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

Arms

69.1

Actual Duration (Months)

2.8

Patients Per Site

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myelogenous, Chronic, Breakpoint Cluster Region-Abelson Proto-oncogene (BCR-ABL) Positive	Drug: Bosutinib Drug: Imatinib	Phase 3

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

Arm	Intervention/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.

Arm

Intervention/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

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

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.
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.
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.
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.
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.
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

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.
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.
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.
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.
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.
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.
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.
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.
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:

Inclusion Criteria:

Molecular diagnosis of CP CML of ≤ 6 months (from initial diagnosis).
Adequate hepatic, renal and pancreatic function.
Age ≥ 18 years.

Exclusion Criteria:

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.
Any past or current Central Nervous System (CNS) involvement, including leptomeningeal leukemia.
Extramedullary disease only.
Major surgery or radiotherapy within 14 days of randomization.
History of clinically significant or uncontrolled cardiac disease.
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.
Recent or ongoing clinically significant GI disorder, e.g. Crohn's Disease, Ulcerative Colitis, or prior total or partial gastrectomy.
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.
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

	Site	City	State	Country	Postal Code
1	Pacific Cancer Medical Center, Inc.	Anaheim	California	United States	92801
2	Emory University Hospital	Atlanta	Georgia	United States	30322
3	The Emory Clinic	Atlanta	Georgia	United States	30322
4	Winship Cancer Institute, Emory University	Atlanta	Georgia	United States	30322
5	Kaiser Permanente Hawaii	Honolulu	Hawaii	United States	96819
6	Saint Alphonsus Regional Medical Center, Cancer Care Center	Boise	Idaho	United States	83706
7	Saint Alphonsus Regional Medical Center	Boise	Idaho	United States	83706
8	Saint Alphonsus Caldwell Cancer Care Center	Caldwell	Idaho	United States	83605
9	Saint Alphonsus Medical Center Nampa	Nampa	Idaho	United States	83686
10	University of Illinois Cancer Center	Chicago	Illinois	United States	60612
11	John H. Stroger, Jr. Hospital of Cook County	Chicago	Illinois	United States	60621
12	Indiana Blood and Marrow Transplantation	Indianapolis	Indiana	United States	46237
13	PHARMACY Department Franciscan St. Francis Health ATTN:Jill Leslie, Pharm D	Indianapolis	Indiana	United States	46237
14	Cancer Center of Acadiana at Lafayette General Medical Center	Lafayette	Louisiana	United States	70503
15	Lafayette General Medical Center	Lafayette	Louisiana	United States	70503
16	LSU Health Sciences Center-Shreveport	Shreveport	Louisiana	United States	71103
17	University Health Shreveport	Shreveport	Louisiana	United States	71103
18	Rcca Md Llc	Bethesda	Maryland	United States	20817
19	University of Massachusetts Memorial Medical Center, ONC/Research Pharmacy	Worcester	Massachusetts	United States	01655
20	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01655
21	St. Joseph Mercy Hospital - Inpatient Pharmacy	Ann Arbor	Michigan	United States	48106
22	St. Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
23	St. Joseph Mercy-Brighton	Brighton	Michigan	United States	48114
24	St. Joseph Mercy-Canton	Canton	Michigan	United States	48188
25	Chelsea Community Hospital	Chelsea	Michigan	United States	48118-1370
26	St. John Hospital&Medical Center	Detroit	Michigan	United States	48236
27	St. John Hospital&Medical Center-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan	United States	48236
28	Van Elslander Cancer Center, Pharmacy	Grosse Pointe Woods	Michigan	United States	48236
29	Minnesota Oncology Hematology, PA	Edina	Minnesota	United States	55435
30	Park Nicollet Frauenshuh Cancer center	Saint Louis Park	Minnesota	United States	55426
31	Lakeview Hospital	Stillwater	Minnesota	United States	55082
32	North Mississippi Medical Center Hematology and Oncology Clinic	Tupelo	Mississippi	United States	38801
33	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
34	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
35	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
36	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
37	NYU Winthrop Hospital - Oncology / Hematology department	Mineola	New York	United States	11501
38	NYU Winthrop Hospital - Pharmacy Department	Mineola	New York	United States	11501
39	Beth Israel Medical Center	New York	New York	United States	10003
40	University of Rochester Investigational Drug Pharmacy	Rochester	New York	United States	14642
41	University of Rochester	Rochester	New York	United States	14642
42	FirstHealth Moore Regional Hospital	Pinehurst	North Carolina	United States	28374
