Paclitaxel With / Without GW572016 (Lapatinib) As First Line Therapy For Women With Advanced Or Metastatic Breast Cancer

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00075270
• Collaborator: (none)
• Enrollment: 580
• Locations: 177
• Arms: 2
• Duration (Months): 98
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy and safety of an oral dual tyrosine kinase inhibitor (GW572016) in combination with paclitaxel compared to paclitaxel alone in first line advanced or metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: Paclitaxel; Drug: GW572016 (Lapatinib)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 580 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, 2-Arm, Phase III Study of Oral GW572016 in Combination With Paclitaxel in Subjects Previously Untreated or Advanced or Metastatic Breast Cancer
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Oct 1, 2006
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Lapatinib 1500 mg, once daily and Paclitaxel 175 mg/m Intravenously over 3 hours ever 3 weeks	Drug: Paclitaxel; Active Comparator; Drug: GW572016 (Lapatinib); Oral GW572016 Lapatinib; Other Names: Paclitaxel
Placebo Comparator: Arm 2 Paclitaxel 175 mg/m Intravenously over 3 hours ever 3 weeks and Placebo	Drug: Paclitaxel; Active Comparator

Outcome Measures

Primary Outcome Measures

1. Time to Progression as Evaluated by the Investigator [Randomization until the date of disease progression or death (average of 26 weeks)]

   Time to progression (TTP) is defined as the interval between the date of randomization and the earliest date of progression of disease (PD) or death due to breast cancer. The investigator assessed PD based on radiological PD (imaging data) and clinical symptomatic progress (Response Evaluation Criteria in Solid Tumors [RECIST] Criteria: target lesion (TL), at least a 20% increase in the sum of largest diameter (LD) of TLs or the appearance of one or more new lesions; non-TL (NTL), the appearance of one or more new lesions and/or unequivocal progression of existing NTLs). TTP was assessed in participants who died due to breast cancer or progressed, as assessed by the investigator, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.

2. Time to Progression as Evaluated by the Independent Review Committee (IRC) [Randomization until the date of disease progression or death (average of 26 weeks)]

   Time to progression is defined as the interval between the date of randomization and the earliest date of progression of disease (PD) or death due to breast cancer. The IRC assessed PD based on radiological PD (imaging data) and clinical symptomatic progress (Response Evaluation Criteria in Solid Tumors [RECIST] Criteria: target lesion (TL), at least a 20% increase in the sum of largest diameter (LD) of TLs or the appearance of one or more new lesions; non-TL (NTL), the appearance of one or more new lesions and/or unequivocal progression of existing NTLs). TTP was assessed in participants who died due to breast cancer or progressed, as assessed by the independent reviewer, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.

Secondary Outcome Measures

1. Number of Participants With Tumor Response as Evaluated by the Investigator [Randomization until the date of disease progression or death (average of 26 weeks)]

   The percentage of participants with tumor response is defined as those participants with measurable disease who achieved either a complete response (CR) or partial response (PR). The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the measurability of tumor lesions, to determine target lesion (TLs) and non-target lesion (NTLs). CR (TLs and NTLs): the disappearance of all TLs and NTLs; PR (for TLs): at least a 30% decrease in the sum of the largest diameter (LD) of TLs, taking as a reference the Baseline sum LD; PR (for NTLs): persistence of one or more lesions.

2. Number of Participants With Tumor Response as Evaluated by the Independent Review Committee [Randomization until the date of disease progression or death (average of 26 weeks)]

   The percentage of participants with tumor response is defined as those participants with measurable disease who achieved either a complete response (CR) or partial response (PR). The RECIST criteria was used to evaluate the measurability of tumor lesions, to determine target lesion (TLs) and non-target lesion (NTLs). CR (TLs and NTLs): the disappearance of all TLs and NTLs; PR (for TLs): at least a 30% decrease in the sum of the largest diameter (LD) of TLs, taking as a reference the Baseline sum LD; PR (for NTLs): persistence of one or more lesions.

3. Percentage of Participants With Clinical Benefit (CB) as Assessed by the Investigator [Randomization until the date of disease progression or death (average of 26 weeks)]

   Percentage of participants. with CB is defined as the percentage of participants with evidence of CR (disappearance of all TLs and NTLs), PR (TLs: a >=30% decrease in the sum of the LD, taking as a reference the Baseline sum LD; NTLs: persistence of >=1 lesion), or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) for >=6 months based on RECIST criteria. PD for TL: a >=20% increase in the sum of the LD of TLs or the appearance of >=1 new lesion. PD for NTLs: the appearance of >=1 new lesion and/or unequivocal progression of existing NTLs.

4. Number of Participants With a Response of CR or PR by the Indicated Study Week [Weeks 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, and 72]

   Time to response (TTR) is defined as the time from randomization until the first documented evidence of CR (disappearance of all TLs and NTLs) or PR (for TLs: a >=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD; for NTLs: the persistence of >=1 lesion) (whichever status was recorded first). TTR data are displayed as the number of participants achieving a CR or PR by the indicated week. The investigator evaluated the TTR, and the analysis was based on responses confirmed at a repeat assessment, with the TTR taken as the first time the response was observed.

5. Duration of Response (DOR) [From the time of the first documented complete or partial response until the first documented evidence of progression or death (average of 26 weeks)]

   The investigator evaluated the DOR for the subset of participants who showed a CR (disappearance of all TLs and NTLs) or PR (TLs: a >=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD; NTLs: persistence of >=1 lesion). DOR is defined as the time from the first documented evidence of PR or CR until the first documented sign of PD (TL: a >=20% increase in the sum of the LD of TLs or the appearance of >=1 new lesion; NTL: the appearance of >=1 new lesion and/or unequivocal progression of existing NTLs) or death due to breast cancer, if sooner.

6. Progression-Free Survival (PFS) [Randomization until the date of disease progression or death (average of 26 weeks)]

   PFS is defined as the interval between the date of randomization and the earliest date of progression disease (PD) or death due to any cause, if sooner. For TLs, progressive disease is defined as at least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions. For NTLs, progressive disease is defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. par., participants.

7. Number of Participants Who Progressed or Died at or Prior to 6 Months, as a Measure of Six Months Progression-free Survival (PFS) [Randomization until the date of disease progression or death (average of 26 weeks)]

   PFS is defined as the interval between the date of randomization and the earliest date of disease progression or death due to any cause, if sooner. Six months PFS is defined as PFS at six months from the time of randomization. Raw data for 6 months PFS are not available; thus, data are presented as the number of participants who progressed or died at or prior to 6 months. For TLs, progressive disease is defined asat least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions. For NTLs, progressive disease is defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. PFS was assessed in participants who died or progressed, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.

8. Overall Survival [Randomization until the date of death due to any cause (average of 24 months)]

   Overall survival is defined as the time from randomization until death due to any cause.

9. Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores [Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal]

   The FACT-B questionnaire was designed to measure multidimensional quality of life (QOL) in participants with breast cancer. The physical and functional well-being subscale scores range from 0 to 28, based on 7 questions (each scored from 0 [not at all] to 4 [very much] for all subscales); the emotional and social/family well-being (1 question optional) subscale scores range from 0 to 24 (based on 6 questions), and the additional concerns subscale score ranges from 0 to 40, based on 10 questions. The FACT-B Total Score (0 [better QOL] to 144 [worse QOL]) is the sum of the subscale scores.

10. Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores [Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal]

    The FACT-G questionnaire was designed to measure multidimensional QOL in participants with cancer and includes subscales for physical, social/family, emotional, and functional well-being. The physical, social/family, and functional well-being subscale scores range from 0 to 28, based on responses to 7 questions (each question scored from 0 [not at all] to 4 [very much]); the emotional well-being subscale score ranges from 0 to 24, based on responses to 6 questions. The FACT-G Total Score (ranging from 0 [better QOL] to 108 [worse QOL]) is the sum of the subscale scores.

11. Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores [Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal]

    The TOI questionnaire was designed to measure multidimensional QOL in participants with cancer and includes subscales for physical, functional well-being, and additional cancer concerns. The physical and functional well-being subscale scores range from 0 to 28, based on 7 questions (each question scored from 0 [not at all] to 4 [very much]); the breast cancer unweighted subscale scores range from 0 to 36, based on 9 questions. The total TOI score (ranging from 0 [better QOL] to 92 [worse QOL]) is the sum of the TOI subscale scores.

12. Number of Participants With the Indicated ErbB2 Status at Baseline [Baseline]

    The Press Laboratory collected tumor tissues of participants for ErbB2 testing. ErbB2 testing is done to detect breast cancer and predict its likely outcome. All samples were analyzed by the Press Laboratory. Participants were categorized as ErbB2 positive (overexpression of the ErbB2 gene), ErbB2 negative, and assay not done (which included participants with no available samples and those with inconclusive results). ErbB2 status is determined by immunohistochemistry (ICH) assay and fluorescence in situ hybridization (FISH) testing. Negative ErbB2 status is defined as 0 or 1+ by IHC, or as 2+ by IHC and FISH.

13. ErbB2 Ratio [Baseline]

    The Press Laboratory collected tumor tissues of participants for biomarker testing. All samples were analyzed by the Press Laboratory. The ratio of ErbB2 gene signals to chromosome 17 signals, which indicates the progression of breast cancer, was calculated. Low levels of amplification (few copies) may have a ratio of 2-5, whereas high levels of amplification may have a ratio >10.

14. Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening [Screening (Day -1)]

    The Press Laboratory tested tumor tissue samples (taken at Screening, prior to randomization to study treatment) to determine intra-tumoral expression levels of ErbB1, ErbB2, and other analytes associated with these pathways by IHC, the process of detecting antigens (e.g., proteins) in cells of a tissue section. The IHC assessment is expressed as: 0, no staining (no cancer cells); 1+, faint staining; 2+, weak to moderate complete staining; 3+, strong complete staining (many cancer cells). A status of "Assay not done" was assigned to participants with no available samples and to those with inconclusive results. If strong staining is observed, breast cancer that has high levels of HER2 expression (overexpression) is indicated. If moderate/weak staining is observed (IHC=2+), breast cancer that has low/moderate expression levels is indicated. When no staining is observed (IHC=0), breast cancer HER2 expression may be below the level of detection of the assay.

15. Number of Participants With the Indicated ErbB2 Fluorescence in Situ Hybridization (FISH) Results [Baseline]

    The Press Laboratory tested participants who were 2+ (weak to moderate complete staining) or 3+ (strong complete staining) for ErbB2 overexpression by IHC for ErbB2 gene amplification using the FISH assay. The results of the FISH assay can be ErbB2 gene "amplification" (increased number of copies of the ErbB2 gene) or "non-amplification" (not many copies of the ErbB2 gene). A status of "Assay not done" was assigned to those participants with no available samples and to those with inconclusive results (e.g., due to hybridization or staining problems).

16. Serum ErbB1 Concentration [Screening (Day-1) and Withdrawal (up to Study Week 129)]

    The Quest Laboratory collected blood samples for quantitative determination of serum ErbB1. The results of serum monitoring were used to compare tumor response rates following randomized therapy.

