Chronic Myelogenous Leukemia (CML) - Follow on: Study of BMS-354825 in Subjects With CML

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00123474
• Collaborator: (none)
• Enrollment: 724
• Locations: 137
• Arms: 4
• Duration (Months): 108
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a phase III study of BMS-354825 in subjects with chronic phase Philadelphia chromosome or BCR-ABL positive chronic myelogenous leukemia, who are resistant or intolerant to imatinib mesylate (Gleevec).

Condition or Disease	Intervention/Treatment	Phase
Myeloid Leukemia, Chronic, Chronic-Phase	Drug: dasatinib; Drug: dasatinib; Drug: dasatinib; Drug: dasatinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 724 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Two-by-Two, Multicenter, Open-Label Phase III Study of BMS-354825 Administered Orally at a Dose of 50 mg or 70 mg Twice Daily or 100 mg or 140 mg Once Daily in Subjects With Chronic Phase Philadelphia Chromosome or BCR-ABL Positive Chronic Myelogenous Leukemia Who Are Resistant or Intolerant to Imatinib Mesylate (Gleevec)
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: dasatinib; Tablets, Oral, 50 mg BID, indefinitely, survival study; Other Names: Sprycel BMS-354825
Experimental: 2	Drug: dasatinib; Tablets, Oral, 70 mg BID, indefinitely, survival study; Other Names: Sprycel BMS-354825
Experimental: 3	Drug: dasatinib; Tablets, Oral, 100 mg QD, indefinitely, survival study; Other Names: Sprycel BMS-354825
Experimental: 4	Drug: dasatinib; Tablets, Oral, 140 mg QD, indefinitely, survival study; Other Names: Sprycel BMS-354825

Outcome Measures

Primary Outcome Measures

1. Percent of Participants With Major Cytogenetic Response (MCyR) at 6 Months Follow-Up [6 months]

   Cytogenetic response (CyR) was based on the number of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Baseline=closest to, but no later than, the first day of study drug for treated participants and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified.

Secondary Outcome Measures

1. Percent of Participants With MCyR At or Prior to 24 Months Follow-Up [24 months]

   CyR was based on the number of Ph+ metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: CCyR: 0% Ph+ cells in metaphase in BM; PCyR: >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR. Baseline=closest to, but no later than, the first day of study drug for treated participants and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified.

2. Percent of Participants With Complete Hematologic Response (CHR) at 6 and 24 Months Follow-Up [6 months, 24 months]

   A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.

3. Time to MCyR in Participants With MCyR at 6 Months Follow-Up [6 months]

   Time to MCyR was defined as the time from the first dosing date until criteria were first met for CCyR or PCyR, whichever occurred first. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders).

4. Time to CHR in Participants With CHR at 6 Months Follow-Up [6 months]

   Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders).

5. Time to MCyR in Participants With MCyR at 24 Months Follow-Up [24 months]

   Time to MCyR was defined as the time from the first dosing date until criteria were first met for CCyR or PCyR, whichever occurred first. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up.

6. Time to CHR in Participants With CHR At 24 Months Follow-Up [24 months]

   Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up.

7. Number of Participants With MCyR Whose Disease Progressed by 24 Months [24 months]

   Progression in a participant=participant achieved a CHR and no longer met the criteria consistently over consecutive 2-weeks after starting their maximum dose; had no CHR after receiving their maximum dose and had an increase in white blood count (WBC) defined as a doubling of the count from the lowest value to >20,000/mm^3 or an increase by > 50,000/mm^3 on two assessments performed at least 2 weeks apart; participant met criteria of accelerated or blast phase CML at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a ≥ 30% absolute increase in the number of Ph+ metaphases. Although a related secondary endpoint was estimated duration of MCyR, medium duration of MCyR could not be estimated because the majority of participants with MCyR continued to respond, or could not be reliably estimated because of the large number of censored participants. Cytogenetic assessments were not done after the 24 month follow-up.

8. Number of Participants With CHR Whose Disease Progressed by 24 Months [24 months]

   Progression in a participant=achieved a CHR and subsequently no longer met the criteria consistently over a consecutive 2-week period after starting their maximum dose; had no CHR after receiving their maximum dose and had an increase in white blood count (WBC) defined as a doubling of the count from the lowest value to >20,000/mm^3 or an increase by > 50,000/mm^3 on two assessments performed at least 2 weeks apart; met the criteria of accelerated or blast phase CML at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a ≥ 30% absolute increase in the number of Ph+ metaphases. Although a related secondary endpoint was estimated duration of CHR, medium duration of CHR could not be estimated because the majority of participants with CHR continued to respond, or could not be reliably estimated because of the large number of censored participants.

9. Number of Participants With MCyR and Baseline BCR-ABL Gene Mutation - All Treated Participants [Baseline up to 24 months]

   BCR-ABL mutations were assessed in participants prior to the start of study drug (baseline) and at the time of disease progression or at end of therapy. Quantification of BCR-ABL transcripts in peripheral blood was evaluated using quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR, RT-PCR).

10. Percent of Imatinib-Resistant Participants With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up [24, 36, 48, 60, 72, and 84 months]

    PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.

11. Percent of Imatinib-Resistant Participants With Overall Survival (OS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up [24, 36, 48, 60, 72, and 84 months]

    Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.

12. Percent of Participants Intolerant to Imatinib With MCyR at 6 Months and at 24 Months Follow-Up, by QD and BID Schedules and by Total Daily Dose [6 months, 24 months]

    CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; PCyR: >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR.

13. Percent of Participants Intolerant to Imatinib With CHR at 6 Months and at 24 Months Follow-Up [6 months, 24 months]

    A CHR was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.

14. Percent of Imatinib Intolerant Participants With Progression Free Survival After 24, 36, 48, 60, 72, and 84 Months of Follow-Up [24, 36, 48, 60, 72, and 84 months]

    PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.

15. Percent of Imatinib Intolerant Participants With Overall Survival After 24, 36, 48, 60, 72, and 84 Months of Follow-up [24, 36, 48, 60, 72, and 84 months]

    Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.

16. Percent of All Randomized Participants With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) at 6 Months Follow-Up [6 months]

    Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM. Partial cytogenetic response (PCyR): >0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.

17. Percent of All Randomized Participants With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) at 24 Months Follow-Up [24 months]

    Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM. Partial cytogenetic response (PCyR): >0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. No cytogenic assessments were made after 2 years of follow-up.

18. Percent of Participants With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up by Dose Schedule and Total Daily Dose - All Randomized Participants [24, 36, 48, 60, 72, and 84 months]

    PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.

19. Percent of Participants Overall Survival at 24, 36, 48, 60, 72, and 84 Months Follow-Up - All Randomized Participants [24, 36, 48, 60, 72, and 84 months]

    Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.

20. Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation at 24 Months of Follow-up [Baseline to 30 days post last dose, up to 24 months]

    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated participants.

21. Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led toTreatment Discontinuation After 7 Year Follow-up [Baseline to 30 days post last dose, up to 7 years (study closure July 2014)]

    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated participants. After the 2-year analysis and Protocol Amendment 02, those on a BID dosing schedule were allowed to switch to a QD dosing schedule. Due to the large number of participants switching from BID dosing to QD dosing, the abbreviated dosing data collection method incorporated in Amendment 03, the overall safety data are presented for the 100 mg QD group and combined for the other treatment groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

• Subjects with Philadelphia chromosome positive (Ph+) (or BCR/ABL+) chronic phase chronic myeloid leukemia whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate.

