Tykerb Evaluation After Chemotherapy (TEACH): Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00374322
• Collaborator: (none)
• Enrollment: 3,166
• Locations: 439
• Arms: 2
• Duration (Months): 83
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study was designed to evaluate and compare the safety and efficacy of an oral dual tyrosine kinase inhibitor, lapatinib, versus placebo in women with early-stage ErbB2-overexpressing breast cancer who have completed their primary neoadjuvant or adjuvant chemotherapy and have no clinical or radiographic evidence of disease.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: lapatinib; Other: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 3166 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Multicenter, Placebo-controlled Study of Adjuvant Lapatinib (GW572016) in Women With Early-Stage ErbB2 Overexpressing Breast Cancer
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 6 tablets daily for 12 months	Other: placebo; 6 tablets daily for 12 months
Experimental: Lapatinib Lapatinib 1500 mg (6 tablets) daily for 12 months	Drug: lapatinib; Lapatinib 1500 mg (6 tablets) daily for 12 months

Outcome Measures

Primary Outcome Measures

1. Number of Participants (Par.) With Any Recurrence of the Initial Disease, Second Primary Cancer, Contralateral Breast Cancer, or Death (Disease-free Survival [DFS]) [From randomization until date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause (assessed up to 6 years; 1 year of treatment, 5 years of follow-up [median of 5.3 years for final analysis])]

   DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ; other second primary cancer (excluding squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast); death from any cause without a prior event. Par. who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Par. who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed.

Secondary Outcome Measures

1. Number of Participants Who Died (Overall Survival) [From the date of randomization until death from any cause (assessed up to 6 years; 1 year of treatment and 5 years of follow-up [median of 5.3 years for final analysis])]

   Overall Survival (OS) is defined as the time from randomization until death from any cause. Data are presented as the number of participants who died. For participants who did not die, time to death was censored at the last date the participant was known to be alive.

2. Percentage of Participants With the Indicated Period of Recurrence-free Survival (Time to First Recurrence) [From the date of randomization until the date of the first occurrence of an objective disease recurrence or contralateral breast cancer (assessed up to 6 years; 1 year of treatment and 5.3 years of follow-up [median of 5 years for final analysis])]

   Recurrence is defined as experiencing a recurrence of initial disease or contralateral breast cancer after randomization. Time to first recurrence is defined as the interval between the date of randomization and the date of the first occurrence of an objective disease recurrence or contralateral breast cancer. Time to first recurrence included the first occurrence at one of the following sites as an event: local recurrence following mastectomy; local recurrence in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ (DCIS).

3. Percentage of Participants With the Indicated Period of Distant Recurrence-free Survival (Time to Distant Recurrence) [From the date of randomization until the date of the first occurrence of a distant recurrence (assessed up to 6 years; 1 year of treatment and 5 years of follow-up [median of 5.3 years for final analysis])]

   Distant recurrence (metastatic disease) is defined as a tumor in any area of the body not including those defined as local or regional recurrence. Sites of distant recurrence include: skin, subcutaneous tissue, and lymph nodes (excluding those described for local and regional recurrence); bone marrow; skeletal; lungs and pleural; ascites and pleural effusions; liver and other viscera; and central nervous system (CNS). Time to distant recurrence is defined as the interval between the date of randomization and the date of the first occurrence of a distant recurrence.

4. Time to Central Nervous System (CNS) Recurrence [From the date of randomization until the date of the first occurrence of a CNS recurrence (assessed up to 6 years [1 year of treatment and 5 years of follow-up; median of 5.3 years for final analysis])]

   Time to CNS recurrence is defined as the interval between the date of randomization and the date of the occurrence of a CNS recurrence if noted as part of the participant's first recurrence. Time to CNS recurrence was not calculated; data are presented as the number of participants with CNS recurrence in the subsequent outcome measure table.

5. Number of Participants With CNS Recurrence [From the date of randomization until the date of the first occurrence of a CNS recurrence (assessed up to 6 years [1 year of treatment and 5 years of follow-up; median of 5.3 years for final analysis])]

   The number of participants experiencing a CNS recurrence was summarized.

6. Modified Disease-free Survival (MDFS) [From the date of randomization until the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause (assessed up to 6 years)]

   Modified disease recurrence=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause. The date of the event=the earliest date of the occurrence of any of the following events: local recurrence following mastectomy; local recurrence in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including DCIS; death from any cause without a prior event. MDFS was not calculated; data are presented as the number of participants with any recurrence of the initial disease, contralateral breast cancer, or death (disease-free survival) in the subsequent outcome measure table.

7. Number of Participants With Any Recurrence of the Initial Disease, Contralateral Breast Cancer, or Death (Disease-free Survival [DFS]) [From the date of randomization until the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause (assessed up to 6 years)]

   DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence and contralateral breast cancer, including ductal carcinoma in situ; or death from any cause without a prior event. Participants who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Participants who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed.

8. Change From Baseline in Short Form-36 Version 2 (SF-36 v2) Scores for the Physical Component Summary (PCS) [Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years)]

   The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health).The PCS score is a summary score representing overall physical health, which is derived from the 8 domain scores. As with each domain score, the PCS score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the last observation carried forward (LOCF) method. The scores were analyzed using an analysis of covariance (ANCOVA) model, adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement.

9. Change From Baseline in SF-36 v2 Scores for the Mental Component Summary (MCS) [Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years)]

   The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health).The MCS score is a summary score representing overall mental health, which is derived from the 8 domain scores. As with each domain score, the MCS score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the LOCF method. The scores were analyzed using an ANCOVA model adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement.

10. Change From Baseline in the SF-36 v2 Domain Scores for Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (MH) [Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years)]

    The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH) perceptions, vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH). Each domain is scored from 0 (poorer health) to 100 (better health); higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the LOCF method. The scores were analyzed using an ANCOVA model, adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement.

11. Number of Participants With Hematology Values Outside the Reference Range for the Indicated Parameters [At Baseline and every 3 months thereafter up to Month 12/Early Withdrawal Visit]

    The hematology parameters assessed were: basophils (Bs) in giga (10^9) per liter (GI/L) and in percentage (%), eosinophils (Eo) in GI/L and %, hematocrit, hemoglobin, lymphocytes (Lmph) in GI/L and %, monocytes (Mono) in GI/L and %, platelet count, Red Blood Cell (RBC) count, total neutrophil count (TNC) in GI/L and %, and White Blood Cell (WBC) count. The Baseline (BL) value is the last available pre-treatment result recorded. "Any post-Baseline value" was based on results recorded at any scheduled or unscheduled post-Baseline visits. The prevalence of values lying outside the reference (ref.) range (high or low) is presented for BL and "any post-Baseline" (APBL) visit. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm. Data for the primary analysis (conducted in 2011) are reported.

12. Number of Participants With Clinical Chemistry Values Outside the Reference Range for the Indicated Parameters [At Baseline and every 6 weeks thereafter up to Month 12/Early Withdrawal Visit]

    The clinical chemistry parameters assessed were: alanine amino transferase (ALT), albumin, alkaline phosphatase (ALP), aspartate amino transferase (AST), bicarbonate, blood urea nitrogen (BUN), bone alkaline phosphatase (Bone ALP), calcium, chloride, creatinine, creatinine clearance (Cr. Clearance), creatinine clearance estimated (Cr. Clrnc. est.), glucose, potassium, sodium, total bilirubin (Total Bln), total protein, urea, and uric acid. The Baseline (BL) value is the last available pre-treatment result recorded. "Any post-Baseline" value was based on results recorded at scheduled or unscheduled post-Baseline visits. The prevalence of values lying outside the reference (ref.) range (high or low) was presented for BL and "any post-Baseline" (APBL) visit. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm.

13. Number of Participants With Non-laboratory Toxicities of the Indicated Toxicity Grades [From the first dose of study treatment up to 12 months]

    Non-laboratory toxicities are defined as adverse events (AEs). The number of partcipants with any treatment-emergent AE of the indicated toxicity grade are summarized. Toxicity grading was according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life threatening; Grade 5=death. The events that were not given a toxicity grade are categorized as "Not Applicable."

14. Number of Participants Experiencing Primary or Secondary Cardiac Events [From the date of randomization up to 12 months]

    A cardiac event is classified as a primary cardiac endpoint (PCE) or a secondary cardiac endpoint (SCE). PCE is defined as: cardiac death (cardiac death due to heart failure, myocardial infarction, or arrhythmia;or probable cardiac death defined as sudden, unexpected death within 24 hours of a definite or probable cardiac event); severe symptomatic congestive heart failure (CHF) (as per New York Heart Association [NYHA] Class III or IV and an absolute decrease in left ventricular ejection fraction [LVEF] of more than 10 percentage points from Baseline and to a left ventricular ejection fraction [LVEF] value below 50%). SCE is defined as asymptomatic or mildly symptomatic cardiac events (NYHA Class I or II) and a significant decrease in LVEF, defined as an absolute decrease in LVEF of more than 10 percentage points from Baseline and to an LVEF value below 50%.

15. Number of Participants With the Indicated Electrocardiogram (ECG) Findings [Screening and Month 12/Early Withdrawal Visit]

    12-lead ECG measurements were taken at Screening and at study conclusion/withdrawal. The number of participants with normal, abnormal clinically significant (CS), and abnormal not clinically significant (NCS) ECG findings, as classified by the investigator, were summarized. Participants with missing values were categorized as missing. Data for the primary analysis (conducted in 2011) are reported.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Have histologically or cytologically confirmed ErbB2-overexpressing invasive carcinoma (TX or T1-4) of the breast at the time of the initial diagnosis and have undergone adequate excision of tumor;

• Had tumors that overexpress ErbB2 defined as 3+ by IHC or c-erbB2 gene amplification by FISH (ErbB2 expression/amplification must be documented prior to study entry; however, a tumor tissue sample must be sent to a central laboratory for subsequent re-analysis of ErbB2 status);

• Have Stage I through Stage IIIc disease according to the American Joint Committee on Cancer (6th edition) staging criteria for breast cancer and meet one of the following criteria:

node-positive disease defined as: one positive lymph node by sentinel node biopsy OR at least 1 positive lymph node found among at least 6 axillary nodes examined on axillary node dissection OR status post axillary radiotherapy for sterilization if clinically evaluated as cN1 or cN2 (if sentinel node biopsy is positive, subject may either undergo an axillary node dissection or radiotherapy to the axilla).

node-positive disease evaluated as: ipsilateral axillary lymph nodes cN0-2 by clinical evaluation and axillary lymph nodes pNX, pN0(i+), or pN1-3 by pathological evaluation [patients with pN3 (Stage IIIc disease) must be disease free following completion of neoadjuvant or adjuvant chemotherapy for at least 12 months and must not have been lost to follow up].

OR node-negative disease defined as: negative sentinel node biopsy OR no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection OR status post axillary radiotherapy for sterilization if clinically evaluated as cN0.

node-negative disease categorized as: high-risk disease (tumor >2.0 cm if ER and/or progesterone receptor (PgR) positive disease is present or tumor >1.0 cm if ER and PgR negative disease) OR intermediate-risk disease (tumor 1.0-2.0 cm and ER and/or PgR positive disease).

• Women with synchronous bilateral invasive breast cancer or synchronous DCIS of either the contralateral or ipsilateral breast at the time of the initial diagnosis are also eligible;

• Have undergone either mastectomy OR lumpectomy;

• Have received and completed treatment with a neoadjuvant or adjuvant chemotherapy regimen containing either an anthracycline or a taxane; or any cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen;

• May continue to receive endocrine therapy while taking study medication, if endocrine therapy was initiated as either adjuvant therapy for treatment of the initial diagnosis of invasive breast cancer or for ovarian function suppression; however, endocrine therapy may not be initiated while taking study medication. Endocrine therapy agents may be switched while participating in this study (e.g., stop tamoxifen and start letrozole);

• May have received prior radiotherapy as treatment for primary tumor; however, is not required for study entry;

• May continue to receive radiotherapy while taking study medication, if radiotherapy was initiated as adjuvant therapy for treatment of the initial diagnosis of invasive breast cancer;

• May continue to receive bisphosphonates only for treatment of documented osteoporosis, but not as treatment or prophylaxis of bone metastases;

• All women eligible for adjuvant treatment with trastuzumab, including those diagnosed and treated within the last six months, must be considered for such treatment prior to being offered participation in this study. Participation in this study will be allowed only if the physician and patient have considered and discussed at length the advantages of trastuzumab, but have mutually decided against initiating trastuzumab therapy.

