A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT02130557
Collaborator
(none)
536
Enrollment
189
Locations
2
Arms
69.1
Actual Duration (Months)
2.8
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase 3, 2-arm, randomized, open label trial. Patients will be randomized to receive bosutinib or imatinib for the duration of the study.

Detailed Description

The study will be open for enrollment until the planned number of approximately 500 Philadelphia Chromosome Positive (Ph+) patients have been randomized (approximately 250 Ph+ patients in each treatment arm; a total of approximately 530 Ph+ and Ph- patients). All patients will be treated and/or followed for approximately 5 years (240 weeks) after randomization until the study has closed. Patients who discontinue study therapy early due to disease progression or intolerance to study medication will continue to be followed yearly for survival for up to approximately 5 years (240 weeks) after randomization.

Study Design

Study Type:
Interventional
Actual Enrollment :
536 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Masking Description:
NOTE: Value was Open Label in old format; This study has an open-label design. Although most efficacy studies have a double blind design, this is not feasible in this trial, due to the complexity of the dose reduction and dose escalation schemes with tablets of various sizes, dosage strengths, as well as the number of tablets that would be required daily. However, the opportunity for bias is mitigated by the use of objective outcome measures (MMR, CCyR, CHR). The Investigators will be instructed to ensure that laboratory/pathology personnel are blinded to treatment information. For these reasons, an open-label, randomized study is appropriate.
Primary Purpose:
Treatment
Official Title:
A MULTICENTER PHASE 3 RANDOMIZED, OPEN-LABEL STUDY OF BOSUTINIB VERSUS IMATINIB IN ADULT PATIENTS WITH NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA
Actual Study Start Date :
Jul 15, 2014
Actual Primary Completion Date :
Aug 11, 2016
Actual Study Completion Date :
Apr 17, 2020

Arms and Interventions

ArmIntervention/Treatment
Experimental: Bosutinib

Bosutinib, 400 mg, oral administration once a day

Drug: Bosutinib
Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual Src-Abl tyrosine kinase inhibitor (TKI) that has been approved for the treatment of adult patients with Philadelphia positive (Ph+) chronic phase (CP), accelerated phase (AP) and blast phase (BP) chronic myelogenous leukemia (CML) previously treated with other TKI inhibitor therapy.[1] This study will investigate the use of bosutinib as first-line treatment for patients with Ph+ CP CML.

Active Comparator: Imatinib

Imatinib, 400 mg, oral administration once a day

Drug: Imatinib
Imatinib mesylate (referred to in this protocol as imatinib) is an inhibitor of the BCR-ABL kinase and been the standard first-line therapy for patients with chronic-phase CML. Imatinib was granted approval by the European Commission in November 2001 and by the FDA in December 2002 for the treatment of newly diagnosed patients with CP Ph+ CML based on results from the IRIS trial. Imatinib is considered the standard of care for both first-line and later line settings, and consequently is an appropriate active comparator.

Outcome Measures

Primary Outcome Measures

  1. Percentage of Participants With Major Molecular Response (MMR) at Month 12 [Month 12]

    MMR was defined as a ratio of breakpoint cluster region to abelson (BCR-ABL/ABL) less than or equal to (<=) 0.1 percent (%) on the international scale (IS) (greater than or equal to [>=] 3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). The percentage of participants with MMR at Month 12 are reported.

Secondary Outcome Measures

  1. Percentage of Participants With Major Molecular Response (MMR) Up to Month 18 [Up to Month 18]

    MMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative RT-qPCR. The percentage of participants with MMR for up to Month 18 are reported.

  2. Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48 [Month 48]

    The Kaplan-Meier curve was generated based on the first date of MMR until the date of the confirmed loss of MMR or censoring, objectively documented, for responders only. Confirmed loss of MMR was BCR-ABL/ABL IS ratio >0.1% in association with a >=5-fold increase in BCR-ABL/ABL IS ratio from the lowest value achieved up to that time-point confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, progressive disease (PD) or death due to PD within 28 days of last dose were considered confirmed loss of MMR. PD was defined as disease progression to accelerated phase (AP) or blast phase (BP) CML.

  3. Percentage of Participants With Complete Cytogenetic Response (CCyR) Up to Month 12 [Up to Month 12]

    Complete Cytogenetic Response (CCyR) was based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow (BM) aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. The percentage of participants with CCyR for up to Month 12 are reported.

  4. Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48 [Month 48]

    The Kaplan-Meier curve was generated based on the first date of CCyR until the date of the confirmed loss of CCyR or censoring, objectively documented, for responders only. Confirmed loss of CCyR was the presence of at least one Ph+ metaphase confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, PD or death due to PD within 28 days of last dose were considered confirmed loss of CCyR. PD was defined as disease progression to AP or BP CML.

  5. Cumulative Incidence of Event Free Survival (EFS) Events [Up to Month 60]

    EFS was defined as time from randomization to death due to any cause, transformation to AP or BP at any time, confirmed loss of complete hematologic response (CHR), confirmed loss of CCyR or censoring. Loss of CHR was defined as a hematologic assessment of non-CHR (chronic phase, AP, or BP) confirmed by 2 assessments at least 4 weeks apart. Loss of CHR was defined as appearance of any of the following: WBC count that rises to >20.0*10^9/L, platelet count rises to >=600*10^9/L, appearance of palpable spleen or other extramedullary involvement proven by biopsy, appearance of 5% myelocytes in peripheral blood, appearance of blasts or promyelocytes in peripheral blood. Loss of CCyR was defined as at least 1 Ph+ metaphase from analysis of <100 metaphases confirmed by follow up cytogenetic analysis after 1 month. Cumulative incidence of EFS was defined as percentage of participants with EFS event at Month 60 and was adjusted for competing risk of treatment discontinuation without event.

  6. Overall Survival (OS) Rate [Up to Month 60]

    OS was defined as the time (in months) from randomization to the occurrence of death due to any cause or censoring. Kaplan-meier analysis was used for determination of OS. Percentage of participants who were alive were estimated in this outcome measure.

Other Outcome Measures

  1. Summary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) of Bosutinib [Pre-dose on Days 28, 56 and 84]

    CCyR was based on the prevalence of Ph+ metaphases among cells in metaphase on a BM aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. Trough plasma concentration of participants who had CCyR are presented in this outcome measure.

  2. Summary of Trough Plasma Concentration by Major Molecular Response (MMR) of Bosutinib [Pre-dose on Days 28, 56 and 84]

    MMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts) by quantitative RT-qPCR. Trough plasma concentration of participants who had MMR are presented in this outcome measure.

  3. Summary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) of Bosutinib [Pre-dose on Days 28, 56 and 84]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening or disabling; urgent intervention indicated; Grade 5= death. Trough plasma concentration of participants who had grade 1 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.

  4. Summary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) of Bosutinib [Pre-dose on Days 28, 56 and 84]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on NCI CTCAE version 4.0. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening or disabling; urgent intervention indicated; Grade 5= death. Trough plasma concentration of participants who had grade 3 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.

  5. Number of Participants With Vital Signs Abnormalities [Baseline up to end of treatment (up to Month 60)]

    Criteria for vital signs abnormalities: systolic blood pressure <80 millimeter of mercury (mmHg), >210 mmHg; diastolic blood pressure <40 mmHg, >130 mmHg; heart rate <40 beats per minute (bpm), >150 bpm; temperature <32 degree celsius, >40 degree celsius; weight >=10% increase from baseline, >=10% decrease from baseline. The number of participants with any vital sign abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article until the last date of test article +28 days.

  6. Number of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 4.03 [Baseline up to end of treatment (up to Month 60)]

    Laboratory parameters included hematological (haemoglobin, lymphocytes [absolute], neutrophils [absolute], platelets and leukocytes) and biochemistry (albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, amylase, bilirubin, creatinine kinase, calcium, creatinine, glucose, potassium, lipase, magnesium, phosphate, sodium, urate) parameters. Abnormalities in laboratory tests were graded by NCI CTCAE version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. The number of participants with laboratory test abnormalities were reported.