43	FirstHealth Outpatient Cancer Center	Pinehurst	North Carolina	United States	28374
44	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
45	UC Health Physicians Office South,	West Chester	Ohio	United States	45069
46	MUSC University Hospital	Charleston	South Carolina	United States	29425
47	MUSC University of South Carolina, Investigational Drug Services	Charleston	South Carolina	United States	29425
48	MUSC-Hollings Cancer Center	Charleston	South Carolina	United States	29425
49	GHS Cancer Institute	Easley	South Carolina	United States	29640
50	GHS Cancer Institute	Greenville	South Carolina	United States	29605
51	GHS Cancer Institute	Greenville	South Carolina	United States	29615
52	GHS Cancer Institute	Greer	South Carolina	United States	29650
53	GHS Cancer Institute	Seneca	South Carolina	United States	29672
54	GHS Cancer Institute	Spartanburg	South Carolina	United States	29307
55	The University of Texas, MD Anderson Cancer Center	Houston	Texas	United States	77030
56	Utah Cancer Specialists	Murray	Utah	United States	84157
57	Utah Cancer Specialists	Salt Lake City	Utah	United States	84106
58	Huntsman Cancer Hospital	Salt Lake City	Utah	United States	84112
59	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
60	Virginia Mason Medical Center	Seattle	Washington	United States	98101
61	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
62	HSHS St. Vincent Hospital Regional Cancer Center at HSHS St. Vincent Hospital	Green Bay	Wisconsin	United States	54301
63	HSHS St. Vincent Hospital	Green Bay	Wisconsin	United States	54301
64	HSHS St. Vincent Hospital Regional Cancer Center at HSHS St. Mary's Hospital Medical Center	Green Bay	Wisconsin	United States	54303
65	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
66	St George Hospital - Hematology Department	Kogarah	New South Wales	Australia	2217
67	Eastern Clinical Research Unit, Level 2	Box Hill	Victoria	Australia	3128
68	UZ Ghent (University Hospital Ghent)	Ghent		Belgium	9000
69	Department of Haematology at UZ Leuven (7 th Floor)	Leuven		Belgium	3000
70	Hematology Department of CHU de Liège	Liège		Belgium	4000
71	Hematology Department CHR Verviers	Verviers		Belgium	4800
72	Horizon Health Network - The Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
73	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
74	Lakeridge Health	Oshawa	Ontario	Canada	L1G 2B9
75	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
76	Hopital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T 2M4
77	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
78	CHU de Québec - Université Laval	Quebec		Canada	G1J 1Z4
79	Fakultní Nemocnice Brno	Brno		Czechia	625 00
80	Fakultní Nemocnice Hradec Králové	Hradec Králové		Czechia	500 05
81	Fakultní nemocnice Olomouc	Olomouc		Czechia	775 20
82	Všeobecná fakultní Nemocnice v Praze	Prague		Czechia	128 08
83	Aalborg University Hospital	Aalborg		Denmark	9000
84	Aarhus University Hospital	Aarhus		Denmark	8000
85	Roskilde Hospital	Roskilde		Denmark	4000
86	Helsinki University Central Hospital	Helsinki		Finland	00029 HUS
87	Oncologie Centre de Radiotherapie	Strasbourg	NC	France	67000
88	Institut Bergonié	Bordeaux		France	33076
89	private Practice of Pr Philippe Rousselot	Le Chesnay		France	78157
90	private Practice of Dr. Viviane Dubruille	Nantes cedex 1		France	44093
91	Hôpital L'Archet 1-CHU Nice	Nice		France	06202
92	Institut de Cancérologie du Gard - Hématologie Clinique	Nimes		France	30029
93	Pr Mauricette Michallet Centre Hospitalier Lyon Sud	Pierre Bénite		France	69495
94	INSERM CIC 1402 - CHU Poitiers	Poitiers		France	86021
95	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse cedex 9		France	31059
96	Universitätsklinikum Bonn	Bonn	RP	Germany	53105
97	Uniklinikum Aachen	Aachen		Germany	52074
98	Charité, CVK, Med. Klinik m.S Hämatologie und Onkologie	Berlin		Germany	13353
99	Universitätsklinikum Freiburg, Klinik für Innere Medizin I	Freiburg		Germany	79106
100	Universitätsklinikum Hamburg-Eppendorf, Onkologisches Zentrum	Hamburg		Germany	20251
101	Universitätsklinikum Jena, Klinik für Innere Medizin II	Jena Lobeda-Ost		Germany	07747
102	Schwerpunktpraxis für Hämatologie und Onkologie	Magdeburg		Germany	39104
103	Semmelweis Egyetem I. Belgyógyászat	Budapest		Hungary	1083
104	Debreceni Egyetem Klinikai Központ, Belgyógyászati Inézet Hematológiai Tanszék	Debrecen		Hungary	4032
105	Petz Aladár Megyei OktatóKórház, II. Belgyógyászati Osztály és Haematológiai Részleg	Györ		Hungary	9023
106	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvár		Hungary	7400
107	Szegedi Tudományegyetem, AOK, Szent-Györgyi Albert Klinikai Központ, II. sz.	Szeged		Hungary	6725
108	Jász-Nagykun-Szolnok Megyei Hetényi, Géza Kórház-Rendelőintézet	Szolnok		Hungary	5000
109	Hematology Department, Rambam Medical Centre	Haifa		Israel	31096
110	Hematology Div. Davidoff Cancer Center, Rabin Medical Center	Petah-Tikva		Israel	49100
111	Azienda Ospedaliero-Universitaria "Policlinico - Vittorio Emanuele" - P.O. G. Rodolico	Catania	CT	Italy	95123
112	USC Ematologia, A. O. Papa Giovanni XXIII	Bergamo		Italy	24127
113	Policlinico S. Orsola - Malpighi,	Bologna		Italy	40138
114	A.O. Brozu - P.O. Armando Businco	Cagliari		Italy	09121
115	Azienda Ospedaliero Universitaria Careggi	Firenze		Italy	50134
116	IRCCS - AOU San Martino_IST, Ematologia 1	Genova		Italy	16132
117	Istituto Scientifico San Raffaele	Milano		Italy	20132
118	Unità di Ricerca Clinica, U.O. Ematologia Adulti	Monza		Italy	20900