• Men and women, 18 years or older

• Adequate hepatic function

• Adequate renal function

• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

• Women who are pregnant or breastfeeding

• Subjects who are eligible and willing to undergo transplantation during the screening period

• A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy

• Uncontrolled or significant cardiovascular disease

• Medications that increase bleeding risk

• Medications that change heart rhythms

• Dementia or altered mental status that would prohibit the understanding or rendering of informed consent

• History of significant bleeding disorder unrelated to CML

• Concurrent incurable malignancy other than CML

• Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy

• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of Alabama At Birmingham	Birmingham	Alabama	United States	35294
2	Central Hematology Oncology Medical Group Inc.	Alhambra	California	United States	91801
3	Pacific Cancer Medical Center Inc	Anaheim	California	United States	92801
4	Loma Linda University Cancer Center	Loma Linda	California	United States	92354
5	Pacific Shores Medical Group	Long Beach	California	United States	90813
6	Ucla Dept. Of Medicine	Los Angeles	California	United States	90095
7	Ventura County Hematology-Oncology Specialists	Oxnard	California	United States	93030
8	Kaiser Permanente Medical Center	Vallejo	California	United States	94589
9	Georgetown University Med Ctr	Washington	District of Columbia	United States	20007
10	Washington Cancer Institute At Washington Hospital Center	Washington	District of Columbia	United States	20010
11	University Of Florida	Gainesville	Florida	United States	32610
12	University Of Miami	Miami	Florida	United States	33136
13	Md Anderson Cancer Center Orlando	Orlando	Florida	United States	32806
14	Emory University School Of Medicine	Atlanta	Georgia	United States	30322
15	Georgia Cancer Specialists	Atlanta	Georgia	United States	30341
16	Gwinnett Hospital System Inc.	Lawrenceville	Georgia	United States	30046
17	Northwestern University Feinberg School Of Medicine	Chicago	Illinois	United States	60611
18	University Of Chicago	Chicago	Illinois	United States	60637
19	Oncology Hematology Associates Of Central Illinois, Pc	Peoria	Illinois	United States	61615
20	Indiana University Cancer Center	Indianapolis	Indiana	United States	46202
21	University Of Kansas Medical Center	Westwood	Kansas	United States	66205
22	University Of Kentucky	Lexington	Kentucky	United States	40536
23	University Of Maryland	Baltimore	Maryland	United States	21201
24	Dana Faber Cancer Institute	Boston	Massachusetts	United States	02215
25	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
26	Washington University School Of Medicine	Saint Louis	Missouri	United States	63110
27	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
28	Devetten, Marcel	Omaha	Nebraska	United States	68198
29	Nevada Cancer Institute	Las Vegas	Nevada	United States	89135
30	The Cancer Center At Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
31	The Cancer Institute Of New Jersey	New Brunswick	New Jersey	United States	08903
32	New York Presbyterian Hospital	New York	New York	United States	10021
33	University Of North Carolina At Chapel Hill	Chapel Hill	North Carolina	United States	27599
34	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
35	Oregon Health & Science University	Portland	Oregon	United States	97239
36	Western Pennsylvania Cancer Institute	Pittsburgh	Pennsylvania	United States	15224
37	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
38	Ut Southwestern Medical Center	Dallas	Texas	United States	75390
39	The University Of Texas Md Anderson Cancer Center	Houston	Texas	United States	77030
40	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
41	Local Institution	La Plata	Buenos Aires	Argentina	1900
42	Local Institution	Buenos Aires		Argentina	1221
43	Local Institution	Capital Federal		Argentina	1280
44	Local Institution	Cordoba		Argentina	X5016KEH
45	Local Institution	Camperdown	New South Wales	Australia	2050
46	Local Institution	St Leonards	New South Wales	Australia	2065
47	Local Institution	South Brisbane	Queensland	Australia	4101
48	Local Institution	Adelaide	South Australia	Australia	SA 5000
49	Local Institution	East Melbourne	Victoria	Australia	3002
50	Local Institution	Perth	Western Australia	Australia	WA 6000
51	Local Institution	Wien		Austria	1090
52	Local Institution	B-leuven		Belgium	3000
53	Local Institution	Brugge		Belgium	8000
54	Local Institution	Bruxelles		Belgium	1000
55	Local Institution	Charleroi		Belgium	6000
56	Local Institution	Edegem		Belgium	2650
57	Local Institution	Yvoir		Belgium	5530
58	Local Institution	Curitiba	Parana	Brazil	80060
59	Local Institution	CEP - Campinas		Brazil	13083
60	Local Institution	Rio de Janeiro		Brazil	20231
61	Local Institution	San Paulo, Sp		Brazil	05403
62	Local Institution	Sao Paulo		Brazil	05652
63	Local Institution	Edmonton	Alberta	Canada	T6G 1Z2
64	Local Institution	Hamilton	Ontario	Canada	L8N 3Z5
65	Local Institution	Montreal	Quebec	Canada	H2W 1S6
66	Local Institution	Brno		Czech Republic	625 00
67	Local Institution	Prague 2		Czech Republic	128 20
68	Local Institution	Aarhus C		Denmark	8000
69	Local Institution	Herlev		Denmark	2730
70	Local Institution	Odense C		Denmark	5000
71	Local Institution	Helsinki		Finland	00029
72	Local Institution	Cedex	Pierre Benite	France	69495
73	Local Institution	Caen		France	14000
74	Local Institution	Creteil Cedex		France	94010
75	Local Institution	Grenoble Cedex 09		France	38043
76	Local Institution	Lille Cedex		France	59037
77	Local Institution	Marseille Cedex 9		France	13273
78	Local Institution	Nantes		France	44000
79	Local Institution	Paris Cedex 10		France	75475
80	Local Institution	Poitiers Cedex		France	86021
81	Local Institution	Strasbourg		France	67091
82	Local Institution	Toulouse Cedex 9		France	31059
83	Local Institution	Dresden		Germany	01307
84	Local Institution	Frankfurt/main		Germany	60590
85	Local Institution	Hamburg		Germany	20246
86	Local Institution	Leipzig		Germany	04103
87	Local Institution	Mainz		Germany	55131
88	Local Institution	Mannheim		Germany	68167
89	Local Institution	Budapest		Hungary	1135
90	Local Institution	Co Galway	Galway	Ireland
91	Local Institution	Dublin		Ireland	8
92	Local Institution	Ramat-gan		Israel	52621
93	Local Institution	Bari		Italy	70124
94	Local Institution	Monza (mi)		Italy	20052
95	Local Institution	Napoli		Italy	80131
96	Local Institution	Orbassano		Italy	10043
97	Local Institution	Roma		Italy	00144
98	Local Institution	Roma		Italy	00161
99	Local Institution	Jeollanam-do		Korea, Republic of	519-809
100	Local Institution	Kyunggi-do		Korea, Republic of	480-130
101	Local Institution	Seoul		Korea, Republic of	110-744
102	Local Institution	Seoul		Korea, Republic of	138-736
103	Local Institution	Distrito Federal		Mexico	02990
104	Local Institution	Nijmegen		Netherlands	6525 GA
105	Local Institution	Rotterdam		Netherlands	3075 EA
106	Local Institution	Trondheim		Norway	7006
107	Local Institution	Jesus Maria	Lima	Peru	11
108	Local Institution	Lima		Peru	34
109	Local Institution	Quezon City		Philippines	1102
110	Local Institution	Gdansk		Poland	80 211
111	Local Institution	Katowice		Poland	40032
112	Local Institution	Krakow		Poland	31501
113	Local Institution	Lodz		Poland	93510
114	Local Institution	Lublin		Poland	20 950
115	Local Institution	Warsaw		Poland	02097
116	Local Institution	Moscow		Russian Federation	125167
117	Local Institution	St.petersburg		Russian Federation	197022
118	Local Institution	Singapore		Singapore	169608
119	Local Institution	Bloemfontein	Free State	South Africa	9301
120	Local Institution	Groenkloof	Gauteng	South Africa	0181
121	Local Institution	Parktown	Gauteng	South Africa	2193
122	Local Institution	Soweto	Gauteng	South Africa	2013
123	Local Institution	Observatory	Western Cape	South Africa	7925
124	Local Institution	Madrid		Spain	28006
125	Local Institution	Madrid		Spain	28034
126	Local Institution	Pamplona		Spain	31008
127	Local Institution	Lund		Sweden	22185
128	Local Institution	Uppsala		Sweden	751 85
129	Local Institution	Basel		Switzerland	4031
130	Local Institution	Taipei		Taiwan	100
131	Local Institution	Taoyuan County		Taiwan	333
132	Local Institution	Cambridge	Cambridgeshire	United Kingdom	CB2 2XY
133	Local Institution	London	Greater London	United Kingdom	W12 OHS
134	Local Institution	Liverpool	Merseyside	United Kingdom	L7 8XP
135	Local Institution	Newcastle	Tyne And Wear	United Kingdom	NE2 2DR
136	Local Institution	Birmingham	West Midlands	United Kingdom	B15 2TH
137	Local Institution	Glasgow		United Kingdom	G12 0ZD

