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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Leukemia, Chronic Myelogenous

Intervention / Treatment
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* Drug: Bosutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosutinib<br>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<br>* All patients will receive bosutinib at a starting dose of 400 mg QD.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major Molecular Response (MMR) by 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. | Up to Month 12 | 
| Percentage of Participants With Major Molecular Response (MMR) by 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. | Up to Month 18 | 
| Percentage of Participants With Complete Cytogenetic Response (CCyR) by 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. | Up to Month 12 | 
| Probability of Maintaining Major Molecular Response (MMR) 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. | At Month 36 | 
| Probability of Maintaining Complete Cytogenetic Response (CCyR) 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. | At Month 36 | 
| Cumulative Incidence of Event Free Survival (EFS) at Month 36 | EFS: time from 1st dose until 1st occurrence of 1 of the following events or censoring: 1)death from any cause 2)transformation to AP or BP 3)loss of complete hematologic response (CHR) 4)loss of CCyR 5)participants not achieving CHR: doubling of WBCs >= 1 month apart with 2nd value >20*10^9/L and maintained in subsequent assessments for >=2 weeks. Loss of CHR: appearance of any of the following confirmed by 2nd determination>=4 weeks later (unless associated with CML-related treatment discontinuation): WBC count: >20.0*10^9/L, platelet count: >=600*10^9/L, appearance of palpable spleen/other extra medullary involvement, appearance of 5% myelocytes or blasts or promyelocytes in peripheral blood. Loss of CCyR:>= one Ph+ metaphase confirmed by 2nd determination >=4 weeks later(unless associated with CML-related treatment discontinuation). Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without event. | Up to Month 36 | 
| Probability of Overall Survival (OS) at 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. | Up to Month 36 | 
| Trough Plasma Concentrations of Bosutinib |  | Pre-dose on Day 1, Day 28, Day 56, Day 84 | 
| Summary and Analysis of Trough Bosutinib Plasma Concentration by Major Molecular Response (MMR) Response | 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. | Pre-dose on Day 28, Day 56 and Day 84 | 
| Summary and Analysis of Trough Bosutinib Plasma Concentration by CCyR Response | 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. | Pre-dose on Day 28, Day 56 and Day 84 | 
| Summary of Trough Bosutinib Plasma Concentration by Total Bilirubin | 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. | Pre-dose on Day 28, Day 56 and Day 84 | 
| Summary of Trough Bosutinib Plasma Concentration by Creatinine Clearance | 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. | Pre-dose on Day 28, Day 56 and Day 84 | 
| Summary of Trough Bosutinib Plasma Concentration by Aspartate Aminotransferase | 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. | Pre-dose on Day 28, Day 56 and Day 84 | 
| Summary of Trough Bosutinib Plasma Concentration by Alanine Aminotransferase | 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. | Pre-dose on Day 28, Day 56 and Day 84 | 
| Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Diarrhea | 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. | 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 | 
| Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Nausea | 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. | 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 | 
| Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Vomiting | 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. | 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 | 
| Summary and Analysis of Trough Bosutinib Plasma Levels by Presence/Absence Grade 1: Thrombocytopenia | 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. | 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 | 
| 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 | 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. | From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months) | 
| Number of Participants With Laboratory Abnormalities, Chemistry: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or 4 | 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. | From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months) | 
| Number of Participants With Laboratory Abnormalities, Hematology: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 or 4 | 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. | From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months) | 
| Number of Participants With Laboratory Abnormalities, Coagulation: National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) Grade 3 | Coagulation parameters include: APTT prolonged (Grade 3: >2.5*ULN and hemorrhage), and INR increased (Grade 3 >2.5*ULN). | From first dose and up to 12 March 2019; maximum of 22 months, approximately | 