119	A.O.U. Policlinico Università degli Studi di Napoli "Federico II"	Napoli		Italy	80131
120	Dipartimento di ematologia	Reggio Calabria		Italy	89124
121	ASL Roma 2 - Ospedale Sant'Eugenio	Roma		Italy	00144
122	Hallym University Sacred Heart Hospital	Anyang-si		Korea, Republic of	14068
123	Dong A University Hospital	Busan		Korea, Republic of	49201
124	Keimyung University Dongsan Hospital	Daegu		Korea, Republic of	41931
125	Chonbuk National University Hospital	Jeonju		Korea, Republic of	54907
126	Kangbuk Samsung Hospital	Seoul		Korea, Republic of	03181
127	Seoul St. Mary's Hospital of the Catholic University of Korea	Seoul		Korea, Republic of	06591
128	Hospital Angeles del Pedregal (S.A. de C.V.)	Mexico City	DF	Mexico	10700
129	Monterrey International Research Center	Monterrey	Nuevo LEON	Mexico	64000
130	VU University Medical Center	Amsterdam	Noord Holland	Netherlands	1081 HV
131	Klinische Farrnacologie en Apotheek	Amsterdam	Noord-holland	Netherlands	1081 BT
132	Haukeland University Hospital Department of Hematology	Bergen		Norway	5021
133	St. Olavs Hospital	Trondheim		Norway	7006
134	Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne	Gdansk	Pomorskie	Poland	80-214
135	SPZOZ ZSM w Chorzowie Oddzial Hematologiczny	Chorzow		Poland	41-500
136	Samodzielny Publiczny Szpital Kliniczny im. A Mielęckiego, ŚUM w Katowicach	Katowice		Poland	40032
137	Szpital Uniwersytecki w Krakowie, Oddział Kliniczny Hematologii	Kraków		Poland	31501
138	SPSK, Klinika Hematoonkologii i Transplantacji Szpiku w Lublinie	Lublin		Poland	20081
139	Universytet Medyczny im. Piastów Śląskich we Wrocławiu Katedra i	Wrocław		Poland	50-367
140	Wojewódzki Szpital Specjalistyczny im M. Kopernika, Klinika Hematologii Uniwersytetu Medycznego	Łódź		Poland	93510
141	National University Hospital, Main Building	Singapore		Singapore	119228
142	Singapore General Hospital	Singapore		Singapore	169608
143	Tan Tock Seng Hospital	Singapore		Singapore	308433
144	Univerzitná Nemocnica Bratislava-Nemocnica sv. Cyrila a Metoda	Bratislava		Slovakia	851 07
145	The Medical Oncology Centre of Rosebank	Johannesburg	Gauteng	South Africa	2196
146	Department of Medical Oncology, University of Pretoria and Steve Biko	Pretoria	Gauteng	South Africa	0002
147	Groenkloof Life hospital.	Pretoria	Gauteng	South Africa	0181
148	Department of Haematology	Cape Town	Western CAPE	South Africa	7935
149	Hospital (Universitari(o)) Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
150	Hospital Universitario La Princesa	Madrid	Málaga	Spain	28006
151	Hospital Vall d'Hebron	Barcelona		Spain	08035
152	Hospital Clínic	Barcelona		Spain	08036
153	Hospital Universitario Gregorio Marañón	Madrid		Spain	28007
154	Hospital Ramón y Cajal	Madrid		Spain	28034
155	Hospital Clinico San Carlos	Madrid		Spain	28040
156	Hospital Universitario de Salamanca	Salamanca		Spain	37007
157	Hospital Virgen de la Salud	Toledo		Spain	45004
158	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
159	Linköping University Hospital	Linköping		Sweden	SE-581 85
160	Skåne University Hospital	Lund		Sweden	SE-221 85
161	Karolinska University Hospital Solna	Stockholm		Sweden	SE-171 76
162	Norrlands University Hospital	Umeå		Sweden	SE-901 85
163	Akademiska Hospital	Uppsala		Sweden	SE-751 85
164	China Medical University Hospital	Taichung city	R.o.c.	Taiwan	40447
165	Chi-Mei Medical Center	Tainan City	R.o.c.	Taiwan	710
166	Mackay Memorial Hospital	Taipei City	R.o.c.	Taiwan	10449
167	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung City		Taiwan	807
168	Division of Hematology, Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital	Muang	Chiang MAI	Thailand	50200
169	King Chulalongkorn Memorial Hospital	Bangkok		Thailand	10330
170	Phramongkutklao Hospital	Bangkok		Thailand	10400
171	Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital	Bangkok		Thailand	10700
172	MI "Cherkasy Regional Oncological Dispensary " of Cherkasy Regional Council	Cherkasy		Ukraine	18009
173	Regional Clinical Hospital in Ivano-Frankivsk, Hematology Department	Ivano-Frankivsk		Ukraine	76008
174	Khmelnytskyi Regional Hospital, Hematology Department	Khmelnytskyi		Ukraine	29000
175	State Institution "National research center for radiation medicine of NAMS of Ukraine",	Kyiv		Ukraine	03115
176	State Institution "National research center for radiation medicine of NAMS of Ukraine"	Kyiv		Ukraine	03115
177	transplantation department of hemotology and transplantology division within Clinical Radiology	Kyiv		Ukraine	03115
178	Chair of internal medicine #2.	Kyiv		Ukraine	04112
179	Kyiv City Clinical Hospital #9, Hematology department #1,	Kyiv		Ukraine	04112
180	State Institution "Institute of Blood Pathology and Transfusion Medicine NAMS of Ukraine"	Lviv		Ukraine	79044
181	Catherine Lewis Centre, Hammersmith Hospital	London	Greater London	United Kingdom	W12 0HS
182	Linda McCartney Centre	Liverpool	Merseyside	United Kingdom	L7 8XP
183	Department of Clinical Haematology	Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
184	Cancer & Haematology Centre, Churchill Hospital	Oxford	Oxfordshire	United Kingdom	OX3 7LE
185	Department of Haematology The Royal Hallamshire Hospital	Sheffield	South Yorkshire	United Kingdom	S10 2JF
186	Heartlands Hospital	Birmingham	WEST Midlands	United Kingdom	B9 5SS
187	St James's Institute of Oncology	Leeds	WEST Yorkshire	United Kingdom	LS9 7TF
188	Department of Haematology	Cardiff		United Kingdom	CF14 4XW
189	The Hope Clinical Trials Facility	Leicester		United Kingdom	LE1 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