17. Serum ErbB2 Concentration [Screening (Day-1) and Withdrawal (up to Study Week 129)]

    The Quest Laboratory collected blood samples for quantitative determination of serum ErbB2. The results of serum monitoring were used to compare tumor response rates following randomized therapy.

18. Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 [Baseline (Day 1) until 30 days after the last dose of randomized therapy (average of 26 weeks)]

    The severity of adverse events was graded per the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3. Grades 1 through 5 have unique clinical descriptions of severity for each AE based on the following general guideline: Grade 1, Mild AE; Grade 2, Moderate AE; Grade 3, Severe AE; Grade 4, Life-threatening or disabling AE; Grade 5, death related to AE.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Signed Informed Consent

• Able to swallow an oral medication

• Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram

• Adequate kidney and liver function

• Adequate bone marrow function

• Tumor tissue available for testing

• Prior adjuvant or neoadjuvant therapy is permitted with an anthracycline or anthracenedione-containing regimen however, subjects must have had cumulative doses of less than 360 mg/m2 of doxorubicin, 720 mg/m2 of epirubicin, or 72 mg/m2 of mitoxantrone

• No Her2/neu overexpression in tumor tissue tested or status unknown if tissue has never been tested

Exclusion criteria:

• Prior treatment regimens for advanced or metastatic breast cancer.

• Pregnant or lactating

• Conditions that would effect the absorption of an oral drug

• Active infection

• Brain metastases

• Treatment with EGFR (Endothelial Growth Factor Receptor) inhibitor.

• Known hypersensitivity to Taxol or excipients of Taxol

• Peripheral neuropathy of Grade 2 or greater is not permitted

• Severe Cardiovascular disease or cardiac disease requiring a device.

• Serious medical or psychiatric disorder that would interfere with the patient's safety or informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Tucson	Arizona	United States	85712
2	GSK Investigational Site	Hot Springs	Arkansas	United States	71913
3	GSK Investigational Site	Jonesboro	Arkansas	United States	72401
4	GSK Investigational Site	Fountain Valley	California	United States	92708
5	GSK Investigational Site	La Jolla	California	United States	92093-0987
6	GSK Investigational Site	Rancho Mirage	California	United States	92270
7	GSK Investigational Site	Vallejo	California	United States	94589
8	GSK Investigational Site	Denver	Colorado	United States	80218
9	GSK Investigational Site	Boca Raton	Florida	United States	33486
10	GSK Investigational Site	Orlando	Florida	United States	32804
11	GSK Investigational Site	Port St. Lucie	Florida	United States	34952
12	GSK Investigational Site	West Palm Beach	Florida	United States	33401
13	GSK Investigational Site	Atlanta	Georgia	United States	30341
14	GSK Investigational Site	Marietta	Georgia	United States	30060
15	GSK Investigational Site	Savannah	Georgia	United States	31405
16	GSK Investigational Site	Savannah	Georgia	United States	31406
17	GSK Investigational Site	Indianapolis	Indiana	United States	46260
18	GSK Investigational Site	Kansas City	Kansas	United States	66160
19	GSK Investigational Site	Metairie	Louisiana	United States	70006
20	GSK Investigational Site	Baltimore	Maryland	United States	21201
21	GSK Investigational Site	Glen Burnie	Maryland	United States	21225
22	GSK Investigational Site	Springfield	Massachusetts	United States	01199
23	GSK Investigational Site	Duluth	Minnesota	United States	55802
24	GSK Investigational Site	Robbinsdale	Minnesota	United States	55422
25	GSK Investigational Site	St. Louis	Missouri	United States	63141
26	GSK Investigational Site	Voorhees	New Jersey	United States	08043
27	GSK Investigational Site	Santa Fe	New Mexico	United States	87505
28	GSK Investigational Site	Nyack	New York	United States	10960
29	GSK Investigational Site	Syracuse	New York	United States	13210
30	GSK Investigational Site	Charlotte	North Carolina	United States	28203
31	GSK Investigational Site	Greenville	North Carolina	United States	27834
32	GSK Investigational Site	Fargo	North Dakota	United States	58103
33	GSK Investigational Site	Canton	Ohio	United States	44718
34	GSK Investigational Site	Portland	Oregon	United States	97227
35	GSK Investigational Site	Columbia	South Carolina	United States	29210
36	GSK Investigational Site	Knoxville	Tennessee	United States	37916
37	GSK Investigational Site	Knoxville	Tennessee	United States	37920
38	GSK Investigational Site	Amarillo	Texas	United States	79106
39	GSK Investigational Site	Fort Worth	Texas	United States	76104
40	GSK Investigational Site	Houston	Texas	United States	77054
41	GSK Investigational Site	San Antonio	Texas	United States	78229
42	GSK Investigational Site	Burlington	Vermont	United States	05401
43	GSK Investigational Site	Norfolk	Virginia	United States	23502
44	GSK Investigational Site	Tacoma	Washington	United States	98405
45	GSK Investigational Site	Milwaukee	Wisconsin	United States	53226
46	GSK Investigational Site	Capital Federal	Buenos Aires	Argentina	C1405CBA
47	GSK Investigational Site	Capital Federal	Buenos Aires	Argentina	C1426ANZ
48	GSK Investigational Site	Buenos Aires		Argentina	1425
49	GSK Investigational Site	Fitzroy	Victoria	Australia	3065
50	GSK Investigational Site	Malvern	Victoria	Australia	3144
51	GSK Investigational Site	Wodonga	Victoria	Australia	3690
52	GSK Investigational Site	Nedlands	Western Australia	Australia	6009
53	GSK Investigational Site	Vienna		Austria	A-1090
54	GSK Investigational Site	Brugge		Belgium	8000
55	GSK Investigational Site	Brussels		Belgium	1070
56	GSK Investigational Site	Brussel		Belgium	1090
57	GSK Investigational Site	Kortrijk		Belgium	8500
58	GSK Investigational Site	Leuven		Belgium	3000
59	GSK Investigational Site	Roeselare		Belgium	8800
60	GSK Investigational Site	Salvador	Bahía	Brazil	41825-010
61	GSK Investigational Site	Rio de Janeiro		Brazil	20560-120
62	GSK Investigational Site	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
63	GSK Investigational Site	Sudbury	Ontario	Canada	P3E 5J1
64	GSK Investigational Site	Thunder Bay	Ontario	Canada	P7B 6V4
65	GSK Investigational Site	Montreal	Quebec	Canada	H3T 1E2
66	GSK Investigational Site	Montreal	Quebec	Canada	H4J 1C5
67	GSK Investigational Site	Sherbrooke	Quebec	Canada	J1H 5N4
68	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500921
69	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7591046
70	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile
71	GSK Investigational Site	Brno		Czech Republic	656 53
72	GSK Investigational Site	Hradec Kralove		Czech Republic	500 05
73	GSK Investigational Site	Olomouc		Czech Republic	775 20
74	GSK Investigational Site	Aalen	Baden-Wuerttemberg	Germany	73428
75	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg	Germany	70190
76	GSK Investigational Site	Ulm	Baden-Wuerttemberg	Germany	89075
77	GSK Investigational Site	Augsburg	Bayern	Germany	86150
78	GSK Investigational Site	Bayreuth	Bayern	Germany	95445
79	GSK Investigational Site	Coburg	Bayern	Germany	96450
80	GSK Investigational Site	Muenchen	Bayern	Germany	80335
81	GSK Investigational Site	Muenchen	Bayern	Germany	80637
82	GSK Investigational Site	Fuerstenwalde	Brandenburg	Germany	15517
83	GSK Investigational Site	Stade	Niedersachsen	Germany	21680
84	GSK Investigational Site	Herne	Nordrhein-Westfalen	Germany	44625
85	GSK Investigational Site	Ibbenbueren	Nordrhein-Westfalen	Germany	49477
86	GSK Investigational Site	Muenster	Nordrhein-Westfalen	Germany	48149
87	GSK Investigational Site	Halle	Sachsen-Anhalt	Germany	06120
88	GSK Investigational Site	Kiel	Schleswig-Holstein	Germany	24103
89	GSK Investigational Site	Jena	Thueringen	Germany	07743
90	GSK Investigational Site	Berlin		Germany	10117
91	GSK Investigational Site	Berlin		Germany	10367
92	GSK Investigational Site	Berlin		Germany	13353
93	GSK Investigational Site	Berlin		Germany	14195
94	GSK Investigational Site	Hamburg		Germany	20259
95	GSK Investigational Site	Hamburg		Germany	22457
96	GSK Investigational Site	Hamburg		Germany	22767
97	GSK Investigational Site	Budapest		Hungary	1082
98	GSK Investigational Site	Nyíregyháza		Hungary	4400
99	GSK Investigational Site	Szombathely		Hungary	9700
100	GSK Investigational Site	Zalaegerszeg-Pózva		Hungary	8900
101	GSK Investigational Site	Benevento	Campania	Italy	82100
102	GSK Investigational Site	Napoli	Campania	Italy	80131
103	GSK Investigational Site	Forlì	Emilia-Romagna	Italy	47100
104	GSK Investigational Site	Parma	Emilia-Romagna	Italy	43100
105	GSK Investigational Site	Ravenna	Emilia-Romagna	Italy	48100
106	GSK Investigational Site	Rimini	Emilia-Romagna	Italy	47900
107	GSK Investigational Site	Roma	Lazio	Italy	00152
108	GSK Investigational Site	Roma	Lazio	Italy	00157
109	GSK Investigational Site	Pietra Ligure (SV)	Liguria	Italy	17027
110	GSK Investigational Site	Bergamo	Lombardia	Italy	24128
111	GSK Investigational Site	Pavia	Lombardia	Italy	27100
112	GSK Investigational Site	Candiolo (TO)	Piemonte	Italy	10060
113	GSK Investigational Site	Torino	Piemonte	Italy	10153
114	GSK Investigational Site	Sassari	Sardegna	Italy	07100
115	GSK Investigational Site	Prato (PO)	Toscana	Italy	59100
116	GSK Investigational Site	Perugia	Umbria	Italy	06122
117	GSK Investigational Site	Gyeonggi-do		Korea, Republic of	411-769
118	GSK Investigational Site	Seoul		Korea, Republic of	135-710
119	GSK Investigational Site	Daugavpils		Latvia	LV5420
120	GSK Investigational Site	Liepaja		Latvia	LV3401
121	GSK Investigational Site	Riga		Latvia	LV 1002
122	GSK Investigational Site	Riga		Latvia	LV 1079
123	GSK Investigational Site	Acapulco	Guerrero	Mexico	39670
124	GSK Investigational Site	Guadalajara	Jalisco	Mexico	CP44280
125	GSK Investigational Site	Colima		Mexico	28010
126	GSK Investigational Site	Durango		Mexico	34000
127	GSK Investigational Site	Amersfoort		Netherlands	3816 CP
128	GSK Investigational Site	Leiden		Netherlands	2333 ZA
129	GSK Investigational Site	Nieuwegein		Netherlands	3435 CM
130	GSK Investigational Site	Utrecht		Netherlands	2584 CX
131	GSK Investigational Site	Utrecht		Netherlands	3584 CX
132	GSK Investigational Site	Auckland		New Zealand	1001
133	GSK Investigational Site	Christchurch		New Zealand	8001
134	GSK Investigational Site	Lahore		Pakistan	54000
135	GSK Investigational Site	Lahore		Pakistan
136	GSK Investigational Site	Callao		Peru	Callao 2
137	GSK Investigational Site	Lima		Peru	Lima 34
138	GSK Investigational Site	Krakow		Poland	31-826
139	GSK Investigational Site	Olsztyn		Poland	10-226
140	GSK Investigational Site	Olsztyn		Poland	10-228
141	GSK Investigational Site	Poznan		Poland	61-866
142	GSK Investigational Site	Warszawa		Poland	02-781
143	GSK Investigational Site	Wroclaw		Poland	53-413
144	GSK Investigational Site	Moscow Region		Russian Federation	143 423
145	GSK Investigational Site	Moscow		Russian Federation	105005
146	GSK Investigational Site	Moscow		Russian Federation	115 478
147	GSK Investigational Site	Moscow		Russian Federation	117997
148	GSK Investigational Site	Moscow		Russian Federation	129 128
149	GSK Investigational Site	Moscow		Russian Federation	129301
150	GSK Investigational Site	St. Petersburg		Russian Federation	197022
151	GSK Investigational Site	St. Petersburg		Russian Federation	197758
152	GSK Investigational Site	Banska Bystrica		Slovakia	975 17
153	GSK Investigational Site	Bratislava		Slovakia	833 10
154	GSK Investigational Site	Kosice		Slovakia	041 91
155	GSK Investigational Site	Poprad		Slovakia	058 01
156	GSK Investigational Site	Parktown	Gauteng	South Africa	2193
157	GSK Investigational Site	Capital Park		South Africa	0002
158	GSK Investigational Site	Overport		South Africa	4001
159	GSK Investigational Site	Parow		South Africa	7525
160	GSK Investigational Site	Port Elizabeth		South Africa	6001
161	GSK Investigational Site	Alcorcón/Madrid		Spain	28922
162	GSK Investigational Site	Baracaldo/Vizcaya		Spain	48903
163	GSK Investigational Site	Caceres		Spain	10003
164	GSK Investigational Site	Cuidad Real		Spain	13002
165	GSK Investigational Site	Jaen		Spain	23007
166	GSK Investigational Site	La Laguna (Santa Cruz de Tenerife)		Spain	38320
167	GSK Investigational Site	Las Palmas De Gran Canaria		Spain	35016
168	GSK Investigational Site	Madrid		Spain	28035
169	GSK Investigational Site	Móstoles/Madrid		Spain	28935
170	GSK Investigational Site	Palma de Mallorca		Spain	07014
171	GSK Investigational Site	Pontevedra		Spain	36071
172	GSK Investigational Site	San Sebastián		Spain	20014
173	GSK Investigational Site	Santa Cruz de Tenerife		Spain	38320
174	GSK Investigational Site	Zaragoza		Spain	50009
175	GSK Investigational Site	Zaragoza		Spain
176	GSK Investigational Site	Istanbul		Turkey	34865
177	GSK Investigational Site	Istanbul		Turkey

