Safety And Efficacy Study Of Bosutinib In Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated With One Or More Tyrosine Kinase Inhibitors

Confirmed MCyR: confirmed (complete cytogenetic response\[CCyR\] or partial cytogenetic response\[PCyR\]) by 1 year for participants entering the study without CCyR or maintenance of confirmed CCyR for at least 1 year after treatment start with bosutinib for participants entering the study with CCyR or at least major molecular response(MMR) by 1 year and a deeper molecular response compared to baseline. Participants with baseline PCyR that did not achieve CCyR were counted as nonresponders. Initial cytogenetic (in absence of MMR) responses must have been confirmed by 2 consecutive assessments \>=28 days apart. CCyR: 0% Ph+ cells from \>=20 metaphases from conventional cytogenetics or \<1% Ph+ cells from \>= 200 cells from fluorescent in situ hybridization(FISH). PCyR: 1 to 35% Ph+ cells. MMR: \<=0.1% BCR-ABL1 on the international scale (IS) with at least 10,000 ABL1 transcripts assessed by central laboratory.

Time frame: Up to 1 year (52 weeks)

Population: Evaluable set for cytogenetic response: treated participants with valid baseline efficacy assessment (\>=20 metaphases from baseline bone marrow or CCyR with \>=200 cells from FISH or baseline MMR). Data for this outcome measure was not planned to be collected and analyzed for AP CML and Ph- participants and planned to be analyzed for 2nd line and 3rd line population.

Confirmed MCyR: confirmed CCyR or PCyR by 1 year for participants entering the study without CCyR or maintenance of confirmed CCyR for at least 1 year after treatment start with bosutinib for participants entering the study with CCyR or at least MMR by 1 year and a deeper molecular response compared to baseline. Participants with baseline PCyR that did not achieve CCyR were counted as nonresponders. Initial cytogenetic (in absence of MMR) responses must have been confirmed by 2 consecutive assessments \>=28 days apart. CCyR: 0% Ph+ cells from \>=20 metaphases from conventional cytogenetics or \<1% Ph+ cells from \>= 200 cells from fluorescent in situ hybridization(FISH). PCyR: 1 to 35% Ph+ cells. MMR: \<=0.1% BCR-ABL1 on the IS with at least 10,000 ABL1 transcripts assessed by central laboratory.

Time frame: Up to 1 year (52 weeks)

Population: Evaluable set cytogenetic response: treated participants with valid baseline efficacy assessment (\>= 20 metaphases from baseline bone marrow or CCyR with \>=200 cells from FISH or baseline MMR). Data for this outcome measure was not planned to be collected and analyzed for AP CML and Ph-participants.

Confirmed OHR was defined as complete hematological response (CHR) or return to chronic phase (RCP) by 1 year in AP and BP participants. CHR was defined as white blood cells (WBC) \<10\*10\^9/L, peripheral blood basophils \<5%, no peripheral blood myelocytes, promyelocytes, myeloblasts in the differential, platelet count \<450\*10\^9/L, spleen not palpable. Hematologic responses must be of \>=4 weeks duration confirmed by 2 assessments \>=4 weeks apart.

Time frame: Up to 1 year (52 weeks)

Population: Evaluable set for hematological response: treated participants with a valid baseline hematologic assessment. Data for this outcome measure was not planned to be collected and analyzed for CP2L, CP3L, CP4L and Ph- CML participants.

Kaplan-Meier analysis. Duration of CCyR: from first date of CCyR to date of confirmed loss of CCyR/disease progression/on-treatment death or censoring, analyzed for responders only. CyR: prevalence of Ph+ cells. CCyR: 0% Ph+ cells from \>=20 metaphases from conventional cytogenetics or \<1% Ph+ cells from \>=200 cells analyzed by FISH or MMR (\<=0.1% BCR-ABL1 on the IS with at least 10,000 ABL1 transcripts assessed by central laboratory). Confirmed loss: 2 consecutive non-response assessments \>=28 days apart. Progression: for CP: participants evolving from CP to AP, loss of CHR; loss of MCyR; in participants without CHR WBC \>20\*10\^9/L on 2 occasions \>=2 weeks apart after the first 4 weeks of treatment; for AP: confirmed BP, loss of previous hematologic response over a 2-week period, loss of CHR, no decrease from baseline levels (if considered clinically relevant) in percentage blasts in peripheral blood or bone marrow on all assessments over a 4-week period.