  7. Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities [Baseline up to end of treatment (up to Month 60)]

    Criteria for ECG abnormalities included heart rate: increase of >15 bpm from baseline value and >=120 bpm, decrease of >15 bpm from baseline value and <=45 bpm; PR interval: change of >=20 msec from baseline value and >=220 milliseconds (msec); QRS interval >=120 msec; QTcB interval >500 msec, increase of >60 msec from baseline; >450 msec (Men) or >470 msec (Women). QT interval using Fridericia's correction (QTcF) >500 msec, increase of >60 msec from baseline, >450 msec (Men) or >470 msec (Women). The number of participants with ECG abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article up until the last date of test article +28 days.

  8. Number of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation [Baseline up to end of treatment (up to Month 60)]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

  9. Number of Participants With Treatment-Emergent Adverse Events by National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.0) [Baseline up to end of treatment (up to Month 60)]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on NCI CTCAE version 4.0. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent events were events between first dose of study drug and up to 60 months that were absent before treatment that worsened relative to pretreatment state. If the same participant in a given treatment had more than 1 adverse event, only the maximum CTCAE was reported.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. Molecular diagnosis of CP CML of ≤ 6 months (from initial diagnosis).

  2. Adequate hepatic, renal and pancreatic function.

  3. Age ≥ 18 years.

Exclusion Criteria:
  1. Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea and/or anagrelide treatment, which are permitted for up to 6 months prior to study entry (signature of ICF) if suitably approved for use in the subject's region.

  2. Any past or current Central Nervous System (CNS) involvement, including leptomeningeal leukemia.

  3. Extramedullary disease only.

  4. Major surgery or radiotherapy within 14 days of randomization.

  5. History of clinically significant or uncontrolled cardiac disease.

  6. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease. Patients with resolved Hepatitis B can be included.

  7. Recent or ongoing clinically significant GI disorder, e.g. Crohn's Disease, Ulcerative Colitis, or prior total or partial gastrectomy.

  8. History of another malignancy within 5 years with the exception of basal cell carcinoma or cervical carcinoma in situ or stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least l2 months.

  9. Current, or recent (within 30 days, or 5 half-lives of investigational product) participation in other clinical trials of investigational agents and/or containing interventional procedures deemed contrary to the objectives and conduct of this trial.