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource

Publications

• Müller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R, Branford S, Hughes TP, Radich JP, Ploughman L, Mukhopadhyay J, Hochhaus A. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009 Dec 3;114(24):4944-53. doi: 10.1182/blood-2009-04-214221. Epub 2009 Sep 24.
• Porkka K, Khoury HJ, Paquette RL, Matloub Y, Sinha R, Cortes JE. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010 Jan 15;116(2):377-86. doi: 10.1002/cncr.24734.
• Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A, Khoroshko N, Paquette RL, Deininger M, Collins RH, Otero I, Hughes T, Bleickardt E, Strauss L, Francis S, Hochhaus A. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008 Jul 1;26(19):3204-12. doi: 10.1200/JCO.2007.14.9260. Epub 2008 Jun 9.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00123474
• Other Study ID Numbers: CA180-034
• First Posted: Jul 25, 2005
• Last Update Posted: Aug 25, 2016
• Last Verified: Jul 1, 2016

• Keywords provided by Bristol-Myers Squibb: Chronic Phase Chronic Myelogenous Leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Dasatinib

Study Results

Participant Flow

Recruitment Details	Study initiated July 2005 and completed July 2014.
Pre-assignment Detail	724 participants were enrolled, 670 were randomized, and 662 were treated with study drug. Reasons for non-randomization: 38 no longer met criteria, 8 other reasons, 7 withdrew consent, and 1 death.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Period Title: Randomized to Treatment
STARTED	167	167	168	168
COMPLETED	166	163	166	167
NOT COMPLETED	1	4	2	1
Period Title: Randomized to Treatment
STARTED	165	163	167	167
COMPLETED	0	0	0	0
NOT COMPLETED	165	163	167	167

Baseline Characteristics

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID	Total
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Total of all reporting groups
Overall Participants	167	167	168	168	670
Age, Customized (participants) [Number]
Less than, equal to (<=) 65 years	121 72.5%	128 76.6%	130 77.4%	125 74.4%	504 75.2%
Greater than (>) 65 years	46 27.5%	39 23.4%	38 22.6%	43 25.6%	166 24.8%
Sex: Female, Male (Count of Participants)
Female	83 49.7%	97 58.1%	83 49.4%	91 54.2%	354 52.8%
Male	84 50.3%	70 41.9%	85 50.6%	77 45.8%	316 47.2%
Imatinib Status (participants) [Number]
Primary Resistance to Imatinib	75 44.9%	78 46.7%	88 52.4%	81 48.2%	322 48.1%
Acquired Resistance to Imatinib	49 29.3%	45 26.9%	36 21.4%	45 26.8%	175 26.1%
Intolerant to Imatinib	43 25.7%	44 26.3%	44 26.2%	42 25%	173 25.8%

Outcome Measures

1. Primary Outcome

Title	Percent of Participants With Major Cytogenetic Response (MCyR) at 6 Months Follow-Up
Description	Cytogenetic response (CyR) was based on the number of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Baseline=closest to, but no later than, the first day of study drug for treated participants and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-resistant participants with available data were summarized.

Arm/Group Title	QD Dasatinib	BID Dasatinib
Arm/Group Description	Participants received either 100 mg or 140 mg once a day (QD) dasatinib until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 50 mg or 70 mg twice a day (BID) dasatinib until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.
Measure Participants	247	251
Number (95% Confidence Interval) [percentage of Participants]	51.8 31%	49.0 29.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QD Dasatinib, BID Dasatinib
	Comments	6 Month Analysis
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% confidence interval (CI) for the MCyRRQD minus MCyRRBID difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; -6.0 to 11.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent of Participants With MCyR At or Prior to 24 Months Follow-Up
Description	CyR was based on the number of Ph+ metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: CCyR: 0% Ph+ cells in metaphase in BM; PCyR: >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR. Baseline=closest to, but no later than, the first day of study drug for treated participants and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-resistant participants with available data were summarized.

Arm/Group Title	Dasatinib QD	Dasatinib BID	Dasatinib 100 mg Total Daily Dose	Dasatinib 140 mg Total Daily Dose
Arm/Group Description	Participants received either 100 mg QD or 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 50 mg BID or 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 100 mg as a total daily dose (either 50 mg BID or 100 mg QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 140 mg as a total daily dose (either 70 mg BID or 140 mg QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.
Measure Participants	247	250	248	249
Number (95% Confidence Interval) [percentage of Participants]	58.3 34.9%	56.4 33.8%	57.3 34.1%	57.4 34.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QD Dasatinib, BID Dasatinib
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% CI for the MCyRRQD minus MCyRRBID difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -6.8 to 10.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dasatinib 100 mg Total Daily Dose, Dasatinib 140 mg Total Daily Dose
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of 100 mg total daily dose relative to 140 mg total daily dose was deduced if the lower bound of the 95% CI for the difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -8.9 to 8.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent of Participants With Complete Hematologic Response (CHR) at 6 and 24 Months Follow-Up
Description	A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.
Time Frame	6 months, 24 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-resistant participants with available data were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	124	123	124	127
6 Months (n=124,123,124,127)	86.3 51.7%	85.4 51.1%	91.1 54.2%	87.4 52%
24 Month (n=124,123,124,126)	88.7 53.1%	86.2 51.6%	91.9 54.7%	88.9 52.9%

4. Secondary Outcome

Title	Time to MCyR in Participants With MCyR at 6 Months Follow-Up
Description	Time to MCyR was defined as the time from the first dosing date until criteria were first met for CCyR or PCyR, whichever occurred first. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Randomized imatinib-resistant participants with MCyR and available data were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	66	62	58	65
Median (95% Confidence Interval) [Months]	2.8	2.8	2.8	2.8

5. Secondary Outcome

Title	Time to CHR in Participants With CHR at 6 Months Follow-Up
Description	Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Randomized imatinib-resistant participants with CHR and available data were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	107	105	113	111
Median (95% Confidence Interval) [Months]	0.5	0.5	0.6	0.7

6. Secondary Outcome

Title	Time to MCyR in Participants With MCyR at 24 Months Follow-Up
Description	Time to MCyR was defined as the time from the first dosing date until criteria were first met for CCyR or PCyR, whichever occurred first. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Randomized imatinib-resistant participants with MCyR were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	73	71	69	72
Median (95% Confidence Interval) [Months]	2.9	2.8	2.9	2.9

7. Secondary Outcome

Title	Time to CHR in Participants With CHR At 24 Months Follow-Up
Description	Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Randomized imatinib-resistant participants with CHR were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	110	106	114	112
Median (95% Confidence Interval) [Months]	0.5	0.5	0.6	0.7