Time frame: At Month 36

Population: Evaluable set for cytogenetic response: treated participants with valid baseline cytogenetic assessment (\>= 20 metaphases from baseline bone marrow or CCyR with \>=200 cells from FISH or baseline MMR) and who achieved CCyR. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure who had CCyR.

Kaplan-Meier analysis. Duration of MMR: from first date of MMR to confirmed loss of MMR/disease progression/on-treatment death or censoring, analyzed for responders only. MMR:\<=0.1% BCR-ABL1 on the IS with at least 10,000 ABL1 transcripts assessed by central laboratory . Confirmed loss: 2 consecutive non-response assessments \>=28 days apart with a \<3-log (\>0.1%) reduction in transcripts one of which corresponds to a \<=2-log reduction (\>=1%). Progression: for CP: participants evolving from CP to AP, loss of CHR; loss of MCyR; in participants without CHR WBC \>20\*10\^9/L on 2 occasions \>=2weeks apart after the first 4 weeks of treatment; for AP: confirmed BP, loss of previous hematologic response over a 2-week period, loss of CHR, no decrease from baseline levels (if considered clinically relevant) in percentage blasts in peripheral blood or bone marrow on all assessments over a 4-week period.

Time frame: At Month 36

Population: Evaluable set for molecular response: treated participants with valid baseline molecular assessment and who achieved MMR. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure who had MMR.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE was any event increasing in severity from baseline or any new event that started during bosutinib therapy or within 28 days of the last dose of study drug. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Number of participants with Grade 3 or 4 TEAEs are reported.

Time frame: First dose of study drug up to 28 days after last dose (up to maximum of 4 years)

Population: The safety analysis set included participants who received at least 1 dose of bosutinib.

Number of participants with any hematological, chemistry and coagulation abnormality of any grade were reported. Hematological: absolute neutrophil count (low), hemoglobin (low), lymphocytes (low), platelets (low) and leukocytes (low). Chemistry: alkaline phosphatase (high), alanine aminotransferase (high), amylase (high), aspartate aminotransferase (high), bilirubin (high), creatinine (high), lipase (high). Coagulation: activated partial prothrombin time (low), prothrombin time (low and high), partial prothrombin time (high).

Time frame: First dose of study drug up to 28 days after last dose (up to maximum of 4 years)

Population: The safety analysis set included participants who received at least 1 dose of bosutinib.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE: any event increasing in severity from baseline or any new event started during bosutinib therapy or within 28 days of the last dose of study drug. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of death); persistent or significant disability/incapacity; congenital anomaly.

Time frame: First dose of study drug up to 28 days after last dose (up to maximum of 4 years)

Population: The safety analysis set included participants who received at least 1 dose of bosutinib.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. TEAE was any event increasing in severity from baseline or any new event that started during bosutinib therapy or within 28 days of the last dose of study drug. Relatedness to drug was assessed by investigator.

Time frame: First dose of study drug up to 28 days after last dose (up to maximum of 4 years)

Population: The safety analysis set included participants who received at least 1 dose of bosutinib.

Confirmed OHR was defined as CHR or RCP in AP and BP participants. CHR was defined as WBC \<10\*10\^9/L, peripheral blood basophils \<5%, no peripheral blood myelocytes, promyelocytes, myeloblasts in the differential, platelet count \<450\*10\^9/L, spleen not palpable. Hematologic responses must be of \>=4 weeks duration confirmed by 2 assessments \>=4 weeks apart.

Time frame: Months 3, 6, 9, 12, 18, and 24

Population: Evaluable set hematological response: treated participants with a valid baseline hematologic assessment. Data for this outcome measure was not planned to be collected and analyzed for CP2L, CP3L, CP4L and Ph- CML participants.