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Pacific Cancer Medical Center, Inc.AnaheimCaliforniaUnited States92801
2Emory University HospitalAtlantaGeorgiaUnited States30322
3The Emory ClinicAtlantaGeorgiaUnited States30322
4Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUnited States30322
5Kaiser Permanente HawaiiHonoluluHawaiiUnited States96819
6Saint Alphonsus Regional Medical Center, Cancer Care CenterBoiseIdahoUnited States83706
7Saint Alphonsus Regional Medical CenterBoiseIdahoUnited States83706
8Saint Alphonsus Caldwell Cancer Care CenterCaldwellIdahoUnited States83605
9Saint Alphonsus Medical Center NampaNampaIdahoUnited States83686
10University of Illinois Cancer CenterChicagoIllinoisUnited States60612
11John H. Stroger, Jr. Hospital of Cook CountyChicagoIllinoisUnited States60621
12Indiana Blood and Marrow TransplantationIndianapolisIndianaUnited States46237
13PHARMACY Department Franciscan St. Francis Health ATTN:Jill Leslie, Pharm DIndianapolisIndianaUnited States46237
14Cancer Center of Acadiana at Lafayette General Medical CenterLafayetteLouisianaUnited States70503
15Lafayette General Medical CenterLafayetteLouisianaUnited States70503
16LSU Health Sciences Center-ShreveportShreveportLouisianaUnited States71103
17University Health ShreveportShreveportLouisianaUnited States71103
18Rcca Md LlcBethesdaMarylandUnited States20817
19University of Massachusetts Memorial Medical Center, ONC/Research PharmacyWorcesterMassachusettsUnited States01655
20University of Massachusetts Memorial Medical CenterWorcesterMassachusettsUnited States01655
21St. Joseph Mercy Hospital - Inpatient PharmacyAnn ArborMichiganUnited States48106
22St. Joseph Mercy HospitalAnn ArborMichiganUnited States48106
23St. Joseph Mercy-BrightonBrightonMichiganUnited States48114
24St. Joseph Mercy-CantonCantonMichiganUnited States48188
25Chelsea Community HospitalChelseaMichiganUnited States48118-1370
26St. John Hospital&Medical CenterDetroitMichiganUnited States48236
27St. John Hospital&Medical Center-Van Elslander Cancer CenterGrosse Pointe WoodsMichiganUnited States48236
28Van Elslander Cancer Center, PharmacyGrosse Pointe WoodsMichiganUnited States48236
29Minnesota Oncology Hematology, PAEdinaMinnesotaUnited States55435
30Park Nicollet Frauenshuh Cancer centerSaint Louis ParkMinnesotaUnited States55426
31Lakeview HospitalStillwaterMinnesotaUnited States55082
32North Mississippi Medical Center Hematology and Oncology ClinicTupeloMississippiUnited States38801
33Nebraska Methodist HospitalOmahaNebraskaUnited States68114
34Hackensack University Medical CenterHackensackNew JerseyUnited States07601
35John Theurer Cancer Center at Hackensack University Medical CenterHackensackNew JerseyUnited States07601
36San Juan Oncology AssociatesFarmingtonNew MexicoUnited States87401
37NYU Winthrop Hospital - Oncology / Hematology departmentMineolaNew YorkUnited States11501
38NYU Winthrop Hospital - Pharmacy DepartmentMineolaNew YorkUnited States11501
39Beth Israel Medical CenterNew YorkNew YorkUnited States10003
40University of Rochester Investigational Drug PharmacyRochesterNew YorkUnited States14642
41University of RochesterRochesterNew YorkUnited States14642
42FirstHealth Moore Regional HospitalPinehurstNorth CarolinaUnited States28374
43FirstHealth Outpatient Cancer CenterPinehurstNorth CarolinaUnited States28374
44University of Cincinnati Medical CenterCincinnatiOhioUnited States45219
45UC Health Physicians Office South,West ChesterOhioUnited States45069
46MUSC University HospitalCharlestonSouth CarolinaUnited States29425
47MUSC University of South Carolina, Investigational Drug ServicesCharlestonSouth CarolinaUnited States29425
48MUSC-Hollings Cancer CenterCharlestonSouth CarolinaUnited States29425
49GHS Cancer InstituteEasleySouth CarolinaUnited States29640
50GHS Cancer InstituteGreenvilleSouth CarolinaUnited States29605
51GHS Cancer InstituteGreenvilleSouth CarolinaUnited States29615
52GHS Cancer InstituteGreerSouth CarolinaUnited States29650
53GHS Cancer InstituteSenecaSouth CarolinaUnited States29672
54GHS Cancer InstituteSpartanburgSouth CarolinaUnited States29307
55The University of Texas, MD Anderson Cancer CenterHoustonTexasUnited States77030
56Utah Cancer SpecialistsMurrayUtahUnited States84157
57Utah Cancer SpecialistsSalt Lake CityUtahUnited States84106
58Huntsman Cancer HospitalSalt Lake CityUtahUnited States84112
59Huntsman Cancer InstituteSalt Lake CityUtahUnited States84112
60Virginia Mason Medical CenterSeattleWashingtonUnited States98101
61Seattle Cancer Care AllianceSeattleWashingtonUnited States98109
62HSHS St. Vincent Hospital Regional Cancer Center at HSHS St. Vincent HospitalGreen BayWisconsinUnited States54301
63HSHS St. Vincent HospitalGreen BayWisconsinUnited States54301
64HSHS St. Vincent Hospital Regional Cancer Center at HSHS St. Mary's Hospital Medical CenterGreen BayWisconsinUnited States54303
65Froedtert Hospital and the Medical College of WisconsinMilwaukeeWisconsinUnited States53226
66St George Hospital - Hematology DepartmentKogarahNew South WalesAustralia2217
67Eastern Clinical Research Unit, Level 2Box HillVictoriaAustralia3128
68UZ Ghent (University Hospital Ghent)GhentBelgium9000
69Department of Haematology at UZ Leuven (7 th Floor)LeuvenBelgium3000
70Hematology Department of CHU de LiègeLiègeBelgium4000
71Hematology Department CHR VerviersVerviersBelgium4800
72Horizon Health Network - The Moncton HospitalMonctonNew BrunswickCanadaE1C 6Z8
73Juravinski Cancer CentreHamiltonOntarioCanadaL8V 5C2
74Lakeridge HealthOshawaOntarioCanadaL1G 2B9
75Princess Margaret Cancer CentreTorontoOntarioCanadaM5G 2M9
76Hopital Maisonneuve-RosemontMontrealQuebecCanadaH1T 2M4
77Saskatoon Cancer CentreSaskatoonSaskatchewanCanadaS7N 4H4
78CHU de Québec - Université LavalQuebecCanadaG1J 1Z4
79Fakultní Nemocnice BrnoBrnoCzechia625 00
80Fakultní Nemocnice Hradec KrálovéHradec KrálovéCzechia500 05
81Fakultní nemocnice OlomoucOlomoucCzechia775 20
82Všeobecná fakultní Nemocnice v PrazePragueCzechia128 08
83Aalborg University HospitalAalborgDenmark9000
84Aarhus University HospitalAarhusDenmark8000
85Roskilde HospitalRoskildeDenmark4000
86Helsinki University Central HospitalHelsinkiFinland00029 HUS
87Oncologie Centre de RadiotherapieStrasbourgNCFrance67000
88Institut BergoniéBordeauxFrance33076
89private Practice of Pr Philippe RousselotLe ChesnayFrance78157
90private Practice of Dr. Viviane DubruilleNantes cedex 1France44093
91Hôpital L'Archet 1-CHU NiceNiceFrance06202
92Institut de Cancérologie du Gard - Hématologie CliniqueNimesFrance30029
93Pr Mauricette Michallet Centre Hospitalier Lyon SudPierre BéniteFrance69495
94INSERM CIC 1402 - CHU PoitiersPoitiersFrance86021
95Institut Universitaire du Cancer de Toulouse - OncopoleToulouse cedex 9France31059
96Universitätsklinikum BonnBonnRPGermany53105
97Uniklinikum AachenAachenGermany52074
98Charité, CVK, Med. Klinik m.S Hämatologie und OnkologieBerlinGermany13353
99Universitätsklinikum Freiburg, Klinik für Innere Medizin IFreiburgGermany79106
100Universitätsklinikum Hamburg-Eppendorf, Onkologisches ZentrumHamburgGermany20251
101Universitätsklinikum Jena, Klinik für Innere Medizin IIJena Lobeda-OstGermany07747
102Schwerpunktpraxis für Hämatologie und OnkologieMagdeburgGermany39104
103Semmelweis Egyetem I. BelgyógyászatBudapestHungary1083
104Debreceni Egyetem Klinikai Központ, Belgyógyászati Inézet Hematológiai TanszékDebrecenHungary4032
105Petz Aladár Megyei OktatóKórház, II. Belgyógyászati Osztály és Haematológiai RészlegGyörHungary9023
106Somogy Megyei Kaposi Mór Oktató KórházKaposvárHungary7400
107Szegedi Tudományegyetem, AOK, Szent-Györgyi Albert Klinikai Központ, II. sz.SzegedHungary6725
108Jász-Nagykun-Szolnok Megyei Hetényi, Géza Kórház-RendelőintézetSzolnokHungary5000
109Hematology Department, Rambam Medical CentreHaifaIsrael31096
110Hematology Div. Davidoff Cancer Center, Rabin Medical CenterPetah-TikvaIsrael49100
111Azienda Ospedaliero-Universitaria "Policlinico - Vittorio Emanuele" - P.O. G. RodolicoCataniaCTItaly95123
112USC Ematologia, A. O. Papa Giovanni XXIIIBergamoItaly24127
113Policlinico S. Orsola - Malpighi,BolognaItaly40138
114A.O. Brozu - P.O. Armando BusincoCagliariItaly09121
115Azienda Ospedaliero Universitaria CareggiFirenzeItaly50134
116IRCCS - AOU San Martino_IST, Ematologia 1GenovaItaly16132
117Istituto Scientifico San RaffaeleMilanoItaly20132
118Unità di Ricerca Clinica, U.O. Ematologia AdultiMonzaItaly20900
119A.O.U. Policlinico Università degli Studi di Napoli "Federico II"NapoliItaly80131
120Dipartimento di ematologiaReggio CalabriaItaly89124
121ASL Roma 2 - Ospedale Sant'EugenioRomaItaly00144
122Hallym University Sacred Heart HospitalAnyang-siKorea, Republic of14068
123Dong A University HospitalBusanKorea, Republic of49201
124Keimyung University Dongsan HospitalDaeguKorea, Republic of41931
125Chonbuk National University HospitalJeonjuKorea, Republic of54907
126Kangbuk Samsung HospitalSeoulKorea, Republic of03181
127Seoul St. Mary's Hospital of the Catholic University of KoreaSeoulKorea, Republic of06591
128Hospital Angeles del Pedregal (S.A. de C.V.)Mexico CityDFMexico10700
129Monterrey International Research CenterMonterreyNuevo LEONMexico64000
130VU University Medical CenterAmsterdamNoord HollandNetherlands1081 HV
131Klinische Farrnacologie en ApotheekAmsterdamNoord-hollandNetherlands1081 BT
132Haukeland University Hospital Department of HematologyBergenNorway5021
133St. Olavs HospitalTrondheimNorway7006
134Klinika Hematologii i Transplantologii Uniwersyteckie Centrum KliniczneGdanskPomorskiePoland80-214
135SPZOZ ZSM w Chorzowie Oddzial HematologicznyChorzowPoland41-500
136Samodzielny Publiczny Szpital Kliniczny im. A Mielęckiego, ŚUM w KatowicachKatowicePoland40032
137Szpital Uniwersytecki w Krakowie, Oddział Kliniczny HematologiiKrakówPoland31501
138SPSK, Klinika Hematoonkologii i Transplantacji Szpiku w LublinieLublinPoland20081
139Universytet Medyczny im. Piastów Śląskich we Wrocławiu Katedra iWrocławPoland50-367
140Wojewódzki Szpital Specjalistyczny im M. Kopernika, Klinika Hematologii Uniwersytetu MedycznegoŁódźPoland93510
141National University Hospital, Main BuildingSingaporeSingapore119228
142Singapore General HospitalSingaporeSingapore169608
143Tan Tock Seng HospitalSingaporeSingapore308433
144Univerzitná Nemocnica Bratislava-Nemocnica sv. Cyrila a MetodaBratislavaSlovakia851 07
145The Medical Oncology Centre of RosebankJohannesburgGautengSouth Africa2196
146Department of Medical Oncology, University of Pretoria and Steve BikoPretoriaGautengSouth Africa0002
147Groenkloof Life hospital.PretoriaGautengSouth Africa0181
148Department of HaematologyCape TownWestern CAPESouth Africa7935
149Hospital (Universitari(o)) Germans Trias i PujolBadalonaBarcelonaSpain08916
150Hospital Universitario La PrincesaMadridMálagaSpain28006
151Hospital Vall d'HebronBarcelonaSpain08035
152Hospital ClínicBarcelonaSpain08036
153Hospital Universitario Gregorio MarañónMadridSpain28007
154Hospital Ramón y CajalMadridSpain28034
155Hospital Clinico San CarlosMadridSpain28040
156Hospital Universitario de SalamancaSalamancaSpain37007
157Hospital Virgen de la SaludToledoSpain45004
158Hospital Clínico Universitario de ValenciaValenciaSpain46010
159Linköping University HospitalLinköpingSwedenSE-581 85
160Skåne University HospitalLundSwedenSE-221 85
161Karolinska University Hospital SolnaStockholmSwedenSE-171 76
162Norrlands University HospitalUmeåSwedenSE-901 85
163Akademiska HospitalUppsalaSwedenSE-751 85
164China Medical University HospitalTaichung cityR.o.c.Taiwan40447
165Chi-Mei Medical CenterTainan CityR.o.c.Taiwan710
166Mackay Memorial HospitalTaipei CityR.o.c.Taiwan10449
167Kaohsiung Medical University Chung-Ho Memorial HospitalKaohsiung CityTaiwan807
168Division of Hematology, Department of Internal Medicine, Maharaj Nakorn Chiang Mai HospitalMuangChiang MAIThailand50200
169King Chulalongkorn Memorial HospitalBangkokThailand10330
170Phramongkutklao HospitalBangkokThailand10400
171Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj HospitalBangkokThailand10700
172MI "Cherkasy Regional Oncological Dispensary " of Cherkasy Regional CouncilCherkasyUkraine18009
173Regional Clinical Hospital in Ivano-Frankivsk, Hematology DepartmentIvano-FrankivskUkraine76008
174Khmelnytskyi Regional Hospital, Hematology DepartmentKhmelnytskyiUkraine29000
175State Institution "National research center for radiation medicine of NAMS of Ukraine",KyivUkraine03115
176State Institution "National research center for radiation medicine of NAMS of Ukraine"KyivUkraine03115
177transplantation department of hemotology and transplantology division within Clinical RadiologyKyivUkraine03115
178Chair of internal medicine #2.KyivUkraine04112
179Kyiv City Clinical Hospital #9, Hematology department #1,KyivUkraine04112
180State Institution "Institute of Blood Pathology and Transfusion Medicine NAMS of Ukraine"LvivUkraine79044
181Catherine Lewis Centre, Hammersmith HospitalLondonGreater LondonUnited KingdomW12 0HS
182Linda McCartney CentreLiverpoolMerseysideUnited KingdomL7 8XP
183Department of Clinical HaematologyNottinghamNottinghamshireUnited KingdomNG5 1PB
184Cancer & Haematology Centre, Churchill HospitalOxfordOxfordshireUnited KingdomOX3 7LE
185Department of Haematology The Royal Hallamshire HospitalSheffieldSouth YorkshireUnited KingdomS10 2JF
186Heartlands HospitalBirminghamWEST MidlandsUnited KingdomB9 5SS
187St James's Institute of OncologyLeedsWEST YorkshireUnited KingdomLS9 7TF
188Department of HaematologyCardiffUnited KingdomCF14 4XW
189The Hope Clinical Trials FacilityLeicesterUnited KingdomLE1 5WW

