A Phase 4 interventional study of Bosutinib in Previously Treated PH + CML, sponsored by Pfizer. Terminated at 48 sites in 8 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-12-30.
Sponsored by Pfizer · Phase 4, Interventional, and Treatment
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).
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Exclusion Criteria:
Drug: Bosutinib
100 mg and 500 mg tablets, once daily dosage up to 4 years duration
Also known as: BOSULIF
Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 2nd and 3rd Line Chronic Phase (CP) Participants
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)
Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 4th or Later Line Chronic Phase (CP) Participants
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)
Percentage of Participants With Cumulative Confirmed Overall Hematological Response (OHR) in Accelerated Phase (AP) Chronic Myelogenous Leukemia (CML) 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)
Percentage of Participants With Cumulative Major Cytogenetic Response (MCyR)
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
Percentage of Participants With Cumulative Confirmed Overall Hematological Response (OHR) in Participants With Accelerated Phase (AP) Chronic Myelogenous Leukemia (CML)
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
Percentage of Participants With Cumulative Best Response
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
Percentage of Participants With Major Cytogenetic Response (MCyR) at Months 3, 6, 12, 18 and 24
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
Percentage of Accelerated Phase Participants With Confirmed Overall Hematological Response (OHR) at Month 3, 6, 9, 12, 18, and 24
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
Percentage of Participants With Cumulative Confirmed Complete Hematological Response (CHR)
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
Percentage of Participants With Cumulative Major Molecular Response (MMR)
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
Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 36
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
Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 36
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
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious AEs
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)
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
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)
Number of Participants With Treatment Related Treatment Emergent Adverse Events (TEAEs)
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)
Number of Participants With Laboratory Abnormalities Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03
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)
Participants with chronic phase (CP), accelerated phase (AP), or blast phase (BP) philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML), or breakpoint cluster region-abelson kinase (BCR-ABL1) positive and Philadelphia chromosome negative (Ph-), who failed prior treatment with commercially available tyrosine kinase inhibitors (TKIs) due to drug resistance or intolerance, or were otherwise contraindicated for treatment with commercially available TKIs were enrolled.
| Milestone | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|
| Started | 46 | 61 | 49 | 4 | 3 |
| Completed | 36 | 43 | 28 | 2 | 1 |
| Not completed | 10 | 18 | 21 | 2 | 2 |
| Withdrew: Death | 5 | 7 | 5 | 0 | 2 |
| Withdrew: Participant refused further follow-up | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Study terminated by sponsor | 3 | 5 | 7 | 0 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 3 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 3 | 2 | 1 | 0 |
| Withdrew: Other | 2 | 3 | 3 | 0 | 0 |
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.
| percentage of participants | Bosutinib, Chronic Phase 2nd and 3rd Line Chronic Myelogenous Leukemia |
|---|---|
| Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 2nd and 3rd Line Chronic Phase (CP) Participants | 76.5 (66.9 to 84.5) |
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.
| percentage of participants | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia |
|---|---|
| Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 4th or Later Line Chronic Phase (CP) Participants | 62.2 (46.5 to 76.2) |
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.
| percentage of participants | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|
| Percentage of Participants With Cumulative Confirmed Overall Hematological Response (OHR) in Accelerated Phase (AP) Chronic Myelogenous Leukemia (CML) Participants | 75.0 (19.4 to 99.4) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| Percentage of Participants With Cumulative Major Cytogenetic Response (MCyR) | 88.4 (74.9 to 96.1) | 85.5 (73.3 to 93.5) | 77.8 (62.9 to 88.8) | 75.0 (19.4 to 99.4) |
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.