• Have clinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry;

• if signs or symptoms suggestive of either recurrence of disease or metastatic disease are present, the appropriate radiological imaging must be performed

• if the following laboratory results are present, the appropriate radiological imaging must be performed:

• for AST/ALT ≥2×ULN or ALP ≥2×ULN (not in the bone fraction), an abdominal CT or MRI must be done

• for ALP≥2×ULN in the bone fraction, a bone scan must be done; a confirmatory x-ray, CT scan or MRI scan or biopsy is required if the results of the bone scan are inconclusive

• Have a unilateral/bilateral mammogram within 12 months prior to study entry;

• Have an analysis of both ER and PgR on the primary tumor prior to study entry;

• Have a cardiac ejection fraction within institutional range of normal as measured by either echocardiogram or multigated acquisition scans;

• Have an Eastern Cooperative Oncology Group Performance Status of 0 to 1;

• Women with a history of non-breast malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence. Women with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical carcinoma in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin;

• Are able to swallow and retain oral medication;

• Have a paraffin-embedded tissue block from an archived tumor tissue from the primary tumor or twenty (20) slides of paraffin-embedded tissue available for biomarker analysis;

• Have adequate organ function defined as: absolute neutrophil count ≥1.5× 10^{9/L; hemoglobin ≥9 g/dL; platelets ≥75 × 10}9/L; albumin ≥2.5 g/dL; serum bilirubin ≤1.25 ×ULN; aspartate aminotransferase and alanine aminotransferase ≤3 × ULN and serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥40 mL/min

• Have signed the informed consent form (ICF);

• Women of child-bearing potential must have a negative serum pregnancy test at screening and agree to complete abstinence from intercourse or consistent and correct use of an acceptable methods of birth control from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication:

Exclusion Criteria:

• Have clinical and radiologic evidence of local or regional recurrence of disease or metastatic disease at the time of study entry;

• Had metachronous invasive breast cancer (breast cancers diagnosed at different times);

• Have a prior history of other breast cancer malignancies, including DCIS;

• Are unable to provide archived tumor tissue samples for assay;

• Had prior therapy with an ErbB1 and/or ErbB2 inhibitor; women who experienced a hypersensitivity or allergic reaction to trastuzumab during the first infusion and were unable to complete this infusion are eligible;

• Receive concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication;

• Have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;

• Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded;

• Have a concurrent disease or condition that would make the woman inappropriate for study participation, or any serious medical disorder that would interfere with the woman's safety;

• Have an active or uncontrolled infection;

• Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;

• Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF;

• Are pregnant or breastfeeding;

• Receive concurrent treatment with an investigational agent; women, who are in follow-up in another clinical trial where the primary endpoint has been met and the interval between assessments is ≥12 months and radiological imaging is not required at these assessments, are eligible;

• Receive concurrent treatment with a selected list of strong inducers and inhibitors of CYP3A4;

• Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication;

• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib or excipients;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Tuscaloosa	Alabama	United States	35406
2	GSK Investigational Site	Phoenix	Arizona	United States	85012
3	GSK Investigational Site	Sedona	Arizona	United States	86336
4	GSK Investigational Site	Tucson	Arizona	United States	85715
5	GSK Investigational Site	Fayetteville	Arkansas	United States	72703
6	GSK Investigational Site	Jonesboro	Arkansas	United States	72401
7	GSK Investigational Site	Little Rock	Arkansas	United States	72205
8	GSK Investigational Site	Anaheim	California	United States	92801
9	GSK Investigational Site	Bakersfield	California	United States	93309
10	GSK Investigational Site	Gilroy	California	United States	95020
11	GSK Investigational Site	La Jolla	California	United States	92037
12	GSK Investigational Site	La Verne	California	United States	91750
13	GSK Investigational Site	Palm Springs	California	United States	92262
14	GSK Investigational Site	Rancho Mirage	California	United States	92270
15	GSK Investigational Site	Denver	Colorado	United States	80220
16	GSK Investigational Site	Fairfield	Connecticut	United States	06824
17	GSK Investigational Site	Norwalk	Connecticut	United States	06856
18	GSK Investigational Site	Torrington	Connecticut	United States	06790
19	GSK Investigational Site	Washington	District of Columbia	United States	20007
20	GSK Investigational Site	Washington	District of Columbia	United States	20010
21	GSK Investigational Site	Boca Raton	Florida	United States	33428
22	GSK Investigational Site	Boynton Beach	Florida	United States	33437
23	GSK Investigational Site	Gainesville	Florida	United States	32605
24	GSK Investigational Site	New Port Richey	Florida	United States	34655
25	GSK Investigational Site	Ocala	Florida	United States	34474
26	GSK Investigational Site	Orlando	Florida	United States	32806
27	GSK Investigational Site	Plantation	Florida	United States	33324
28	GSK Investigational Site	Port St. Lucie	Florida	United States	34952
29	GSK Investigational Site	Augusta	Georgia	United States	30901
30	GSK Investigational Site	Marietta	Georgia	United States	30060
31	GSK Investigational Site	Chicago	Illinois	United States	60611-2906
32	GSK Investigational Site	Chicago	Illinois	United States	60611
33	GSK Investigational Site	Joliet	Illinois	United States	60435
34	GSK Investigational Site	Park Ridge	Illinois	United States	60068
35	GSK Investigational Site	Indianapolis	Indiana	United States	46219
36	GSK Investigational Site	Ames	Iowa	United States	50010
37	GSK Investigational Site	Sioux City	Iowa	United States	51101-1733
38	GSK Investigational Site	Wichita	Kansas	United States	67214
39	GSK Investigational Site	Louisville	Kentucky	United States	40245
40	GSK Investigational Site	Marrero	Louisiana	United States	70072
41	GSK Investigational Site	Scarborough	Maine	United States	4074
42	GSK Investigational Site	Bethesda	Maryland	United States	20817
43	GSK Investigational Site	Boston	Massachusetts	United States	02114
44	GSK Investigational Site	Danvers	Massachusetts	United States	01923
45	GSK Investigational Site	Newton	Massachusetts	United States	02462
46	GSK Investigational Site	Kalamazoo	Michigan	United States	49048
47	GSK Investigational Site	Duluth	Minnesota	United States	55805
48	GSK Investigational Site	Edina	Minnesota	United States	55435
49	GSK Investigational Site	Minneapolis	Minnesota	United States	55404
50	GSK Investigational Site	Robbinsdale	Minnesota	United States	55422
51	GSK Investigational Site	Columbia	Missouri	United States	65201
52	GSK Investigational Site	Kansas City	Missouri	United States	64118
53	GSK Investigational Site	Saint Louis	Missouri	United States	63109
54	GSK Investigational Site	St. Joseph	Missouri	United States	64507
55	GSK Investigational Site	St. Louis	Missouri	United States	63141
56	GSK Investigational Site	Hooksett	New Hampshire	United States	03106
57	GSK Investigational Site	Cherry Hill	New Jersey	United States	08003
58	GSK Investigational Site	Morristown	New Jersey	United States	07962
59	GSK Investigational Site	Paramus	New Jersey	United States	07652
60	GSK Investigational Site	Sparta	New Jersey	United States	07871
61	GSK Investigational Site	Albany	New York	United States	12206
62	GSK Investigational Site	East Setauket	New York	United States	11733
63	GSK Investigational Site	Mount Kisco	New York	United States	10590
64	GSK Investigational Site	New York	New York	United States	10003
65	GSK Investigational Site	New York	New York	United States	10016
66	GSK Investigational Site	Rochester	New York	United States	14623
67	GSK Investigational Site	Charleston	North Carolina	United States	29406
68	GSK Investigational Site	Gastonia	North Carolina	United States	28054
69	GSK Investigational Site	Greensboro	North Carolina	United States	27403
70	GSK Investigational Site	Hickory	North Carolina	United States	28602
71	GSK Investigational Site	Cleveland	Ohio	United States	44106
72	GSK Investigational Site	Cleveland	Ohio	United States	44195
73	GSK Investigational Site	Columbus	Ohio	United States	43215
74	GSK Investigational Site	Middletown	Ohio	United States	45042
75	GSK Investigational Site	Drexel Hill	Pennsylvania	United States	19026
76	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19107
77	GSK Investigational Site	Charleston	South Carolina	United States	29414
78	GSK Investigational Site	Chattanooga	Tennessee	United States	37403
79	GSK Investigational Site	Germantown	Tennessee	United States	38138
80	GSK Investigational Site	Memphis	Tennessee	United States	38120
81	GSK Investigational Site	Austin	Texas	United States	78705
82	GSK Investigational Site	Austin	Texas	United States	78759
83	GSK Investigational Site	Bedford	Texas	United States	76022
84	GSK Investigational Site	Dallas	Texas	United States	75230
85	GSK Investigational Site	Dallas	Texas	United States	75231
86	GSK Investigational Site	Dallas	Texas	United States	75246
87	GSK Investigational Site	Duncanville	Texas	United States	75137
88	GSK Investigational Site	El Paso	Texas	United States	79902
89	GSK Investigational Site	Fort Worth	Texas	United States	76104
90	GSK Investigational Site	Houston	Texas	United States	77024
91	GSK Investigational Site	Houston	Texas	United States	77030
92	GSK Investigational Site	Round Rock	Texas	United States	78681
93	GSK Investigational Site	San Antonio	Texas	United States	78229
94	GSK Investigational Site	Tyler	Texas	United States	75702
95	GSK Investigational Site	Waco	Texas	United States	76712
96	GSK Investigational Site	Ogden	Utah	United States	84403
97	GSK Investigational Site	Chesapeake	Virginia	United States	23320
98	GSK Investigational Site	Fairfax	Virginia	United States	22031
99	GSK Investigational Site	Richland	Virginia	United States	24641
100	GSK Investigational Site	Kirkland	Washington	United States
101	GSK Investigational Site	Seattle	Washington	United States	98104
102	GSK Investigational Site	Vancouver	Washington	United States	98684
103	GSK Investigational Site	Yakima	Washington	United States	98902
104	GSK Investigational Site	Capital Federal	Buenos Aires	Argentina	C1405CUB
105	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1185AAT
106	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1405BCH
107	GSK Investigational Site	Córdoba	Córdova	Argentina	X5006HBF
108	GSK Investigational Site	Neuquen	Neuquén	Argentina	Q8300HDH
109	GSK Investigational Site	Rosario	Santa Fe	Argentina	S2000KZE
110	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1417DTN
111	GSK Investigational Site	Quilmes		Argentina	1878
112	GSK Investigational Site	San Miguel de Tucumán		Argentina	T4000IAK
113	GSK Investigational Site	Santa Fe		Argentina	3000
114	GSK Investigational Site	Campbelltown	New South Wales	Australia	2560
115	GSK Investigational Site	Darlinghurst	New South Wales	Australia	2010
116	GSK Investigational Site	Kogarah	New South Wales	Australia	2217
117	GSK Investigational Site	Liverpool	New South Wales	Australia	2170
118	GSK Investigational Site	North Sydney	New South Wales	Australia	2060
119	GSK Investigational Site	Douglas	Queensland	Australia	4814
120	GSK Investigational Site	Herston	Queensland	Australia	4029
121	GSK Investigational Site	Redcliffe	Queensland	Australia	4020
122	GSK Investigational Site	South Brisbane	Queensland	Australia	4101
123	GSK Investigational Site	Bedford Park	South Australia	Australia	5042
124	GSK Investigational Site	Elizabeth Vale	South Australia	Australia	5112
125	GSK Investigational Site	Woodville	South Australia	Australia	5011
126	GSK Investigational Site	Box Hill	Victoria	Australia	3128
127	GSK Investigational Site	East Melbourne	Victoria	Australia	3002
128	GSK Investigational Site	Fitzroy	Victoria	Australia	3065
129	GSK Investigational Site	Footscray	Victoria	Australia	3011
130	GSK Investigational Site	Heidelberg	Victoria	Australia	3084
131	GSK Investigational Site	Parkville	Victoria	Australia	3050
132	GSK Investigational Site	Ringwood East	Victoria	Australia	3135
133	GSK Investigational Site	Wodonga	Victoria	Australia	3690
134	GSK Investigational Site	Nedlands	Western Australia	Australia	6009
135	GSK Investigational Site	Perth	Western Australia	Australia	6000
136	GSK Investigational Site	Bruxelles		Belgium	1000
137	GSK Investigational Site	Belo Horizonte	Minas Gerais	Brazil	30.140-001
138	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul	Brazil	90020-090
139	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610 000
140	GSK Investigational Site	Santo Andre	São Paulo	Brazil	09060-670
141	GSK Investigational Site	Rio de Janeiro		Brazil	21941-913
142	GSK Investigational Site	São Paulo		Brazil	03102-002
143	GSK Investigational Site	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
144	GSK Investigational Site	Halifax	Nova Scotia	Canada	B3H 1V7
145	GSK Investigational Site	Barrie	Ontario	Canada	L4M 6M2
146	GSK Investigational Site	Brampton	Ontario	Canada	L6W 2Z8
147	GSK Investigational Site	Kingston	Ontario	Canada	K7L 5P9
148	GSK Investigational Site	London	Ontario	Canada	N6A 4L6
149	GSK Investigational Site	Mississauga	Ontario	Canada	L5M 2N1
150	GSK Investigational Site	Oshawa	Ontario	Canada	L1G 2B9
151	GSK Investigational Site	Ottawa	Ontario	Canada	K1H 8L6
152	GSK Investigational Site	Toronto	Ontario	Canada	M4C 3E7
153	GSK Investigational Site	Toronto	Ontario	Canada	M4N 3M5
154	GSK Investigational Site	Toronto	Ontario	Canada	M5B 1W8
155	GSK Investigational Site	Toronto	Ontario	Canada	M6R 1B5
156	GSK Investigational Site	Greenfield Park	Quebec	Canada	J4V 2H1
157	GSK Investigational Site	Montreal	Quebec	Canada	H3T 1E2
158	GSK Investigational Site	Saskatoon	Saskatchewan	Canada	S7N 4H4
159	GSK Investigational Site	Quebec		Canada	G1S 4L8
160	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	750 1088
161	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500921
162	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7591046
163	GSK Investigational Site	Viña del Mar	Valparaíso	Chile	254-0364
164	GSK Investigational Site	Guangzhou	Guangdong	China	510060
165	GSK Investigational Site	Wuhan	Hubei	China	430030
166	GSK Investigational Site	Jinan	Shandong	China	250117
167	GSK Investigational Site	Beijing		China	100021
168	GSK Investigational Site	Beijing		China	100036
169	GSK Investigational Site	Beijing		China	100071
170	GSK Investigational Site	Shanghai		China	200032
171	GSK Investigational Site	Tianjin		China	300060
172	GSK Investigational Site	Osijek		Croatia	31000
173	GSK Investigational Site	Pula		Croatia	52 100
174	GSK Investigational Site	Rijeka		Croatia	51000
175	GSK Investigational Site	Split		Croatia	21000
176	GSK Investigational Site	Zagreb		Croatia	10 000
177	GSK Investigational Site	Brno		Czech Republic	656 53
178	GSK Investigational Site	Prague 2		Czech Republic	121 00
179	GSK Investigational Site	Praha 8		Czech Republic	180 00
180	GSK Investigational Site	Aalborg		Denmark	9100
181	GSK Investigational Site	Copenhagen		Denmark	DK-2100
182	GSK Investigational Site	Esbjerg		Denmark	6700
183	GSK Investigational Site	Herlev		Denmark	DK-2730
184	GSK Investigational Site	Naestved		Denmark	4700
185	GSK Investigational Site	Odense		Denmark	5000
186	GSK Investigational Site	Roskilde		Denmark	4000
187	GSK Investigational Site	Vejle		Denmark	7100
188	GSK Investigational Site	Angers		France	49933
189	GSK Investigational Site	Besançon		France	25030
190	GSK Investigational Site	Bordeaux		France	33000
191	GSK Investigational Site	Caen Cedex 05		France	14076
192	GSK Investigational Site	Clermont Ferrand		France	63000
193	GSK Investigational Site	Colmar Cedex		France	68024
194	GSK Investigational Site	Dijon Cedex		France	21079
195	GSK Investigational Site	Lille cedex		France	59020
196	GSK Investigational Site	Lille		France	59000
197	GSK Investigational Site	Lyon Cedex 08		France	69373
198	GSK Investigational Site	Lyon		France	69008
199	GSK Investigational Site	Marseille Cedex 09		France	13273
200	GSK Investigational Site	Montbeliard		France	25200
201	GSK Investigational Site	Montpellier Cedex 5		France	34298
202	GSK Investigational Site	Nantes cedex		France	44202
203	GSK Investigational Site	Nice Cedex 2		France	06189
204	GSK Investigational Site	Paris Cedex 15		France	75908
205	GSK Investigational Site	Reims		France	51100
206	GSK Investigational Site	Rennes		France	35042
207	GSK Investigational Site	Saint Grégoire		France	35760
208	GSK Investigational Site	Saint-Cloud		France	92210
209	GSK Investigational Site	Saint-Herblain		France	44805
210	GSK Investigational Site	Strasbourg		France	67000
211	GSK Investigational Site	Toulouse Cedex 3		France	31076
212	GSK Investigational Site	Toulouse Cedex 9		France	31059
213	GSK Investigational Site	Tourcoing		France	59200
214	GSK Investigational Site	Vandoeuvre-Les-Nancy		France	54511
215	GSK Investigational Site	Villejuif Cedex		France	94805
216	GSK Investigational Site	Villejuif		France	94804
217	GSK Investigational Site	Freiburg	Baden-Wuerttemberg	Germany	79106
218	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg	Germany	69115
219	GSK Investigational Site	Konstanz	Baden-Wuerttemberg	Germany	78464
220	GSK Investigational Site	Mannheim	Baden-Wuerttemberg	Germany	68161
221	GSK Investigational Site	Mayen	Baden-Wuerttemberg	Germany	56727
222	GSK Investigational Site	Mutlangen	Baden-Wuerttemberg	Germany	73557
223	GSK Investigational Site	Rheinfelden	Baden-Wuerttemberg	Germany	79618
224	GSK Investigational Site	Schwetzingen	Baden-Wuerttemberg	Germany	68723
225	GSK Investigational Site	Singen	Baden-Wuerttemberg	Germany	78224
226	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg	Germany	70190
227	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg	Germany	70376
228	GSK Investigational Site	Tuebingen	Baden-Wuerttemberg	Germany	72076
229	GSK Investigational Site	Ulm	Baden-Wuerttemberg	Germany	89075
230	GSK Investigational Site	Amberg	Bayern	Germany	92224
231	GSK Investigational Site	Aschaffenburg	Bayern	Germany	63739
232	GSK Investigational Site	Bayreuth	Bayern	Germany	95445
233	GSK Investigational Site	Deggendorf	Bayern	Germany	94469
234	GSK Investigational Site	Ebersberg	Bayern	Germany	85560
235	GSK Investigational Site	Eggenfelden	Bayern	Germany	84307
236	GSK Investigational Site	Erlangen	Bayern	Germany	91054
237	GSK Investigational Site	Fuerth	Bayern	Germany	90766
238	GSK Investigational Site	Kempten	Bayern	Germany	87439
239	GSK Investigational Site	Krumbach	Bayern	Germany	86381
240	GSK Investigational Site	Marktredwitz	Bayern	Germany	95615
241	GSK Investigational Site	Memmingen	Bayern	Germany	87700
242	GSK Investigational Site	Muenchen	Bayern	Germany	80331
243	GSK Investigational Site	Muenchen	Bayern	Germany	80335
244	GSK Investigational Site	Muenchen	Bayern	Germany	80337
245	GSK Investigational Site	Muenchen	Bayern	Germany	80637
246	GSK Investigational Site	Muenchen	Bayern	Germany	81377
247	GSK Investigational Site	Rehling	Bayern	Germany	86508
248	GSK Investigational Site	Rosenheim	Bayern	Germany	83022
249	GSK Investigational Site	Roth	Bayern	Germany	91154
250	GSK Investigational Site	Schwandorf	Bayern	Germany	92421
251	GSK Investigational Site	Weiden	Bayern	Germany	92637
252	GSK Investigational Site	Cottbus	Brandenburg	Germany	03046
253	GSK Investigational Site	Fuerstenwalde	Brandenburg	Germany	15517
254	GSK Investigational Site	Frankfurt am Main	Hessen	Germany	60590
255	GSK Investigational Site	Frankfurt	Hessen	Germany	60389
256	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
257	GSK Investigational Site	Frankfurt	Hessen	Germany	65929
258	GSK Investigational Site	Kassel	Hessen	Germany	34117
259	GSK Investigational Site	Kassel	Hessen	Germany	34131
260	GSK Investigational Site	Wiesbaden	Hessen	Germany	65191
261	GSK Investigational Site	Guestrow	Mecklenburg-Vorpommern	Germany	18273
262	GSK Investigational Site	Goslar	Niedersachsen	Germany	38642
263	GSK Investigational Site	Hannover	Niedersachsen	Germany	30625
264	GSK Investigational Site	Hildesheim	Niedersachsen	Germany	31134
265	GSK Investigational Site	Salzgitter	Niedersachsen	Germany	38226
266	GSK Investigational Site	Bochum	Nordrhein-Westfalen	Germany	44799
267	GSK Investigational Site	Bonn	Nordrhein-Westfalen	Germany	53113
268	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen	Germany	40235
269	GSK Investigational Site	Duisburg	Nordrhein-Westfalen	Germany	47051
270	GSK Investigational Site	Duisburg	Nordrhein-Westfalen	Germany	47166
271	GSK Investigational Site	Essen	Nordrhein-Westfalen	Germany	45130
272	GSK Investigational Site	Herne	Nordrhein-Westfalen	Germany	44623
273	GSK Investigational Site	Hilden	Nordrhein-Westfalen	Germany	40724
274	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50677
275	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50937
276	GSK Investigational Site	Muelheim	Nordrhein-Westfalen	Germany	45473
277	GSK Investigational Site	Porta Westfalica	Nordrhein-Westfalen	Germany	32457
278	GSK Investigational Site	Recklinghausen	Nordrhein-Westfalen	Germany	45657
279	GSK Investigational Site	Troisdorf	Nordrhein-Westfalen	Germany	53840
280	GSK Investigational Site	Velbert	Nordrhein-Westfalen	Germany	42551
281	GSK Investigational Site	Witten	Nordrhein-Westfalen	Germany	58452
282	GSK Investigational Site	Koblenz	Rheinland-Pfalz	Germany	56068
283	GSK Investigational Site	Mainz	Rheinland-Pfalz	Germany	55131
284	GSK Investigational Site	Homburg/Saar	Saarland	Germany	66421
285	GSK Investigational Site	Neunkirchen	Saarland	Germany	66538
286	GSK Investigational Site	Saarbruecken	Saarland	Germany	66113
287	GSK Investigational Site	Blankenburg	Sachsen-Anhalt	Germany	38889
288	GSK Investigational Site	Halle	Sachsen-Anhalt	Germany	06120
289	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39104
290	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39108
291	GSK Investigational Site	Stendal	Sachsen-Anhalt	Germany	39576
292	GSK Investigational Site	Chemnitz	Sachsen	Germany	09116
293	GSK Investigational Site	Dresden	Sachsen	Germany	01307
294	GSK Investigational Site	Kauschwitz	Sachsen	Germany	08525
295	GSK Investigational Site	Neustadt	Sachsen	Germany	01844
296	GSK Investigational Site	Spremberg	Sachsen	Germany	03130
297	GSK Investigational Site	Zittau	Sachsen	Germany	02763
298	GSK Investigational Site	Zwickau	Sachsen	Germany	08060
299	GSK Investigational Site	Kiel	Schleswig-Holstein	Germany	24103
300	GSK Investigational Site	Luebeck	Schleswig-Holstein	Germany	23538
301	GSK Investigational Site	Eisenach	Thueringen	Germany	99817
302	GSK Investigational Site	Jena	Thueringen	Germany	07743
303	GSK Investigational Site	Berlin		Germany	10117
304	GSK Investigational Site	Berlin		Germany	10367
305	GSK Investigational Site	Berlin		Germany	12683
306	GSK Investigational Site	Berlin		Germany	13125
307	GSK Investigational Site	Berlin		Germany	13156
308	GSK Investigational Site	Berlin		Germany	14169
309	GSK Investigational Site	Berlin		Germany	14197
310	GSK Investigational Site	Bremen		Germany	28177
311	GSK Investigational Site	Bremen		Germany	28209
312	GSK Investigational Site	Hamburg		Germany	20246
313	GSK Investigational Site	Hamburg		Germany	22081
314	GSK Investigational Site	Hamburg		Germany	22457
315	GSK Investigational Site	Athens		Greece	115 27
316	GSK Investigational Site	Athens		Greece	11527
317	GSK Investigational Site	Athens		Greece	185 37
318	GSK Investigational Site	Chania		Greece	73100
319	GSK Investigational Site	Heraklion, Crete		Greece	71110
320	GSK Investigational Site	Hong Kong		Hong Kong
321	GSK Investigational Site	Shatin		Hong Kong
322	GSK Investigational Site	Wanchai		Hong Kong
323	GSK Investigational Site	Budapest		Hungary	1076
324	GSK Investigational Site	Budapest		Hungary
325	GSK Investigational Site	Győr		Hungary	9023
326	GSK Investigational Site	Kaposvár		Hungary	7400
327	GSK Investigational Site	Kistarcsa		Hungary	2143
328	GSK Investigational Site	Pécs		Hungary	7624
329	GSK Investigational Site	Szeged		Hungary	6720
330	GSK Investigational Site	Chennai		India	600035
331	GSK Investigational Site	Hyderabad		India	500082
332	GSK Investigational Site	Jaipur		India	302013
333	GSK Investigational Site	Mumbai		India	400012
334	GSK Investigational Site	New Delhi		India
335	GSK Investigational Site	Pune		India	411001
336	GSK Investigational Site	Ashkelon		Israel	78278
337	GSK Investigational Site	Haifa		Israel	34362
338	GSK Investigational Site	Jerusalem		Israel	91120
339	GSK Investigational Site	Kfar Saba		Israel	44281
340	GSK Investigational Site	Ramat Gan		Israel	52621
341	GSK Investigational Site	Rehovot		Israel	76100
342	GSK Investigational Site	Tel Aviv		Israel	64239
343	GSK Investigational Site	Avellino	Campania	Italy	83100
344	GSK Investigational Site	Piacenza	Emilia-Romagna	Italy	29100
345	GSK Investigational Site	Genova	Liguria	Italy	16132
346	GSK Investigational Site	Sassari	Sardegna	Italy	07100
347	GSK Investigational Site	Perugia	Umbria	Italy	06132
348	GSK Investigational Site	Negrar (Verona)	Veneto	Italy	37024
349	GSK Investigational Site	Goyang-si, Gyeonggi-do		Korea, Republic of	410-769
350	GSK Investigational Site	Seoul		Korea, Republic of	110-744
351	GSK Investigational Site	Seoul		Korea, Republic of	135-710
352	GSK Investigational Site	songpa-gu, Seoul		Korea, Republic of	138-736
353	GSK Investigational Site	Liepaja		Latvia	LV3401
354	GSK Investigational Site	Riga		Latvia	LV 1002
355	GSK Investigational Site	Riga		Latvia	LV 1079
356	GSK Investigational Site	Kaunas		Lithuania	LT-50009
357	GSK Investigational Site	Klaipeda		Lithuania	LT-92228
358	GSK Investigational Site	Vilnius		Lithuania	LT-08660
359	GSK Investigational Site	Mérida	Yucatán	Mexico	97500
360	GSK Investigational Site	Chihuahua		Mexico	31000
361	GSK Investigational Site	DF.		Mexico	01120
362	GSK Investigational Site	Mexico City		Mexico	CP 14080
363	GSK Investigational Site	México D.F.		Mexico	11000
364	GSK Investigational Site	Auckland		New Zealand	1023
365	GSK Investigational Site	Christchurch		New Zealand	8001
366	GSK Investigational Site	Hamilton		New Zealand	2001
367	GSK Investigational Site	Lima		Peru	Lima 11
368	GSK Investigational Site	Lima		Peru	Lima 13
369	GSK Investigational Site	Lima		Peru	Lima 34
370	GSK Investigational Site	Baguio City, Benguet		Philippines	2600
371	GSK Investigational Site	Cebu		Philippines	6000
372	GSK Investigational Site	Pasig City		Philippines	1600
373	GSK Investigational Site	Quezon City		Philippines	1101
374	GSK Investigational Site	Bydgoszcz		Poland	85-792
375	GSK Investigational Site	Krakow		Poland	31-115
376	GSK Investigational Site	Olsztyn		Poland	10-226
377	GSK Investigational Site	Olsztyn		Poland	10-228
378	GSK Investigational Site	Torun		Poland	87-100
379	GSK Investigational Site	Warszawa		Poland	00-909
380	GSK Investigational Site	Moscow		Russian Federation	115 478
381	GSK Investigational Site	Moscow		Russian Federation	117997
382	GSK Investigational Site	Moscow		Russian Federation	129301
383	GSK Investigational Site	Ryazan		Russian Federation	390011
384	GSK Investigational Site	St. Petersburg		Russian Federation	197022
385	GSK Investigational Site	St. Petersburg		Russian Federation	197758
386	GSK Investigational Site	Yaroslavl		Russian Federation	150054
387	GSK Investigational Site	Banska Bystrica		Slovakia	975 17
388	GSK Investigational Site	Bardejov		Slovakia	085 01
389	GSK Investigational Site	Bratislava		Slovakia	833 10
390	GSK Investigational Site	Nitra		Slovakia	950 01
391	GSK Investigational Site	Tygerberg	Western Province	South Africa	7505
392	GSK Investigational Site	Athlone Park, Amanzimtoti		South Africa	4126
393	GSK Investigational Site	Groenkloof		South Africa	0181
394	GSK Investigational Site	Kraaifontein		South Africa	7570
395	GSK Investigational Site	Overport		South Africa	4091
396	GSK Investigational Site	Parktown		South Africa	2193
397	GSK Investigational Site	Port Elizabeth		South Africa	6045
398	GSK Investigational Site	Sandton		South Africa	2199
399	GSK Investigational Site	Saxonwold, Johannesburg		South Africa	2196
400	GSK Investigational Site	Alcorcon		Spain	28922
401	GSK Investigational Site	Barcelona		Spain	08003
402	GSK Investigational Site	Barcelona		Spain	08035
403	GSK Investigational Site	Cáceres		Spain	10003
404	GSK Investigational Site	Girona		Spain	17007
405	GSK Investigational Site	Jaén		Spain	23007
406	GSK Investigational Site	Lerida		Spain	25198
407	GSK Investigational Site	Llobregat		Spain	08907
408	GSK Investigational Site	Madrid		Spain	28034
409	GSK Investigational Site	Madrid		Spain	28040
410	GSK Investigational Site	Mataró		Spain	08304
411	GSK Investigational Site	Orense		Spain	32005
412	GSK Investigational Site	Palma de Mallorca		Spain	07010
413	GSK Investigational Site	Palma de Mallorca		Spain	07198
414	GSK Investigational Site	Santa Cruz de Tenerife		Spain	38320
415	GSK Investigational Site	Santander		Spain	39008
416	GSK Investigational Site	Santiago de Compostela		Spain	15706
417	GSK Investigational Site	Valencia		Spain	46010
418	GSK Investigational Site	Zaragoza		Spain	50009
419	GSK Investigational Site	Dnepropetrovsk		Ukraine	49102
420	GSK Investigational Site	Kyiv		Ukraine	03115
421	GSK Investigational Site	Lvov		Ukraine	79031
422	GSK Investigational Site	Uzhgorod		Ukraine	88017
423	GSK Investigational Site	Chelmsford	Essex	United Kingdom	CM1 7ET
424	GSK Investigational Site	Manchester	Lancashire	United Kingdom	M20 4BX
425	GSK Investigational Site	Sutton	Surrey	United Kingdom	SM2 5PT
426	GSK Investigational Site	Bournemouth		United Kingdom	BH7 7DW
427	GSK Investigational Site	Edgbaston, Birmingham		United Kingdom	B15 2TH
428	GSK Investigational Site	Glasgow		United Kingdom	G12 OYN
429	GSK Investigational Site	Lindley		United Kingdom	HD3 3EA
430	GSK Investigational Site	London		United Kingdom	NW1 2PG
431	GSK Investigational Site	London		United Kingdom	NW3 2QG
432	GSK Investigational Site	London		United Kingdom	SE1 9RT
433	GSK Investigational Site	London		United Kingdom	SW3 6JJ
434	GSK Investigational Site	Maidstone		United Kingdom	ME16 9QQ
435	GSK Investigational Site	Manchester		United Kingdom	M23 9LT
436	GSK Investigational Site	Newcastle upon Tyne		United Kingdom	NE7 7DN
437	GSK Investigational Site	Nottingham		United Kingdom	NG5 1PB
438	GSK Investigational Site	Sheffield		United Kingdom	S10 2SJ
439	GSK Investigational Site	Shrewsbury		United Kingdom	SY3 8XQ