Sponsors and Collaborators

  • Pfizer

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02130557
Other Study ID Numbers:
  • AV001
  • 2013-005101-31
  • B1871053
First Posted:
May 5, 2014
Last Update Posted:
May 18, 2021
Last Verified:
Apr 1, 2021

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive chronic myeloid leukemia (CML) received bosutinib tablets at a dose of 400 milligram (mg), orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Period Title: Overall Study
STARTED268268
Treated268265
mITT Population246241
COMPLETED232231
NOT COMPLETED3637

Baseline Characteristics

Arm/Group TitleBosutinibImatinibTotal
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Total of all reporting groups
Overall Participants268268536
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
50.8
(15.40)
50.9
(14.43)
50.9
(14.91)
Sex: Female, Male (Count of Participants)
Female
112
41.8%
113
42.2%
225
42%
Male
156
58.2%
155
57.8%
311
58%

Outcome Measures

1. Primary Outcome
TitlePercentage of Participants With Major Molecular Response (MMR) at Month 12
DescriptionMMR was defined as a ratio of breakpoint cluster region to abelson (BCR-ABL/ABL) less than or equal to (<=) 0.1 percent (%) on the international scale (IS) (greater than or equal to [>=] 3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). The percentage of participants with MMR at Month 12 are reported.
Time FrameMonth 12

Outcome Measure Data

Analysis Population Description
Modified intent-to-treat (mITT) population included all randomized participants with Philadelphia chromosome positive (Ph+) CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies greater than (>) 0 with study drug assignment designated according to initial randomization.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants246241
Number (95% Confidence Interval) [percentage of participants]
47.2
17.6%
36.9
13.8%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments A total sample size of 500 Ph+ participants is required for the study to provide >= 90% power to detect at least 15% difference (assuming 25% in the imatinib vs 40% in the bosutinib arm) in the MMR rates at 12 months (48 weeks) with a 1-sided alpha of 2.5%, and 2 interim futility analyses at 33% and 66% of patients with adequate follow-up with early stopping for futility only (non-binding, O'Brien-Fleming analog beta spending function).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.0100
Comments1-sided p-value based on CMH test for general association between treatment and response with stratification by sokal risk group (low, intermediate, high) and region (1-3) at time of randomization. Statistical significance threshold: 1-sided 0.025.
MethodCochran-Mantel-Haenszel
Comments
Method of EstimationEstimation ParameterOdds Ratio (OR)
Estimated Value1.547
Confidence Interval (2-Sided) 95%
1.072 to 2.233
Parameter Dispersion Type:
Value:
Estimation Comments95% Confidence Interval (CI) for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.
2. Secondary Outcome
TitlePercentage of Participants With Major Molecular Response (MMR) Up to Month 18
DescriptionMMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative RT-qPCR. The percentage of participants with MMR for up to Month 18 are reported.
Time FrameUp to Month 18

Outcome Measure Data

Analysis Population Description
mITT population included all randomized participants with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomization.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants246241
Number (95% Confidence Interval) [percentage of participants]
61.0
22.8%
52.7
19.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments If the primary analysis was significant, each member of the short-term family (CCyR by Month 12, MMR by Month 18) was tested via Bonferroni's procedure at the 1-sided level of 0.0125.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.0303
Comments1-sided p-value based on CMH test for general association between treatment and response with stratification by sokal risk group (low, intermediate, high) and region (1-3) at time of randomization. Statistical significance threshold: 1-sided 0.0125.
MethodCochran-Mantel-Haenszel
Comments
Method of EstimationEstimation ParameterOdds Ratio (OR)
Estimated Value1.418
Confidence Interval (2-Sided) 95%
0.986 to 2.037
Parameter Dispersion Type:
Value:
Estimation Comments95% CI for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.
3. Secondary Outcome
TitleKaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48
DescriptionThe Kaplan-Meier curve was generated based on the first date of MMR until the date of the confirmed loss of MMR or censoring, objectively documented, for responders only. Confirmed loss of MMR was BCR-ABL/ABL IS ratio >0.1% in association with a >=5-fold increase in BCR-ABL/ABL IS ratio from the lowest value achieved up to that time-point confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, progressive disease (PD) or death due to PD within 28 days of last dose were considered confirmed loss of MMR. PD was defined as disease progression to accelerated phase (AP) or blast phase (BP) CML.
Time FrameMonth 48

Outcome Measure Data

Analysis Population Description
mITT population included all randomized participants with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomization and who achieved MMR (responders). Here, "Overall number of Participants Analyzed (N)" signifies number of participants evaluable for this outcome measure.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants182158
Number (95% Confidence Interval) [percentage of participants]
92.2
34.4%
92.0
34.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments The medians have not been reached in either arm, as such, the premature estimated hazard ratio is provided.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value
Comments
Method
Comments
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value1.09
Confidence Interval (2-Sided) 95%
0.49 to 2.44
Parameter Dispersion Type:
Value:
Estimation CommentsHazard ratio (95% CIs) are based on the treatment effect (Bosutinib compared with Imatinib) in a stratified (by Sokal risk group at randomization and region) Cox proportional hazards model for the hazard of the respective event.
4. Secondary Outcome
TitlePercentage of Participants With Complete Cytogenetic Response (CCyR) Up to Month 12
DescriptionComplete Cytogenetic Response (CCyR) was based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow (BM) aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. The percentage of participants with CCyR for up to Month 12 are reported.
Time FrameUp to Month 12

