Month 36
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
80.0
133.3%
35. Secondary Outcome
Title Percentage of Participants With Cumulative Complete Haematological Response (CHR)
Description 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.
Time Frame Up to Month 36

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
91.7
152.8%
36. Secondary Outcome
Title Cumulative Incidence of Transformation to Accelerated Phase (AP) and Blast Phase (BP) at Month 36
Description 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

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 60
Number (90% Confidence Interval) [Percentage of participants]
NA
NaN
37. Secondary Outcome
Title Number of Participants With BCR-ABL Mutation at Treatment Discontinuation
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Bosutinib
Arm/Group Description 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.
Measure Participants 24
Count of Participants [Participants]
0
0%

Adverse Events

Time Frame From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months)
Adverse Event Reporting Description The total number of deaths occurring during study, from first dose and up to end of the study are reported for all treated participants and includes deaths which occurred after 28 days post last study drug dose. Same event may appear as AE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another participant or 1 participant may have experienced both serious and non-serious event during study. Safety population evaluated.
Arm/Group Title Bosutinib
Arm/Group Description 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.
All Cause Mortality
Bosutinib
Affected / at Risk (%) # Events
Total 2/60 (3.3%)
Serious Adverse Events
Bosutinib
Affected / at Risk (%) # Events
Total 14/60 (23.3%)
Eye disorders
Diabetic retinopathy 1/60 (1.7%)
Gastrointestinal disorders
Diarrhoea 2/60 (3.3%)
Vomiting 1/60 (1.7%)
Ileus 1/60 (1.7%)
General disorders
Pyrexia 1/60 (1.7%)
Hepatobiliary disorders
Drug-induced liver injury 1/60 (1.7%)
Liver disorder 2/60 (3.3%)
Infections and infestations
Gastroenteritis 1/60 (1.7%)
Pneumonia 2/60 (3.3%)
Pyelonephritis 1/60 (1.7%)
Sepsis 1/60 (1.7%)
Wound infection 1/60 (1.7%)
Influenza 1/60 (1.7%)
Injury, poisoning and procedural complications
Ankle fracture 1/60 (1.7%)
Investigations
Alanine aminotransferase increased 1/60 (1.7%)
Aspartate aminotransferase increased 1/60 (1.7%)
Metabolism and nutrition disorders
Dehydration 2/60 (3.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer 1/60 (1.7%)
Renal and urinary disorders
Acute kidney injury 1/60 (1.7%)
Nephropathy toxic 1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion 1/60 (1.7%)
Skin and subcutaneous tissue disorders
Drug eruption 1/60 (1.7%)
Erythema multiforme 1/60 (1.7%)
Other (Not Including Serious) Adverse Events
Bosutinib
Affected / at Risk (%) # Events
Total 60/60 (100%)
Blood and lymphatic system disorders
Anaemia 10/60 (16.7%)
Lymphopenia 4/60 (6.7%)
Thrombocytopenia 5/60 (8.3%)
Gastrointestinal disorders
Abdominal pain upper 6/60 (10%)
Constipation 8/60 (13.3%)
Diarrhoea 52/60 (86.7%)
Nausea 17/60 (28.3%)
Vomiting 16/60 (26.7%)
Stomatitis 6/60 (10%)
General disorders
Pyrexia 15/60 (25%)
Hepatobiliary disorders
Liver disorder 7/60 (11.7%)
Infections and infestations
Influenza 6/60 (10%)
Nasopharyngitis 23/60 (38.3%)
Upper respiratory tract infection 8/60 (13.3%)
Gastroenteritis 5/60 (8.3%)
Investigations
Alanine aminotransferase increased 33/60 (55%)
Amylase increased 10/60 (16.7%)
Aspartate aminotransferase increased 28/60 (46.7%)
Blood alkaline phosphatase increased 16/60 (26.7%)
Blood creatine phosphokinase increased 6/60 (10%)
Gamma-glutamyltransferase increased 11/60 (18.3%)
Lipase increased 17/60 (28.3%)
Lymphocyte count decreased 7/60 (11.7%)
Neutrophil count decreased 7/60 (11.7%)
Platelet count decreased 13/60 (21.7%)
White blood cell count decreased 5/60 (8.3%)
Blood creatinine increased 6/60 (10%)
Metabolism and nutrition disorders
Hypocalcaemia 5/60 (8.3%)
Hypokalaemia 4/60 (6.7%)
Musculoskeletal and connective tissue disorders
Back pain 10/60 (16.7%)
Myalgia 5/60 (8.3%)
Pain in extremity 4/60 (6.7%)
Arthralgia 9/60 (15%)
Nervous system disorders
Headache 7/60 (11.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion 8/60 (13.3%)
Upper respiratory tract inflammation 5/60 (8.3%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform 4/60 (6.7%)
Eczema asteatotic 4/60 (6.7%)
Photosensitivity reaction 4/60 (6.7%)
Pruritus 4/60 (6.7%)
Rash 18/60 (30%)
Rash maculo-papular 8/60 (13.3%)
Eczema 4/60 (6.7%)
Urticaria 4/60 (6.7%)
Vascular disorders
Hypertension 4/60 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Results Point of Contact

Name/Title Pfizer ClinicalTrials.gov Call Center
Organization Pfizer Inc.
Phone 1-800-718-1021
Email ClinicalTrials.gov_Inquiries@pfizer.com
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT03128411
Other Study ID Numbers:
  • B1871048
First Posted:
Apr 25, 2017
Last Update Posted:
May 19, 2022
Last Verified:
Apr 1, 2022