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

• P Goss, I Smith, J O'Shaughnessy, B Ejlertsen, M Kaufmann, F Boyle, A Buzdar, P Fumoleau, W Gradishar, M Martin, B Moy, M Piccart-Gebhart, K I Pritchard, D Lindquist, Y Chavarri-Guerra, G Aktan, E Rappold, L S Williams, D M Finkelstein. Resubmission: A Randomized Trial of Adjuvant Lapatinib in Women with Early Stage HER2 Overexpressing Breast Cancer. Lancet Oncol. 2012;S 1470-2045(12):70508-9.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00374322
• Other Study ID Numbers: EGF105485
• First Posted: Sep 11, 2006
• Last Update Posted: Aug 18, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by GlaxoSmithKline: Breast Cancer; ErbB2-overexpressing; early-stage breast cancer; adjuvant
• Additional relevant MeSH terms: Breast Neoplasms; Lapatinib

Study Results

Participant Flow

Recruitment Details	Women with early-stage ErbB2-overexpressing breast cancer who had not been previously treated with trastuzumab were enrolled in this Phase III study. Women who subsequently had no clinical or radiologic evidence of disease were enrolled after completion of primary neoadjuvant/adjuvant chemotherapy.
Pre-assignment Detail	The study consisted of a Screening Period, a 1-year Treatment Period, and a Follow-up (FU) Period of up to 5 years after the date of study drug withdrawal/completion, for disease status/survival. A total of 3161 eligible participants (par.) (of the 3166 enrolled) were randomized, out of which 3147 par. received at least one dose of study treatment.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Period Title: Overall Study
STARTED	1579	1582
Received >=1 Dose of Study Treatment	1571	1576
COMPLETED	322	278
NOT COMPLETED	1257	1304

Baseline Characteristics

Arm/Group Title	Lapatinib 1500 mg	Placebo	Total
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Total of all reporting groups
Overall Participants	1571	1576	3147
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.7 (9.89)	52.3 (9.94)	52.0 (9.92)
Sex: Female, Male (Count of Participants)
Female	1571 100%	1576 100%	3147 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
African American/ African Heritage	53 3.4%	62 3.9%	115 3.7%
American Indian or Alaskan Native	65 4.1%	67 4.3%	132 4.2%
Asian - Central/South Asian Heritage	20 1.3%	19 1.2%	39 1.2%
Asian - East Asian Heritage	236 15%	229 14.5%	465 14.8%
Asian - Japanese Heritage	1 0.1%	2 0.1%	3 0.1%
Asian - South East Asian Heritage	81 5.2%	81 5.1%	162 5.1%
Native Hawaiian or Other Pacific Islander	5 0.3%	11 0.7%	16 0.5%
White - Arabic/North African Heritage	3 0.2%	11 0.7%	14 0.4%
White - White/Caucasian/European Heritage	1126 71.7%	1121 71.1%	2247 71.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants (Par.) With Any Recurrence of the Initial Disease, Second Primary Cancer, Contralateral Breast Cancer, or Death (Disease-free Survival [DFS])
Description	DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ; other second primary cancer (excluding squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast); death from any cause without a prior event. Par. who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Par. who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed.
Time Frame	From randomization until date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause (assessed up to 6 years; 1 year of treatment, 5 years of follow-up [median of 5.3 years for final analysis])

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants who received at least one dose of randomized treatment (lapatinib or placebo). Data for the end-of-study analysis (conducted in 2013) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1571	1576
Any recurrence or death	252 16%	290 18.4%
Censored, New Anti-cancer Agent/Radiotherapy	1 0.1%	1 0.1%
Censored, Follow-up Ended	1318 83.9%	1285 81.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.286
	Comments	The p-value was calculated from a stratified log-rank test, stratifying for hormone receptor status, time since initial diagnosis, and lymph node involvement.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the treatment hazard ratio (HR) was calcuated using the pike estimator.