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Pfizer

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Neoplasms by Histologic Type

Bone Marrow Diseases

Hematologic Diseases

Translocation, Genetic

Pathologic Processes

Imatinib

Therapeutic Uses

Pharmacologic Actions

Molecular Mechanisms of Pharmacological Action

Additional relevant MeSH terms:

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Leukemia, Myeloid, Chronic-Phase

Imatinib Mesylate

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail

Arm/Group Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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
STARTED	268	268
Treated	268	265
mITT Population	246	241
COMPLETED	232	231
NOT COMPLETED	36	37

Baseline Characteristics

Arm/Group Title	Bosutinib	Imatinib	Total
Arm/Group Description	Participants 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 Participants	268	268	536
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

Title	Percentage of Participants With Major Molecular Response (MMR) at Month 12
Description	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.
Time Frame	Month 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	246	241
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 Hypothesis	p-Value	0.0100
	Comments	1-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.
	Method	Cochran-Mantel-Haenszel
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.547
	Confidence Interval	(2-Sided) 95% 1.072 to 2.233
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% Confidence Interval (CI) for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.

2. Secondary Outcome

Title	Percentage of Participants With Major Molecular Response (MMR) Up to Month 18
Description	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.
Time Frame	Up 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	246	241
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 Hypothesis	p-Value	0.0303
	Comments	1-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.
	Method	Cochran-Mantel-Haenszel
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.418
	Confidence Interval	(2-Sided) 95% 0.986 to 2.037
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.

3. Secondary Outcome

Title	Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48
Description	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.
Time Frame	Month 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	182	158
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 Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95% 0.49 to 2.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

4. Secondary Outcome

Title	Percentage of Participants With Complete Cytogenetic Response (CCyR) Up to Month 12
Description	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.
Time Frame	Up 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	246	241
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 Hypothesis	p-Value	0.0037
	Comments	1-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.
	Method	Cochran-Mantel-Haenszel
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.740
	Confidence Interval	(2-Sided) 95% 1.160 to 2.610
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for the odds ratio adjusted for sokal risk group and region are based on Mantel-Haenszel confidence limits.

5. Secondary Outcome

Title	Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48
Description	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.
Time Frame	Month 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	205	185
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 Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95% 0.14 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

6. Secondary Outcome

Title	Cumulative Incidence of Event Free Survival (EFS) Events
Description	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 >20.010^9/L, platelet count rises to >=60010^9/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 Frame	Up 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	246	241
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 Hypothesis	p-Value	0.0749
	Comments	1-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.
	Method	Gray's test
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95% 0.35 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (95% CIs) are based on the proportional subdistribution hazards model stratified by Sokal risk group and region.

7. Secondary Outcome

Title	Overall Survival (OS) Rate
Description	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.
Time Frame	Up 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	246	241
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 Hypothesis	p-Value	0.2827
	Comments	1-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.
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95% 0.37 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 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

Title	Summary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) of Bosutinib
Description	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.
Time Frame	Pre-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.

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 Title	Bosutinib
Arm/Group Description	Participants 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 Participants	191
Day 28	71.282 (46.0545)
Day 56	73.069 (45.1349)
Day 84	83.973 (64.3206)

9. Other Pre-specified Outcome

Title	Summary of Trough Plasma Concentration by Major Molecular Response (MMR) of Bosutinib
Description	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.
Time Frame	Pre-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.