Hierarchy best response: %participants with best response among molecular/cytogenetic/hematologic response. Molecular response:MR4.5/MR4/MMR defined as \<=0.0032/0.01/0.1% BCR-ABL1 ratio on IS corresponding to \>=4.5/4/3-log reduction from standardised baseline with at least 32,000/10,000/10,000 ABL1 assessed by central laboratory. CyR:based on prevalence of Ph+cells. CCyR: 0% Ph+cells from \>=20 metaphases from conventional cytogenetics or \<1%Ph+cells from \>=200 cells from FISH. PCyR:1 to 35% Ph+cells. CHR:WBC \<10\*10\^9/L, peripheral blood basophils\<5%, no peripheral blood myelocytes, promyelocytes, myeloblasts in differential, platelet count\<450\*10\^9/L, spleen not palpable.

Time frame: Up to 4 years

Population: Evaluable set:treated participants with valid baseline molecular, cytogenetic or hematologic assessment. Data for this outcome measure (all categories including OHR) was not planned to be collected and analyzed for Ph- CML participants. Data for OHR was not planned to be collected and analyzed for CP CML participants.

CHR was defined as WBC \<10\*10\^9/L, peripheral blood basophils \<5%, no peripheral blood myelocytes, promyelocytes, myeloblasts in the differential, platelet count \<450\*10\^9/L, spleen not palpable. Hematologic responses must be of \>=4 weeks duration confirmed by 2 assessments \>=4 weeks apart.

Time frame: Up to 4 years

Population: Evaluable set for hematological response: treated participants with a valid baseline hematologic assessment. Data for this outcome measure was not planned to be collected and analyzed for Ph- participants.

Confirmed OHR was defined as CHR or RCP in AP and BP participants. CHR was defined as WBC \<10\*10\^9/L, peripheral blood basophils \<5%, no peripheral blood myelocytes, promyelocytes, myeloblasts in the differential, platelet count \<450\*10\^9/L, spleen not palpable. Hematologic responses must be of \>=4 weeks duration confirmed by 2 assessments \>=4 weeks apart.

Time frame: Up to 4 years

Population: Evaluable set for hematological response: treated participants with a valid baseline hematologic assessment. Data for this outcome measure was not planned to be collected and analyzed for CP2L, CP3L, CP4L and Ph- CML participants.

CyR was based on prevalence of Ph+ cells. CCyR was achieved when there was 0 % Ph+ cells from \>=20 metaphases from conventional bone marrow cytogenetics or \<1% Ph+ cells from \>=200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. MCyR was categorized as either CCyR or PCyR. Participants with MMR or better at baseline were counted as CCyR if baseline response was maintained or improved while on treatment.

Time frame: Up to 4 years

Population: Evaluable set cytogenetic response: treated participants with valid baseline efficacy assessment (\>=20 metaphases from baseline bone marrow or CCyR with \>=200 cells from FISH or baseline MMR). Data for this outcome measure was not planned to be collected and analyzed for Ph- participants.

Molecular response: MR4.5/MR4/MMR defined as \<=0.0032/0.01/0.1% BCR-ABL1 ratio respectively, on IS corresponding to \>=4.5/4/3-log reduction from standardized baseline with at least 32,000/10,000/10,000 ABL1 assessed by central laboratory. To be considered a responder, the participant must have had maintenance of baseline response while on-treatment or an improvement from baseline.

Time frame: Up to 4 years

Population: Evaluable set for molecular response: treated participants with a valid baseline molecular assessment. Data for this outcome measure was not planned to be collected and analyzed for Ph- participants.

CyR was based on prevalence of Ph+ cells. CCyR was achieved when there was 0 % Ph+ cells from \>=20 metaphases from conventional bone marrow cytogenetics or \<1% Ph+ cells from \>=200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. MCyR was categorized as either CCyR or PCyR. Participants with MMR or better at baseline were counted as CCyR if baseline response was maintained or improved while on treatment.

Time frame: Months 3, 6, 12, 18, and 24

Population: Evaluable set cytogenetic response: treated participants with valid baseline efficacy assessment (\>= 20 metaphases from baseline bone marrow or CCyR with \>=200 cells from FISH or baseline MMR). Data for this outcome measure was not planned to be collected and analyzed for Ph- participants.