2. Secondary Outcome

Title	Number of Participants Who Died (Overall Survival)
Description	Overall Survival (OS) is defined as the time from randomization until death from any cause. Data are presented as the number of participants who died. For participants who did not die, time to death was censored at the last date the participant was known to be alive.
Time Frame	From the date of randomization until death from any cause (assessed up to 6 years; 1 year of treatment and 5 years of follow-up [median of 5.3 years for final analysis])

Outcome Measure Data

Analysis Population Description

ITT Population. Data for the primary analysis (conducted in 2011) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1571	1576
Died	115 7.3%	126 8%
Censored, Follow-up Ended	1456 92.7%	1450 92%

3. Secondary Outcome

Title	Percentage of Participants With the Indicated Period of Recurrence-free Survival (Time to First Recurrence)
Description	Recurrence is defined as experiencing a recurrence of initial disease or contralateral breast cancer after randomization. Time to first recurrence is defined as the interval between the date of randomization and the date of the first occurrence of an objective disease recurrence or contralateral breast cancer. Time to first recurrence included the first occurrence at one of the following sites as an event: local recurrence following mastectomy; local recurrence in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ (DCIS).
Time Frame	From the date of randomization until the date of the first occurrence of an objective disease recurrence or contralateral breast cancer (assessed up to 6 years; 1 year of treatment and 5.3 years of follow-up [median of 5 years for final analysis])

Outcome Measure Data

Analysis Population Description

ITT Population. Data for the primary analysis (conducted in 2011) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1571	1576
6 Months	1.3 0.1%	2.8 0.2%
1Year	3.7 0.2%	5.4 0.3%
18 Months	5.6 0.4%	8.2 0.5%
2 Years	7.7 0.5%	9.9 0.6%
3 Years	10.6 0.7%	12.6 0.8%
4 Years	13.3 0.8%	15.8 1%
5 Years	NA NaN	24.9 1.6%

4. Secondary Outcome

Title	Percentage of Participants With the Indicated Period of Distant Recurrence-free Survival (Time to Distant Recurrence)
Description	Distant recurrence (metastatic disease) is defined as a tumor in any area of the body not including those defined as local or regional recurrence. Sites of distant recurrence include: skin, subcutaneous tissue, and lymph nodes (excluding those described for local and regional recurrence); bone marrow; skeletal; lungs and pleural; ascites and pleural effusions; liver and other viscera; and central nervous system (CNS). Time to distant recurrence is defined as the interval between the date of randomization and the date of the first occurrence of a distant recurrence.
Time Frame	From the date of randomization until the date of the first occurrence of a distant recurrence (assessed up to 6 years; 1 year of treatment and 5 years of follow-up [median of 5.3 years for final analysis])

Outcome Measure Data

Analysis Population Description

ITT Population. Data for the primary analysis (conducted in 2011) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1571	1576
6 Months	0.9 0.1%	1.9 0.1%
1Year	2.9 0.2%	3.8 0.2%
18 Months	4.3 0.3%	6.0 0.4%
2 Years	5.9 0.4%	7.2 0.5%
3 Years	8.1 0.5%	9.1 0.6%
4 Years	9.3 0.6%	11.1 0.7%
5 Years	NA NaN	14.2 0.9%

5. Secondary Outcome

Title	Time to Central Nervous System (CNS) Recurrence
Description	Time to CNS recurrence is defined as the interval between the date of randomization and the date of the occurrence of a CNS recurrence if noted as part of the participant's first recurrence. Time to CNS recurrence was not calculated; data are presented as the number of participants with CNS recurrence in the subsequent outcome measure table.
Time Frame	From the date of randomization until the date of the first occurrence of a CNS recurrence (assessed up to 6 years [1 year of treatment and 5 years of follow-up; median of 5.3 years for final analysis])

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	0	0

6. Secondary Outcome

Title	Number of Participants With CNS Recurrence
Description	The number of participants experiencing a CNS recurrence was summarized.
Time Frame	From the date of randomization until the date of the first occurrence of a CNS recurrence (assessed up to 6 years [1 year of treatment and 5 years of follow-up; median of 5.3 years for final analysis])

Outcome Measure Data

Analysis Population Description

ITT Population. Data for the end-of-study analysis (conducted in 2013) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1571	1576
Number [Participants]	15 1%	21 1.3%

7. Secondary Outcome

Title	Modified Disease-free Survival (MDFS)
Description	Modified disease recurrence=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause. The date of the event=the earliest date of the occurrence of any of the following events: local recurrence following mastectomy; local recurrence in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including DCIS; death from any cause without a prior event. MDFS was not calculated; data are presented as the number of participants with any recurrence of the initial disease, contralateral breast cancer, or death (disease-free survival) in the subsequent outcome measure table.
Time Frame	From the date of randomization until the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause (assessed up to 6 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	0	0

8. Secondary Outcome

Title	Number of Participants With Any Recurrence of the Initial Disease, Contralateral Breast Cancer, or Death (Disease-free Survival [DFS])
Description	DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence and contralateral breast cancer, including ductal carcinoma in situ; or death from any cause without a prior event. Participants who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Participants who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed.
Time Frame	From the date of randomization until the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause (assessed up to 6 years)

Outcome Measure Data

Analysis Population Description

ITT Population. Data for the end-of-study analysis (conducted in 2013) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1571	1576
Number [Participants]	184 11.7%	231 14.7%

9. Secondary Outcome

Title	Change From Baseline in Short Form-36 Version 2 (SF-36 v2) Scores for the Physical Component Summary (PCS)
Description	The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health).The PCS score is a summary score representing overall physical health, which is derived from the 8 domain scores. As with each domain score, the PCS score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the last observation carried forward (LOCF) method. The scores were analyzed using an analysis of covariance (ANCOVA) model, adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement.
Time Frame	Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years)

Outcome Measure Data

Analysis Population Description

ITT Population (primary analysis [conducted in 2011]). Only those participants available (represented as n=X, X in the category titles) at the specified time points were analyzed.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal
Measure Participants	1092	1283
Month 6, n=1092, 1283	-0.78 (0.217)	-0.44 (0.211)
Month 12, n=1007, 1204	-0.84 (0.251)	-0.54 (0.242)
Follow-up, Month 6, n= 983, 1074	-0.53 (0.287)	-0.87 (0.281)
Follow-up, Month 12, n= 940, 988	-0.88 (0.290)	-0.82 (0.289)
Follow-up, Month 18, n=834, 889	-0.61 (0.350)	-0.89 (0.346)
Follow-up, Month 24, n=807, 824	-0.99 (0.412)	-0.66 (0.417)
Early inv. product discontinuation, n=289, 120	-4.39 (0.712)	-4.00 (0.886)

10. Secondary Outcome

Title	Change From Baseline in SF-36 v2 Scores for the Mental Component Summary (MCS)
Description	The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health).The MCS score is a summary score representing overall mental health, which is derived from the 8 domain scores. As with each domain score, the MCS score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the LOCF method. The scores were analyzed using an ANCOVA model adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement.
Time Frame	Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years)

Outcome Measure Data

Analysis Population Description

ITT Population (primary analysis [conducted in 2011]). Only those participants available (represented as n=X, X in the category titles) at the specified time points were analyzed.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1092	1283
Month 6, n=1092, 1283	-2.34 (0.306)	-1.74 (0.297)
Month 12, n=1007, 1204	-2.74 (0.332)	-2.29 (0.322)
Follw-up, Month 6, n=983, 1074	-2.22 (0.368)	-1.87 (0.361)
Follow-up, Month 12, n= 940, 988	-3.08 (0.393)	-2.76 (0.392)
Follow-up, Month 18, n=834, 889	-2.38 (0.480)	-2.08 (0.475)
Follow-up, Month 24, n=807, 824	-2.78 (0.547)	-3.05 (0.554)
Early inv. product discontinuation, n=289, 120	-6.65 (0.985)	-8.11 (1.221)

11. Secondary Outcome

Title	Change From Baseline in the SF-36 v2 Domain Scores for Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (MH)
Description	The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH) perceptions, vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH). Each domain is scored from 0 (poorer health) to 100 (better health); higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the LOCF method. The scores were analyzed using an ANCOVA model, adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement.
Time Frame	Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years)