| percentage of participants | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|
| Percentage of Participants With Cumulative Confirmed Overall Hematological Response (OHR) in Participants With Accelerated Phase (AP) Chronic Myelogenous Leukemia (CML) | 75.0 (19.4 to 99.4) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| MR4.5 | 17.4 (7.8 to 31.4) | 14.8 (7.0 to 26.2) | 8.2 (2.3 to 19.6) | 25.0 (0.6 to 80.6) |
| MR4 | 15.2 (6.3 to 28.9) | 11.5 (4.7 to 22.2) | 6.1 (1.3 to 16.9) | 0.0 (0.0 to 60.2) |
| MMR | 8.7 (2.4 to 20.8) | 11.5 (4.7 to 22.2) | 14.3 (5.9 to 27.2) | 25.0 (0.6 to 80.6) |
| CCyR | 2.2 (0.1 to 11.5) | 13.1 (5.8 to 24.2) | 14.3 (5.9 to 27.2) | 25.0 (0.6 to 80.6) |
| PCyR | 2.2 (0.1 to 11.5) | 1.6 (0.0 to 8.8) | 4.1 (0.5 to 14.0) | 0.0 (0.0 to 60.2) |
| CHR | 10.9 (3.6 to 23.6) | 8.2 (2.7 to 18.1) | 16.3 (7.3 to 29.7) | 0.0 (0.0 to 60.2) |
| OHR | — | — | — | 0.0 (0.0 to 60.2) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| At 3 months | 81.4 (66.6 to 91.6) | 80.0 (67.0 to 89.6) | 55.6 (40.0 to 70.4) | 75.0 (19.4 to 99.4) |
| At 6 months | 69.8 (53.9 to 82.8) | 63.6 (49.6 to 76.2) | 62.2 (46.5 to 76.2) | 25.0 (0.6 to 80.6) |
| At 12 months | 69.8 (53.9 to 82.8) | 65.5 (51.4 to 77.8) | 48.9 (33.7 to 64.2) | 25.0 (0.6 to 80.6) |
| At 18 months | 67.4 (51.5 to 80.9) | 63.6 (49.6 to 76.2) | 42.2 (27.7 to 57.8) | 25.0 (0.6 to 80.6) |
| At 24 months | 67.4 (51.5 to 80.9) | 54.5 (40.6 to 68.0) | 44.4 (29.6 to 60.0) | 25.0 (0.6 to 80.6) |
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.
| percentage of participants | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|
| At 3 months | 75.0 (19.4 to 99.4) |
| At 6 months | 50.0 (6.8 to 93.2) |
| At 9 months | 75.0 (19.4 to 99.4) |
| At 12 months | 75.0 (19.4 to 99.4) |
| At 18 months | 25.0 (0.6 to 80.6) |
| At 24 months | 0.0 (0.0 to 60.2) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| Percentage of Participants With Cumulative Confirmed Complete Hematological Response (CHR) | 91.3 (79.2 to 97.6) | 82.0 (70.0 to 90.6) | 77.1 (62.7 to 88.0) | 75.0 (19.4 to 99.4) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| MMR | 82.6 (68.6 to 92.2) | 76.4 (63.0 to 86.8) | 56.3 (41.2 to 70.5) | 50.0 (6.8 to 93.2) |
| MR4 | 73.9 (58.9 to 85.7) | 63.6 (49.6 to 76.2) | 41.7 (27.6 to 56.8) | 25.0 (0.6 to 80.6) |
| MR4.5 | 58.7 (43.2 to 73.0) | 50.9 (37.1 to 64.6) | 35.4 (22.2 to 50.5) | 25.0 (0.6 to 80.6) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 36 | 96.4 (77.2 to 99.5) | 94.4 (79.2 to 98.6) | 100.0 (100.0 to 100.0) | 100.0 (100.0 to 100.0) |
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.
| percentage of participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia |
|---|---|---|---|---|
| Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 36 | 90.7 (73.9 to 96.9) | 81.5 (63.2 to 91.3) | 90.2 (65.9 to 97.5) | 100.0 (100.0 to 100.0) |
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.
| Participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Bosutinib: Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|---|
| TEAEs | 46 | 61 | 48 | 4 | 3 | 162 |
| Treatment-emergent SAEs | 21 | 30 | 14 | 1 | 3 | 69 |
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.
| Participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Bosutinib: Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|---|
| 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 | 36 | 49 | 39 | 2 | 3 | 129 |
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.
| Participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Bosutinib: Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|---|
| Number of Participants With Treatment Related Treatment Emergent Adverse Events (TEAEs) | 46 | 61 | 48 | 4 | 3 | 162 |
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).