8. Secondary Outcome

Title	Number of Participants With MCyR Whose Disease Progressed by 24 Months
Description	Progression in a participant=participant achieved a CHR and no longer met the criteria consistently over consecutive 2-weeks after starting their maximum dose; had no CHR after receiving their maximum dose and had an increase in white blood count (WBC) defined as a doubling of the count from the lowest value to >20,000/mm^3 or an increase by > 50,000/mm^3 on two assessments performed at least 2 weeks apart; participant met criteria of accelerated or blast phase CML at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a ≥ 30% absolute increase in the number of Ph+ metaphases. Although a related secondary endpoint was estimated duration of MCyR, medium duration of MCyR could not be estimated because the majority of participants with MCyR continued to respond, or could not be reliably estimated because of the large number of censored participants. Cytogenetic assessments were not done after the 24 month follow-up.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All imatinib-resistant participants who had achieved MCyR and experienced disease progression were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	73	71	69	72
Number [participants]	5 3%	17 10.2%	6 3.6%	9 5.4%

9. Secondary Outcome

Title	Number of Participants With CHR Whose Disease Progressed by 24 Months
Description	Progression in a participant=achieved a CHR and subsequently no longer met the criteria consistently over a consecutive 2-week period after starting their maximum dose; had no CHR after receiving their maximum dose and had an increase in white blood count (WBC) defined as a doubling of the count from the lowest value to >20,000/mm^3 or an increase by > 50,000/mm^3 on two assessments performed at least 2 weeks apart; met the criteria of accelerated or blast phase CML at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a ≥ 30% absolute increase in the number of Ph+ metaphases. Although a related secondary endpoint was estimated duration of CHR, medium duration of CHR could not be estimated because the majority of participants with CHR continued to respond, or could not be reliably estimated because of the large number of censored participants.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All imatinib-resistant participants who achieved CHR and then experienced disease progression were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	110	106	114	112
Number [participants]	18 10.8%	28 16.8%	22 13.1%	24 14.3%

10. Secondary Outcome

Title	Number of Participants With MCyR and Baseline BCR-ABL Gene Mutation - All Treated Participants
Description	BCR-ABL mutations were assessed in participants prior to the start of study drug (baseline) and at the time of disease progression or at end of therapy. Quantification of BCR-ABL transcripts in peripheral blood was evaluated using quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR, RT-PCR).
Time Frame	Baseline up to 24 months

Outcome Measure Data

Analysis Population Description

All randomized, treated participants with available mutation data were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	147	139	149	146
Imatinib-resistant Mutations	49 29.3%	49 29.3%	62 36.9%	48 28.6%
Mutations with unknown Imatinib-resistance status	0 0%	1 0.6%	1 0.6%	2 1.2%
Imatinib Resistant or unknown mutations	49 29.3%	50 29.9%	63 37.5%	50 29.8%
Polymorphisms	0 0%	2 1.2%	0 0%	0 0%
No Mutations	98 58.7%	87 52.1%	86 51.2%	96 57.1%

11. Secondary Outcome

Title	Percent of Imatinib-Resistant Participants With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up
Description	PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.
Time Frame	24, 36, 48, 60, 72, and 84 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-resistant participants were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	124	123	124	126
24 Months (n=124,123,124, 127)	75.2 45%	61.3 36.7%	70.3 41.8%	70.8 42.1%
36 Months (n=124,123,124, 127)	64.8 38.8%	47.4 28.4%	67.1 39.9%	58.2 34.6%
48 Months (n=124,123,124, 127)	57.8 34.6%	40.0 24%	63.8 38%	55.1 32.8%
60 Months (n=124,123,124, 127)	50.2 30.1%	36.4 21.8%	57.4 34.2%	50.2 29.9%
72 Months (n=124,123,124, 127)	44.0 26.3%	31.4 18.8%	50.7 30.2%	45.3 27%
84 Months (n=124,123,124, 127)	39.0 23.4%	30.2 18.1%	42.1 25.1%	41.3 24.6%

12. Secondary Outcome

Title	Percent of Imatinib-Resistant Participants With Overall Survival (OS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up
Description	Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.
Time Frame	24, 36, 48, 60, 72, and 84 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-resistant participants were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	124	123	124	126
24 Months (n=124,123,124,127)	90.1 54%	93.9 56.2%	88.9 52.9%	85.1 50.7%
36 Months (n=124,123,124,127)	87.5 52.4%	83.8 50.2%	83.5 49.7%	76.5 45.5%
48 Months (n=124,123,124,127)	79.7 47.7%	82.0 49.1%	80.7 48%	71.1 42.3%
60 Months (n=124,123,124,127)	75.1 45%	78.0 46.7%	73.6 43.8%	69.1 41.1%
72 Months (n=124,123,124,127)	67.9 40.7%	72.6 43.5%	71.4 42.5%	67.1 39.9%
84 Months (n=124,123,124,127)	62.6 37.5%	68.1 40.8%	67.9 40.4%	65.0 38.7%

13. Secondary Outcome

Title	Percent of Participants Intolerant to Imatinib With MCyR at 6 Months and at 24 Months Follow-Up, by QD and BID Schedules and by Total Daily Dose
Description	CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; PCyR: >0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: >35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: >65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: >95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR.
Time Frame	6 months, 24 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-intolerant participants with available data were summarized.

Arm/Group Title	QD Dasatinib	BID Dasatinib	Total Daily Dose 100 mg	Total Daily Dose 140 mg
Arm/Group Description	Participants received either 100 mg or 140 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 50 mg or 70 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 100 mg QD or 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 140 mg QD or 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.
Measure Participants	87	85	87	86
6 Month	72.4 43.4%	70.6 42.3%	73.6 43.8%	69.4 41.3%
24 Month	77.0 46.1%	75.6 45.3%	77.0 45.8%	75.6 45%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QD Dasatinib, BID Dasatinib
	Comments	6 Month Analysis
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% CI for the MCyRRQD minus MCyRRBID difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -11.7 to 15.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dasatinib 100 mg Total Daily Dose, Dasatinib 140 mg Total Daily Dose
	Comments	6 Month Analysis
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of 100 mg QD Total Daily Dose relative to 140 mg QD Total Daily Dose was deduced if the lower bound of the 95% CI difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	4.2
	Confidence Interval	(2-Sided) 95%; -9.3 to 17.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	QD Dasatinib, BID Dasatinib
	Comments	24 Month Analysis
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of the QD schedule relative to the BID schedule was deduced if the lower bound of the 95% CI for the MCyRRQD minus MCyRRBID difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -11.2 to 14.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Dasatinib 100 mg Total Daily Dose, Dasatinib 140 mg Total Daily Dose
	Comments	24 Month Analysis
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of 100 mg QD Total Daily Dose relative to 140 mg QD Total Daily Dose was deduced if the lower bound of the 95% CI difference was greater than or equal to -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -11.2 to 14.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Percent of Participants Intolerant to Imatinib With CHR at 6 Months and at 24 Months Follow-Up
Description	A CHR was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.
Time Frame	6 months, 24 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-intolerant participants were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	43	44	44	42
6 Months (n=43,44,44,41)	100 59.9%	86 51.5%	93 55.4%	85 50.6%
24 Months (n=43,44,44,42)	100 59.9%	89 53.3%	93 55.4%	86 51.2%

15. Secondary Outcome

Title	Percent of Imatinib Intolerant Participants With Progression Free Survival After 24, 36, 48, 60, 72, and 84 Months of Follow-Up
Description	PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.
Time Frame	24, 36, 48, 60, 72, and 84 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-intolerant participants with available data were summarized

Arm/Group Title	100mg QD	140mg QD	50mg BID	70mg BID
Arm/Group Description	Participants received 100 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.	Participants received 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.
Measure Participants	43	44	44	42
24 Months (n=43,44,44,42)	83.6 50.1%	87.7 52.5%	77.4 46.1%	83.7 49.8%
36 Months (n=43,44,44,42)	71.7 42.9%	76.0 45.5%	68.6 40.8%	77.4 46.1%
48 Months (n=43,44,44,42)	62.7 37.5%	76.0 45.5%	62.0 36.9%	66.9 39.8%
60 Months (n=43,44,44,42)	59.2 35.4%	71.2 42.6%	62.0 36.9%	59.5 35.4%
72 Months (n=43,44,44,42)	59.2 35.4%	66.5 39.8%	58.2 34.6%	55.2 32.9%
84 Months (n=43,44,44,42)	50.9 30.5%	66.5 39.8%	47.5 28.3%	50.2 29.9%

16. Secondary Outcome

Title	Percent of Imatinib Intolerant Participants With Overall Survival After 24, 36, 48, 60, 72, and 84 Months of Follow-up
Description	Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.
Time Frame	24, 36, 48, 60, 72, and 84 months

Outcome Measure Data

Analysis Population Description

All randomized imatinib-intolerant participants were summarized.