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

• Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A. Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol. 2009 Aug 20;27(24):3908-15. doi: 10.1200/JCO.2008.18.1925. Epub 2009 Jul 20.
• Tenori L, Oakman C, Claudino WM, Bernini P, Cappadona S, Nepi S, Biganzoli L, Arbushites MC, Luchinat C, Bertini I, Di Leo A. Exploration of serum metabolomic profiles and outcomes in women with metastatic breast cancer: a pilot study. Mol Oncol. 2012 Aug;6(4):437-44. doi: 10.1016/j.molonc.2012.05.003. Epub 2012 Jun 1.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00075270
• Other Study ID Numbers: EGF30001; NCT00085046
• First Posted: Jan 9, 2004
• Last Update Posted: May 6, 2015
• Last Verified: Feb 1, 2014

• Keywords provided by GlaxoSmithKline: metastatic breast cancer; ErbB1; kinase inhibitor; ErbB2; EGFR; lapatinib; Her2-neu
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Lapatinib

Study Results

Participant Flow

Pre-assignment Detail	A total of 580 participants were enrolled and randomized to treatment; however one participant withdrew from the study before taking any medication. Thus, only 579 participants were included in the Intent-to-Treat Population (comprised of all randomized participants who had received at least one dose of randomized therapy [lapatinib or placebo]).

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Period Title: Overall Study
STARTED	291	288
Missing	26	13
COMPLETED	5	4
NOT COMPLETED	286	284

Baseline Characteristics

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel	Total
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Total of all reporting groups
Overall Participants	291	288	579
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.3 (10.45)	52.4 (10.98)	51.8 (10.72)
Sex: Female, Male (Count of Participants)
Female	291 100%	288 100%	579 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	190 65.3%	182 63.2%	372 64.2%
Black	10 3.4%	10 3.5%	20 3.5%
Asian	30 10.3%	35 12.2%	65 11.2%
American Hispanic	54 18.6%	53 18.4%	107 18.5%
Unknown	7 2.4%	8 2.8%	15 2.6%

Outcome Measures

1. Primary Outcome

Title	Time to Progression as Evaluated by the Investigator
Description	Time to progression (TTP) is defined as the interval between the date of randomization and the earliest date of progression of disease (PD) or death due to breast cancer. The investigator assessed PD based on radiological PD (imaging data) and clinical symptomatic progress (Response Evaluation Criteria in Solid Tumors [RECIST] Criteria: target lesion (TL), at least a 20% increase in the sum of largest diameter (LD) of TLs or the appearance of one or more new lesions; non-TL (NTL), the appearance of one or more new lesions and/or unequivocal progression of existing NTLs). TTP was assessed in participants who died due to breast cancer or progressed, as assessed by the investigator, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants who had received at least one dose of randomized therapy (lapatinib or placebo)

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Median (Inter-Quartile Range) [weeks]	29.0	22.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib With Paclitaxel, Placebo With Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.142
	Comments	P-value from stratified log-rank test, stratifying for stage of disease and site of disease at screening
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate of the treatment hazard ratio is based on the log-rank test.

2. Primary Outcome

Title	Time to Progression as Evaluated by the Independent Review Committee (IRC)
Description	Time to progression is defined as the interval between the date of randomization and the earliest date of progression of disease (PD) or death due to breast cancer. The IRC assessed PD based on radiological PD (imaging data) and clinical symptomatic progress (Response Evaluation Criteria in Solid Tumors [RECIST] Criteria: target lesion (TL), at least a 20% increase in the sum of largest diameter (LD) of TLs or the appearance of one or more new lesions; non-TL (NTL), the appearance of one or more new lesions and/or unequivocal progression of existing NTLs). TTP was assessed in participants who died due to breast cancer or progressed, as assessed by the independent reviewer, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Median (Inter-Quartile Range) [weeks]	33.7	26.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib With Paclitaxel, Placebo With Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.094
	Comments	P-value from stratified log-rank test, stratifying for stage of disease and site of disease at screening
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate of the treatment hazard ratio was based on the log-rank test.

3. Secondary Outcome

Title	Number of Participants With Tumor Response as Evaluated by the Investigator
Description	The percentage of participants with tumor response is defined as those participants with measurable disease who achieved either a complete response (CR) or partial response (PR). The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the measurability of tumor lesions, to determine target lesion (TLs) and non-target lesion (NTLs). CR (TLs and NTLs): the disappearance of all TLs and NTLs; PR (for TLs): at least a 30% decrease in the sum of the largest diameter (LD) of TLs, taking as a reference the Baseline sum LD; PR (for NTLs): persistence of one or more lesions.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
CR	14 4.8%	6 2.1%
PR	88 30.2%	67 23.3%

4. Secondary Outcome

Title	Number of Participants With Tumor Response as Evaluated by the Independent Review Committee
Description	The percentage of participants with tumor response is defined as those participants with measurable disease who achieved either a complete response (CR) or partial response (PR). The RECIST criteria was used to evaluate the measurability of tumor lesions, to determine target lesion (TLs) and non-target lesion (NTLs). CR (TLs and NTLs): the disappearance of all TLs and NTLs; PR (for TLs): at least a 30% decrease in the sum of the largest diameter (LD) of TLs, taking as a reference the Baseline sum LD; PR (for NTLs): persistence of one or more lesions.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
CR	1 0.3%	1 0.3%
PR	77 26.5%	53 18.4%

5. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit (CB) as Assessed by the Investigator
Description	Percentage of participants. with CB is defined as the percentage of participants with evidence of CR (disappearance of all TLs and NTLs), PR (TLs: a >=30% decrease in the sum of the LD, taking as a reference the Baseline sum LD; NTLs: persistence of >=1 lesion), or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) for >=6 months based on RECIST criteria. PD for TL: a >=20% increase in the sum of the LD of TLs or the appearance of >=1 new lesion. PD for NTLs: the appearance of >=1 new lesion and/or unequivocal progression of existing NTLs.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Number [Percentage of participants]	40.5 13.9%	31.9 11.1%

6. Secondary Outcome

Title	Number of Participants With a Response of CR or PR by the Indicated Study Week
Description	Time to response (TTR) is defined as the time from randomization until the first documented evidence of CR (disappearance of all TLs and NTLs) or PR (for TLs: a >=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD; for NTLs: the persistence of >=1 lesion) (whichever status was recorded first). TTR data are displayed as the number of participants achieving a CR or PR by the indicated week. The investigator evaluated the TTR, and the analysis was based on responses confirmed at a repeat assessment, with the TTR taken as the first time the response was observed.
Time Frame	Weeks 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, and 72

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Week 6	3 1%	0 0%
Week 12	83 28.5%	55 19.1%
Week 18	86 29.6%	57 19.8%
Week 24	98 33.7%	69 24%
Week 30	98 33.7%	69 24%
Week 36	101 34.7%	71 24.7%
Week 42	102 35.1%	72 25%
Week 48	102 35.1%	72 25%
Week 54	102 35.1%	72 25%
Week 60	102 35.1%	72 25%
Week 66	102 35.1%	72 25%
Week 72	102 35.1%	73 25.3%

7. Secondary Outcome

Title	Duration of Response (DOR)
Description	The investigator evaluated the DOR for the subset of participants who showed a CR (disappearance of all TLs and NTLs) or PR (TLs: a >=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD; NTLs: persistence of >=1 lesion). DOR is defined as the time from the first documented evidence of PR or CR until the first documented sign of PD (TL: a >=20% increase in the sum of the LD of TLs or the appearance of >=1 new lesion; NTL: the appearance of >=1 new lesion and/or unequivocal progression of existing NTLs) or death due to breast cancer, if sooner.
Time Frame	From the time of the first documented complete or partial response until the first documented evidence of progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants who had a CR or PR were evaluated.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	102	73
Median (Inter-Quartile Range) [weeks]	28.3	27.1

8. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as the interval between the date of randomization and the earliest date of progression disease (PD) or death due to any cause, if sooner. For TLs, progressive disease is defined as at least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions. For NTLs, progressive disease is defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. par., participants.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population. PFS was assessed in par. who died or progressed, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored par. (those without a documented date of disease progression/death due to any cause), the date of the last radiographic assessment was used.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Median (95% Confidence Interval) [weeks]	25.1	22.6

9. Secondary Outcome

Title	Number of Participants Who Progressed or Died at or Prior to 6 Months, as a Measure of Six Months Progression-free Survival (PFS)
Description	PFS is defined as the interval between the date of randomization and the earliest date of disease progression or death due to any cause, if sooner. Six months PFS is defined as PFS at six months from the time of randomization. Raw data for 6 months PFS are not available; thus, data are presented as the number of participants who progressed or died at or prior to 6 months. For TLs, progressive disease is defined asat least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions. For NTLs, progressive disease is defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. PFS was assessed in participants who died or progressed, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.
Time Frame	Randomization until the date of disease progression or death (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Number [participants]	133 45.7%	153 53.1%

10. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from randomization until death due to any cause.
Time Frame	Randomization until the date of death due to any cause (average of 24 months)

Outcome Measure Data

Analysis Population Description

ITT population. Overall survival was assessed in participants who died as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those still alive), the date of the last contact was used.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Median (95% Confidence Interval) [months]	23.82	20.17

11. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores
Description	The FACT-B questionnaire was designed to measure multidimensional quality of life (QOL) in participants with breast cancer. The physical and functional well-being subscale scores range from 0 to 28, based on 7 questions (each scored from 0 [not at all] to 4 [very much] for all subscales); the emotional and social/family well-being (1 question optional) subscale scores range from 0 to 24 (based on 6 questions), and the additional concerns subscale score ranges from 0 to 40, based on 10 questions. The FACT-B Total Score (0 [better QOL] to 144 [worse QOL]) is the sum of the subscale scores.
Time Frame	Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the last observation carried forward (LOCF) method: the last available on-therapy observation for a participant was used to estimate missing data points.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	208	230
Week 9, n=208, 230	-1.1 (16.09)	-2.3 (16.27)
Week 21, n=126, 125	1.0 (16.63)	-1.3 (17.13)
Week 33, n=72, 64	1.4 (17.39)	-2.0 (12.75)
Week 45, n=35, 38	2.3 (22.05)	-1.4 (10.79)
Withdrawal, n=190, 212	-5.0 (19.53)	-8.4 (17.99)

12. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores
Description	The FACT-G questionnaire was designed to measure multidimensional QOL in participants with cancer and includes subscales for physical, social/family, emotional, and functional well-being. The physical, social/family, and functional well-being subscale scores range from 0 to 28, based on responses to 7 questions (each question scored from 0 [not at all] to 4 [very much]); the emotional well-being subscale score ranges from 0 to 24, based on responses to 6 questions. The FACT-G Total Score (ranging from 0 [better QOL] to 108 [worse QOL]) is the sum of the subscale scores.
Time Frame	Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	213	232
Week 9, n=213, 232	-0.7 (13.35)	-1.3 (13.26)
Week 21, n=127, 125	0.4 (13.97)	-0.2 (14.38)
Week 33, n=71, 65	1.1 (14.80)	-1.7 (10.81)
Week 45, n=34, 39	0.9 (17.68)	-1.6 (10.41)
Withdrawal, n=193, 214	-4.4 (16.11)	-7.5 (15.02)

13. Secondary Outcome

Title	Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores
Description	The TOI questionnaire was designed to measure multidimensional QOL in participants with cancer and includes subscales for physical, functional well-being, and additional cancer concerns. The physical and functional well-being subscale scores range from 0 to 28, based on 7 questions (each question scored from 0 [not at all] to 4 [very much]); the breast cancer unweighted subscale scores range from 0 to 36, based on 9 questions. The total TOI score (ranging from 0 [better QOL] to 92 [worse QOL]) is the sum of the TOI subscale scores.
Time Frame	Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	208	232
Week 9, n=208, 232	-2.3 (12.32)	-2.6 (11.88)
Week 21, n=126, 125	-0.5 (11.99)	-2.7 (12.42)
Week 33, n=72, 65	-0.1 (12.83)	-2.9 (9.05)
Week 45, n=36, 38	1.5 (15.91)	-2.8 (8.98)
Withdrawal, n=190, 212	-4.4 (14.30)	-6.1 (12.84)

14. Secondary Outcome

Title	Number of Participants With the Indicated ErbB2 Status at Baseline
Description	The Press Laboratory collected tumor tissues of participants for ErbB2 testing. ErbB2 testing is done to detect breast cancer and predict its likely outcome. All samples were analyzed by the Press Laboratory. Participants were categorized as ErbB2 positive (overexpression of the ErbB2 gene), ErbB2 negative, and assay not done (which included participants with no available samples and those with inconclusive results). ErbB2 status is determined by immunohistochemistry (ICH) assay and fluorescence in situ hybridization (FISH) testing. Negative ErbB2 status is defined as 0 or 1+ by IHC, or as 2+ by IHC and FISH.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Positive	52 17.9%	39 13.5%
Negative	199 68.4%	202 70.1%
Assay not done	40 13.7%	47 16.3%

15. Secondary Outcome

Title	ErbB2 Ratio
Description	The Press Laboratory collected tumor tissues of participants for biomarker testing. All samples were analyzed by the Press Laboratory. The ratio of ErbB2 gene signals to chromosome 17 signals, which indicates the progression of breast cancer, was calculated. Low levels of amplification (few copies) may have a ratio of 2-5, whereas high levels of amplification may have a ratio >10.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	220	200
Mean (Standard Deviation) [ratio of signals]	2.23 (2.301)	2.14 (2.214)

16. Secondary Outcome

Title	Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening
Description	The Press Laboratory tested tumor tissue samples (taken at Screening, prior to randomization to study treatment) to determine intra-tumoral expression levels of ErbB1, ErbB2, and other analytes associated with these pathways by IHC, the process of detecting antigens (e.g., proteins) in cells of a tissue section. The IHC assessment is expressed as: 0, no staining (no cancer cells); 1+, faint staining; 2+, weak to moderate complete staining; 3+, strong complete staining (many cancer cells). A status of "Assay not done" was assigned to participants with no available samples and to those with inconclusive results. If strong staining is observed, breast cancer that has high levels of HER2 expression (overexpression) is indicated. If moderate/weak staining is observed (IHC=2+), breast cancer that has low/moderate expression levels is indicated. When no staining is observed (IHC=0), breast cancer HER2 expression may be below the level of detection of the assay.
Time Frame	Screening (Day -1)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
0	139 47.8%	139 48.3%
1+	50 17.2%	51 17.7%
2+	15 5.2%	22 7.6%
3+	40 13.7%	28 9.7%
Assay not done	47 16.2%	48 16.7%

17. Secondary Outcome

Title	Number of Participants With the Indicated ErbB2 Fluorescence in Situ Hybridization (FISH) Results
Description	The Press Laboratory tested participants who were 2+ (weak to moderate complete staining) or 3+ (strong complete staining) for ErbB2 overexpression by IHC for ErbB2 gene amplification using the FISH assay. The results of the FISH assay can be ErbB2 gene "amplification" (increased number of copies of the ErbB2 gene) or "non-amplification" (not many copies of the ErbB2 gene). A status of "Assay not done" was assigned to those participants with no available samples and to those with inconclusive results (e.g., due to hybridization or staining problems).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	291	288
Amplified	45 15.5%	35 12.2%
Non-amplified	175 60.1%	165 57.3%
Assay not done	71 24.4%	88 30.6%

18. Secondary Outcome

Title	Serum ErbB1 Concentration
Description	The Quest Laboratory collected blood samples for quantitative determination of serum ErbB1. The results of serum monitoring were used to compare tumor response rates following randomized therapy.
Time Frame	Screening (Day-1) and Withdrawal (up to Study Week 129)

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	269	265
Screening, n=269, 265	58.6 (20.30)	59.5 (44.20)
Withdrawal, n=145, 157	59.0 (30.22)	61.5 (16.74)

19. Secondary Outcome

Title	Serum ErbB2 Concentration
Description	The Quest Laboratory collected blood samples for quantitative determination of serum ErbB2. The results of serum monitoring were used to compare tumor response rates following randomized therapy.
Time Frame	Screening (Day-1) and Withdrawal (up to Study Week 129)

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	270	265
Screening, n=270, 265	37.67 (95.883)	36.19 (87.629)
Withdrawal, n=145, 158	37.31 (98.257)	39.95 (96.327)

20. Secondary Outcome

Title	Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4
Description	The severity of adverse events was graded per the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3. Grades 1 through 5 have unique clinical descriptions of severity for each AE based on the following general guideline: Grade 1, Mild AE; Grade 2, Moderate AE; Grade 3, Severe AE; Grade 4, Life-threatening or disabling AE; Grade 5, death related to AE.
Time Frame	Baseline (Day 1) until 30 days after the last dose of randomized therapy (average of 26 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least one dose of investigational product (based on the actual treatment received if this differed from that to which the participant was randomized). Two participants randomized to the placebo group actually received lapatinib.

Arm/Group Title	Lapatinib With Paclitaxel	Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Measure Participants	293	286
Diarrhea; Grade 3	43 14.8%	4 1.4%
Diarrhea; Grade 4	1 0.3%	0 0%
Alopecia; Grade 3	10 3.4%	15 5.2%
Alopecia; Grade 4	0 0%	0 0%
Rash; Grade 3	15 5.2%	1 0.3%
Rash; Grade 4	0 0%	0 0%
Nausea; Grade 3	7 2.4%	2 0.7%
Nausea; Grade 4	0 0%	0 0%
Myalgia; Grade 3	6 2.1%	2 0.7%
Myalgia; Grade 4	0 0%	0 0%
Neutropenia; Grade 3	30 10.3%	20 6.9%
Neutropenia; Grade 4	23 7.9%	14 4.9%
Vomiting; Grade 3	5 1.7%	4 1.4%
Vomiting; Grade 4	0 0%	0 0%
Arthralgia; Grade 3	7 2.4%	4 1.4%
Arthralgia; Grade 4	0 0%	0 0%
Fatigue; Grade 3	5 1.7%	5 1.7%
Fatigue; Grade 4	0 0%	0 0%
Asthenia; Grade 3	1 0.3%	4 1.4%
Asthenia; Grade 4	1 0.3%	0 0%
Neuropathy; Grade 3	7 2.4%	3 1%
Neuropathy; Grade 4	0 0%	0 0%
Decreased appetite; Grade 3	1 0.3%	0 0%
Decreased appetite; Grade 4	0 0%	0 0%
Pain in extremity; Grade 3	2 0.7%	3 1%
Pain in extremity; Grade 4	2 0.7%	0 0%
Peripheral sensory neuropathy; Grade 3	6 2.1%	4 1.4%
Peripheral sensory neuropathy; Grade 4	0 0%	0 0%
Pruritis; Grade 3	2 0.7%	0 0%
Pruritis; Grade 4	0 0%	0 0%
Paraesthesia; Grade 3	2 0.7%	1 0.3%
Paraesthesia; Grade 4	0 0%	0 0%
Constipation; Grade 3	0 0%	0 0%
Constipation; Grade 4	0 0%	0 0%
Cough; Grade 3	1 0.3%	1 0.3%
Cough; Grade 4	0 0%	0 0%