Outcome Measure Data

Analysis Population Description

ITT Population (primary analysis [conducted in 2011]). Only those participants available (represented as n=X, X in the category titles) at the specified time points were analyzed.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1132	1345
PF, Month 6, n=1132, 1345	-0.52 (0.235)	-0.65 (0.227)
PF, Month 12, n=1025, 1234	-0.59 (0.269)	-0.91 (0.260)
PF, Follow-up, Month 6, n=997, 1097	-0.45 (0.296)	-0.81 (0.289)
PF, Follow-up, Month 12, n=955, 1013	-1.11 (0.317)	-1.40 (0.316)
PF, Follow-up, Month 18, n=851, 913	-0.80 (0.363)	-1.10 (0.358)
PF, Follow-up, Month 24, n=818, 845	-1.06 (0.438)	-1.17 (0.442)
PF, Early inv. Product discontinuation, n=304, 128	-4.30 (0.755)	-4.43 (0.928)
RP, Month 6, n=1130, 1335	-1.37 (0.276)	-0.87 (0.267)
RP, Month 12, n=1023, 1230	-1.52 (0.303)	-0.83 (0.293)
RP, Follow-up, Month 6, n=997, 1094	-1.14 (0.328)	-1.45 (0.322)
RP, Follow-up, Month 12, n=955, 1009	-1.78 (0.344)	-1.47 (0.343)
RP, Follow-up, Month 18, n=851, 909	-1.72 (0.410)	-1.68 (0.405)
RP, Follow-up, Month 24, n=818, 842	-1.77 (0.486)	-1.54 (0.491)
RP, Early inv. product discontinuation, n=303, 127	-6.96 (0.882)	-7.09 (1.087)
BP, Month 6, n=1130, 1331	-1.58 (0.304)	-1.31 (0.295)
BP, Month 12, n=1024, 1229	-1.75 (0.338)	-1.62 (0.326)
BP, Follow-up, Month 6, n=995, 1094	-1.13 (0.376)	-1.35 (0.368)
BP, Follow-up, Month 12, n=954, 1007	-1.06 (0.383)	-1.19 (0.382)
BP, Follow-up, Month 18, n=847, 909	-0.69 (0.461)	-1.07 (0.455)
BP, Follow-up, Month 24, n=817, 840	-1.69 (0.547)	-1.41 (0.553)
BP, Early inv. product discontinuation, n=302, 126	-4.92 (0.950)	-4.97 (1.164)
GH, Month 6, n=1124, 1319	-1.01 (0.244)	-0.34 (0.236)
GH, Month 12, n=1020, 1221	-1.33 (0.275)	-0.70 (0.266)
GH, Follow-up, Month 6, n=994, 1085	-1.25 (0.314)	-1.34 (0.308)
GH, Follow-up, Month 12, n=951, 1002	-1.93 (0.330)	-1.48 (0.329)
GH, Follow-up, Month 18, n=844, 902	-1.28 (0.397)	-1.28 (0.392)
GH, Follow-up, Month 24, n=813, 835	-1.29 (0.471)	-1.02 (0.476)
GH, Early inv. product discontinuation, n=299, 124	-5.12 (0.775)	-6.30 (0.965)
VT, Month 6, n=1126, 1332	-2.30 (0.283)	-1.83 (0.274)
VT, Month 12, n=1022, 1225	-2.49 (0.309)	-1.88 (0.299)
VT, Follow-up, Month 6, n=993, 1090	-1.55 (0.335)	-1.61 (0.328)
VT, Follow-up, Month 12, n=953, 1006	-2.45 (0.355)	-2.01 (0.354)
VT, Follow-up, Month 18, n=848, 906	-1.53 (0.426)	-1.25 (0.421)
VT, Follow-up, Month 24, n=817, 837	-2.03 (0.501)	-1.96 (0.507)
VT, Early inv. product discontinuation, n=303, 125	-5.54 (0.867)	-5.78 (1.067)
SF, Month 6, n=1138, 1347	-2.34 (0.299)	-1.42 (0.289)
SF, Month 12, n=1025, 1234	-2.63 (0.333)	-2.05 (0.322)
SF, Follow-up, Month 6, n=997, 1098	-1.80 (0.371)	-1.51 (0.363)
SF, Follow-up, Month 12, n=957, 1011	-2.47 (0.383)	-2.17 (0.382)
SF, Follow-up, Month 18, n=850, 912	-1.96 (0.462)	-2.01 (0.456)
SF, Follow-up, Month 24, n=819, 843	-2.94 (0.526)	-2.75 (0.532)
SF, Early inv. product discontinuation, n=305, 127	-7.05 (1.017)	-7.94 (1.247)
RE, Month 6, n=1124, 1328	-1.80 (0.335)	-1.69 (0.325)
RE, Month 12, n=1023, 1226	-1.99 (0.357)	-1.99 (0.345)
RE, Follow-up, Month 6, n=996, 1091	-1.87 (0.393)	-1.88 (0.385)
RE, Follow-up, Month 12, n=955, 1004	-2.88 (0.425)	-2.72 (0.425)
RE, Follow-up,Month 18, n=851, 905	-2.47 (0.509)	-2.50 (0.503)
RE, Follow-up,Month 24, n=818, 839	-2.75 (0.582)	-2.95 (0.589)
RE, Early inv. product discontinuation, n=303, 126	-6.85 (1.020)	-8.00 (1.258)
MH, Month 6, n=1124, 1332	-1.96 (0.303)	-1.46 (0.293)
MH, Month 12, n=1021, 1225	-2.38 (0.333)	-2.11 (0.322)
MH, Follow-up, Month 6, n=993, 1090	-1.92 (0.367)	-1.70 (0.360)
MH, Follow-up, Month 12, n=953, 1006	-2.47 (0.390)	-2.47 (0.389)
MH, Follow-up, Month 18, n=848, 906	-1.91 (0.469)	-1.58 (0.464)
MH, Follow-up, Month 24, n=817, 837	-2.16 (0.545)	-2.54 (0.552)
MH, Early inv. product discontinuation, n=303, 125	-5.96 (0.964)	-7.87 (1.187)

12. Secondary Outcome

Title	Number of Participants With Hematology Values Outside the Reference Range for the Indicated Parameters
Description	The hematology parameters assessed were: basophils (Bs) in giga (10^9) per liter (GI/L) and in percentage (%), eosinophils (Eo) in GI/L and %, hematocrit, hemoglobin, lymphocytes (Lmph) in GI/L and %, monocytes (Mono) in GI/L and %, platelet count, Red Blood Cell (RBC) count, total neutrophil count (TNC) in GI/L and %, and White Blood Cell (WBC) count. The Baseline (BL) value is the last available pre-treatment result recorded. "Any post-Baseline value" was based on results recorded at any scheduled or unscheduled post-Baseline visits. The prevalence of values lying outside the reference (ref.) range (high or low) is presented for BL and "any post-Baseline" (APBL) visit. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm. Data for the primary analysis (conducted in 2011) are reported.
Time Frame	At Baseline and every 3 months thereafter up to Month 12/Early Withdrawal Visit

Outcome Measure Data

Analysis Population Description

Safety Population (SP): all randomized participants (par.) who received >=1 dose of randomized treatment. Only those par. available (n=X, X in the category titles) at the specified time points were analyzed. Different par. may have been analyzed for different parameters, so the overall number of par. analyzed reflects everyone in the SP.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1573	1574
Bs (GI/L), BL, ref. range high, n=1555, 1563	0 0%	1 0.1%
Bs (GI/L), BL, ref. range low, n=1555, 1563	0 0%	0 0%
Bs (GI/L), APBL, ref. range high, n=1466, 1537	7 0.4%	7 0.4%
Bs (GI/L), APBL, ref. range low, n=1466, 1537	7 0.4%	2 0.1%
Eo (GI/L), BL, ref. range high, n=1557, 1562	34 2.2%	35 2.2%
Eo (GI/L), BL, ref. range low, n=1557, 1562	242 15.4%	184 11.7%
Eo (GI/L), APBL, ref. range high, n=1466, 1537	84 5.3%	75 4.8%
Eo (GI/L), APBL, ref. range low, n=1466, 1537	322 20.5%	370 23.5%
Hematocrit, BL, ref. range high, n=1560, 1563	20 1.3%	30 1.9%
Hematocrit, BL, ref. range low, n=1560, 1563	72 4.6%	96 6.1%
Hematocrit, APBL, ref. range high, n=1474, 1538	46 2.9%	65 4.1%
Hematocrit, APBL, ref. range low, n=1474, 1538	196 12.5%	145 9.2%
Hemoglobin, BL, ref. range high, n=1560, 1563	8 0.5%	16 1%
Hemoglobin, BL, ref. range low, n=1560, 1563	148 9.4%	160 10.2%
Hemoglobin, APBL, ref. range high, n=1474, 1538	32 2%	34 2.2%
Hemoglobin, APBL, ref. range low, n=1474, 1538	295 18.8%	212 13.5%
Lmph (GI/L), BL, ref. range high, n=1557, 1562	5 0.3%	1 0.1%
Lmph (GI/L), BL, ref. range low, n=1557, 1562	80 5.1%	89 5.6%
Lmph (GI/L), APBL, ref. range high, n=1468, 1538	12 0.8%	11 0.7%
Lmph (GI/L), APBL, ref. range low, n=1468, 1538	106 6.7%	100 6.3%
Mono (GI/L), BL, ref. range high, n=1557, 1562	2 0.1%	4 0.3%
Mono (GI/L), BL, ref. range low, n=1557, 1562	236 15%	239 15.2%
Mono (GI/L), APBL, ref. range high, n=1466, 1538	7 0.4%	7 0.4%
Mono (GI/L), APBL, ref. range low, n=1466, 1538	425 27.1%	431 27.3%
Platelet count, BL, ref. range high, n=1553, 1559	34 2.2%	33 2.1%
Platelet count, BL, ref. range low, n=1553, 1559	21 1.3%	15 1%
Platelet count, APBL, ref. range high, n=1473, 153	95 6%	56 3.6%
Platelet count, APBL, ref. range low, n=1473, 1538	40 2.5%	37 2.3%
RBC count, BL, ref. range high, n=1559, 1563	10 0.6%	18 1.1%
RBC count, BL, ref. range low, n=1559, 1563	144 9.2%	148 9.4%
RBC count, APBL, ref. range high, n=1474, 1538	25 1.6%	36 2.3%
RBC count, APBL, ref. range low, n=1474, 1538	270 17.2%	207 13.1%
TNC (GI/L), BL, ref. range high, n=1557, 1563	17 1.1%	15 1%
TNC (GI/L), BL, ref. range low, n=1557, 1563	47 3%	41 2.6%
TNC (GI/L), APBL, ref. range high, n=1469, 1538	38 2.4%	53 3.4%
TNC (GI/L), APBL, ref. range low, n=1469, 1538	115 7.3%	161 10.2%
WBC count, BL, ref. range high, n=1559, 1563	18 1.1%	14 0.9%
WBC count, BL, ref. range low, n=1559, 1563	142 9%	104 6.6%
WBC count, APBL, ref. range high, n=1471, 1537	42 2.7%	57 3.6%
WBC count, APBL, ref. range low, n=1471, 1537	191 12.2%	198 12.6%
Bs (%), BL, ref. range high, n=64, 55	8 0.5%	4 0.3%
Bs (%), BL, ref. range low, n=64, 55	1 0.1%	0 0%
Bs (%), APBL, ref. range high, n=131, 131	17 1.1%	18 1.1%
Bs (%), APBL, ref. range low, n=131, 131	4 0.3%	1 0.1%
Eo (%), BL, ref. range high, n=65, 55	7 0.4%	9 0.6%
Eo (%), BL, ref. range low, n=65, 55	2 0.1%	1 0.1%
Eo (%), APBL, ref. range high, n=135, 132	16 1%	20 1.3%
Eo (%), APBL, ref. range low, n=135, 132	9 0.6%	4 0.3%
Lmph (%), BL, ref. range high, n=68, 57	4 0.3%	3 0.2%
Lmph (%), BL, ref. range low, n=68, 57	10 0.6%	10 0.6%
Lmph (%), APBL, ref. range high, n=152, 143	14 0.9%	18 1.1%
Lmph (%), APBL, ref. range low, n=152, 143	19 1.2%	16 1%
Mono (%), BL, ref. range high, n=67, 54	13 0.8%	11 0.7%
Mono (%), BL, ref. range low, n=67, 54	0 0%	0 0%
Mono (%), APBL, ref. range high, n=137, 139	28 1.8%	11 0.7%
Mono (%), APBL, ref. range low, n=137, 139	6 0.4%	4 0.3%
TNC (%), BL, ref. range high, n=68, 58	7 0.4%	2 0.1%
TNC (%), BL, ref. range low, n=68, 58	5 0.3%	4 0.3%
TNC (%), APBL, ref. range high, n=150, 145	9 0.6%	10 0.6%
TNC (%), APBL, ref. range low, n=150, 145	19 1.2%	12 0.8%

13. Secondary Outcome

Title	Number of Participants With Clinical Chemistry Values Outside the Reference Range for the Indicated Parameters
Description	The clinical chemistry parameters assessed were: alanine amino transferase (ALT), albumin, alkaline phosphatase (ALP), aspartate amino transferase (AST), bicarbonate, blood urea nitrogen (BUN), bone alkaline phosphatase (Bone ALP), calcium, chloride, creatinine, creatinine clearance (Cr. Clearance), creatinine clearance estimated (Cr. Clrnc. est.), glucose, potassium, sodium, total bilirubin (Total Bln), total protein, urea, and uric acid. The Baseline (BL) value is the last available pre-treatment result recorded. "Any post-Baseline" value was based on results recorded at scheduled or unscheduled post-Baseline visits. The prevalence of values lying outside the reference (ref.) range (high or low) was presented for BL and "any post-Baseline" (APBL) visit. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm.
Time Frame	At Baseline and every 6 weeks thereafter up to Month 12/Early Withdrawal Visit