| Number of Participants With Clinically Significant Vital Signs Findings | 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. | From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months) | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings | ECG parameters included: QTc corrected by Bazett's (QTcB) interval: >500 msec (milliseconds), QTc corrected by Fridericia's (QTcF) interval: >500 msec and >450 msec (men) or >470 msec (women). | From first dose and up to 28 days after the last dose of study drug (maximum up to 45 months) | 
| Number of Participants Assessed for Left Ventricular Ejection Fraction | Interpretation categories included: a) normal, b) abnormal, not clinically significant and c) abnormal, clinically significant. | At end of treatment for patients who discontinued treatment post initial dose (up to 12 March 2019) | 
| Percentage of Participants With Major Molecular Response (MMR) at Months 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. | Month 3, 6, 9 and 18 | 
| Percentage of Participants With Molecular Response 1 (MR1) at Month 3 | MR1 is defined as <= 10% BCR-ABL with a minimum of 3,000 ABL transcripts assessed by the central laboratory. | Month 3 | 
| Percentage of Participants With Molecular Response 2 (MR2) at Month 6 | MR2 is defined as <= 1% BCR-ABL with a minimum of 3,000 ABL transcripts assessed by the central laboratory. | Month 6 | 
| Percentage of Participants With Molecular Response 4.0 (MR4.0) and Molecular Response 4.5 (MR4.5) at 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. | Months 3, 6, 9 and 12 | 
| Cumulative Incidence of Major Molecular Response (MMR) at Month 36 | Percentage of participants with MMR at Month 36. Cumulative incidence of MMR was measured from first dose to the first date of response. Documented participants who did not have an MMR response were censored at the last molecular assessment. A MMR is defined as <=0.1% BCR-ABL transcripts on the international scale, corresponding to a >=3-log reduction from standardized baseline with at least 3000 ABL assessed by the central laboratory. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event. | At Month 36 | 
| Cumulative Incidence of Molecular Response 4.0 (MR4.0) at Month 36 | Percentage of participants with MR4.0 at month 36. Cumulative incidence of MR4.0, was measured from first dose to the first date of MR 4.0. Documented participants who did not have an MR4.0 response were censored at the last molecular assessment. MR4.0 defined as either 1) detectable disease with <=0.01% BCR-ABL IS or 2) undetectable disease in cDNA with a minimum number of 9800 ABL transcripts specified by the central laboratory. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event. | At Month 36 | 
| Cumulative Incidence of Molecular Response 4.5 (MR4.5) at Month 36 | Percentage of participants with MR4.5 at Month 36. Cumulative incidence of MR 4.5 was measured from first dose to the first date of MR 4.5. Documented participants who did not have an MR4.5 response were censored at the last molecular assessment. MR 4.5 defined as either 1) detectable disease with <=0.0032% BCR-ABL IS or 2) undetectable disease in cDNA with a minimum number of 30990 ABL transcripts specified by the central laboratory in the same volume of cDNA used to test for BCR-ABL. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event. | At Month 36 | 
| Cumulative Incidence of Complete Cytogenetic Response (CCyR) at Month 36 | Percentage of participants with CCyR at Month 36. Cumulative incidence of CCyR, was measured from first dose to the first date of CCyR. Documented participants who did not have a CCyR response were censored at the last cytogenetic assessment. CCyR was defined as absence of detectable Philadelphia chromosome positive cells. CCyR was achieved when there were 0 Philadelphia chromosome positive metaphases among at least 20 metaphases from a bone marrow sample or when MMR was achieved if no bone marrow analysis was performed. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event. | At Month 36 | 
| Percentage of Participants With Cumulative Complete Haematological Response (CHR) | 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. | Up to Month 36 | 
| Cumulative Incidence of Transformation to Accelerated Phase (AP) and Blast Phase (BP) at Month 36 | Percentage of participants with transformation to AP and BP at Month 36. Transformation to AP or to BP CML defined as the time from first dose to the first date of transformation to accelerated phase or to blast phase CML. Documented participants who did not progress to AP or BP were censored at the last hematologic assessment. The transformation to AP or to BP was counted while participants were on treatment up to 28 days after last dose. Cumulative incidence: % of participants with event at month 36 adjusted for competing risk of treatment discontinuation without the event. | At Month 36 | 
| Number of Participants With BCR-ABL Mutation at Treatment Discontinuation | Mutation analysis was performed in case of either lack of response, suboptimal response or loss of response, or at the End of Treatment/Withdrawal visit. | Maximum up to 44 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Chronic Myelogenous