Outcome Measure Data

Analysis Population Description
mITT population included all randomized participants with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomization.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants246241
Number (95% Confidence Interval) [percentage of participants]
77.2
28.8%
66.4
24.8%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments If the primary analysis was significant, each member of the short-term family (CCyR by Month 12, MMR by Month 18) was tested via Bonferroni's procedure at the 1-sided level of 0.0125.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.0037
Comments1-sided p-value based on CMH test for general association between treatment and response with stratification by sokal risk group (low, intermediate, high) and region (1-3) at time of randomization. Statistical significance threshold: 1-sided 0.0125.
MethodCochran-Mantel-Haenszel
Comments
Method of EstimationEstimation ParameterOdds Ratio (OR)
Estimated Value1.740
Confidence Interval (2-Sided) 95%
1.160 to 2.610
Parameter Dispersion Type:
Value:
Estimation Comments95% CI for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.
5. Secondary Outcome
TitleKaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48
DescriptionThe Kaplan-Meier curve was generated based on the first date of CCyR until the date of the confirmed loss of CCyR or censoring, objectively documented, for responders only. Confirmed loss of CCyR was the presence of at least one Ph+ metaphase confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, PD or death due to PD within 28 days of last dose were considered confirmed loss of CCyR. PD was defined as disease progression to AP or BP CML.
Time FrameMonth 48

Outcome Measure Data

Analysis Population Description
mITT population included all randomized participants with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomization and who achieved CCyR (responders). Here, "N" signifies number of participants evaluable for this outcome measure.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants205185
Number (95% Confidence Interval) [percentage of participants]
97.4
36.3%
93.7
35%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments The medians have not been reached in either arm, as such, the premature estimated hazard ratio is provided.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value
Comments
Method
Comments
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value0.39
Confidence Interval (2-Sided) 95%
0.14 to 1.13
Parameter Dispersion Type:
Value:
Estimation CommentsHazard ratio (95% CIs) are based on the treatment effect (Bosutinib compared with Imatinib) in a stratified (by Sokal risk group at randomization and region) Cox proportional hazards model for the hazard of the respective event.
6. Secondary Outcome
TitleCumulative Incidence of Event Free Survival (EFS) Events
DescriptionEFS was defined as time from randomization to death due to any cause, transformation to AP or BP at any time, confirmed loss of complete hematologic response (CHR), confirmed loss of CCyR or censoring. Loss of CHR was defined as a hematologic assessment of non-CHR (chronic phase, AP, or BP) confirmed by 2 assessments at least 4 weeks apart. Loss of CHR was defined as appearance of any of the following: WBC count that rises to >20.0*10^9/L, platelet count rises to >=600*10^9/L, appearance of palpable spleen or other extramedullary involvement proven by biopsy, appearance of 5% myelocytes in peripheral blood, appearance of blasts or promyelocytes in peripheral blood. Loss of CCyR was defined as at least 1 Ph+ metaphase from analysis of <100 metaphases confirmed by follow up cytogenetic analysis after 1 month. Cumulative incidence of EFS was defined as percentage of participants with EFS event at Month 60 and was adjusted for competing risk of treatment discontinuation without event.
Time FrameUp to Month 60

Outcome Measure Data

Analysis Population Description
mITT population included all randomized participants with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomization.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants246241
Number (95% Confidence Interval) [percentage of participants]
6.9
2.6%
10.4
3.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments If each member of the short-term family (CCyR by Month 12, MMR by Month 18) was significant, EFS and OS were tested sequentially via the Holm's testing procedure at the 1-sided family wise level of 0.025. If one member of the short-term family was significant, EFS and OS were tested sequentially at 1-sided 0.0125.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.0749
Comments1-sided p-value based on Gray's test for comparing cumulative incidence function between treatment arms stratified by sokal risk group (low, intermediate, high) and region (1-3). Statistical significance threshold: 1-sided 0.0125.
MethodGray's test
Comments
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value0.64
Confidence Interval (2-Sided) 95%
0.35 to 1.17
Parameter Dispersion Type:
Value:
Estimation CommentsThe hazard ratio (95% CIs) are based on the proportional subdistribution hazards model stratified by Sokal risk group and region.
7. Secondary Outcome
TitleOverall Survival (OS) Rate
DescriptionOS was defined as the time (in months) from randomization to the occurrence of death due to any cause or censoring. Kaplan-meier analysis was used for determination of OS. Percentage of participants who were alive were estimated in this outcome measure.
Time FrameUp to Month 60

Outcome Measure Data

Analysis Population Description
mITT population included all randomized participants with Ph+ CML harboring the b2a2 and/or b3a2 transcript and baseline BCR-ABL copies >0 with study drug assignment designated according to initial randomization.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants246241
Number (95% Confidence Interval) [percentage of participants]
94.9
35.4%
94.0
35.1%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib, Imatinib
Comments If each member of the short-term family (CCyR by Month 12, MMR by Month 18) was significant, EFS and OS were tested sequentially via the Holm's testing procedure at the 1-sided family wise level of 0.025. If one member of the short-term family was significant, EFS and OS were tested sequentially at 1-sided 0.0125.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.2827
Comments1-sided p-value based on log-rank test for comparing survival curves between treatment arms stratified by sokal risk group and region. OS was not tested as EFS was not significant.
MethodLog Rank
Comments
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value0.80
Confidence Interval (2-Sided) 95%
0.37 to 1.73
Parameter Dispersion Type:
Value:
Estimation CommentsThe hazard ratio (95% CIs) are based on the treatment effect (Bosutinib compared with Imatinib) in a stratified (by Sokal risk group at randomization and region) Cox proportional hazards model for the hazard of the respective event.
8. Other Pre-specified Outcome
TitleSummary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) of Bosutinib
DescriptionCCyR was based on the prevalence of Ph+ metaphases among cells in metaphase on a BM aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. Trough plasma concentration of participants who had CCyR are presented in this outcome measure.
Time FramePre-dose on Days 28, 56 and 84

Outcome Measure Data

Analysis Population Description
Pharmacokinetic (PK) population included all enrolled participants who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N" signifies number of participants evaluable for this outcome measure and "number analyzed (n)" signifies participants evaluable at specified time points only. Data for this outcome measure was not planned to be collected and analyzed for Imatinib arm as pre-specified in the protocol.
Arm/Group TitleBosutinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants191
Day 28
71.282
(46.0545)
Day 56
73.069
(45.1349)
Day 84
83.973
(64.3206)
9. Other Pre-specified Outcome
TitleSummary of Trough Plasma Concentration by Major Molecular Response (MMR) of Bosutinib
DescriptionMMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts) by quantitative RT-qPCR. Trough plasma concentration of participants who had MMR are presented in this outcome measure.
Time FramePre-dose on Days 28, 56 and 84

Outcome Measure Data

Analysis Population Description
PK population included all enrolled participants who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N" signifies number of participants evaluable for this outcome measure and "n" signifies participants evaluable at specified time points only. Data for this outcome measure was not planned to be collected and analyzed for Imatinib arm as pre-specified in the protocol.
Arm/Group TitleBosutinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants141
Day 28
75.050
(51.9551)
Day 56
78.437
(43.6019)
Day 84
91.081
(72.1500)
10. Other Pre-specified Outcome
TitleSummary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) of Bosutinib
DescriptionAn AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening or disabling; urgent intervention indicated; Grade 5= death. Trough plasma concentration of participants who had grade 1 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.
Time FramePre-dose on Days 28, 56 and 84

Outcome Measure Data

Analysis Population Description
PK population included all enrolled participants who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N" signifies number of participants evaluable for this outcome measure and "n" signifies participants evaluable at specified time points only. Data for this outcome measure was not planned to be collected and analyzed for Imatinib arm as pre-specified in the protocol.
Arm/Group TitleBosutinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants177
Day 28: Diarrhea
69.402
(55.5005)
Day 28: Thrombocytopenia
63.529
(40.9949)
Day 28: Rash
74.779
(60.6257)
Day 28: Nausea
66.011
(42.6437)
Day 28: Vomiting
71.684
(60.7208)
Day 56: Diarrhea
68.834
(42.6621)
Day 56: Thrombocytopenia
65.327
(43.2859)
Day 56: Rash
70.016
(38.7506)
Day 56: Nausea
61.626
(44.4007)
Day 56: Vomiting
65.980
(45.9064)
Day 84: Diarrhea
81.269
(64.6462)
Day 84: Thrombocytopenia
71.585
(33.6674)
Day 84: Rash
89.080
(69.5237)
Day 84: Nausea
77.702
(61.6179)
Day 84: Vomiting
86.949
(55.3041)
11. Other Pre-specified Outcome
TitleSummary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) of Bosutinib
DescriptionAn AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on NCI CTCAE version 4.0. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening or disabling; urgent intervention indicated; Grade 5= death. Trough plasma concentration of participants who had grade 3 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.
Time FramePre-dose on Days 28, 56 and 84