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 Title	Bosutinib
Arm/Group Description	Participants 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 Participants	141
Day 28	75.050 (51.9551)
Day 56	78.437 (43.6019)
Day 84	91.081 (72.1500)

10. Other Pre-specified Outcome

Title	Summary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) of Bosutinib
Description	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.
Time Frame	Pre-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.

Analysis Population Description

Arm/Group Title	Bosutinib
Arm/Group Description	Participants 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 Participants	177
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

Title	Summary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) of Bosutinib
Description	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.
Time Frame	Pre-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.

Analysis Population Description

Arm/Group Title	Bosutinib
Arm/Group Description	Participants 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 Participants	24
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

Title	Number of Participants With Vital Signs Abnormalities
Description	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.
Time Frame	Baseline 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	262	263
Count of Participants [Participants]	107 39.9%	109 40.7%

13. Other Pre-specified Outcome

Title	Number of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 4.03
Description	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.
Time Frame	Baseline 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	268	265
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

Title	Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
Description	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.
Time Frame	Baseline 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	266	262
Count of Participants [Participants]	16 6%	13 4.9%

15. Other Pre-specified Outcome

Title	Number of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time Frame	Baseline 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	268	265
Count of Participants [Participants]	68 25.4%	38 14.2%

16. Other Pre-specified Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events by National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.0)
Description	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.
Time Frame	Baseline 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 Title	Bosutinib	Imatinib
Arm/Group Description	Participants 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 Participants	268	265
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

