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

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).

Study Overview

• Status: Terminated
• Conditions: Previously Treated PH + CML
• Intervention / Treatment: Drug: Bosutinib

• Study Type: Interventional
• Enrollment (Actual): 163
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universitaet Innsbruck
  • Linz, Austria, 4010
    • Ordensklinikum Linz GmbH Barmherzige Schwestern
• France
  • Bordeaux Cedex 09, France, 33076
    • Institut Bergonie
  • Le Chesnay Cedex, France, 78157
    • Centre Hospitalier de Versailles (CHV)-Hopital Andre Mignot Service d'Hematologie Clinique- Oncology
  • Marseille, France, 13009
    • Centre Regional De Lutte Contre Le Cancer
  • Nice Cedex 3, France, 06202
    • Hopital Archet I
  • Toulouse Cedex 9, France, 31059
    • Institut Universitaire du Cancer Toulouse - Oncopole
  • Vandoeuvre-les-Nancy cedex, France, 54511
    • CHU Brabois
• Germany
  • Aachen, Germany, 52074
    • RWTH Uniklinik Aachen Klinik fur Onkologie, Hamatologie und Stammzelltransplantation
  • Berlin, Germany, 13353
    • Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum (CVK)
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Jena, Germany, 07747
    • Klinik fur Innere Medizin II
  • Koeln, Germany, 50937
    • Universitaetsklinikum Koeln (AoeR)
  • Mannheim, Germany, D-68167
    • III. Medizinische Klinik Universitaetsmedizin Mannheim
• Italy
  • Catania, Italy, 95123
    • AOU Policlinico Vittorio Emanuele-P.O.G. Rodolico
  • Firenze, Italy, 50134
    • SOD Ematologia
  • Milano, Italy, 20162
    • A.O. Ospedale Niguarda Ca Granda - SC Ematologia
  • BA
    • Bari, BA, Italy, 70124
      • AOU Policlinico Consorziale di Bari - UO Ematologia con Trapianto
  • BO
    • Bologna, BO, Italy, 40138
      • A.O.U. Policlinico S. Orsola-Malpighi
  • MB
    • Monza, MB, Italy, 20900
      • Azienda Socio Sanitaria Territoriale - ASST Monza
  • RM
    • Rome, RM, Italy, 00144
      • Ospedale S. Eugenio - UOC Ematologia
  • TO
    • Orbassano, TO, Italy, 10043
      • AOU San Luigi Gonzaga SCDU Medicina Interna II ad indirizzo Ematologico
• Norway
  • Bergen, Norway, 5021
    • Haukeland Universitetssjukehus
  • Trondheim, Norway, 7030
    • St Olav Hospital
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d' Hebrón
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28006
    • Hospital Universitario de la Princesa
  • Salamanca, Spain, 37007
    • Hospital Clínico Universitario de Salamanca
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
  • Zaragoza, Spain, 50012
    • Hospital de Dia Quiron Zaragoza
  • Madrid
    • Pozuelo de Alarcon, Madrid, Spain, 28223
      • Hospital Universitario Quiron Madrid
• Sweden
  • Stockholm, Sweden, 171 76
    • Hematologiskt centrum
  • Uppsala, Sweden, 751 85
    • Akademiska Sjukhuset
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • Keck Hospital of USC
    • Los Angeles, California, United States, 90033
      • LAC+USC Medical Center
  • Florida
    • Deerfield Beach, Florida, United States, 33442
      • Sylvester Deerfield Beach
    • Miami, Florida, United States, 33136
      • University of Miami Hospital & Clinics
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indiana Blood and Marrow Transplantation-Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Missouri
    • Creve Coeur, Missouri, United States, 63141-6337
      • Siteman Cancer Center - West County
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
    • Saint Louis, Missouri, United States, 63129
      • Siteman Cancer Center - South County
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical College - New York-Presbyterian Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed Philadelphia Chromosome positive Chronic Myeloid Leukemia or Confirmed BCR-ABL1 (Abelson-break point cluster) Positive if Philadelphia Chromosome negative Chronic Myeloid Leukemia (from initial diagnosis).
• Prior treatment with 1 or more tyrosine kinase inhibitor drugs (imatinib, dasatinib and/or nilotinib) for Philadelphia Chromosome positive Chronic Myeloid Leukemia (CML).
• Any Chronic Myeloid Leukemia disease phase, as long as the patient is unable to receive treatment with imatinib, dasatinib and/or nilotinib for any reason.

Exclusion Criteria:

• Participation in any other clinical studies involving investigational drug(s) within 14 days or within 3 half-lives of drug levels in blood (whichever is longer) prior to the first dose of bosutinib.
• Prior treatment with bosutinib.
• Prior treatment with ponatinib.
• Known T315I or V299L mutation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosutinib	Drug: Bosutinib; 100 mg and 500 mg tablets, once daily dosage up to 4 years duration; Other Names: BOSULIF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	Up to 1 year (52 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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).	First dose of study drug up to 28 days after last dose (up to maximum of 4 years)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Developmental Therapeutics Consortium

Publications and helpful links

General Publications

• Takahashi N, Cortes JE, Sakaida E, Ishizawa K, Ono T, Doki N, Matsumura I, Garcia-Gutierrez V, Rosti G, Ono C, Ohkura M, Tanetsugu Y, Viqueira A, Brummendorf TH. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis. Int J Hematol. 2022 Jun;115(6):838-851. doi: 10.1007/s12185-022-03314-y. Epub 2022 Mar 2.
• Hochhaus A, Gambacorti-Passerini C, Abboud C, Gjertsen BT, Brummendorf TH, Smith BD, Ernst T, Giraldo-Castellano P, Olsson-Stromberg U, Saussele S, Bardy-Bouxin N, Viqueira A, Leip E, Russell-Smith TA, Leone J, Rosti G, Watts J, Giles FJ; BYOND Study Investigators. Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study. Leukemia. 2020 Aug;34(8):2125-2137. doi: 10.1038/s41375-020-0915-9. Epub 2020 Jun 22.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2014
• Primary Completion (Actual): October 13, 2020
• Study Completion (Actual): October 13, 2020

Study Registration Dates

• First Submitted: August 27, 2014
• First Submitted That Met QC Criteria: August 27, 2014
• First Posted (Estimate): August 29, 2014

Study Record Updates

• Last Update Posted (Actual): December 30, 2021
• Last Update Submitted That Met QC Criteria: December 2, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Leukemia; Chronic Myeloid Leukemia; CML; Chronic; Bosutinib; Myelogenous; BC-ABL Positive
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome
• Other Study ID Numbers: B1871039; 2013-003250-25 (EudraCT Number); BYOND (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: 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.