Outcome Measure Data

Analysis Population Description
PK population included all enrolled participants who received at least 1 dose of bosutinib and had sufficient plasma results available. Here, "N" signifies number of participants evaluable for this outcome measure and "n" signifies participants evaluable at specified time points only. Data for this outcome measure was not planned to be collected and analyzed for Imatinib arm as pre-specified in the protocol.
Arm/Group TitleBosutinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants24
Day 28: Diarrhea
87.769
(102.6181)
Day 28: Thrombocytopenia
49.220
(36.3461)
Day 28: Rash
71.150
(43.3246)
Day 28: Vomiting
14.663
(21.5799)
Day 56: Diarrhea
68.513
(45.2672)
Day 56: Thrombocytopenia
56.853
(34.3892)
Day 56: Rash
58.925
(18.8656)
Day 56: Vomiting
38.200
(NA)
Day 84: Diarrhea
76.782
(46.3006)
Day 84: Thrombocytopenia
67.623
(35.3084)
Day 84: Rash
83.967
(19.2542)
Day 84: Vomiting
12.400
(NA)
12. Other Pre-specified Outcome
TitleNumber of Participants With Vital Signs Abnormalities
DescriptionCriteria for vital signs abnormalities: systolic blood pressure <80 millimeter of mercury (mmHg), >210 mmHg; diastolic blood pressure <40 mmHg, >130 mmHg; heart rate <40 beats per minute (bpm), >150 bpm; temperature <32 degree celsius, >40 degree celsius; weight >=10% increase from baseline, >=10% decrease from baseline. The number of participants with any vital sign abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article until the last date of test article +28 days.
Time FrameBaseline up to end of treatment (up to Month 60)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received. Here, "N" signifies number of participants evaluable for this outcome measure.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants262263
Count of Participants [Participants]
107
39.9%
109
40.7%
13. Other Pre-specified Outcome
TitleNumber of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 4.03
DescriptionLaboratory parameters included hematological (haemoglobin, lymphocytes [absolute], neutrophils [absolute], platelets and leukocytes) and biochemistry (albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, amylase, bilirubin, creatinine kinase, calcium, creatinine, glucose, potassium, lipase, magnesium, phosphate, sodium, urate) parameters. Abnormalities in laboratory tests were graded by NCI CTCAE version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. The number of participants with laboratory test abnormalities were reported.
Time FrameBaseline up to end of treatment (up to Month 60)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants268265
Grade 1
6
2.2%
7
2.6%
Grade 2
67
25%
59
22%
Grade 3
133
49.6%
154
57.5%
Grade 4
61
22.8%
45
16.8%
14. Other Pre-specified Outcome
TitleNumber of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
DescriptionCriteria for ECG abnormalities included heart rate: increase of >15 bpm from baseline value and >=120 bpm, decrease of >15 bpm from baseline value and <=45 bpm; PR interval: change of >=20 msec from baseline value and >=220 milliseconds (msec); QRS interval >=120 msec; QTcB interval >500 msec, increase of >60 msec from baseline; >450 msec (Men) or >470 msec (Women). QT interval using Fridericia's correction (QTcF) >500 msec, increase of >60 msec from baseline, >450 msec (Men) or >470 msec (Women). The number of participants with ECG abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article up until the last date of test article +28 days.
Time FrameBaseline up to end of treatment (up to Month 60)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received. Here, "N" signifies number of participants evaluable for this outcome measure.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants266262
Count of Participants [Participants]
16
6%
13
4.9%
15. Other Pre-specified Outcome
TitleNumber of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation
DescriptionAn AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time FrameBaseline up to end of treatment (up to Month 60)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants268265
Count of Participants [Participants]
68
25.4%
38
14.2%
16. Other Pre-specified Outcome
TitleNumber of Participants With Treatment-Emergent Adverse Events by National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.0)
DescriptionAn AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on NCI CTCAE version 4.0. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent events were events between first dose of study drug and up to 60 months that were absent before treatment that worsened relative to pretreatment state. If the same participant in a given treatment had more than 1 adverse event, only the maximum CTCAE was reported.
Time FrameBaseline up to end of treatment (up to Month 60)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received at least 1 dose of study medication with treatment assignments designated to actual study treatment received.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
Measure Participants268265
Grade 1
7
2.6%
24
9%
Grade 2
61
22.8%
86
32.1%
Grade 3
144
53.7%
120
44.8%
Grade 4
50
18.7%
28
10.4%
Grade 5
3
1.1%
4
1.5%