Adverse Events

Time Frame	Serious adverse events (SAEs) and adverse events were collected from the first dose of randomized therapy until 30 days after the last dose of randomized therapy (average of 26 weeks).
Adverse Event Reporting Description	SAEs and AEs were collected in the Safety Population, comprised of all randomized participants who received at least one dose of investigational product (based on the actual treatment received if this differed from that to which the participant was randomized). Two participants randomized to the placebo group actually received lapatinib.
Arm/Group Title	Lapatinib With Paclitaxel		Placebo With Paclitaxel
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.		Participants received matching placebo orally OD with paclitaxel (175 mg/m^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
All Cause Mortality
	Lapatinib With Paclitaxel		Placebo With Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lapatinib With Paclitaxel		Placebo With Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/293 (35.2%)		63/286 (22%)
Blood and lymphatic system disorders
Neutropenia	22/293 (7.5%)		14/286 (4.9%)
Febrile neutropenia	10/293 (3.4%)		3/286 (1%)
Disseminated intravascular coagulation	0/293 (0%)		1/286 (0.3%)
Leukopenia	0/293 (0%)		1/286 (0.3%)
Thrombocythemia	1/293 (0.3%)		0/286 (0%)
Cardiac disorders
Left ventricular dysfunction	2/293 (0.7%)		1/286 (0.3%)
Atrial fibrillation	1/293 (0.3%)		0/286 (0%)
Cardiac arrest	1/293 (0.3%)		0/286 (0%)
Cardiac failure	1/293 (0.3%)		0/286 (0%)
Myocardial infarction	0/293 (0%)		1/286 (0.3%)
Ventricular arrhythmia	1/293 (0.3%)		0/286 (0%)
Eye disorders
Retinal detachment	1/293 (0.3%)		1/286 (0.3%)
Ulcerative keratitis	1/293 (0.3%)		0/286 (0%)
Pterygium	1/293 (0.3%)		0/286 (0%)
Gastrointestinal disorders
Diarrhea	24/293 (8.2%)		2/286 (0.7%)
Vomiting	4/293 (1.4%)		4/286 (1.4%)
Abdominal pain	2/293 (0.7%)		0/286 (0%)
Nausea	1/293 (0.3%)		1/286 (0.3%)
Ascites	1/293 (0.3%)		0/286 (0%)
Constipation	0/293 (0%)		1/286 (0.3%)
Gastrointestinal toxicity	1/293 (0.3%)		0/286 (0%)
Ileus	1/293 (0.3%)		0/286 (0%)
Intestinal ischemia	1/293 (0.3%)		0/286 (0%)
Esophagitis	1/293 (0.3%)		0/286 (0%)
Rectal hemorrhage	0/293 (0%)		1/286 (0.3%)
Stomatitis	1/293 (0.3%)		0/286 (0%)
General disorders
Pyrexia	7/293 (2.4%)		2/286 (0.7%)
Mucosal inflammation	6/293 (2%)		1/286 (0.3%)
Chest pain	2/293 (0.7%)		2/286 (0.7%)
Asthenia	1/293 (0.3%)		0/286 (0%)
Death	0/293 (0%)		1/286 (0.3%)
Edema peripheral	1/293 (0.3%)		0/286 (0%)
Performance status decreased	1/293 (0.3%)		0/286 (0%)
Hepatobiliary disorders
Cholecystitis	1/293 (0.3%)		0/286 (0%)
Cholecystitis chronic	0/293 (0%)		1/286 (0.3%)
Cholelithiasis	1/293 (0.3%)		0/286 (0%)
Hepatotoxicity	1/293 (0.3%)		0/286 (0%)
Jaundice cholestatic	0/293 (0%)		1/286 (0.3%)
Immune system disorders
Hypersensitivity	2/293 (0.7%)		1/286 (0.3%)
Anaphylactic reaction	1/293 (0.3%)		0/286 (0%)
Infections and infestations
Pneumonia	3/293 (1%)		2/286 (0.7%)
Device related infection	2/293 (0.7%)		1/286 (0.3%)
Sepsis	2/293 (0.7%)		1/286 (0.3%)
Septic shock	2/293 (0.7%)		0/286 (0%)
Staphylococcal infection	1/293 (0.3%)		1/286 (0.3%)
Urinary tract infection	2/293 (0.7%)		0/286 (0%)
Acarodermatitis	1/293 (0.3%)		0/286 (0%)
Breast abscess	0/293 (0%)		1/286 (0.3%)
Bronchopneumonia	0/293 (0%)		1/286 (0.3%)
Catheter site infection	1/293 (0.3%)		0/286 (0%)
Cellulitis	0/293 (0%)		1/286 (0.3%)
Enterocolitis infectious	1/293 (0.3%)		0/286 (0%)
Gallbladder abscess	1/293 (0.3%)		0/286 (0%)
Lower respiratory tract infection	1/293 (0.3%)		0/286 (0%)
Lung infection	0/293 (0%)		1/286 (0.3%)
Lymphangitis	1/293 (0.3%)		0/286 (0%)
Oral candidiasis	1/293 (0.3%)		0/286 (0%)
Pneumonia primary atypical	1/293 (0.3%)		0/286 (0%)
Pyelonephritis	0/293 (0%)		1/286 (0.3%)
Skin infection	0/293 (0%)		1/286 (0.3%)
Urosepsis	0/293 (0%)		1/286 (0.3%)
Injury, poisoning and procedural complications
Ankle fracture	0/293 (0%)		1/286 (0.3%)
Femur fracture	1/293 (0.3%)		0/286 (0%)
Foot fracture	1/293 (0.3%)		0/286 (0%)
Poisoning	1/293 (0.3%)		0/286 (0%)
Investigations
Ejection fraction decreased	5/293 (1.7%)		5/286 (1.7%)
Hemoglobin decreased	1/293 (0.3%)		1/286 (0.3%)
Alanine aminotransferase increased	1/293 (0.3%)		0/286 (0%)
Blood creatinine increased	0/293 (0%)		1/286 (0.3%)
Blood uric acid increased	0/293 (0%)		1/286 (0.3%)
Body temperature increased	1/293 (0.3%)		0/286 (0%)
Neutrophil count decreased	1/293 (0.3%)		0/286 (0%)
Metabolism and nutrition disorders
Hypercalcemia	4/293 (1.4%)		3/286 (1%)
Dehydration	4/293 (1.4%)		0/286 (0%)
Hypokalemia	2/293 (0.7%)		0/286 (0%)
Fluid overload	0/293 (0%)		1/286 (0.3%)
Hyperglycemia	1/293 (0.3%)		0/286 (0%)
Hyperkalemia	0/293 (0%)		1/286 (0.3%)
Hypernatremia	0/293 (0%)		1/286 (0.3%)
Hyperuricemia	1/293 (0.3%)		0/286 (0%)
Hypocalcemia	1/293 (0.3%)		0/286 (0%)
Hypoglycemia	1/293 (0.3%)		0/286 (0%)
Hypomagnesemia	1/293 (0.3%)		0/286 (0%)
Hyponatremia	1/293 (0.3%)		0/286 (0%)
Hypovolemia	1/293 (0.3%)		0/286 (0%)
Tetany	1/293 (0.3%)		0/286 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	3/293 (1%)		0/286 (0%)
Arthralgia	2/293 (0.7%)		0/286 (0%)
Pathological fracture	1/293 (0.3%)		1/286 (0.3%)
Back pain	1/293 (0.3%)		0/286 (0%)
Intervertebral disc disorder	0/293 (0%)		1/286 (0.3%)
Joint effusion	1/293 (0.3%)		0/286 (0%)
Muscular weakness	1/293 (0.3%)		0/286 (0%)
Myalgia	0/293 (0%)		1/286 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/293 (0%)		1/286 (0.3%)
Metastases to central nervous system	1/293 (0.3%)		0/286 (0%)
Tumor hemorrhage	1/293 (0.3%)		0/286 (0%)
Nervous system disorders
Convulsion	1/293 (0.3%)		1/286 (0.3%)
Cerebral infarction	0/293 (0%)		1/286 (0.3%)
Cerebrovascular disorder	1/293 (0.3%)		0/286 (0%)
Headache	1/293 (0.3%)		0/286 (0%)
Hemiplegia	0/293 (0%)		1/286 (0.3%)
Lumber radiculopathy	0/293 (0%)		1/286 (0.3%)
Mental impairment	1/293 (0.3%)		0/286 (0%)
Neuralgia	1/293 (0.3%)		0/286 (0%)
Peripheral motor neuropathy	0/293 (0%)		1/286 (0.3%)
Peripheral sensory neuropathy	0/293 (0%)		1/286 (0.3%)
Somnolence	1/293 (0.3%)		0/286 (0%)
Syncope	1/293 (0.3%)		0/286 (0%)
Psychiatric disorders
Anxiety	0/293 (0%)		1/286 (0.3%)
Confusional state	0/293 (0%)		1/286 (0.3%)
Mental status changes	0/293 (0%)		1/286 (0.3%)
Renal and urinary disorders
Renal colic	1/293 (0.3%)		0/286 (0%)
Renal failure acute	1/293 (0.3%)		0/286 (0%)
Urinary retention	0/293 (0%)		1/286 (0.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/293 (1%)		3/286 (1%)
Pulmonary embolism	2/293 (0.7%)		0/286 (0%)
Cough	1/293 (0.3%)		0/286 (0%)
Epistaxis	1/293 (0.3%)		0/286 (0%)
Hemothorax	0/293 (0%)		1/286 (0.3%)
Hypoxia	0/293 (0%)		1/286 (0.3%)
Pleural effusion	0/293 (0%)		1/286 (0.3%)
Pneumonitis	0/293 (0%)		1/286 (0.3%)
Pulmonary hemorrhage	1/293 (0.3%)		0/286 (0%)
Pulmonary edema	1/293 (0.3%)		0/286 (0%)
Wheezing	1/293 (0.3%)		0/286 (0%)
Skin and subcutaneous tissue disorders
Rash	4/293 (1.4%)		0/286 (0%)
Erythema multiforme	1/293 (0.3%)		0/286 (0%)