| Participants | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Bosutinib: Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|---|
| Hematology | 38 | 56 | 40 | 4 | 3 | 141 |
| Chemistry | 46 | 61 | 49 | 4 | 3 | 163 |
| Coagulation | 18 | 25 | 12 | 2 | 1 | 58 |
Collected over From first dose of study drug up to 28 days after last dose (up to maximum of 4 years). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | 5/46 (10.9%) | 21/46 (45.7%) | 46/46 (100%) |
| Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | 7/61 (11.5%) | 30/61 (49.2%) | 61/61 (100%) |
| Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | 5/49 (10.2%) | 14/49 (28.6%) | 48/49 (98%) |
| Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | 0/4 (0%) | 1/4 (25%) | 4/4 (100%) |
| Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | 2/3 (66.7%) | 3/3 (100%) | 3/3 (100%) |
| Bosutinib: Chronic Myelogenous Leukemia | 19/163 (11.7%) | 69/163 (42.3%) | 162/163 (99.4%) |
| Event | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Bosutinib: Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|---|
| PancytopeniaBlood and lymphatic system disorders | 0/46 | 0/61 | 0/49 | 0/4 | 1/3 | 1/163 |
| Pericardial effusionCardiac disorders | 2/46 | 0/61 | 1/49 | 0/4 | 1/3 | 4/163 |
| Diabetes mellitusMetabolism and nutrition disorders | 0/46 | 0/61 | 0/49 | 0/4 | 1/3 | 1/163 |
| Adenocarcinoma of colonNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/46 | 0/61 | 0/49 | 0/4 | 1/3 | 1/163 |
| Lung neoplasm malignantNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/46 | 0/61 | 0/49 | 0/4 | 1/3 | 1/163 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 2/46 | 1/61 | 3/49 | 0/4 | 1/3 | 7/163 |
| Shock haemorrhagicVascular disorders | 0/46 | 0/61 | 0/49 | 0/4 | 1/3 | 1/163 |
| CellulitisInfections and infestations | 0/46 | 0/61 | 1/49 | 1/4 | 0/3 | 2/163 |
| Atrial fibrillationCardiac disorders | 3/46 | 1/61 | 1/49 | 0/4 | 0/3 | 5/163 |
| PneumoniaInfections and infestations | 0/46 | 2/61 | 3/49 | 0/4 | 0/3 | 5/163 |
| Event | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Bosutinib: Chronic Myelogenous Leukemia |
|---|---|---|---|---|---|---|
| DiarrhoeaGastrointestinal disorders | 43/46 | 54/61 | 42/49 | 4/4 | 2/3 | 145/163 |
| AnaemiaBlood and lymphatic system disorders | 7/46 | 14/61 | 5/49 | 0/4 | 2/3 | 28/163 |
| Muscle spasmsMusculoskeletal and connective tissue disorders | 2/46 | 5/61 | 2/49 | 0/4 | 2/3 | 11/163 |
| NauseaGastrointestinal disorders | 15/46 | 29/61 | 25/49 | 1/4 | 0/3 | 70/163 |
| Abdominal painGastrointestinal disorders | 14/46 | 17/61 | 16/49 | 2/4 | 0/3 | 49/163 |
| HeadacheNervous system disorders | 14/46 | 17/61 | 14/49 | 2/4 | 0/3 | 47/163 |
| Dry skinSkin and subcutaneous tissue disorders | 3/46 | 3/61 | 5/49 | 2/4 | 0/3 | 13/163 |
| AstheniaGeneral disorders | 20/46 | 9/61 | 6/49 | 1/4 | 0/3 | 36/163 |
| Abdominal pain upperGastrointestinal disorders | 19/46 | 8/61 | 9/49 | 0/4 | 1/3 | 37/163 |
| VomitingGastrointestinal disorders | 13/46 | 22/61 | 19/49 | 0/4 | 1/3 | 55/163 |
Safety analysis set included all participants who received at least 1 dose of bosutinib
| Age, Continuous(Years) | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Total |
|---|---|---|---|---|---|---|
| Mean | 55.8 ± 15.4 | 61.8 ± 15.0 | 59.4 ± 15.3 | 40.8 ± 11.0 | 64.3 ± 7.1 | 58.9 ± 15.4 |
| Sex: Female, Male(Participants) | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Total |
|---|---|---|---|---|---|---|
| Female | 23 | 24 | 28 | 0 | 0 | 75 |
| Male | 23 | 37 | 21 | 4 | 3 | 88 |
| Race (NIH/OMB)(Participants) | Bosutinib: Chronic Phase 2nd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 3rd Line Chronic Myelogenous Leukemia | Bosutinib: Chronic Phase 4th Line Chronic Myelogenous Leukemia | Bosutinib: Accelerated Phase Chronic Myelogenous Leukemia | Bosutinib: Philadelphia Chromosome Negative Chronic Myelogenous Leukemia | Total |
|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 1 | 0 | 0 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 2 | 1 | 1 | 0 | 0 | 4 |
| White | 39 | 55 | 44 | 2 | 3 | 143 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 5 | 4 | 4 | 2 | 0 | 15 |
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Plan to share: Yes — 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.
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