Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Translocation, Genetic

Chromosome Aberrations

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Amino Acids

Bosutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

100 mg and 500 mg tablets, once daily dosage up to 4 years duration

Pfizer CT.gov Call Center

The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients with high unmet medical need, including 75 Chronic Phase, Accelerated Phase or Blast Phase patients in the fourth or later line treatment setting (i.e., after treatment with at least 3 other Tyrosine Kinase Inhibitors).

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

A PHASE 4 SAFETY AND EFFICACY STUDY OF BOSUTINIB (BOSULIF (REGISTERED)) IN PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE CHRONIC MYELOID LEUKEMIA PREVIOUSLY TREATED WITH ONE OR MORE TYROSINE KINASE INHIBITORS

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

Developmental Therapeutics Consortium

Pfizer

The total number of deaths occurring during study, from first dose and up to the 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 both an AE and Serious Adverse Events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis performed on safety set.

Participants with philadelphia chromosome positive chronic phase 2nd line chronic myelogenous leukemia.

Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia

Participants with philadelphia chromosome positive chronic Phase 3rd line chronic myelogenous leukemia.

Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia

Participants with philadelphia chromosome positive chronic phase 4th line chronic myelogenous leukemia.

Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia

Participants with philadelphia chromosome positive accelerated phase chronic myelogenous leukemia.

Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia

Participants with BCR-ABL1 positive and philadelphia chromosome negative chronic myelogenous leukemia.

Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia

Participants with Philadelphia chromosome positive chronic phase 2nd, 3rd and 4th line chronic myelogenous leukemia, Philadelphia chromosome positive accelerated phase chronic myelogenous leukemia and BCR-ABL1-chronic myelogenous leukemia/Philadelphia chromosome negative chronic myelogenous leukemia.

Bosutinib: Chronic Myelogenous Leukemia

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Safety analysis set included all participants who received at least 1 dose of bosutinib

Pfizer ClinicalTrials.gov Call Center

Participants with philadelphia chromosome positive chronic phase 2nd and 3rd line chronic myelogenous leukemia.

Bosutinib, Chronic Phase 2nd and 3rd Line Chronic Myelogenous Leukemia

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.

Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 2nd and 3rd Line Chronic Phase (CP) Participants

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.

Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 4th or Later Line Chronic Phase (CP) Participants

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.

Percentage of Participants With Cumulative Confirmed Overall Hematological Response (OHR) in Accelerated Phase (AP) Chronic Myelogenous Leukemia (CML) Participants

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.

Percentage of Participants With Cumulative Major Cytogenetic Response (MCyR)

Percentage of Participants With Cumulative Confirmed Overall Hematological Response (OHR) in Participants With Accelerated Phase (AP) Chronic Myelogenous Leukemia (CML)

MR4.5

CCyR

PCyR

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.

Percentage of Participants With Cumulative Best Response

At 3 months

At 6 months

At 12 months

At 18 months

At 24 months

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.

Percentage of Participants With Major Cytogenetic Response (MCyR) at Months 3, 6, 12, 18 and 24

At 9 months

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.

Percentage of Accelerated Phase Participants With Confirmed Overall Hematological Response (OHR) at Month 3, 6, 9, 12, 18, and 24

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.

Percentage of Participants With Cumulative Confirmed Complete Hematological Response (CHR)

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.

Percentage of Participants With Cumulative Major Molecular Response (MMR)

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 Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 36

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.

Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 36

TEAEs

Treatment-emergent SAEs

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

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious AEs

Number of Participants With Grade 3 or 4 Treatment Emergent Adverse Events (TEAEs) Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

Number of Participants With Treatment Related Treatment Emergent Adverse Events (TEAEs)

Hematology

Chemistry

Coagulation

Number of Participants With Laboratory Abnormalities Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03

Participants with philadelphia chromosome positive chronic phase 2nd line chronic myelogenous leukemia resistant or intolerant to imatinib, dasatinib, or nilotinib received bosutinib 500 milligram (mg), orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, death or discontinuation of study (up to maximum of 4 years). Participants who discontinued bosutinib prior to completing at least 4 years of therapy were followed for survival until they completed at least 4 years of follow-up from the time of first dose.

Participants with philadelphia chromosome positive chronic Phase 3rd line chronic myelogenous leukemia resistant or intolerant to imatinib and/or dasatinib and/or nilotinib received bosutinib 500 mg, orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, death or discontinuation of study (up to maximum of 4 years). Participants who discontinued bosutinib prior to completing at least 4 years of therapy were followed for survival until they completed at least 4 years of follow-up from the time of first dose.

Participants with philadelphia chromosome positive chronic phase 4th line chronic myelogenous leukemia resistant or intolerant to imatinib and dasatinib and nilotinib received bosutinib 500 mg, orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, death or discontinuation of study (up to maximum of 4 years). Participants who discontinued bosutinib prior to completing at least 4 years of therapy were followed for survival until they completed at least 4 years of follow-up from the time of first dose.

Participants with philadelphia chromosome positive accelerated phase chronic myelogenous leukemia resistant or intolerant to at least one tyrosine kinase inhibitor among imatinib, dasatinib, or nilotinib received bosutinib 500 mg, orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, death or discontinuation of study (up to maximum of 4 years). Participants who discontinued bosutinib prior to completing at least 4 years of therapy were followed for survival until they completed at least 4 years of follow-up from the time of first dose.

Participants with BCR-ABL1 positive and philadelphia chromosome negative chronic myelogenous leukemia received bosutinib 500 mg, orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, death or discontinuation of study (up to maximum of 4 years). Participants who discontinued bosutinib prior to completing at least 4 years of therapy were followed for survival until they completed at least 4 years of follow-up from the time of first dose.

Spots Global Cancer Trial Database for previously treated ph + cml