Intertrigo	0/293 (0%)		1/286 (0.3%)
Rash erythematous	1/293 (0.3%)		0/286 (0%)
Rash generalized	0/293 (0%)		1/286 (0.3%)
Vascular disorders
Hypotension	3/293 (1%)		0/286 (0%)
Thrombosis	1/293 (0.3%)		2/286 (0.7%)
Deep vein thrombosis	2/293 (0.7%)		0/286 (0%)
Hypertension	0/293 (0%)		2/286 (0.7%)
Embolism	1/293 (0.3%)		0/286 (0%)
Hemorrhage	1/293 (0.3%)		0/286 (0%)
Hypertensive crisis	1/293 (0.3%)		0/286 (0%)
Phlebitis	0/293 (0%)		1/286 (0.3%)
Other (Not Including Serious) Adverse Events
	Lapatinib With Paclitaxel		Placebo With Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	287/293 (98%)		278/286 (97.2%)
Blood and lymphatic system disorders
Neutropenia	76/293 (25.9%)		58/286 (20.3%)
Anemia	32/293 (10.9%)		35/286 (12.2%)
Leukopenia	26/293 (8.9%)		25/286 (8.7%)
Febrile neutropenia	12/293 (4.1%)		4/286 (1.4%)
Leukocytosis	2/293 (0.7%)		5/286 (1.7%)
Thrombocytopenia	2/293 (0.7%)		4/286 (1.4%)
Lymphopenia	2/293 (0.7%)		1/286 (0.3%)
Lymph node pain	1/293 (0.3%)		1/286 (0.3%)
Thrombocytosis	1/293 (0.3%)		1/286 (0.3%)
Disseminated intravascular coagulation	0/293 (0%)		1/286 (0.3%)
Eosinophilia	1/293 (0.3%)		0/286 (0%)
Hyperchromasia	1/293 (0.3%)		0/286 (0%)
Monocytosis	1/293 (0.3%)		0/286 (0%)
Pancytopenia	1/293 (0.3%)		0/286 (0%)
Ear and labyrinth disorders
Vertigo	4/293 (1.4%)		7/286 (2.4%)
Tinnitus	2/293 (0.7%)		1/286 (0.3%)
Deafness	1/293 (0.3%)		0/286 (0%)
Ear pain	1/293 (0.3%)		0/286 (0%)
Hypoacusis	0/293 (0%)		1/286 (0.3%)
Endocrine disorders
Cushingoid	1/293 (0.3%)		0/286 (0%)
Hypothyroidism	0/293 (0%)		1/286 (0.3%)
Gastrointestinal disorders
Diarrhea	171/293 (58.4%)		73/286 (25.5%)
Nausea	100/293 (34.1%)		85/286 (29.7%)
Vomiting	74/293 (25.3%)		48/286 (16.8%)
Constipation	35/293 (11.9%)		48/286 (16.8%)
Dyspepsia	38/293 (13%)		13/286 (4.5%)
Abdominal pain	33/293 (11.3%)		17/286 (5.9%)
Stomatitis	21/293 (7.2%)		13/286 (4.5%)
Abdominal pain upper	12/293 (4.1%)		16/286 (5.6%)
Abdominal distension	14/293 (4.8%)		9/286 (3.1%)
Dry mouth	9/293 (3.1%)		5/286 (1.7%)
Hemorrhoids	6/293 (2%)		4/286 (1.4%)
Flatulence	5/293 (1.7%)		3/286 (1%)
Gastroesophageal reflux disease	4/293 (1.4%)		4/286 (1.4%)
Dysphagia	5/293 (1.7%)		2/286 (0.7%)
Cheilitis	3/293 (1%)		3/286 (1%)
Epigastric discomfort	2/293 (0.7%)		4/286 (1.4%)
Mouth ulceration	2/293 (0.7%)		0/286 (0%)
Esophagitis	4/293 (1.4%)		1/286 (0.3%)
Abdominal discomfort	2/293 (0.7%)		3/286 (1%)
Colitis	3/293 (1%)		1/286 (0.3%)
Gastritis	2/293 (0.7%)		2/286 (0.7%)
Retching	1/293 (0.3%)		3/286 (1%)
Toothache	3/293 (1%)		1/286 (0.3%)
Abdominal pain lower	2/293 (0.7%)		1/286 (0.3%)
Anal hemorrhage	3/293 (1%)		0/286 (0%)
Rectal hemorrhage	1/293 (0.3%)		2/286 (0.7%)
Abdominal tenderness	2/293 (0.7%)		0/286 (0%)
Apthous stomatitis	2/293 (0.7%)		0/286 (0%)
Ascites	1/293 (0.3%)		1/286 (0.3%)
Gingival pain	0/293 (0%)		1/286 (0.3%)
Gingivitis	1/293 (0.3%)		1/286 (0.3%)
Hematochezia	1/293 (0.3%)		1/286 (0.3%)
Oral discomfort	0/293 (0%)		2/286 (0.7%)
Oral pain	2/293 (0.7%)		0/286 (0%)
Proctalgia	2/293 (0.7%)		0/286 (0%)
Abdominal rigidity	1/293 (0.3%)		0/286 (0%)
Anorectal discomfort	1/293 (0.3%)		0/286 (0%)
Anal fissure	1/293 (0.3%)		0/286 (0%)
Anal ulcer	0/293 (0%)		1/286 (0.3%)
Diabetic gastropathy	1/293 (0.3%)		0/286 (0%)
Fecaloma	1/293 (0.3%)		0/286 (0%)
Gastric disorder	0/293 (0%)		1/286 (0.3%)
Gastrointestinal pain	0/293 (0%)		1/286 (0.3%)
Gastrointestinal toxicity	1/293 (0.3%)		0/286 (0%)
Gingival bleeding	0/293 (0%)		1/286 (0.3%)
Glossodynia	1/293 (0.3%)		0/286 (0%)
Hemorrhoidal hemorrhage	1/293 (0.3%)		0/286 (0%)
Hiatus hernia	0/293 (0%)		1/286 (0.3%)
Hyperchlorhydria	1/293 (0.3%)		0/286 (0%)
Hypoaesthesia oral	1/293 (0.3%)		0/286 (0%)
Ileus	1/293 (0.3%)		0/286 (0%)
Impaired gastric emptying	1/293 (0.3%)		0/286 (0%)
Intestinal ischemia	1/293 (0.3%)		0/286 (0%)
Lip dry	0/293 (0%)		1/286 (0.3%)
Lip edema	1/293 (0.3%)		0/286 (0%)
Loose tooth	0/293 (0%)		1/286 (0.3%)
Melena	1/293 (0.3%)		0/286 (0%)
Odynophagia	1/293 (0.3%)		0/286 (0%)
Esophageal discomfort	1/293 (0.3%)		0/286 (0%)
Pancreatitis	0/293 (0%)		1/286 (0.3%)
Parasthesia oral	1/293 (0.3%)		0/286 (0%)
Reflux gastritis	0/293 (0%)		1/286 (0.3%)
Subileus	1/293 (0.3%)		0/286 (0%)
Tongue pigmentation	1/293 (0.3%)		0/286 (0%)
Tongue ulceration	1/293 (0.3%)		0/286 (0%)
General disorders
Fatigue	65/293 (22.2%)		61/286 (21.3%)
Asthenia	62/293 (21.2%)		36/286 (12.6%)
Pyrexia	32/293 (10.9%)		33/286 (11.5%)
Mucosal inflammation	38/293 (13%)		9/286 (3.1%)
Edema perpheral	18/293 (6.1%)		19/286 (6.6%)
Pain	19/293 (6.5%)		16/286 (5.6%)
Chest pain	19/293 (6.5%)		14/286 (4.9%)
Chills	6/293 (2%)		8/286 (2.8%)
Malaise	6/293 (2%)		7/286 (2.4%)
Chest discomfort	6/293 (2%)		4/286 (1.4%)
Axillary pain	4/293 (1.4%)		4/286 (1.4%)
Influenza like illness	4/293 (1.4%)		5/286 (1.7%)
Face edema	4/293 (1.4%)		2/286 (0.7%)
Edema	3/293 (1%)		3/286 (1%)
Catheter site pain	1/293 (0.3%)		2/286 (0.7%)
Inflammation	3/293 (1%)		0/286 (0%)
Adverse drug reaction	0/293 (0%)		2/286 (0.7%)
Discomfort	0/293 (0%)		2/286 (0.7%)
Injection site reaction	1/293 (0.3%)		1/286 (0.3%)
Irritability	0/293 (0%)		2/286 (0.7%)
Breakthrough pain	1/293 (0.3%)		0/286 (0%)
Catheter site inflammation	1/293 (0.3%)		0/286 (0%)
Catheter site related reaction	1/293 (0.3%)		0/286 (0%)
Death	0/293 (0%)		1/286 (0.3%)
Early satiety	0/293 (0%)		1/286 (0.3%)
Extravasation	1/293 (0.3%)		0/286 (0%)
Facial pain	1/293 (0.3%)		0/286 (0%)
Granuloma	0/293 (0%)		1/286 (0.3%)
Implant site scar	1/293 (0.3%)		0/286 (0%)
Infusion site extravasation	0/293 (0%)		1/286 (0.3%)
Infusion site edema	0/293 (0%)		1/286 (0.3%)
Infusion site pain	0/293 (0%)		1/286 (0.3%)
Local swelling	0/293 (0%)		1/286 (0.3%)
Localized edema	1/293 (0.3%)		0/286 (0%)
Non-cardiac chest pain	0/293 (0%)		1/286 (0.3%)
Performance status decreased	1/293 (0.3%)		0/286 (0%)
Vessel puncture site pain	1/293 (0.3%)		0/286 (0%)
Thirst	1/293 (0.3%)		0/286 (0%)
Vessel puncture site reaction	1/293 (0.3%)		0/286 (0%)
Generalized edema	0/293 (0%)		1/286 (0.3%)
Injection site pain	1/293 (0.3%)		0/286 (0%)
Hepatobiliary disorders
Hyperbilirubinemia	6/293 (2%)		4/286 (1.4%)
Jaundice	2/293 (0.7%)		1/286 (0.3%)
Cholecystitis	2/293 (0.7%)		0/286 (0%)
Hepatotoxicity	1/293 (0.3%)		1/286 (0.3%)
Cholecystitis chronic	0/293 (0%)		1/286 (0.3%)
Cholelithiasis	1/293 (0.3%)		0/286 (0%)
Jaundice cholestatic	0/293 (0%)		1/286 (0.3%)
Immune system disorders
Hypersensitivity	11/293 (3.8%)		3/286 (1%)
Drug hypersensitivity	3/293 (1%)		1/286 (0.3%)
Anaphylactic reaction	1/293 (0.3%)		1/286 (0.3%)
Anaphylactic shock	1/293 (0.3%)		0/286 (0%)
Multiple allergies	0/293 (0%)		1/286 (0.3%)
Contrast media allergy	1/293 (0.3%)		0/286 (0%)
Infections and infestations
Nasopharyngitis	17/293 (5.8%)		7/286 (2.4%)
Upper respiratory tract infection	8/293 (2.7%)		15/286 (5.2%)
Urinary tract infection	15/293 (5.1%)		8/286 (2.8%)
Influenza	5/293 (1.7%)		9/286 (3.1%)
Pharyngitis	9/293 (3.1%)		3/286 (1%)
Cellulitis	4/293 (1.4%)		5/286 (1.7%)
Rhinitis	7/293 (2.4%)		2/286 (0.7%)