	Bosutinib		Imatinib
Time Frame	From 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 Title	Bosutinib		Imatinib
Arm/Group Description	Participants 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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/268 (5.2%)		14/268 (5.2%)
Serious Adverse Events
	Bosutinib		Imatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	98/268 (36.6%)		68/265 (25.7%)
Blood and lymphatic system disorders
Anaemia	1/268 (0.4%)		3/265 (1.1%)
Thrombocytopenia	2/268 (0.7%)		1/265 (0.4%)
Febrile neutropenia	0/268 (0%)		2/265 (0.8%)
Agranulocytosis	1/268 (0.4%)		0/265 (0%)
Haemolysis	0/268 (0%)		1/265 (0.4%)
Haemolytic anaemia	0/268 (0%)		1/265 (0.4%)
Cardiac disorders
Myocardial ischaemia	4/268 (1.5%)		0/265 (0%)
Atrial fibrillation	2/268 (0.7%)		1/265 (0.4%)
Cardiac failure acute	2/268 (0.7%)		0/265 (0%)
Coronary artery disease	2/268 (0.7%)		0/265 (0%)
Pericarditis	2/268 (0.7%)		0/265 (0%)
Angina pectoris	1/268 (0.4%)		0/265 (0%)
Pericardial effusion	1/268 (0.4%)		0/265 (0%)
Acute coronary syndrome	1/268 (0.4%)		0/265 (0%)
Acute myocardial infarction	1/268 (0.4%)		0/265 (0%)
Atrial thrombosis	1/268 (0.4%)		0/265 (0%)
Cardiac failure	1/268 (0.4%)		0/265 (0%)
Cardiac failure congestive	1/268 (0.4%)		0/265 (0%)
Cardio-respiratory arrest	1/268 (0.4%)		0/265 (0%)
Coronary artery occlusion	1/268 (0.4%)		0/265 (0%)
Pleuropericarditis	1/268 (0.4%)		0/265 (0%)
Sinus node dysfunction	1/268 (0.4%)		0/265 (0%)
Supraventricular tachycardia	1/268 (0.4%)		0/265 (0%)
Congenital, familial and genetic disorders
Hydrocele	1/268 (0.4%)		0/265 (0%)
Ear and labyrinth disorders
Vertigo positional	1/268 (0.4%)		0/265 (0%)
Endocrine disorders
Thyroid disorder	0/268 (0%)		1/265 (0.4%)
Eye disorders
Eye haemorrhage	1/268 (0.4%)		0/265 (0%)
Ocular hypertension	1/268 (0.4%)		0/265 (0%)
Retinal vein occlusion	1/268 (0.4%)		0/265 (0%)
Retinopathy	1/268 (0.4%)		0/265 (0%)
Gastrointestinal disorders
Diarrhoea	5/268 (1.9%)		1/265 (0.4%)
Gastritis	1/268 (0.4%)		1/265 (0.4%)
Pancreatitis acute	1/268 (0.4%)		1/265 (0.4%)
Necrotising oesophagitis	1/268 (0.4%)		0/265 (0%)
Abdominal pain	1/268 (0.4%)		0/265 (0%)
Abdominal pain upper	0/268 (0%)		1/265 (0.4%)
Abdominal wall haematoma	1/268 (0.4%)		0/265 (0%)
Anal fissure	1/268 (0.4%)		0/265 (0%)
Colitis	0/268 (0%)		1/265 (0.4%)
Diverticulum intestinal	1/268 (0.4%)		0/265 (0%)
Duodenal ulcer	1/268 (0.4%)		0/265 (0%)
Food poisoning	1/268 (0.4%)		0/265 (0%)
Gastric ulcer	0/268 (0%)		1/265 (0.4%)
Gastrointestinal haemorrhage	0/268 (0%)		1/265 (0.4%)
Haemorrhoids	1/268 (0.4%)		0/265 (0%)
Hypoaesthesia oral	0/268 (0%)		1/265 (0.4%)
Inguinal hernia	1/268 (0.4%)		0/265 (0%)
Intra-abdominal haematoma	0/268 (0%)		1/265 (0.4%)
Large intestine polyp	0/268 (0%)		1/265 (0.4%)
Oedematous pancreatitis	1/268 (0.4%)		0/265 (0%)
Pancreatitis	1/268 (0.4%)		0/265 (0%)
Rectal haemorrhage	1/268 (0.4%)		0/265 (0%)
Small intestinal obstruction	1/268 (0.4%)		0/265 (0%)
General disorders
Pyrexia	5/268 (1.9%)		1/265 (0.4%)
General physical health deterioration	0/268 (0%)		1/265 (0.4%)
Hyperthermia	0/268 (0%)		1/265 (0.4%)
Implant site haematoma	1/268 (0.4%)		0/265 (0%)
Non-cardiac chest pain	1/268 (0.4%)		0/265 (0%)
Swelling face	0/268 (0%)		1/265 (0.4%)
Hepatobiliary disorders
Cholecystitis acute	2/268 (0.7%)		0/265 (0%)
Cholelithiasis	0/268 (0%)		2/265 (0.8%)
Hepatitis	2/268 (0.7%)		0/265 (0%)
Hepatotoxicity	2/268 (0.7%)		0/265 (0%)
Cholecystitis	1/268 (0.4%)		0/265 (0%)
Portal vein thrombosis	0/268 (0%)		1/265 (0.4%)
Immune system disorders
Drug hypersensitivity	1/268 (0.4%)		0/265 (0%)
Infections and infestations
Pneumonia	8/268 (3%)		5/265 (1.9%)
Gastroenteritis	6/268 (2.2%)		1/265 (0.4%)
Cellulitis	3/268 (1.1%)		2/265 (0.8%)
Influenza	1/268 (0.4%)		2/265 (0.8%)
Sepsis	0/268 (0%)		3/265 (1.1%)
Urinary tract infection	1/268 (0.4%)		2/265 (0.8%)
Abscess	1/268 (0.4%)		1/265 (0.4%)
Abscess limb	0/268 (0%)		2/265 (0.8%)
Appendicitis	0/268 (0%)		2/265 (0.8%)
Appendicitis perforated	0/268 (0%)		1/265 (0.4%)
Bacteraemia	1/268 (0.4%)		0/265 (0%)
Bronchitis	0/268 (0%)		1/265 (0.4%)
Candida pneumonia	1/268 (0.4%)		0/265 (0%)
Cholecystitis infective	1/268 (0.4%)		0/265 (0%)
Fournier's gangrene	0/268 (0%)		1/265 (0.4%)
Hepatitis E	1/268 (0.4%)		0/265 (0%)
Infected dermal cyst	0/268 (0%)		1/265 (0.4%)
Infective pericardial effusion	1/268 (0.4%)		0/265 (0%)
Liver abscess	0/268 (0%)		1/265 (0.4%)
Lower respiratory tract infection	1/268 (0.4%)		0/265 (0%)