Arm/Group Title	100mg QD	140mg QD	50mg BID	70mg BID
Arm/Group Description	Participants received 100 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.	Participants received 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.
Measure Participants	43	44	44	42
24 Months (n=43,44,44,42)	94.9 56.8%	92.8 55.6%	95.3 56.7%	97.4 58%
36 Months (n=43,44,44,42)	89.7 53.7%	92.8 55.6%	90.4 53.8%	94.7 56.4%
48 Months (n=43,44,44,42)	84.5 50.6%	87.5 52.4%	85.1 50.7%	86.8 51.7%
60 Months (n=43,44,44,42)	81.8 49%	87.5 52.4%	82.4 49%	81.1 48.3%
72 Months (n=43,44,44,42)	79.0 47.3%	87.5 52.4%	79.6 47.4%	81.1 48.3%
84 Months (n=43,44,44,42)	70.0 41.9%	87.5 52.4%	76.6 45.6%	77.7 46.3%

17. Secondary Outcome

Title	Percent of All Randomized Participants With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) at 6 Months Follow-Up
Description	Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM. Partial cytogenetic response (PCyR): >0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized participants were summarized.

Arm/Group Title	QD Dasatinib	BID Dasatinib	Total Daily Dose 100 mg	Total Daily Dose 140 mg
Arm/Group Description	Participants received either 100 mg or 140 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 50 mg or 70 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 100 mg QD or 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 140 mg QD or 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.
Measure Participants	334	336	335	335
MCyR (n=334,336,335,335)	57.2 34.3%	54.5 32.6%	56.1 33.4%	55.5 33%
CHR(n=334,336,335,335)	87.7 52.5%	89.3 53.5%	90.7 54%	86.3 51.4%

18. Secondary Outcome

Title	Percent of All Randomized Participants With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) at 24 Months Follow-Up
Description	Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM. Partial cytogenetic response (PCyR): >0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets < 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); < 5% myelocytes plus metamyelocytes in PB; Basophils in PB < 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. No cytogenic assessments were made after 2 years of follow-up.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All randomized participants were summarized.

Arm/Group Title	QD Dasatinib	BID Dasatinib	Total Daily Dose 100 mg	Total Daily Dose 140 mg
Arm/Group Description	Participants received either 100 mg or 140 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 50 mg or 70 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 100 mg QD or 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received either 140 mg QD or 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.
Measure Participants	334	336	335	335
MCyR(n=334,336,335,335)	63.2 37.8%	61.3 36.7%	62.4 37.1%	62.1 37%
CHR (n=334,336,335,335)	89.2 53.4%	90.2 54%	91.9 54.7%	87.5 52.1%

19. Secondary Outcome

Title	Percent of Participants With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up by Dose Schedule and Total Daily Dose - All Randomized Participants
Description	PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to > 20,000/mm^3 or an increase by > 50,000/mm^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.
Time Frame	24, 36, 48, 60, 72, and 84 months

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment arm were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	167	167	168	168
24 Months (n=167, 167, 168, 168)	77.4 46.3%	67.7 40.5%	72.2 43%	73.9 44%
36 Months (n=167, 167, 168, 168)	66.6 39.9%	54.0 32.3%	67.5 40.2%	62.8 37.4%
48 Months (n=167, 167, 168, 168)	59.1 35.4%	48.0 28.7%	63.3 37.7%	58.7 34.9%
60 Months (n=167, 167, 168, 168)	52.5 31.4%	44.2 26.5%	58.7 34.9%	52.5 31.3%
72 Months (n=167, 167, 168, 168)	40.0 24%	39.2 23.5%	52.8 31.4%	47.7 28.4%
84 Months (n=167, 167, 168, 168)	42.1 25.2%	38.2 22.9%	43.9 26.1%	43.5 25.9%

20. Secondary Outcome

Title	Percent of Participants Overall Survival at 24, 36, 48, 60, 72, and 84 Months Follow-Up - All Randomized Participants
Description	Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.
Time Frame	24, 36, 48, 60, 72, and 84 months

Outcome Measure Data

Analysis Population Description

All participants who were randomized to a treatment arm were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	167	167	168	168
24 Months (n=167, 167, 168, 168)	91.3 54.7%	93.6 56%	90.6 53.9%	88.1 52.4%
36 Months (n=167, 167, 168, 168)	88.1 52.8%	86.2 51.6%	85.3 50.8%	80.9 48.2%
48 Months (n=167, 167, 168, 168)	81.0 48.5%	83.4 49.9%	81.8 48.7%	74.9 44.6%
60 Months (n=167, 167, 168, 168)	76.8 46%	80.5 48.2%	75.9 45.2%	72.0 42.9%
72 Months (n=167, 167, 168, 168)	70.9 42.5%	76.6 45.9%	73.6 43.8%	70.5 42%
84 Months (n=167, 167, 168, 168)	64.6 38.7%	73.4 44%	70.3 41.8%	68.1 40.5%

21. Secondary Outcome

Title	Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation at 24 Months of Follow-up
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated participants.
Time Frame	Baseline to 30 days post last dose, up to 24 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug were summarized.

Arm/Group Title	Dasatinib 100 mg QD	Dasatinib 140 mg QD	Dasatinib 50 mg BID	Dasatinib 70 mg BID
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 50 mg twice a day (BID) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.	Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.
Measure Participants	165	163	167	167
Any SAE	58 34.7%	67 40.1%	73 43.5%	78 46.4%
Drug-Related SAE	32 19.2%	40 24%	47 28%	55 32.7%
Drug-Related AEs that led to discontinuationt	14 8.4%	24 14.4%	20 11.9%	25 14.9%
Death within 30 days of last dose	3 1.8%	2 1.2%	6 3.6%	5 3%

22. Secondary Outcome

Title	Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led toTreatment Discontinuation After 7 Year Follow-up
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated participants. After the 2-year analysis and Protocol Amendment 02, those on a BID dosing schedule were allowed to switch to a QD dosing schedule. Due to the large number of participants switching from BID dosing to QD dosing, the abbreviated dosing data collection method incorporated in Amendment 03, the overall safety data are presented for the 100 mg QD group and combined for the other treatment groups.
Time Frame	Baseline to 30 days post last dose, up to 7 years (study closure July 2014)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug were summarized.