Pneumonia	4/293 (1.4%)		4/286 (1.4%)
Bronchitis	5/293 (1.7%)		4/286 (1.4%)
Infection	6/293 (2%)		1/286 (0.3%)
Respiratory tract infection	5/293 (1.7%)		2/286 (0.7%)
Cystitis	2/293 (0.7%)		4/286 (1.4%)
Herpes simplex	1/293 (0.3%)		1/286 (0.3%)
Herpes zoster	3/293 (1%)		3/286 (1%)
Oral candidiasis	4/293 (1.4%)		2/286 (0.7%)
Device related infection	2/293 (0.7%)		3/286 (1%)
Folliculitis	3/293 (1%)		2/286 (0.7%)
Oral herpes	5/293 (1.7%)		0/286 (0%)
Acarodermatitis	4/293 (1.4%)		0/286 (0%)
Fungal infection	2/293 (0.7%)		1/286 (0.3%)
Laryngitis	1/293 (0.3%)		3/286 (1%)
Lung infection	1/293 (0.3%)		3/286 (1%)
Paronychia	5/293 (1.7%)		0/286 (0%)
Breast infection	0/293 (0%)		3/286 (1%)
Lower respiratory tract infection	2/293 (0.7%)		1/286 (0.3%)
Nail infection	3/293 (1%)		0/286 (0%)
Sepsis	2/293 (0.7%)		1/286 (0.3%)
Sinusitis	1/293 (0.3%)		2/286 (0.7%)
Tonsillitis	3/293 (1%)		0/286 (0%)
Candidiasis	2/293 (0.7%)		0/286 (0%)
Catheter site infection	1/293 (0.3%)		1/286 (0.3%)
Gastroenteritis	2/293 (0.7%)		0/286 (0%)
Kidney infection	2/293 (0.7%)		0/286 (0%)
Lymphangitis	2/293 (0.7%)		0/286 (0%)
Otiits externa	2/293 (0.7%)		0/286 (0%)
Otitis media chronic	2/293 (0.7%)		0/286 (0%)
Respiratory tract infection viral	0/293 (0%)		2/286 (0.7%)
Septic shock	2/293 (0.7%)		0/286 (0%)
Skin infection	0/293 (0%)		2/286 (0.7%)
Staphylococcal infection	1/293 (0.3%)		1/286 (0.3%)
Viral infection	2/293 (0.7%)		0/286 (0%)
Vulvovaginal mycotic infection	2/293 (0.7%)		0/286 (0%)
Breast abscess	0/293 (0%)		1/286 (0.3%)
Bronchopneumonia	0/293 (0%)		1/286 (0.3%)
Catheter site cellulitis	1/293 (0.3%)		0/286 (0%)
Clostridial infection	0/293 (0%)		1/286 (0.3%)
Clostridium difficile colitis	1/293 (0.3%)		0/286 (0%)
Enterocolitis infection	1/293 (0.3%)		0/286 (0%)
Epstein-Barr virus infection	1/293 (0.3%)		0/286 (0%)
Erysipelas	1/293 (0.3%)		0/286 (0%)
Furuncle	1/293 (0.3%)		0/286 (0%)
Gallbladder abscess	1/293 (0.3%)		0/286 (0%)
Gastrointestinal fungal infection	1/293 (0.3%)		0/286 (0%)
Fungal skin infection	0/293 (0%)		3/286 (1%)
Genital candidiasis	1/293 (0.3%)		0/286 (0%)
Klebsiella infection	1/293 (0.3%)		0/286 (0%)
Localized infection	1/293 (0.3%)		0/286 (0%)
Omphalitis	1/293 (0.3%)		0/286 (0%)
Oral fungal infection	1/293 (0.3%)		0/286 (0%)
Pneumonia primary atypical	1/293 (0.3%)		0/286 (0%)
Postoperative wound infection	1/293 (0.3%)		0/286 (0%)
Pyelonephritis	0/293 (0%)		1/286 (0.3%)
Subcutaneous abscess	1/293 (0.3%)		0/286 (0%)
Tooth abscess	1/293 (0.3%)		0/286 (0%)
Tuberculosis	0/293 (0%)		1/286 (0.3%)
Urosepsis	0/293 (0%)		1/286 (0.3%)
Vaginal infection	1/293 (0.3%)		0/286 (0%)
Viral rash	1/293 (0.3%)		0/286 (0%)
Viral upper respiratory tract infection	1/293 (0.3%)		0/286 (0%)
Injury, poisoning and procedural complications
Upper limb fracture	0/293 (0%)		1/286 (0.3%)
Wound secretion	1/293 (0.3%)		0/286 (0%)
Investigations
Alanine aminotransferase increased	27/293 (9.2%)		23/286 (8%)
Aspartete aminotransferase increased	22/293 (7.5%)		20/286 (7%)
Blood alkaline phosphatase increased	19/293 (6.5%)		19/286 (6.6%)
Weight decreased	17/293 (5.8%)		14/286 (4.9%)
Ejection fraction decreased	6/293 (2%)		6/286 (2.1%)
Hemoglobin decreased	8/293 (2.7%)		4/286 (1.4%)
Blood urea increased	2/293 (0.7%)		3/286 (1%)
Weight increased	1/293 (0.3%)		9/286 (3.1%)
Neutrophil count decreased	5/293 (1.7%)		3/286 (1%)
White blood cell count decreased	5/293 (1.7%)		1/286 (0.3%)
Body temperature increased	2/293 (0.7%)		3/286 (1%)
Gamma-glutamyltransferase increased	3/293 (1%)		2/286 (0.7%)
Blood albumin decreased	3/293 (1%)		1/286 (0.3%)
Blood creatinine increased	2/293 (0.7%)		2/286 (0.7%)
Blood lactate dehydogenase increased	2/293 (0.7%)		2/286 (0.7%)
Blood bilirubin increased	2/293 (0.7%)		1/286 (0.3%)
Blood potassium decreased	2/293 (0.7%)		1/286 (0.3%)
Blood glucose increased	1/293 (0.3%)		1/286 (0.3%)
Blood uric acid increased	0/293 (0%)		2/286 (0.7%)
International normalized ratio increased	2/293 (0.7%)		0/286 (0%)
Activated partial thromboplastin time prolonged	1/293 (0.3%)		0/286 (0%)
Blood bilirubin decreased	1/293 (0.3%)		0/286 (0%)
Blood calcium decreased	1/293 (0.3%)		0/286 (0%)
Blood homocysteine increased	1/293 (0.3%)		0/286 (0%)
Blood pressure increased	1/293 (0.3%)		0/286 (0%)
Blood sodium increased	1/293 (0.3%)		0/286 (0%)
Blood urine present	1/293 (0.3%)		0/286 (0%)
Hemoglobin	1/293 (0.3%)		0/286 (0%)
Heart rate irregular	1/293 (0.3%)		0/286 (0%)
Platelet count decreased	0/293 (0%)		1/286 (0.3%)
Prothrombin level decreased	1/293 (0.3%)		0/286 (0%)
Prothrombin time prolonged	1/293 (0.3%)		0/286 (0%)
White blood cell count increased	1/293 (0.3%)		0/286 (0%)
Metabolism and nutrition disorders
Decreased appetite	50/293 (17.1%)		32/286 (11.2%)
Hypercalcemia	7/293 (2.4%)		8/286 (2.8%)
Hyperglycemia	7/293 (2.4%)		8/286 (2.8%)
Dehydration	12/293 (4.1%)		2/286 (0.7%)
Hypokalemia	12/293 (4.1%)		2/286 (0.7%)
Hyperuricemia	5/293 (1.7%)		7/286 (2.4%)
Hyponatremia	4/293 (1.4%)		2/286 (0.7%)
Hyperkalemia	3/293 (1%)		3/286 (1%)
Hypoalbuminemia	3/293 (1%)		2/286 (0.7%)
Hypocalcemia	3/293 (1%)		2/286 (0.7%)
Hypernatremia	2/293 (0.7%)		3/286 (1%)
Hypoglycemia	2/293 (0.7%)		2/286 (0.7%)
Hypercholesterolemia	2/293 (0.7%)		0/286 (0%)
Diabetes mellitus	0/293 (0%)		1/286 (0.3%)
Fluid overload	0/293 (0%)		1/286 (0.3%)
Hyperchloremia	0/293 (0%)		1/286 (0.3%)
Hyperphagia	0/293 (0%)		1/286 (0.3%)
Hyperproteinemia	1/293 (0.3%)		0/286 (0%)
Hypomagnesemia	1/293 (0.3%)		0/286 (0%)
Hypophosphatemia	1/293 (0.3%)		0/286 (0%)
Hypoproteinemia	0/293 (0%)		1/286 (0.3%)
Hypovolemia	1/293 (0.3%)		0/286 (0%)
Tumor lysis syndrome	1/293 (0.3%)		0/286 (0%)
Tetany	1/293 (0.3%)		0/286 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	94/293 (32.1%)		74/286 (25.9%)
Arthralgia	70/293 (23.9%)		58/286 (20.3%)
Pain in extremity	50/293 (17.1%)		50/286 (17.5%)
Bone pain	34/293 (11.6%)		32/286 (11.2%)
Back pain	26/293 (8.9%)		29/286 (10.1%)
Musculoskeletal pain	23/293 (7.8%)		27/286 (9.4%)
Musculoskeletal chest pain	3/293 (1%)		12/286 (4.2%)
Muscular weakness	8/293 (2.7%)		4/286 (1.4%)
Neck pain	6/293 (2%)		4/286 (1.4%)
Muscle spasms	4/293 (1.4%)		5/286 (1.7%)
Groin pain	2/293 (0.7%)		2/286 (0.7%)
Musculoskeletal discomfort	2/293 (0.7%)		2/286 (0.7%)
Musculoskeletal stiffness	2/293 (0.7%)		1/286 (0.3%)
Arthritis	0/293 (0%)		2/286 (0.7%)
Flank pain	1/293 (0.3%)		1/286 (0.3%)
Pain in jaw	1/293 (0.3%)		1/286 (0.3%)
Pathological fracture	1/293 (0.3%)		1/286 (0.3%)
Intervertebral disc disorder	0/293 (0%)		1/286 (0.3%)
Joint effusion	1/293 (0.3%)		0/286 (0%)
Joint swelling	0/293 (0%)		1/286 (0.3%)
Myopathy	0/293 (0%)		1/286 (0.3%)
Myositis	0/293 (0%)		1/286 (0.3%)
Nodule on extremity	0/293 (0%)		1/286 (0.3%)
Osteoporosis	0/293 (0%)		1/286 (0.3%)
Sensation of heaviness	0/293 (0%)		1/286 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	2/293 (0.7%)		5/286 (1.7%)
Breast cancer	0/293 (0%)		1/286 (0.3%)
Hemangioma	0/293 (0%)		1/286 (0.3%)