Outcome Measure Data

Analysis Population Description

Safety Population (primary analysis [conducted in 2011]). Only those participants available (represented as n=X, X in the category titles) at the specified time points were analyzed. Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1573	1574
ALT, BL, ref. range high, n=1569, 1569	55 3.5%	78 4.9%
ALT, BL, ref. range low, n=1569, 1569	1 0.1%	1 0.1%
ALT, APBL, ref. range high, n=1478, 1542	271 17.3%	141 8.9%
ALT, APBL, ref. range low, n=1478, 1542	3 0.2%	5 0.3%
Albumin, BL, ref. range high, n=1568, 1568	36 2.3%	41 2.6%
Albumin, BL, ref. range low, n=1568, 1568	0 0%	0 0%
Albumin, APBL, ref. range high, n=1475, 1542	51 3.2%	70 4.4%
Albumin, APBL, ref. range low, n=1475, 1542	11 0.7%	8 0.5%
ALP, BL, ref. range high, n=1569, 1569	68 4.3%	66 4.2%
ALP, BL, ref. range low, n=1569, 1569	0 0%	0 0%
ALP, APBL, ref. range high, n=1477, 1542	213 13.6%	155 9.8%
ALP, APBL, ref. range low, n=1477, 1542	4 0.3%	5 0.3%
AST, BL, ref. range high, n=1569, 1565	49 3.1%	59 3.7%
AST, BL, ref. range low, n=1569, 1565	0 0%	0 0%
AST, APBL, ref. range high, n=1478, 1541	260 16.5%	139 8.8%
AST, APBL, ref. range low, n=1478, 1541	0 0%	3 0.2%
Bicarbonate, BL, ref. range high, n=36, 33	0 0%	3 0.2%
Bicarbonate, BL, ref. range low, n=36, 33	4 0.3%	3 0.2%
Bicarbonate, APBL, ref. range high, n=60, 71	3 0.2%	2 0.1%
Bicarbonate, APBL, ref. range low, n=60, 71	4 0.3%	9 0.6%
BUN, BL, ref. range high, n=63, 56	8 0.5%	4 0.3%
BUN, BL, ref. range low, n=63, 56	0 0%	0 0%
BUN, APBL, ref. range high, n=161, 155	15 1%	17 1.1%
BUN, APBL, ref. range low, n=161, 155	6 0.4%	4 0.3%
Bone ALP, BL, ref. range high, n=230, 219	0 0%	0 0%
Bone ALP, BL, ref. range low, n=230, 219	0 0%	0 0%
Bone ALP, APBL, ref. range high, n=188, 160	0 0%	0 0%
Bone ALP, APBL, ref. range low, n=188, 160	0 0%	0 0%
Calcium, BL, ref. range high, n=1568, 1565	17 1.1%	36 2.3%
Calcium, BL, ref. range low, n=1568, 1565	16 1%	14 0.9%
Calcium, APBL, ref. range high, n=1476, 1542	56 3.6%	84 5.3%
Calcium, APBL, ref. range low, n=1476, 1542	66 4.2%	79 5%
Chloride, BL, ref. range high, n=52, 46	2 0.1%	2 0.1%
Chloride, BL, ref. range low, n=52, 46	0 0%	1 0.1%
Chloride, APBL, ref. range high, n=102, 108	10 0.6%	5 0.3%
Chloride, APBL, ref. range low, n=102, 108	2 0.1%	5 0.3%
Creatinine, BL, ref. range high, n=1569, 1569	5 0.3%	4 0.3%
Creatinine, BL, ref. range low, n=1569, 1569	7 0.4%	8 0.5%
Creatinine, APBL, ref. range high, n=1479, 1542	16 1%	13 0.8%
Creatinine, APBL, ref. range low, n=1479, 1542	22 1.4%	27 1.7%
Cr. Clearance, BL, ref. range high, n=4, 9	2 0.1%	2 0.1%
Cr. Clearance, BL, ref. range low, n=4, 9	1 0.1%	0 0%
Cr. Clearance, APBL, ref. range high, n=11, 10	0 0%	1 0.1%
Cr. Clearance, APBL, ref. range low, n=11, 10	2 0.1%	2 0.1%
Cr. Clrnc. est., BL, ref. range high, n=373, 388	0 0%	0 0%
Cr. Clrnc. est., BL, ref. range low, n=373, 388	0 0%	0 0%
Cr. Clrnc. est., APBL, ref. range high, n=380, 418	0 0%	0 0%
Cr. Clrnc. est., APBL, ref. range low, n=380, 418	0 0%	0 0%
Glucose, BL, ref. range high, n=1566, 1569	170 10.8%	143 9.1%
Glucose, BL, ref. range low, n=1566, 1569	31 2%	32 2%
Glucose, APBL, ref. range high, n=1475, 1541	245 15.6%	329 20.9%
Glucose, APBL, ref. range low, n=1475, 1541	94 6%	94 6%
Potassium, BL, ref. range high, n=1567, 1565	13 0.8%	13 0.8%
Potassium, BL, ref. range low, n=1567, 1565	21 1.3%	11 0.7%
Potassium, APBL, ref. range high, n=1476, 1542	28 1.8%	54 3.4%
Potassium, APBL, ref. range low, n=1476, 1542	54 3.4%	44 2.8%
Sodium, BL, ref. range high, n=1568, 1568	9 0.6%	4 0.3%
Sodium, BL, ref. range low, n=1568, 1568	7 0.4%	9 0.6%
Sodium, APBL, ref. range high, n=1477, 1542	29 1.8%	27 1.7%
Sodium, APBL, ref. range low, n=1477, 1542	24 1.5%	30 1.9%
Total Bln., BL, ref. range high, n=1569, 1569	14 0.9%	19 1.2%
Total Bln., BL, ref. range low, n=1569, 1569	1 0.1%	0 0%
Total Bln., APBL, ref. range high, n=1478, 1542	152 9.7%	46 2.9%
Total Bln., APBL, ref. range low, n=1478, 1542	4 0.3%	3 0.2%
Total Protein, BL, ref. range high, n=1566, 1568	3 0.2%	9 0.6%
Total Protein, BL, ref. range low, n=1566, 1568	4 0.3%	1 0.1%
Total Protein, APBL, ref. range high, n=1476, 1542	27 1.7%	38 2.4%
Total Protein, APBL, ref. range low, n=1476, 1542	11 0.7%	13 0.8%
Urea, BL, ref. range high, n=1560, 1566	18 1.1%	19 1.2%
Urea, BL, ref. range low, n=1560, 1566	17 1.1%	24 1.5%
Urea, APBL, ref. range high, n=1465, 1535	35 2.2%	48 3%
Urea, APBL, ref. range low, n=1465, 1535	45 2.9%	48 3%
Uric acid, BL, ref. range high, n=37, 26	7 0.4%	5 0.3%
Uric acid, BL, ref. range low, n=37, 26	0 0%	1 0.1%
Uric acid, APBL, ref. range high, n=73, 76	10 0.6%	12 0.8%
Uric acid, APBL, ref. range low, n=73, 76	3 0.2%	4 0.3%

14. Secondary Outcome

Title	Number of Participants With Non-laboratory Toxicities of the Indicated Toxicity Grades
Description	Non-laboratory toxicities are defined as adverse events (AEs). The number of partcipants with any treatment-emergent AE of the indicated toxicity grade are summarized. Toxicity grading was according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life threatening; Grade 5=death. The events that were not given a toxicity grade are categorized as "Not Applicable."
Time Frame	From the first dose of study treatment up to 12 months

Outcome Measure Data

Analysis Population Description

Safety Population. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm. Data for the primary analysis (conducted in 2011) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1573	1574
Grade 1	414 26.4%	558 35.4%
Grade 2	674 42.9%	505 32%
Grade 3	333 21.2%	104 6.6%
Grade 4	21 1.3%	15 1%
Grade 5	3 0.2%	3 0.2%
Not Applicable	5 0.3%	8 0.5%

15. Secondary Outcome

Title	Number of Participants Experiencing Primary or Secondary Cardiac Events
Description	A cardiac event is classified as a primary cardiac endpoint (PCE) or a secondary cardiac endpoint (SCE). PCE is defined as: cardiac death (cardiac death due to heart failure, myocardial infarction, or arrhythmia;or probable cardiac death defined as sudden, unexpected death within 24 hours of a definite or probable cardiac event); severe symptomatic congestive heart failure (CHF) (as per New York Heart Association [NYHA] Class III or IV and an absolute decrease in left ventricular ejection fraction [LVEF] of more than 10 percentage points from Baseline and to a left ventricular ejection fraction [LVEF] value below 50%). SCE is defined as asymptomatic or mildly symptomatic cardiac events (NYHA Class I or II) and a significant decrease in LVEF, defined as an absolute decrease in LVEF of more than 10 percentage points from Baseline and to an LVEF value below 50%.
Time Frame	From the date of randomization up to 12 months

Outcome Measure Data

Analysis Population Description

Safety Population (SP). Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm. Data for the primary analysis (conducted in 2011) are reported.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1573	1574
PCE, Cardiac death	0 0%	1 0.1%
PCE, Severe symptomatic CHF	2 0.1%	3 0.2%
SCE	6 0.4%	6 0.4%

16. Secondary Outcome

Title	Number of Participants With the Indicated Electrocardiogram (ECG) Findings
Description	12-lead ECG measurements were taken at Screening and at study conclusion/withdrawal. The number of participants with normal, abnormal clinically significant (CS), and abnormal not clinically significant (NCS) ECG findings, as classified by the investigator, were summarized. Participants with missing values were categorized as missing. Data for the primary analysis (conducted in 2011) are reported.
Time Frame	Screening and Month 12/Early Withdrawal Visit

Outcome Measure Data

Analysis Population Description

SP. Only those participants (par.) available at the specified time points were analyzed. Two par. were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm.

Arm/Group Title	Lapatinib 1500 mg	Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.	Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
Measure Participants	1543	1549
Screening, normal, n=1543, 1549	1203 76.6%	1197 76%
Screening, abnormal CS, n=1543, 1549	0 0%	1 0.1%
Screening, abnormal NCS, n=1543, 1549	339 21.6%	351 22.3%
Screening, missing, n=1543, 1549	1 0.1%	0 0%
Conclusion/ Withdrawal, normal, n=1243, 1306	960 61.1%	979 62.1%
Conclusion/ Withdrawal, abnormal CS, n=1243, 1306	5 0.3%	3 0.2%
Conclusion/ Withdrawal, abnormal NCS, n=1243, 1306	276 17.6%	323 20.5%
Conclusion/ Withdrawal, missing, n=1243, 1306	2 0.1%	1 0.1%