Arm/Group Title	100 mg QD	Other Treatment Groups	Total
Arm/Group Description	Participants received 100 mg once a day (QD) until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants participated in all other treatment arms until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.	Participants received study drug in any schedule or total daily dose until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw.
Measure Participants	165	497	662
All Deaths	51 30.5%	133 79.6%	184 109.5%
Deaths on-study or within 30 days post dose	11 6.6%	15 9%	26 15.5%
SAEs	75 44.9%	259 155.1%	334 198.8%
AEs Leading to Discontinuation of Treatment	43 25.7%	153 91.6%	196 116.7%

Adverse Events

Time Frame	Baseline to 30 days post last dose, up to 7 years (study closure July 2014)
Arm/Group Title	100mg QD		140mg QD		50mg BID		70mg BID
Arm/Group Description	Participants received 100 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing schedule were allowed to switch to a QD dosing schedule.		Participants received 140 mg QD until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.		Participants received 50 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.		Participants received 70 mg BID until progression of disease, development of intolerable toxicity, or the participant's decision to withdraw. After the 2-year analysis, and with Protocol Amendment 02, participants on a BID dosing.
All Cause Mortality
	100mg QD		140mg QD		50mg BID		70mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	100mg QD		140mg QD		50mg BID		70mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/165 (45.5%)		78/163 (47.9%)		89/167 (53.3%)		92/167 (55.1%)
Blood and lymphatic system disorders
Anaemia	1/165 (0.6%)		3/163 (1.8%)		3/167 (1.8%)		5/167 (3%)
Febrile neutropenia	2/165 (1.2%)		2/163 (1.2%)		3/167 (1.8%)		6/167 (3.6%)
Pancytopenia	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Thrombocytopenia	2/165 (1.2%)		4/163 (2.5%)		6/167 (3.6%)		9/167 (5.4%)
Neutropenia	2/165 (1.2%)		2/163 (1.2%)		2/167 (1.2%)		3/167 (1.8%)
Lymphadenopathy	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Cardiac disorders
Arrhythmia supraventricular	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Cardiac valve disease	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Palpitations	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Angina pectoris	0/165 (0%)		0/163 (0%)		0/167 (0%)		2/167 (1.2%)
Cardiac failure	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		1/167 (0.6%)
Pericarditis	1/165 (0.6%)		2/163 (1.2%)		2/167 (1.2%)		0/167 (0%)
Ventricular arrhythmia	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Acute myocardial infarction	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Myocardial ischaemia	1/165 (0.6%)		2/163 (1.2%)		2/167 (1.2%)		2/167 (1.2%)
Restrictive cardiomyopathy	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Acute coronary syndrome	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		2/167 (1.2%)
Pericardial effusion	2/165 (1.2%)		3/163 (1.8%)		3/167 (1.8%)		3/167 (1.8%)
Cardiac arrest	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Cardiac failure congestive	0/165 (0%)		3/163 (1.8%)		2/167 (1.2%)		5/167 (3%)
Cardio-respiratory arrest	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Cor pulmonale	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Cardiac failure acute	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Stress cardiomyopathy	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Bradycardia	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Left ventricular dysfunction	0/165 (0%)		2/163 (1.2%)		0/167 (0%)		2/167 (1.2%)
Myocardial infarction	2/165 (1.2%)		1/163 (0.6%)		2/167 (1.2%)		0/167 (0%)
Tachycardia	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Atrial fibrillation	0/165 (0%)		0/163 (0%)		4/167 (2.4%)		3/167 (1.8%)
Congenital, familial and genetic disorders
Atrial septal defect	1/165 (0.6%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Endocrine disorders
Hypothyroidism	0/165 (0%)		0/163 (0%)		2/167 (1.2%)		0/167 (0%)
Goitre	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Eye disorders
Amaurosis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Vitreous haemorrhage	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Retinal haemorrhage	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Diplopia	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Cataract	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/165 (0.6%)		1/163 (0.6%)		4/167 (2.4%)		3/167 (1.8%)
Gastrointestinal necrosis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Gingival bleeding	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Loose tooth	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Anal fistula	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Constipation	2/165 (1.2%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Gastritis erosive	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Dental caries	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Diarrhoea	5/165 (3%)		12/163 (7.4%)		5/167 (3%)		4/167 (2.4%)
Intestinal obstruction	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Lower gastrointestinal haemorrhage	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Haemorrhoids	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Large intestine polyp	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Vomiting	2/165 (1.2%)		5/163 (3.1%)		6/167 (3.6%)		1/167 (0.6%)
Colitis	0/165 (0%)		2/163 (1.2%)		0/167 (0%)		2/167 (1.2%)
Enteritis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Gastritis	1/165 (0.6%)		2/163 (1.2%)		1/167 (0.6%)		1/167 (0.6%)
Inguinal hernia	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Oesophageal pain	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Pancreatitis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Rectal haemorrhage	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		2/167 (1.2%)
Small intestinal obstruction	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Enterocolitis	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Toothache	0/165 (0%)		2/163 (1.2%)		0/167 (0%)		0/167 (0%)
Abdominal pain	2/165 (1.2%)		2/163 (1.2%)		4/167 (2.4%)		3/167 (1.8%)
Abdominal pain upper	0/165 (0%)		2/163 (1.2%)		1/167 (0.6%)		1/167 (0.6%)
Ileus	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Irritable bowel syndrome	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Nausea	2/165 (1.2%)		3/163 (1.8%)		2/167 (1.2%)		0/167 (0%)
Oesophagitis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Upper gastrointestinal haemorrhage	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
General disorders
Fatigue	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Sudden death	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Chest pain	4/165 (2.4%)		2/163 (1.2%)		3/167 (1.8%)		3/167 (1.8%)
Device failure	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Oedema peripheral	2/165 (1.2%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Device malfunction	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Malaise	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Multi-organ failure	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Thrombosis in device	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Chills	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Non-cardiac chest pain	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Serositis	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Chest discomfort	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Death	2/165 (1.2%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Medical device pain	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Pyrexia	3/165 (1.8%)		11/163 (6.7%)		6/167 (3.6%)		9/167 (5.4%)
Hepatobiliary disorders
Bile duct stone	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Cholangitis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Cholecystitis	1/165 (0.6%)		3/163 (1.8%)		1/167 (0.6%)		2/167 (1.2%)
Cholecystitis acute	1/165 (0.6%)		2/163 (1.2%)		0/167 (0%)		0/167 (0%)
Immune system disorders
Allergy to arthropod sting	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Hypersensitivity	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Anaphylactoid reaction	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Infections and infestations
Abdominal infection	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Enteritis infectious	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Lung infection	3/165 (1.8%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Septic shock	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Bronchopneumonia	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Gastrointestinal infection	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Infection	5/165 (3%)		0/163 (0%)		2/167 (1.2%)		2/167 (1.2%)
Nasopharyngitis	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Periodontitis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Pharyngitis	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Sinusitis	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Skin infection	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		1/167 (0.6%)
Viral infection	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Neutropenic sepsis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Postoperative wound infection	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Tuberculosis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Appendicitis	0/165 (0%)		2/163 (1.2%)		0/167 (0%)		1/167 (0.6%)