Meningococcal sepsis	0/268 (0%)		1/265 (0.4%)
Neutropenic infection	0/268 (0%)		1/265 (0.4%)
Orchitis	0/268 (0%)		1/265 (0.4%)
Oropharyngitis fungal	1/268 (0.4%)		0/265 (0%)
Pelvic abscess	1/268 (0.4%)		0/265 (0%)
Periorbital cellulitis	1/268 (0.4%)		0/265 (0%)
Pyelonephritis	1/268 (0.4%)		0/265 (0%)
Respiratory tract infection viral	0/268 (0%)		1/265 (0.4%)
Splenic infection	0/268 (0%)		1/265 (0.4%)
Upper respiratory tract infection	1/268 (0.4%)		0/265 (0%)
Injury, poisoning and procedural complications
Fall	1/268 (0.4%)		1/265 (0.4%)
Femoral neck fracture	2/268 (0.7%)		0/265 (0%)
Hip fracture	0/268 (0%)		1/265 (0.4%)
Patella fracture	0/268 (0%)		1/265 (0.4%)
Post procedural haemorrhage	1/268 (0.4%)		0/265 (0%)
Road traffic accident	1/268 (0.4%)		0/265 (0%)
Subdural haematoma	1/268 (0.4%)		0/265 (0%)
Tendon rupture	1/268 (0.4%)		0/265 (0%)
Investigations
Alanine aminotransferase increased	6/268 (2.2%)		0/265 (0%)
Aspartate aminotransferase increased	2/268 (0.7%)		0/265 (0%)
Blood creatine phosphokinase increased	0/268 (0%)		1/265 (0.4%)
Blood sodium decreased	0/268 (0%)		1/265 (0.4%)
Lipase increased	1/268 (0.4%)		0/265 (0%)
Transaminases increased	1/268 (0.4%)		0/265 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/268 (0.4%)		0/265 (0%)
Hypomagnesaemia	1/268 (0.4%)		0/265 (0%)
Tumour lysis syndrome	1/268 (0.4%)		0/265 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/268 (0.4%)		2/265 (0.8%)
Musculoskeletal chest pain	2/268 (0.7%)		0/265 (0%)
Osteochondrosis	1/268 (0.4%)		1/265 (0.4%)
Arthralgia	1/268 (0.4%)		0/265 (0%)
Back pain	0/268 (0%)		1/265 (0.4%)
Intervertebral disc protrusion	1/268 (0.4%)		0/265 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer	2/268 (0.7%)		0/265 (0%)
Chronic myeloid leukaemia	0/268 (0%)		1/265 (0.4%)
Bladder papilloma	0/268 (0%)		1/265 (0.4%)
Carcinoid tumour of the caecum	1/268 (0.4%)		0/265 (0%)
Colon cancer	1/268 (0.4%)		0/265 (0%)
Colon cancer metastatic	1/268 (0.4%)		0/265 (0%)
Endometrial cancer metastatic	1/268 (0.4%)		0/265 (0%)
Fallopian tube cancer stage III	1/268 (0.4%)		0/265 (0%)
Fibromatosis	0/268 (0%)		1/265 (0.4%)
Hepatocellular carcinoma	0/268 (0%)		1/265 (0.4%)
Invasive ductal breast carcinoma	1/268 (0.4%)		0/265 (0%)
Lung neoplasm malignant	1/268 (0.4%)		0/265 (0%)
Myelodysplastic syndrome	1/268 (0.4%)		0/265 (0%)
Prostate cancer	0/268 (0%)		1/265 (0.4%)
Prostatic adenoma	0/268 (0%)		1/265 (0.4%)
Squamous cell carcinoma	0/268 (0%)		1/265 (0.4%)
Transitional cell carcinoma	1/268 (0.4%)		0/265 (0%)
Nervous system disorders
Haemorrhagic stroke	1/268 (0.4%)		1/265 (0.4%)
Cerebral haemorrhage	1/268 (0.4%)		0/265 (0%)
Cerebrovascular accident	0/268 (0%)		1/265 (0.4%)
Headache	1/268 (0.4%)		0/265 (0%)
Syncope	0/268 (0%)		1/265 (0.4%)
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy	2/268 (0.7%)		0/265 (0%)
Renal and urinary disorders
Acute kidney injury	4/268 (1.5%)		0/265 (0%)
Chronic kidney disease	2/268 (0.7%)		0/265 (0%)
Haematuria	2/268 (0.7%)		0/265 (0%)
Renal failure	1/268 (0.4%)		0/265 (0%)
Calculus bladder	0/268 (0%)		1/265 (0.4%)
Nephrotic syndrome	0/268 (0%)		1/265 (0.4%)
Ureterolithiasis	0/268 (0%)		1/265 (0.4%)
Urinary incontinence	0/268 (0%)		1/265 (0.4%)
Urinary retention	0/268 (0%)		1/265 (0.4%)
Reproductive system and breast disorders
Ovarian cyst	0/268 (0%)		1/265 (0.4%)
Prostatic dysplasia	0/268 (0%)		1/265 (0.4%)
Uterine haemorrhage	1/268 (0.4%)		0/265 (0%)
Vaginal haemorrhage	1/268 (0.4%)		0/265 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	4/268 (1.5%)		1/265 (0.4%)
Dyspnoea	2/268 (0.7%)		2/265 (0.8%)
Chronic obstructive pulmonary disease	1/268 (0.4%)		1/265 (0.4%)
Respiratory failure	2/268 (0.7%)		0/265 (0%)
Pneumothorax	1/268 (0.4%)		0/265 (0%)
Acute respiratory failure	0/268 (0%)		1/265 (0.4%)
Pulmonary hypertension	1/268 (0.4%)		0/265 (0%)
Pulmonary oedema	1/268 (0.4%)		0/265 (0%)
Pulmonary toxicity	0/268 (0%)		1/265 (0.4%)
Respiratory disorder	1/268 (0.4%)		0/265 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/268 (0%)		2/265 (0.8%)
Dermatitis allergic	1/268 (0.4%)		0/265 (0%)
Lichen planus	0/268 (0%)		1/265 (0.4%)
Rash	1/268 (0.4%)		0/265 (0%)
Rash maculo-papular	1/268 (0.4%)		0/265 (0%)
Social circumstances
Pregnancy of partner	2/268 (0.7%)		1/265 (0.4%)
Vascular disorders
Embolism	1/268 (0.4%)		1/265 (0.4%)
Hypertensive crisis	2/268 (0.7%)		0/265 (0%)
Deep vein thrombosis	1/268 (0.4%)		0/265 (0%)