Adverse Events

Time FrameFrom first dose of drug up to 28 days after last dose (up to Month 60)
Adverse Event Reporting Description All-cause mortality: The total number of deaths occurred during study (from randomization and up to month 60) are reported for all randomized participants, not only for treated participants, and included deaths which occurred after 28 days post last study drug dose. Serious AEs and other AEs: Analysis performed on safety population. The safety population included all participants, regardless of Philadelphia chromosome or transcript status, who received at least 1 dose of study medication.
Arm/Group TitleBosutinibImatinib
Arm/Group DescriptionParticipants with Philadelphia chromosome-positive CML received bosutinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.Participants with Philadelphia chromosome-positive CML received imatinib tablets at a dose of 400 mg, orally once daily in the core treatment phase of 12 months and continued the same treatment into the extension phase or followed up for safety for up to approximately 4 years, until the end of the study, treatment failure, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.
All Cause Mortality
BosutinibImatinib
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total14/268 (5.2%) 14/268 (5.2%)
Serious Adverse Events
BosutinibImatinib
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total98/268 (36.6%) 68/265 (25.7%)
Blood and lymphatic system disorders
Anaemia1/268 (0.4%) 3/265 (1.1%)
Thrombocytopenia2/268 (0.7%) 1/265 (0.4%)
Febrile neutropenia0/268 (0%) 2/265 (0.8%)
Agranulocytosis1/268 (0.4%) 0/265 (0%)
Haemolysis0/268 (0%) 1/265 (0.4%)
Haemolytic anaemia0/268 (0%) 1/265 (0.4%)
Cardiac disorders
Myocardial ischaemia4/268 (1.5%) 0/265 (0%)
Atrial fibrillation2/268 (0.7%) 1/265 (0.4%)
Cardiac failure acute2/268 (0.7%) 0/265 (0%)
Coronary artery disease2/268 (0.7%) 0/265 (0%)
Pericarditis2/268 (0.7%) 0/265 (0%)
Angina pectoris1/268 (0.4%) 0/265 (0%)
Pericardial effusion1/268 (0.4%) 0/265 (0%)
Acute coronary syndrome1/268 (0.4%) 0/265 (0%)
Acute myocardial infarction1/268 (0.4%) 0/265 (0%)
Atrial thrombosis1/268 (0.4%) 0/265 (0%)
Cardiac failure1/268 (0.4%) 0/265 (0%)
Cardiac failure congestive1/268 (0.4%) 0/265 (0%)
Cardio-respiratory arrest1/268 (0.4%) 0/265 (0%)
Coronary artery occlusion1/268 (0.4%) 0/265 (0%)
Pleuropericarditis1/268 (0.4%) 0/265 (0%)
Sinus node dysfunction1/268 (0.4%) 0/265 (0%)
Supraventricular tachycardia1/268 (0.4%) 0/265 (0%)
Congenital, familial and genetic disorders
Hydrocele1/268 (0.4%) 0/265 (0%)
Ear and labyrinth disorders
Vertigo positional1/268 (0.4%) 0/265 (0%)
Endocrine disorders
Thyroid disorder0/268 (0%) 1/265 (0.4%)
Eye disorders
Eye haemorrhage1/268 (0.4%) 0/265 (0%)
Ocular hypertension1/268 (0.4%) 0/265 (0%)
Retinal vein occlusion1/268 (0.4%) 0/265 (0%)
Retinopathy1/268 (0.4%) 0/265 (0%)
Gastrointestinal disorders
Diarrhoea5/268 (1.9%) 1/265 (0.4%)
Gastritis1/268 (0.4%) 1/265 (0.4%)
Pancreatitis acute1/268 (0.4%) 1/265 (0.4%)
Necrotising oesophagitis1/268 (0.4%) 0/265 (0%)
Abdominal pain1/268 (0.4%) 0/265 (0%)
Abdominal pain upper0/268 (0%) 1/265 (0.4%)
Abdominal wall haematoma1/268 (0.4%) 0/265 (0%)
Anal fissure1/268 (0.4%) 0/265 (0%)
Colitis0/268 (0%) 1/265 (0.4%)
Diverticulum intestinal1/268 (0.4%) 0/265 (0%)
Duodenal ulcer1/268 (0.4%) 0/265 (0%)
Food poisoning1/268 (0.4%) 0/265 (0%)
Gastric ulcer0/268 (0%) 1/265 (0.4%)
Gastrointestinal haemorrhage0/268 (0%) 1/265 (0.4%)
Haemorrhoids1/268 (0.4%) 0/265 (0%)
Hypoaesthesia oral0/268 (0%) 1/265 (0.4%)
Inguinal hernia1/268 (0.4%) 0/265 (0%)
Intra-abdominal haematoma0/268 (0%) 1/265 (0.4%)
Large intestine polyp0/268 (0%) 1/265 (0.4%)
Oedematous pancreatitis1/268 (0.4%) 0/265 (0%)
Pancreatitis1/268 (0.4%) 0/265 (0%)
Rectal haemorrhage1/268 (0.4%) 0/265 (0%)
Small intestinal obstruction1/268 (0.4%) 0/265 (0%)
General disorders
Pyrexia5/268 (1.9%) 1/265 (0.4%)
General physical health deterioration0/268 (0%) 1/265 (0.4%)
Hyperthermia0/268 (0%) 1/265 (0.4%)
Implant site haematoma1/268 (0.4%) 0/265 (0%)
Non-cardiac chest pain1/268 (0.4%) 0/265 (0%)
Swelling face0/268 (0%) 1/265 (0.4%)
Hepatobiliary disorders
Cholecystitis acute2/268 (0.7%) 0/265 (0%)
Cholelithiasis0/268 (0%) 2/265 (0.8%)
Hepatitis2/268 (0.7%) 0/265 (0%)
Hepatotoxicity2/268 (0.7%) 0/265 (0%)
Cholecystitis1/268 (0.4%) 0/265 (0%)
Portal vein thrombosis0/268 (0%) 1/265 (0.4%)
Immune system disorders
Drug hypersensitivity1/268 (0.4%) 0/265 (0%)
Infections and infestations
Pneumonia8/268 (3%) 5/265 (1.9%)
Gastroenteritis6/268 (2.2%) 1/265 (0.4%)
Cellulitis3/268 (1.1%) 2/265 (0.8%)
Influenza1/268 (0.4%) 2/265 (0.8%)
Sepsis0/268 (0%) 3/265 (1.1%)
Urinary tract infection1/268 (0.4%) 2/265 (0.8%)
Abscess1/268 (0.4%) 1/265 (0.4%)
Abscess limb0/268 (0%) 2/265 (0.8%)
Appendicitis0/268 (0%) 2/265 (0.8%)
Appendicitis perforated0/268 (0%) 1/265 (0.4%)
Bacteraemia1/268 (0.4%) 0/265 (0%)
Bronchitis0/268 (0%) 1/265 (0.4%)
Candida pneumonia1/268 (0.4%) 0/265 (0%)
Cholecystitis infective1/268 (0.4%) 0/265 (0%)
Fournier's gangrene0/268 (0%) 1/265 (0.4%)
Hepatitis E1/268 (0.4%) 0/265 (0%)
Infected dermal cyst0/268 (0%) 1/265 (0.4%)
Infective pericardial effusion1/268 (0.4%) 0/265 (0%)
Liver abscess0/268 (0%) 1/265 (0.4%)
Lower respiratory tract infection1/268 (0.4%) 0/265 (0%)
Meningococcal sepsis0/268 (0%) 1/265 (0.4%)
Neutropenic infection0/268 (0%) 1/265 (0.4%)
Orchitis0/268 (0%) 1/265 (0.4%)
Oropharyngitis fungal1/268 (0.4%) 0/265 (0%)
Pelvic abscess1/268 (0.4%) 0/265 (0%)
Periorbital cellulitis1/268 (0.4%) 0/265 (0%)
Pyelonephritis1/268 (0.4%) 0/265 (0%)
Respiratory tract infection viral0/268 (0%) 1/265 (0.4%)
Splenic infection0/268 (0%) 1/265 (0.4%)
Upper respiratory tract infection1/268 (0.4%) 0/265 (0%)
Injury, poisoning and procedural complications
Fall1/268 (0.4%) 1/265 (0.4%)
Femoral neck fracture2/268 (0.7%) 0/265 (0%)
Hip fracture0/268 (0%) 1/265 (0.4%)
Patella fracture0/268 (0%) 1/265 (0.4%)
Post procedural haemorrhage1/268 (0.4%) 0/265 (0%)
Road traffic accident1/268 (0.4%) 0/265 (0%)
Subdural haematoma1/268 (0.4%) 0/265 (0%)
Tendon rupture1/268 (0.4%) 0/265 (0%)
Investigations
Alanine aminotransferase increased6/268 (2.2%) 0/265 (0%)
Aspartate aminotransferase increased2/268 (0.7%) 0/265 (0%)
Blood creatine phosphokinase increased0/268 (0%) 1/265 (0.4%)
Blood sodium decreased0/268 (0%) 1/265 (0.4%)
Lipase increased1/268 (0.4%) 0/265 (0%)
Transaminases increased1/268 (0.4%) 0/265 (0%)
Metabolism and nutrition disorders
Decreased appetite1/268 (0.4%) 0/265 (0%)
Hypomagnesaemia1/268 (0.4%) 0/265 (0%)
Tumour lysis syndrome1/268 (0.4%) 0/265 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis1/268 (0.4%) 2/265 (0.8%)