Campylobacter gastroenteritis	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Clostridium difficile colitis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Gastroenteritis viral	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Herpes zoster	1/165 (0.6%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Bronchitis	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Erysipelas	0/165 (0%)		1/163 (0.6%)		2/167 (1.2%)		0/167 (0%)
Infectious colitis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Lower respiratory tract infection	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Soft tissue infection	2/165 (1.2%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Endocarditis	0/165 (0%)		0/163 (0%)		2/167 (1.2%)		0/167 (0%)
Gastrointestinal viral infection	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Pseudomembranous colitis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Skin bacterial infection	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Anal abscess	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Cellulitis	5/165 (3%)		2/163 (1.2%)		0/167 (0%)		4/167 (2.4%)
Clostridium difficile infection	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Haematoma infection	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Pharyngotonsillitis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Pneumonia	4/165 (2.4%)		15/163 (9.2%)		10/167 (6%)		8/167 (4.8%)
Upper respiratory tract infection	0/165 (0%)		2/163 (1.2%)		1/167 (0.6%)		0/167 (0%)
Urinary tract infection	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		2/167 (1.2%)
Bacteraemia	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Campylobacter infection	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Endocarditis bacterial	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Endocarditis enterococcal	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Gastroenteritis	0/165 (0%)		2/163 (1.2%)		1/167 (0.6%)		2/167 (1.2%)
Gastroenteritis clostridial	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Influenza	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Lobar pneumonia	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Sepsis	1/165 (0.6%)		1/163 (0.6%)		3/167 (1.8%)		4/167 (2.4%)
Wound infection	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Injury, poisoning and procedural complications
Incisional hernia, obstructive	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Fibula fracture	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Procedural intestinal perforation	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Brain contusion	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Fracture	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Rib fracture	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Spinal compression fracture	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Injury	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Postoperative thoracic procedure complication	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Road traffic accident	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Accidental overdose	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Jaw fracture	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Joint injury	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Overdose	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Laceration	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Ligament sprain	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Lumbar vertebral fracture	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Muscle strain	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Investigations
Blood creatinine increased	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Haemoglobin decreased	3/165 (1.8%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Aspartate aminotransferase increased	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Clostridium test positive	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Platelet count increased	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Alanine aminotransferase increased	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Blast cell count increased	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Neutrophil count decreased	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Platelet count decreased	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
White blood cell count decreased	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Haemoglobin	3/165 (1.8%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Electrocardiogram QT prolonged	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Metabolism and nutrition disorders
Hyperkalaemia	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Fluid retention	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Diabetes mellitus	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Dehydration	0/165 (0%)		0/163 (0%)		2/167 (1.2%)		3/167 (1.8%)
Fluid overload	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Hypokalaemia	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Hyponatraemia	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Pain in extremity	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Back pain	1/165 (0.6%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Osteoarthritis	0/165 (0%)		2/163 (1.2%)		0/167 (0%)		0/167 (0%)
Arthralgia	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Flank pain	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Myalgia	1/165 (0.6%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Myositis	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Lumbar spinal stenosis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Muscle spasms	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Arthritis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Osteonecrosis	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		1/167 (0.6%)
Neck pain	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lip neoplasm malignant stage unspecified	1/165 (0.6%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Squamous cell carcinoma	3/165 (1.8%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Chronic lymphocytic leukaemia	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Chronic myeloid leukaemia transformation	0/165 (0%)		0/163 (0%)		2/167 (1.2%)		0/167 (0%)
Prostate cancer	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Skin cancer metastatic	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Pituitary tumour	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Thyroid adenoma	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Tongue neoplasm malignant stage unspecified	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Chronic myeloid leukaemia	1/165 (0.6%)		1/163 (0.6%)		0/167 (0%)		2/167 (1.2%)
Skin cancer	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Vulval cancer	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Blast cell crisis	0/165 (0%)		0/163 (0%)		3/167 (1.8%)		1/167 (0.6%)
Adenoma benign	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Blast cell proliferation	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Squamous cell carcinoma of skin	1/165 (0.6%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Basal cell carcinoma	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		1/167 (0.6%)
Blast crisis in myelogenous leukaemia	0/165 (0%)		2/163 (1.2%)		1/167 (0.6%)		0/167 (0%)
Renal cell carcinoma	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Breast cancer	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Intraductal proliferative breast lesion	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Leukaemia	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Nervous system disorders
Cognitive disorder	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Myasthenia gravis	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Cerebrovascular accident	2/165 (1.2%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Peripheral sensory neuropathy	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Cerebral ischaemia	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Dizziness	2/165 (1.2%)		2/163 (1.2%)		0/167 (0%)		0/167 (0%)
Migraine	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Cerebellar infarction	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Cerebral haematoma	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Syncope	1/165 (0.6%)		2/163 (1.2%)		0/167 (0%)		2/167 (1.2%)
Transient ischaemic attack	2/165 (1.2%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
VIIth nerve paralysis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Headache	0/165 (0%)		2/163 (1.2%)		1/167 (0.6%)		1/167 (0.6%)
Central nervous system haemorrhage	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Neuropathy peripheral	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Paraesthesia	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Hypoaesthesia	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Psychiatric disorders
Completed suicide	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Depressed mood	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Confusional state	3/165 (1.8%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Mental status changes	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Depression	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Psychotic disorder	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Renal and urinary disorders