Haematoma	1/268 (0.4%)		0/265 (0%)
Hypotension	0/268 (0%)		1/265 (0.4%)
Hypovolaemic shock	1/268 (0.4%)		0/265 (0%)
Other (Not Including Serious) Adverse Events
	Bosutinib		Imatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	264/268 (98.5%)		260/265 (98.1%)
Blood and lymphatic system disorders
Thrombocytopenia	96/268 (35.8%)		53/265 (20%)
Anaemia	59/268 (22%)		59/265 (22.3%)
Neutropenia	33/268 (12.3%)		61/265 (23%)
Leukopenia	18/268 (6.7%)		34/265 (12.8%)
Lymphopenia	15/268 (5.6%)		8/265 (3%)
Eye disorders
Periorbital oedema	4/268 (1.5%)		44/265 (16.6%)
Eyelid oedema	3/268 (1.1%)		24/265 (9.1%)
Conjunctival haemorrhage	2/268 (0.7%)		18/265 (6.8%)
Dry eye	4/268 (1.5%)		16/265 (6%)
Lacrimation increased	1/268 (0.4%)		18/265 (6.8%)
Vision blurred	5/268 (1.9%)		14/265 (5.3%)
Gastrointestinal disorders
Diarrhoea	201/268 (75%)		106/265 (40%)
Nausea	100/268 (37.3%)		112/265 (42.3%)
Vomiting	55/268 (20.5%)		54/265 (20.4%)
Abdominal pain	61/268 (22.8%)		25/265 (9.4%)
Abdominal pain upper	28/268 (10.4%)		26/265 (9.8%)
Constipation	36/268 (13.4%)		17/265 (6.4%)
Dyspepsia	26/268 (9.7%)		24/265 (9.1%)
Abdominal distension	14/268 (5.2%)		8/265 (3%)
Gastrooesophageal reflux disease	8/268 (3%)		14/265 (5.3%)
Toothache	14/268 (5.2%)		7/265 (2.6%)
General disorders
Fatigue	57/268 (21.3%)		54/265 (20.4%)
Pyrexia	44/268 (16.4%)		29/265 (10.9%)
Oedema peripheral	20/268 (7.5%)		43/265 (16.2%)
Asthenia	34/268 (12.7%)		24/265 (9.1%)
Face oedema	7/268 (2.6%)		17/265 (6.4%)
Influenza like illness	16/268 (6%)		6/265 (2.3%)
Infections and infestations
Upper respiratory tract infection	36/268 (13.4%)		33/265 (12.5%)
Nasopharyngitis	36/268 (13.4%)		30/265 (11.3%)
Urinary tract infection	26/268 (9.7%)		18/265 (6.8%)
Influenza	24/268 (9%)		14/265 (5.3%)
Gastroenteritis	12/268 (4.5%)		17/265 (6.4%)
Bronchitis	19/268 (7.1%)		6/265 (2.3%)
Sinusitis	15/268 (5.6%)		8/265 (3%)
Investigations
Alanine aminotransferase increased	90/268 (33.6%)		16/265 (6%)
Aspartate aminotransferase increased	69/268 (25.7%)		18/265 (6.8%)
Lipase increased	56/268 (20.9%)		30/265 (11.3%)
Blood creatine phosphokinase increased	14/268 (5.2%)		33/265 (12.5%)
Blood creatinine increased	18/268 (6.7%)		22/265 (8.3%)
Amylase increased	25/268 (9.3%)		10/265 (3.8%)
Weight increased	8/268 (3%)		20/265 (7.5%)
Blood alkaline phosphatase increased	17/268 (6.3%)		7/265 (2.6%)
Blood bilirubin increased	17/268 (6.3%)		7/265 (2.6%)
Metabolism and nutrition disorders
Decreased appetite	29/268 (10.8%)		17/265 (6.4%)
Hypokalaemia	6/268 (2.2%)		23/265 (8.7%)
Hypophosphataemia	7/268 (2.6%)		19/265 (7.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	48/268 (17.9%)		49/265 (18.5%)
Muscle spasms	10/268 (3.7%)		81/265 (30.6%)
Pain in extremity	26/268 (9.7%)		39/265 (14.7%)
Myalgia	13/268 (4.9%)		48/265 (18.1%)
Back pain	32/268 (11.9%)		25/265 (9.4%)
Bone pain	8/268 (3%)		19/265 (7.2%)
Nervous system disorders
Headache	58/268 (21.6%)		41/265 (15.5%)
Dizziness	25/268 (9.3%)		23/265 (8.7%)
Psychiatric disorders
Insomnia	18/268 (6.7%)		19/265 (7.2%)
Anxiety	15/268 (5.6%)		15/265 (5.7%)
Depression	9/268 (3.4%)		14/265 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	30/268 (11.2%)		26/265 (9.8%)
Dyspnoea	29/268 (10.8%)		14/265 (5.3%)
Oropharyngeal pain	17/268 (6.3%)		10/265 (3.8%)
Skin and subcutaneous tissue disorders
Rash	61/268 (22.8%)		39/265 (14.7%)
Pruritus	30/268 (11.2%)		10/265 (3.8%)
Dry skin	20/268 (7.5%)		14/265 (5.3%)
Alopecia	15/268 (5.6%)		14/265 (5.3%)
Rash maculo-papular	13/268 (4.9%)		16/265 (6%)
Night sweats	5/268 (1.9%)		14/265 (5.3%)
Vascular disorders
Hypertension	26/268 (9.7%)		29/265 (10.9%)

Limitations/Caveats

[Not Specified]

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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/Title	Pfizer ClinicalTrials.gov Call Center
Organization	Pfizer Inc.
Phone	1-800-718-1021
Email	ClinicalTrials.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

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

Study Details

Study Description

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Outcome Measures

Primary Outcome Measures

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Other Outcome Measures

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Study Results

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Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

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