Musculoskeletal chest pain2/268 (0.7%) 0/265 (0%)
Osteochondrosis1/268 (0.4%) 1/265 (0.4%)
Arthralgia1/268 (0.4%) 0/265 (0%)
Back pain0/268 (0%) 1/265 (0.4%)
Intervertebral disc protrusion1/268 (0.4%) 0/265 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer2/268 (0.7%) 0/265 (0%)
Chronic myeloid leukaemia0/268 (0%) 1/265 (0.4%)
Bladder papilloma0/268 (0%) 1/265 (0.4%)
Carcinoid tumour of the caecum1/268 (0.4%) 0/265 (0%)
Colon cancer1/268 (0.4%) 0/265 (0%)
Colon cancer metastatic1/268 (0.4%) 0/265 (0%)
Endometrial cancer metastatic1/268 (0.4%) 0/265 (0%)
Fallopian tube cancer stage III1/268 (0.4%) 0/265 (0%)
Fibromatosis0/268 (0%) 1/265 (0.4%)
Hepatocellular carcinoma0/268 (0%) 1/265 (0.4%)
Invasive ductal breast carcinoma1/268 (0.4%) 0/265 (0%)
Lung neoplasm malignant1/268 (0.4%) 0/265 (0%)
Myelodysplastic syndrome1/268 (0.4%) 0/265 (0%)
Prostate cancer0/268 (0%) 1/265 (0.4%)
Prostatic adenoma0/268 (0%) 1/265 (0.4%)
Squamous cell carcinoma0/268 (0%) 1/265 (0.4%)
Transitional cell carcinoma1/268 (0.4%) 0/265 (0%)
Nervous system disorders
Haemorrhagic stroke1/268 (0.4%) 1/265 (0.4%)
Cerebral haemorrhage1/268 (0.4%) 0/265 (0%)
Cerebrovascular accident0/268 (0%) 1/265 (0.4%)
Headache1/268 (0.4%) 0/265 (0%)
Syncope0/268 (0%) 1/265 (0.4%)
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy2/268 (0.7%) 0/265 (0%)
Renal and urinary disorders
Acute kidney injury4/268 (1.5%) 0/265 (0%)
Chronic kidney disease2/268 (0.7%) 0/265 (0%)
Haematuria2/268 (0.7%) 0/265 (0%)
Renal failure1/268 (0.4%) 0/265 (0%)
Calculus bladder0/268 (0%) 1/265 (0.4%)
Nephrotic syndrome0/268 (0%) 1/265 (0.4%)
Ureterolithiasis0/268 (0%) 1/265 (0.4%)
Urinary incontinence0/268 (0%) 1/265 (0.4%)
Urinary retention0/268 (0%) 1/265 (0.4%)
Reproductive system and breast disorders
Ovarian cyst0/268 (0%) 1/265 (0.4%)
Prostatic dysplasia0/268 (0%) 1/265 (0.4%)
Uterine haemorrhage1/268 (0.4%) 0/265 (0%)
Vaginal haemorrhage1/268 (0.4%) 0/265 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion4/268 (1.5%) 1/265 (0.4%)
Dyspnoea2/268 (0.7%) 2/265 (0.8%)
Chronic obstructive pulmonary disease1/268 (0.4%) 1/265 (0.4%)
Respiratory failure2/268 (0.7%) 0/265 (0%)
Pneumothorax1/268 (0.4%) 0/265 (0%)
Acute respiratory failure0/268 (0%) 1/265 (0.4%)
Pulmonary hypertension1/268 (0.4%) 0/265 (0%)
Pulmonary oedema1/268 (0.4%) 0/265 (0%)
Pulmonary toxicity0/268 (0%) 1/265 (0.4%)
Respiratory disorder1/268 (0.4%) 0/265 (0%)
Skin and subcutaneous tissue disorders
Angioedema0/268 (0%) 2/265 (0.8%)
Dermatitis allergic1/268 (0.4%) 0/265 (0%)
Lichen planus0/268 (0%) 1/265 (0.4%)
Rash1/268 (0.4%) 0/265 (0%)
Rash maculo-papular1/268 (0.4%) 0/265 (0%)
Social circumstances
Pregnancy of partner2/268 (0.7%) 1/265 (0.4%)
Vascular disorders
Embolism1/268 (0.4%) 1/265 (0.4%)
Hypertensive crisis2/268 (0.7%) 0/265 (0%)
Deep vein thrombosis1/268 (0.4%) 0/265 (0%)
Haematoma1/268 (0.4%) 0/265 (0%)
Hypotension0/268 (0%) 1/265 (0.4%)
Hypovolaemic shock1/268 (0.4%) 0/265 (0%)
Other (Not Including Serious) Adverse Events
BosutinibImatinib
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total264/268 (98.5%) 260/265 (98.1%)
Blood and lymphatic system disorders
Thrombocytopenia96/268 (35.8%) 53/265 (20%)
Anaemia59/268 (22%) 59/265 (22.3%)
Neutropenia33/268 (12.3%) 61/265 (23%)
Leukopenia18/268 (6.7%) 34/265 (12.8%)
Lymphopenia15/268 (5.6%) 8/265 (3%)
Eye disorders
Periorbital oedema4/268 (1.5%) 44/265 (16.6%)
Eyelid oedema3/268 (1.1%) 24/265 (9.1%)
Conjunctival haemorrhage2/268 (0.7%) 18/265 (6.8%)
Dry eye4/268 (1.5%) 16/265 (6%)
Lacrimation increased1/268 (0.4%) 18/265 (6.8%)
Vision blurred5/268 (1.9%) 14/265 (5.3%)
Gastrointestinal disorders
Diarrhoea201/268 (75%) 106/265 (40%)
Nausea100/268 (37.3%) 112/265 (42.3%)
Vomiting55/268 (20.5%) 54/265 (20.4%)
Abdominal pain61/268 (22.8%) 25/265 (9.4%)
Abdominal pain upper28/268 (10.4%) 26/265 (9.8%)
Constipation36/268 (13.4%) 17/265 (6.4%)
Dyspepsia26/268 (9.7%) 24/265 (9.1%)
Abdominal distension14/268 (5.2%) 8/265 (3%)
Gastrooesophageal reflux disease8/268 (3%) 14/265 (5.3%)
Toothache14/268 (5.2%) 7/265 (2.6%)
General disorders
Fatigue57/268 (21.3%) 54/265 (20.4%)
Pyrexia44/268 (16.4%) 29/265 (10.9%)
Oedema peripheral20/268 (7.5%) 43/265 (16.2%)
Asthenia34/268 (12.7%) 24/265 (9.1%)
Face oedema7/268 (2.6%) 17/265 (6.4%)
Influenza like illness16/268 (6%) 6/265 (2.3%)
Infections and infestations
Upper respiratory tract infection36/268 (13.4%) 33/265 (12.5%)
Nasopharyngitis36/268 (13.4%) 30/265 (11.3%)
Urinary tract infection26/268 (9.7%) 18/265 (6.8%)
Influenza24/268 (9%) 14/265 (5.3%)
Gastroenteritis12/268 (4.5%) 17/265 (6.4%)
Bronchitis19/268 (7.1%) 6/265 (2.3%)
Sinusitis15/268 (5.6%) 8/265 (3%)
Investigations
Alanine aminotransferase increased90/268 (33.6%) 16/265 (6%)
Aspartate aminotransferase increased69/268 (25.7%) 18/265 (6.8%)
Lipase increased56/268 (20.9%) 30/265 (11.3%)
Blood creatine phosphokinase increased14/268 (5.2%) 33/265 (12.5%)
Blood creatinine increased18/268 (6.7%) 22/265 (8.3%)
Amylase increased25/268 (9.3%) 10/265 (3.8%)
Weight increased8/268 (3%) 20/265 (7.5%)
Blood alkaline phosphatase increased17/268 (6.3%) 7/265 (2.6%)
Blood bilirubin increased17/268 (6.3%) 7/265 (2.6%)
Metabolism and nutrition disorders
Decreased appetite29/268 (10.8%) 17/265 (6.4%)
Hypokalaemia6/268 (2.2%) 23/265 (8.7%)
Hypophosphataemia7/268 (2.6%) 19/265 (7.2%)
Musculoskeletal and connective tissue disorders
Arthralgia48/268 (17.9%) 49/265 (18.5%)
Muscle spasms10/268 (3.7%) 81/265 (30.6%)
Pain in extremity26/268 (9.7%) 39/265 (14.7%)
Myalgia13/268 (4.9%) 48/265 (18.1%)
Back pain32/268 (11.9%) 25/265 (9.4%)
Bone pain8/268 (3%) 19/265 (7.2%)
Nervous system disorders
Headache58/268 (21.6%) 41/265 (15.5%)
Dizziness25/268 (9.3%) 23/265 (8.7%)
Psychiatric disorders
Insomnia18/268 (6.7%) 19/265 (7.2%)
Anxiety15/268 (5.6%) 15/265 (5.7%)
Depression9/268 (3.4%) 14/265 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough30/268 (11.2%) 26/265 (9.8%)
Dyspnoea29/268 (10.8%) 14/265 (5.3%)
Oropharyngeal pain17/268 (6.3%) 10/265 (3.8%)
Skin and subcutaneous tissue disorders
Rash61/268 (22.8%) 39/265 (14.7%)
Pruritus30/268 (11.2%) 10/265 (3.8%)
Dry skin20/268 (7.5%) 14/265 (5.3%)
Alopecia15/268 (5.6%) 14/265 (5.3%)
Rash maculo-papular13/268 (4.9%) 16/265 (6%)
Night sweats5/268 (1.9%) 14/265 (5.3%)
Vascular disorders
Hypertension26/268 (9.7%) 29/265 (10.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Name/TitlePfizer ClinicalTrials.gov Call Center
OrganizationPfizer Inc.
Phone1-800-718-1021
EmailClinicalTrials.gov_Inquiries@pfizer.com
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02130557
Other Study ID Numbers:
  • AV001
  • 2013-005101-31
  • B1871053
First Posted:
May 5, 2014
Last Update Posted:
May 18, 2021
Last Verified:
Apr 1, 2021