Adverse Events

Time Frame	Non-serious adverse events (AEs): collected from start of treatment until up to 5 days after the last dose of study treatment (up to 12 months). SAEs: collected up to any time during the follow-up period post discontinuation of study drug (up to 6 years).
Adverse Event Reporting Description	Non-serious AEs and SAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of randomized treatment. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm.
Arm/Group Title	Lapatinib 1500 mg		Placebo
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.		Participants received matching placebo orally once daily. Treatment was continued for a maximum of 12 months or until disease recurrence or development of a second primary cancer, withdrawal from study treatment due to unacceptable toxicity, or consent withdrawal.
All Cause Mortality
	Lapatinib 1500 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lapatinib 1500 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/1573 (6.3%)		78/1574 (5%)
Blood and lymphatic system disorders
Neutropenia	2/1573 (0.1%)		0/1574 (0%)
Cardiac disorders
Left ventricular dysfunction	3/1573 (0.2%)		1/1574 (0.1%)
Cardiac failure	0/1573 (0%)		3/1574 (0.2%)
Myocardial infarction	2/1573 (0.1%)		0/1574 (0%)
Acute myocardial infarction	0/1573 (0%)		1/1574 (0.1%)
Atrial fibrillation	0/1573 (0%)		1/1574 (0.1%)
Atrioventricular block first degree	1/1573 (0.1%)		0/1574 (0%)
Myocardial ischaemia	0/1573 (0%)		1/1574 (0.1%)
Pericardial effusion	1/1573 (0.1%)		0/1574 (0%)
Tachycardia	0/1573 (0%)		1/1574 (0.1%)
Ear and labyrinth disorders
Vertigo	1/1573 (0.1%)		0/1574 (0%)
Endocrine disorders
Thyroiditis subacute	0/1573 (0%)		1/1574 (0.1%)
Gastrointestinal disorders
Diarrhoea	7/1573 (0.4%)		0/1574 (0%)
Abdominal pain	3/1573 (0.2%)		0/1574 (0%)
Enteritis	1/1573 (0.1%)		1/1574 (0.1%)
Gastritis	0/1573 (0%)		2/1574 (0.1%)
Nausea	0/1573 (0%)		2/1574 (0.1%)
Abdominal hernia	1/1573 (0.1%)		0/1574 (0%)
Abdominal pain upper	1/1573 (0.1%)		0/1574 (0%)
Enterocolitis	1/1573 (0.1%)		0/1574 (0%)
Gastric ulcer	1/1573 (0.1%)		0/1574 (0%)
Haematochezia	1/1573 (0.1%)		0/1574 (0%)
Haemorrhoids	1/1573 (0.1%)		0/1574 (0%)
Intestinal obstruction	1/1573 (0.1%)		0/1574 (0%)
Intestinal perforation	1/1573 (0.1%)		0/1574 (0%)
Pancreatitis	0/1573 (0%)		1/1574 (0.1%)
Umbilical hernia	0/1573 (0%)		1/1574 (0.1%)
General disorders
Asthenia	0/1573 (0%)		2/1574 (0.1%)
Death	1/1573 (0.1%)		0/1574 (0%)
Non-cardiac chest pain	0/1573 (0%)		1/1574 (0.1%)
Oedema peripheral	0/1573 (0%)		1/1574 (0.1%)
Hepatobiliary disorders
Hepatotoxicity	2/1573 (0.1%)		0/1574 (0%)
Cholecystitis	0/1573 (0%)		1/1574 (0.1%)
Cholelithiasis	1/1573 (0.1%)		0/1574 (0%)
Cytolytic hepatitis	1/1573 (0.1%)		0/1574 (0%)
Hepatitis	1/1573 (0.1%)		0/1574 (0%)
Hepatitis toxic	1/1573 (0.1%)		0/1574 (0%)
Immune system disorders
Drug hypersensitivity	1/1573 (0.1%)		0/1574 (0%)
Hypersensitivity	1/1573 (0.1%)		0/1574 (0%)
Infections and infestations
Erysipelas	8/1573 (0.5%)		0/1574 (0%)
Cellulitis	5/1573 (0.3%)		0/1574 (0%)
Pneumonia	3/1573 (0.2%)		2/1574 (0.1%)
Appendicitis	1/1573 (0.1%)		1/1574 (0.1%)
Gastroenteritis	1/1573 (0.1%)		1/1574 (0.1%)
Herpes zoster	2/1573 (0.1%)		0/1574 (0%)
Abscess	1/1573 (0.1%)		0/1574 (0%)
Breast abscess	0/1573 (0%)		1/1574 (0.1%)
Breast cellulitis	1/1573 (0.1%)		0/1574 (0%)
Bronchitis	0/1573 (0%)		1/1574 (0.1%)
Bronchopneumonia	1/1573 (0.1%)		0/1574 (0%)
Cystitis	0/1573 (0%)		1/1574 (0.1%)
Device related infection	0/1573 (0%)		1/1574 (0.1%)
Gastroenteritis viral	1/1573 (0.1%)		0/1574 (0%)
Implant site cellulitis	1/1573 (0.1%)		0/1574 (0%)
Influenza	1/1573 (0.1%)		0/1574 (0%)
Lobar pneumonia	0/1573 (0%)		1/1574 (0.1%)
Pyelonephritis	0/1573 (0%)		1/1574 (0.1%)
Sepsis	1/1573 (0.1%)		0/1574 (0%)
Sinusitis	1/1573 (0.1%)		0/1574 (0%)
Streptococcal sepsis	1/1573 (0.1%)		0/1574 (0%)
Urinary tract infection	1/1573 (0.1%)		0/1574 (0%)
Urosepsis	0/1573 (0%)		1/1574 (0.1%)
Wound infection	1/1573 (0.1%)		0/1574 (0%)
Vomiting	0/1573 (0%)		2/1574 (0.1%)
Injury, poisoning and procedural complications
Ankle fracture	1/1573 (0.1%)		1/1574 (0.1%)
Accidental overdose	1/1573 (0.1%)		0/1574 (0%)
Chest injury	1/1573 (0.1%)		0/1574 (0%)
Femoral neck fracture	1/1573 (0.1%)		0/1574 (0%)
Foot fracture	0/1573 (0%)		1/1574 (0.1%)
Fracture	0/1573 (0%)		1/1574 (0.1%)
Humerus fracture	1/1573 (0.1%)		0/1574 (0%)
Muscle strain	1/1573 (0.1%)		0/1574 (0%)
Rib fracture	0/1573 (0%)		1/1574 (0.1%)
Road tracffic accident	1/1573 (0.1%)		0/1574 (0%)
Transplant failure	1/1573 (0.1%)		0/1574 (0%)
Ulna fracture	0/1573 (0%)		1/1574 (0.1%)
Wound dehiscence	1/1573 (0.1%)		0/1574 (0%)
Investigations
Ejection fraction decreased	5/1573 (0.3%)		6/1574 (0.4%)
Alanine aminotransferase increased	1/1573 (0.1%)		0/1574 (0%)
Blood bilirubin abnormal	1/1573 (0.1%)		0/1574 (0%)
Transaminases increased	1/1573 (0.1%)		0/1574 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/1573 (0.1%)		2/1574 (0.1%)
Dehydration	0/1573 (0%)		1/1574 (0.1%)
Diabetes mellitus	0/1573 (0%)		1/1574 (0.1%)
Electrolyte imbalance	1/1573 (0.1%)		0/1574 (0%)
Hyperkalaemia	0/1573 (0%)		1/1574 (0.1%)
Hypocalcaemia	0/1573 (0%)		1/1574 (0.1%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/1573 (0%)		2/1574 (0.1%)
Arthropathy	0/1573 (0%)		1/1574 (0.1%)
Back pain	1/1573 (0.1%)		0/1574 (0%)
Bone pain	0/1573 (0%)		1/1574 (0.1%)
Costochondritis	0/1573 (0%)		1/1574 (0.1%)
Intervertebral disc compression	0/1573 (0%)		1/1574 (0.1%)
Myalgia	0/1573 (0%)		1/1574 (0.1%)
Osteochondrosis	1/1573 (0.1%)		0/1574 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/1573 (0%)		2/1574 (0.1%)
Colon cancer	1/1573 (0.1%)		2/1574 (0.1%)
Endometrial cancer	2/1573 (0.1%)		1/1574 (0.1%)
Basal cell carcinoma	0/1573 (0%)		2/1574 (0.1%)
Contralataral breast cancer	1/1573 (0.1%)		1/1574 (0.1%)
Acute myeloid leukaemia	0/1573 (0%)		1/1574 (0.1%)
Benign breast neoplasm	1/1573 (0.1%)		0/1574 (0%)
Bladder papilloma	1/1573 (0.1%)		0/1574 (0%)
Breast cancer in situ	0/1573 (0%)		1/1574 (0.1%)
Cardiac neoplasm unspecified	1/1573 (0.1%)		0/1574 (0%)
Cervix carcinoma	0/1573 (0%)		1/1574 (0.1%)
Haemangioma of liver	1/1573 (0.1%)		0/1574 (0%)
Intraductal papilloma of breast	0/1573 (0%)		1/1574 (0.1%)
Leiomyosarcoma	0/1573 (0%)		1/1574 (0.1%)
Malignant melanoma in situ	1/1573 (0.1%)		0/1574 (0%)
Ovarian epithelial cancer	1/1573 (0.1%)		0/1574 (0%)
Ovarian germ cell teratoma benign	1/1573 (0.1%)		0/1574 (0%)
Pancreatic carcinaom metastatic	1/1573 (0.1%)		0/1574 (0%)
Skin cancer	1/1573 (0.1%)		0/1574 (0%)
Thyroid cancer	1/1573 (0.1%)		0/1574 (0%)
Uterine cancer	0/1573 (0%)		1/1574 (0.1%)
Uterine leiomyoma	1/1573 (0.1%)		0/1574 (0%)
Uterine leiomyosarcoma	1/1573 (0.1%)		0/1574 (0%)
Nervous system disorders
Carotid artery stenosis	1/1573 (0.1%)		0/1574 (0%)
Cerebellar infarction	0/1573 (0%)		1/1574 (0.1%)
Cerebral haemorrhage	0/1573 (0%)		1/1574 (0.1%)
Cerebral infarction	0/1573 (0%)		1/1574 (0.1%)
Cerebral ischaemia	0/1573 (0%)		1/1574 (0.1%)
Cerebrovascular accident	0/1573 (0%)		1/1574 (0.1%)
Convulsion	1/1573 (0.1%)		0/1574 (0%)
Headache	0/1573 (0%)		1/1574 (0.1%)
Paraesthesia	0/1573 (0%)		1/1574 (0.1%)
Syncope	1/1573 (0.1%)		0/1574 (0%)
Psychiatric disorders
Depression	1/1573 (0.1%)		1/1574 (0.1%)
Suicide attempt	1/1573 (0.1%)		1/1574 (0.1%)
Suicidal ideation	1/1573 (0.1%)		0/1574 (0%)
Renal and urinary disorders
Nephrolithiasis	0/1573 (0%)		1/1574 (0.1%)
Reproductive system and breast disorders
Breast disorder	1/1573 (0.1%)		0/1574 (0%)
Breast mass	1/1573 (0.1%)		0/1574 (0%)
Menometrorrhagia	0/1573 (0%)		1/1574 (0.1%)
Menstrual disorder	0/1573 (0%)		1/1574 (0.1%)
Ovarian cyst	0/1573 (0%)		1/1574 (0.1%)
Ovarian enlargement	0/1573 (0%)		1/1574 (0.1%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/1573 (0.1%)		0/1574 (0%)
Dyspnoea exertional	0/1573 (0%)		1/1574 (0.1%)
Laryngeal oedema	1/1573 (0.1%)		0/1574 (0%)
Pulmonary embolism	0/1573 (0%)		1/1574 (0.1%)
Skin and subcutaneous tissue disorders
Rash	2/1573 (0.1%)		0/1574 (0%)
Vascular disorders
Capillary leak syndrome	1/1573 (0.1%)		0/1574 (0%)
Femoral artery occlusion	0/1573 (0%)		1/1574 (0.1%)
Hypertensive crisis	0/1573 (0%)		1/1574 (0.1%)
Thrombosis	1/1573 (0.1%)		0/1574 (0%)
Other (Not Including Serious) Adverse Events
	Lapatinib 1500 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1443/1573 (91.7%)		1175/1574 (74.7%)
Eye disorders
Stomatitis	98/1573 (6.2%)		30/1574 (1.9%)
Gastrointestinal disorders
Diarrhoea	955/1573 (60.7%)		256/1574 (16.3%)
Nausea	279/1573 (17.7%)		179/1574 (11.4%)
Vomiting	104/1573 (6.6%)		71/1574 (4.5%)
Dyspepsia	106/1573 (6.7%)		57/1574 (3.6%)
Abdominal pain	105/1573 (6.7%)		56/1574 (3.6%)
General disorders
Fatigue	251/1573 (16%)		202/1574 (12.8%)
Infections and infestations
Paronychia	154/1573 (9.8%)		5/1574 (0.3%)
Metabolism and nutrition disorders
Decreased appetite	99/1573 (6.3%)		36/1574 (2.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	69/1573 (4.4%)		113/1574 (7.2%)
Nervous system disorders
Headache	140/1573 (8.9%)		185/1574 (11.8%)
Respiratory, thoracic and mediastinal disorders
Cough	75/1573 (4.8%)		103/1574 (6.5%)
Epistaxis	118/1573 (7.5%)		8/1574 (0.5%)
Skin and subcutaneous tissue disorders
Rash	922/1573 (58.6%)		243/1574 (15.4%)
Dry skin	220/1573 (14%)		45/1574 (2.9%)
Pruritus	130/1573 (8.3%)		49/1574 (3.1%)
Alopecia	135/1573 (8.6%)		25/1574 (1.6%)
Nail disorder	131/1573 (8.3%)		16/1574 (1%)
Skin fissures	83/1573 (5.3%)		1/1574 (0.1%)

Limitations/Caveats

[Not Specified]

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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.