Pollakiuria	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Renal failure acute	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Nephrolithiasis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Renal failure	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Reproductive system and breast disorders
Uterine haemorrhage	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Endometriosis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Menorrhagia	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Menstrual disorder	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Pleural effusion	16/165 (9.7%)		27/163 (16.6%)		18/167 (10.8%)		25/167 (15%)
Pleurisy	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Pneumonitis	2/165 (1.2%)		2/163 (1.2%)		0/167 (0%)		2/167 (1.2%)
Pulmonary arterial hypertension	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Pulmonary oedema	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		2/167 (1.2%)
Chronic obstructive pulmonary disease	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Cough	1/165 (0.6%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Obstructive airways disorder	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Asthma	0/165 (0%)		1/163 (0.6%)		2/167 (1.2%)		0/167 (0%)
Bronchospasm	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Dyspnoea	5/165 (3%)		7/163 (4.3%)		8/167 (4.8%)		10/167 (6%)
Laryngeal oedema	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Oropharyngeal pain	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Dyspnoea exertional	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Pulmonary congestion	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Respiratory failure	1/165 (0.6%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Alveolar proteinosis	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Lung infiltration	1/165 (0.6%)		2/163 (1.2%)		1/167 (0.6%)		0/167 (0%)
Interstitial lung disease	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Pneumothorax	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Pulmonary hypertension	2/165 (1.2%)		2/163 (1.2%)		0/167 (0%)		2/167 (1.2%)
Skin and subcutaneous tissue disorders
Pyoderma gangrenosum	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Acute febrile neutrophilic dermatosis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Pruritus	2/165 (1.2%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Rash generalised	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Decubitus ulcer	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Erythema nodosum	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Exfoliative rash	0/165 (0%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Skin lesion	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Angioedema	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Dermatosis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Rash	3/165 (1.8%)		1/163 (0.6%)		0/167 (0%)		3/167 (1.8%)
Vascular disorders
Extremity necrosis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		1/167 (0.6%)
Hypertension	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		1/167 (0.6%)
Poor peripheral circulation	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Hypotension	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		1/167 (0.6%)
Peripheral artery thrombosis	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Haemorrhage	0/165 (0%)		1/163 (0.6%)		1/167 (0.6%)		0/167 (0%)
Deep vein thrombosis	1/165 (0.6%)		0/163 (0%)		0/167 (0%)		0/167 (0%)
Haematoma	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Peripheral ischaemia	0/165 (0%)		0/163 (0%)		1/167 (0.6%)		0/167 (0%)
Thrombosis	0/165 (0%)		1/163 (0.6%)		0/167 (0%)		0/167 (0%)
Other (Not Including Serious) Adverse Events
	100mg QD		140mg QD		50mg BID		70mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/165 (97%)		155/163 (95.1%)		160/167 (95.8%)		165/167 (98.8%)
Blood and lymphatic system disorders
Anaemia	23/165 (13.9%)		14/163 (8.6%)		26/167 (15.6%)		23/167 (13.8%)
Thrombocytopenia	22/165 (13.3%)		38/163 (23.3%)		29/167 (17.4%)		27/167 (16.2%)
Neutropenia	23/165 (13.9%)		28/163 (17.2%)		29/167 (17.4%)		28/167 (16.8%)
Cardiac disorders
Palpitations	13/165 (7.9%)		7/163 (4.3%)		8/167 (4.8%)		11/167 (6.6%)
Pericardial effusion	3/165 (1.8%)		9/163 (5.5%)		10/167 (6%)		7/167 (4.2%)
Eye disorders
Vision blurred	11/165 (6.7%)		8/163 (4.9%)		5/167 (3%)		5/167 (3%)
Periorbital oedema	8/165 (4.8%)		4/163 (2.5%)		17/167 (10.2%)		5/167 (3%)
Gastrointestinal disorders
Constipation	31/165 (18.8%)		20/163 (12.3%)		25/167 (15%)		20/167 (12%)
Dyspepsia	13/165 (7.9%)		25/163 (15.3%)		13/167 (7.8%)		16/167 (9.6%)
Diarrhoea	67/165 (40.6%)		70/163 (42.9%)		73/167 (43.7%)		82/167 (49.1%)
Stomatitis	5/165 (3%)		7/163 (4.3%)		12/167 (7.2%)		7/167 (4.2%)
Vomiting	23/165 (13.9%)		29/163 (17.8%)		32/167 (19.2%)		52/167 (31.1%)
Abdominal distension	13/165 (7.9%)		8/163 (4.9%)		9/167 (5.4%)		7/167 (4.2%)
Gastritis	4/165 (2.4%)		11/163 (6.7%)		7/167 (4.2%)		7/167 (4.2%)
Flatulence	9/165 (5.5%)		5/163 (3.1%)		6/167 (3.6%)		3/167 (1.8%)
Toothache	10/165 (6.1%)		15/163 (9.2%)		8/167 (4.8%)		8/167 (4.8%)
Abdominal pain	25/165 (15.2%)		26/163 (16%)		24/167 (14.4%)		20/167 (12%)
Abdominal pain upper	13/165 (7.9%)		24/163 (14.7%)		17/167 (10.2%)		18/167 (10.8%)
Nausea	37/165 (22.4%)		54/163 (33.1%)		52/167 (31.1%)		69/167 (41.3%)
General disorders
Fatigue	62/165 (37.6%)		62/163 (38%)		56/167 (33.5%)		49/167 (29.3%)
Chest pain	21/165 (12.7%)		16/163 (9.8%)		19/167 (11.4%)		17/167 (10.2%)
Oedema peripheral	30/165 (18.2%)		29/163 (17.8%)		30/167 (18%)		36/167 (21.6%)
Pain	19/165 (11.5%)		10/163 (6.1%)		12/167 (7.2%)		10/167 (6%)
Chills	11/165 (6.7%)		11/163 (6.7%)		16/167 (9.6%)		14/167 (8.4%)
Influenza like illness	14/165 (8.5%)		17/163 (10.4%)		9/167 (5.4%)		13/167 (7.8%)
Asthenia	15/165 (9.1%)		16/163 (9.8%)		23/167 (13.8%)		27/167 (16.2%)
Pyrexia	32/165 (19.4%)		40/163 (24.5%)		43/167 (25.7%)		44/167 (26.3%)
Infections and infestations
Infection	9/165 (5.5%)		4/163 (2.5%)		8/167 (4.8%)		2/167 (1.2%)
Nasopharyngitis	23/165 (13.9%)		13/163 (8%)		22/167 (13.2%)		13/167 (7.8%)
Oral herpes	13/165 (7.9%)		5/163 (3.1%)		9/167 (5.4%)		8/167 (4.8%)
Sinusitis	19/165 (11.5%)		8/163 (4.9%)		17/167 (10.2%)		12/167 (7.2%)
Bronchitis	14/165 (8.5%)		5/163 (3.1%)		16/167 (9.6%)		11/167 (6.6%)
Conjunctivitis	3/165 (1.8%)		11/163 (6.7%)		7/167 (4.2%)		6/167 (3.6%)
Pneumonia	5/165 (3%)		5/163 (3.1%)		10/167 (6%)		13/167 (7.8%)
Upper respiratory tract infection	28/165 (17%)		26/163 (16%)		35/167 (21%)		23/167 (13.8%)
Urinary tract infection	15/165 (9.1%)		13/163 (8%)		12/167 (7.2%)		9/167 (5.4%)
Influenza	13/165 (7.9%)		4/163 (2.5%)		17/167 (10.2%)		11/167 (6.6%)
Injury, poisoning and procedural complications
Contusion	4/165 (2.4%)		10/163 (6.1%)		12/167 (7.2%)		3/167 (1.8%)
Investigations
Weight decreased	14/165 (8.5%)		19/163 (11.7%)		18/167 (10.8%)		27/167 (16.2%)
Weight increased	18/165 (10.9%)		8/163 (4.9%)		13/167 (7.8%)		11/167 (6.6%)
Metabolism and nutrition disorders
Decreased appetite	16/165 (9.7%)		21/163 (12.9%)		21/167 (12.6%)		24/167 (14.4%)
Musculoskeletal and connective tissue disorders
Pain in extremity	33/165 (20%)		29/163 (17.8%)		24/167 (14.4%)		22/167 (13.2%)
Back pain	26/165 (15.8%)		29/163 (17.8%)		28/167 (16.8%)		24/167 (14.4%)
Arthralgia	47/165 (28.5%)		39/163 (23.9%)		36/167 (21.6%)		30/167 (18%)
Myalgia	27/165 (16.4%)		26/163 (16%)		24/167 (14.4%)		22/167 (13.2%)
Bone pain	20/165 (12.1%)		25/163 (15.3%)		15/167 (9%)		15/167 (9%)
Muscle spasms	10/165 (6.1%)		4/163 (2.5%)		14/167 (8.4%)		8/167 (4.8%)
Musculoskeletal pain	24/165 (14.5%)		13/163 (8%)		15/167 (9%)		18/167 (10.8%)
Neck pain	10/165 (6.1%)		6/163 (3.7%)		5/167 (3%)		6/167 (3.6%)
Nervous system disorders
Dizziness	24/165 (14.5%)		26/163 (16%)		25/167 (15%)		25/167 (15%)
Headache	75/165 (45.5%)		73/163 (44.8%)		60/167 (35.9%)		76/167 (45.5%)
Paraesthesia	12/165 (7.3%)		11/163 (6.7%)		10/167 (6%)		7/167 (4.2%)
Psychiatric disorders
Anxiety	6/165 (3.6%)		9/163 (5.5%)		15/167 (9%)		12/167 (7.2%)
Depression	16/165 (9.7%)		12/163 (7.4%)		14/167 (8.4%)		11/167 (6.6%)
Insomnia	19/165 (11.5%)		20/163 (12.3%)		14/167 (8.4%)		12/167 (7.2%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	41/165 (24.8%)		51/163 (31.3%)		54/167 (32.3%)		51/167 (30.5%)
Cough	53/165 (32.1%)		42/163 (25.8%)		57/167 (34.1%)		54/167 (32.3%)
Dyspnoea	49/165 (29.7%)		51/163 (31.3%)		53/167 (31.7%)		43/167 (25.7%)
Oropharyngeal pain	20/165 (12.1%)		16/163 (9.8%)		19/167 (11.4%)		17/167 (10.2%)
Dyspnoea exertional	11/165 (6.7%)		8/163 (4.9%)		9/167 (5.4%)		2/167 (1.2%)
Epistaxis	15/165 (9.1%)		15/163 (9.2%)		7/167 (4.2%)		12/167 (7.2%)
Skin and subcutaneous tissue disorders
Acne	5/165 (3%)		7/163 (4.3%)		7/167 (4.2%)		9/167 (5.4%)
Erythema	5/165 (3%)		7/163 (4.3%)		9/167 (5.4%)		5/167 (3%)
Pruritus	24/165 (14.5%)		22/163 (13.5%)		17/167 (10.2%)		23/167 (13.8%)
Night sweats	7/165 (4.2%)		10/163 (6.1%)		12/167 (7.2%)		10/167 (6%)
Alopecia	13/165 (7.9%)		8/163 (4.9%)		7/167 (4.2%)		13/167 (7.8%)
Dry skin	10/165 (6.1%)		8/163 (4.9%)		8/167 (4.8%)		6/167 (3.6%)
Hyperhidrosis	11/165 (6.7%)		4/163 (2.5%)		9/167 (5.4%)		1/167 (0.6%)
Rash	37/165 (22.4%)		52/163 (31.9%)		43/167 (25.7%)		43/167 (25.7%)
Dermatitis acneiform	4/165 (2.4%)		8/163 (4.9%)		8/167 (4.8%)		11/167 (6.6%)
Petechiae	1/165 (0.6%)		11/163 (6.7%)		4/167 (2.4%)		6/167 (3.6%)
Vascular disorders
Hypertension	15/165 (9.1%)		12/163 (7.4%)		13/167 (7.8%)		20/167 (12%)
Flushing	9/165 (5.5%)		5/163 (3.1%)		5/167 (3%)		7/167 (4.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.