Metastases to central nervous system	1/293 (0.3%)		0/286 (0%)
Metastases to liver	1/293 (0.3%)		0/286 (0%)
Pyogenic granuloma	1/293 (0.3%)		0/286 (0%)
Salivary gland adenoma	1/293 (0.3%)		0/286 (0%)
Squamous cell carcinoma	1/293 (0.3%)		0/286 (0%)
Tumor hemorrhage	1/293 (0.3%)		0/286 (0%)
Uterine leiomyoma	1/293 (0.3%)		0/286 (0%)
Nervous system disorders
Peripheral sensory neuropathy	48/293 (16.4%)		54/286 (18.9%)
Paraesthesia	43/293 (14.7%)		42/286 (14.7%)
Headache	32/293 (10.9%)		30/286 (10.5%)
Neuropathy peripheral	54/293 (18.4%)		32/286 (11.2%)
Dysgeusia	12/293 (4.1%)		11/286 (3.8%)
Dizziness	13/293 (4.4%)		9/286 (3.1%)
Hypoaesthesia	11/293 (3.8%)		10/286 (3.5%)
Polyneuropathy	9/293 (3.1%)		3/286 (1%)
Peripheral motor neuropathy	8/293 (2.7%)		4/286 (1.4%)
Neuralgia	3/293 (1%)		4/286 (1.4%)
Memory impairment	3/293 (1%)		3/286 (1%)
Syncope	3/293 (1%)		2/286 (0.7%)
Convulsion	2/293 (0.7%)		1/286 (0.3%)
Neurotoxicity	1/293 (0.3%)		2/286 (0.7%)
Somnolence	2/293 (0.7%)		1/286 (0.3%)
Tremor	1/293 (0.3%)		2/286 (0.7%)
Cerebral infarction	1/293 (0.3%)		1/286 (0.3%)
Disturbance in attention	1/293 (0.3%)		1/286 (0.3%)
Hemiplegia	1/293 (0.3%)		1/286 (0.3%)
Migraine	1/293 (0.3%)		1/286 (0.3%)
Restless legs syndrome	2/293 (0.7%)		0/286 (0%)
Sinus headache	1/293 (0.3%)		1/286 (0.3%)
Aphasia	1/293 (0.3%)		0/286 (0%)
Aphonia	1/293 (0.3%)		0/286 (0%)
Brain edema	1/293 (0.3%)		0/286 (0%)
Carpal tunnel syndrome	0/293 (0%)		1/286 (0.3%)
Cerebrovascular disorder	1/293 (0.3%)		0/286 (0%)
Coma hepatic	0/293 (0%)		1/286 (0.3%)
Convulsions local	0/293 (0%)		1/286 (0.3%)
Depressed level of consiousness	0/293 (0%)		1/286 (0.3%)
Dysaesthesia	1/293 (0.3%)		0/286 (0%)
Epilepsy	0/293 (0%)		1/286 (0.3%)
Facial palsy	0/293 (0%)		1/286 (0.3%)
Hyperaesthesia	0/293 (0%)		1/286 (0.3%)
Hypersomnia	1/293 (0.3%)		0/286 (0%)
Hyporeflexia	0/293 (0%)		1/286 (0.3%)
Intracranial pressure increased	1/293 (0.3%)		0/286 (0%)
Lethargy	1/293 (0.3%)		0/286 (0%)
Loss of consciousness	1/293 (0.3%)		0/286 (0%)
Lumbar radiculopathy	0/293 (0%)		1/286 (0.3%)
Mental impairment	1/293 (0.3%)		0/286 (0%)
Motor dysfunction	1/293 (0.3%)		0/286 (0%)
Neuritis	0/293 (0%)		1/286 (0.3%)
Paraparesis	0/293 (0%)		1/286 (0.3%)
Parosmia	1/293 (0.3%)		0/286 (0%)
Peripheral sensorimotor neurophathy	0/293 (0%)		1/286 (0.3%)
Sciatica	0/293 (0%)		1/286 (0.3%)
Sensory loss	1/293 (0.3%)		0/286 (0%)
Psychiatric disorders
Insomnia	34/293 (11.6%)		29/286 (10.1%)
Anxiety	13/293 (4.4%)		13/286 (4.5%)
Depression	10/293 (3.4%)		13/286 (4.5%)
Depressed mood	4/293 (1.4%)		4/286 (1.4%)
Confusional state	2/293 (0.7%)		3/286 (1%)
Restlessness	1/293 (0.3%)		2/286 (0.7%)
Hallucination	1/293 (0.3%)		1/286 (0.3%)
Mood altered	2/293 (0.7%)		0/286 (0%)
Eating disorder	1/293 (0.3%)		0/286 (0%)
Emotional distress	0/293 (0%)		1/286 (0.3%)
Mental status changes	0/293 (0%)		1/286 (0.3%)
Nervousness	1/293 (0.3%)		0/286 (0%)
Panic attack	1/293 (0.3%)		0/286 (0%)
Personality change	1/293 (0.3%)		0/286 (0%)
Personality disorder	1/293 (0.3%)		0/286 (0%)
Psychotic disorder	0/293 (0%)		1/286 (0.3%)
Suicidal ideation	1/293 (0.3%)		0/286 (0%)
Renal and urinary disorders
Dysuria	6/293 (2%)		2/286 (0.7%)
Hematuria	3/293 (1%)		0/286 (0%)
Urinary incontinence	1/293 (0.3%)		3/286 (1%)
Hydronephrosis	1/293 (0.3%)		2/286 (0.7%)
Polyuria	2/293 (0.7%)		0/286 (0%)
Enuresis	0/293 (0%)		1/286 (0.3%)
Micturition disorder	1/293 (0.3%)		0/286 (0%)
Pollakiuria	0/293 (0%)		1/286 (0.3%)
Renal colic	1/293 (0.3%)		0/286 (0%)
Renal failure acute	1/293 (0.3%)		0/286 (0%)
Urinary retention	0/293 (0%)		1/286 (0.3%)
Respiratory, thoracic and mediastinal disorders
Cough	33/293 (11.3%)		42/286 (14.7%)
Dyspnoea	29/293 (9.9%)		28/286 (9.8%)
Oropharyngeal pain	12/293 (4.1%)		10/286 (3.5%)
Epistaxis	13/293 (4.4%)		4/286 (1.4%)
Dysphonia	8/293 (2.7%)		6/286 (2.1%)
Productive cough	5/293 (1.7%)		2/286 (0.7%)
Dyspnoea exertional	3/293 (1%)		1/286 (0.3%)
Rhinitis allergic	2/293 (0.7%)		2/286 (0.7%)
Hemoptysis	0/293 (0%)		3/286 (1%)
Nasal congestion	1/293 (0.3%)		1/286 (0.3%)
Nasal dryness	2/293 (0.7%)		1/286 (0.3%)
Wheezing	1/293 (0.3%)		2/286 (0.7%)
Asthma	1/293 (0.3%)		1/286 (0.3%)
Bronchospasm	1/293 (0.3%)		1/286 (0.3%)
Hypoxia	0/293 (0%)		3/286 (1%)
Increased upper airway secretion	1/293 (0.3%)		1/286 (0.3%)
Nasal inflammation	2/293 (0.7%)		0/286 (0%)
Pharyngeal erythema	1/293 (0.3%)		1/286 (0.3%)
Pleural effusion	1/293 (0.3%)		1/286 (0.3%)
Pulmonary embolism	2/293 (0.7%)		0/286 (0%)
Pleuritic pain	1/293 (0.3%)		0/286 (0%)
Atelectasis	0/293 (0%)		1/286 (0.3%)
Bronchostenosis	0/293 (0%)		1/286 (0.3%)
Hemothorax	0/293 (0%)		1/286 (0.3%)
Lung infiltration	0/293 (0%)		1/286 (0.3%)
Nasal discomfort	1/293 (0.3%)		0/286 (0%)
Nasal ulcer	0/293 (0%)		1/286 (0.3%)
Pain respiration	1/293 (0.3%)		0/286 (0%)
Pleural fibrosis	1/293 (0.3%)		0/286 (0%)
Pneumonitis	0/293 (0%)		1/286 (0.3%)
Pulmonary hemorrhage	1/293 (0.3%)		0/286 (0%)
Pulmonary edema	1/293 (0.3%)		0/286 (0%)
Rales	1/293 (0.3%)		0/286 (0%)
Respiratory disorder	1/293 (0.3%)		0/286 (0%)
Rhinorrhoea	1/293 (0.3%)		0/286 (0%)
Sinus congestion	0/293 (0%)		1/286 (0.3%)
Sputum discoloured	1/293 (0.3%)		0/286 (0%)
Upper airway obstruction	0/293 (0%)		1/286 (0.3%)
Skin and subcutaneous tissue disorders
Alopecia	153/293 (52.2%)		183/286 (64%)
Rash	145/293 (49.5%)		66/286 (23.1%)
Pruritus	46/293 (15.7%)		37/286 (12.9%)
Dry skin	13/293 (4.4%)		8/286 (2.8%)
Nail disorder	8/293 (2.7%)		5/286 (1.7%)
Pain of skin	4/293 (1.4%)		4/286 (1.4%)
Skin hyperpigmentation	7/293 (2.4%)		1/286 (0.3%)
Hyperhidrosis	3/293 (1%)		3/286 (1%)
Rash generalized	3/293 (1%)		2/286 (0.7%)
Palmar-plantar erythrodysaesthesia syndrome	5/293 (1.7%)		1/286 (0.3%)
Urticaria	2/293 (0.7%)		3/286 (1%)
Ecchymosis	1/293 (0.3%)		2/286 (0.7%)
Rash erythematous	2/293 (0.7%)		1/286 (0.3%)
Dermatitis allergic	2/293 (0.7%)		1/286 (0.3%)
Nail discoloration	1/293 (0.3%)		1/286 (0.3%)
Night sweats	1/293 (0.3%)		1/286 (0.3%)
Pruritus generalized	0/293 (0%)		2/286 (0.7%)
Skin exfoliation	0/293 (0%)		2/286 (0.7%)
Skin fissures	1/293 (0.3%)		1/286 (0.3%)
Blister	0/293 (0%)		1/286 (0.3%)
Butterfly rash	0/293 (0%)		1/286 (0.3%)
Cold sweat	0/293 (0%)		1/286 (0.3%)
Erythema multiforme	1/293 (0.3%)		0/286 (0%)
Hemorrhage subcutaneous	0/293 (0%)		1/286 (0.3%)
Hair growth abnormal	1/293 (0.3%)		0/286 (0%)
Hirsutism	1/293 (0.3%)		0/286 (0%)
Hypertrichosis	1/293 (0.3%)		0/286 (0%)
Hypoaesthesia facial	1/293 (0.3%)		0/286 (0%)
Ingrowing nail	1/293 (0.3%)		0/286 (0%)
Intertrigo	0/293 (0%)		1/286 (0.3%)
Madarosis	0/293 (0%)		1/286 (0.3%)
Onychalgia	1/293 (0.3%)		0/286 (0%)
Onycholysis	1/293 (0.3%)		0/286 (0%)
Periorbital edema	1/293 (0.3%)		0/286 (0%)
Rosacea	1/293 (0.3%)		0/286 (0%)
Skin chapped	1/293 (0.3%)		0/286 (0%)
Skin discomfort	1/293 (0.3%)		0/286 (0%)
Skin disorder	0/293 (0%)		1/286 (0.3%)
Skin lesion	1/293 (0.3%)		0/286 (0%)
Swelling face	1/293 (0.3%)		0/286 (0%)
Social circumstances
Immobile	0/293 (0%)		1/286 (0.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.