Pazopanib Plus Lapatinib Compared to Lapatinib Alone and Pazopanib Alone In Subjects With Metastatic Cervical Cancer

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00430781
• Collaborator: (none)
• Enrollment: 228
• Locations: 63
• Arms: 3
• Duration (Months): 56
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is being conducted to compare the efficacy and safety of pazopanib in combination with lapatinib with that of lapatinib alone or pazopanib alone in subjects with metastatic cervical cancer

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Uterine Cervix; Metastatic Cervical Cancer	Drug: pazopanib (GW786034); Drug: lapatinib (GW572016)	Phase 2

Detailed Description

A Phase II, Open-Label, Randomized, Multicenter Trial of Pazopanib (GW786034) in Combination with Lapatinib (GW572016) Compared to Pazopanib Monotherapy and Lapatinib Monotherapy in Subjects with International Federation of Gynecology (FIGO) Stage IVB or Recurrent or Persistent Cervical Cancer with Zero or One Prior Chemotherapy Regimen for Advanced/Recurrent Disease

Study Design

• Study Type: Interventional
• Actual Enrollment: 228 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-Label, Randomized, Multicenter Trial of Pazopanib (GW786034) in Combination With Lapatinib (GW572016) Compared to Pazopanib Monotherapy and Lapatinib Monotherapy in Subjects With FIGO Stage IVB or Recurrent or Persistent Cervical Cancer With Zero or One Prior Chemotherapy Regimen
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination arm Pazopanib plus lapatinib	Drug: lapatinib (GW572016)
Active Comparator: Lapatinib monotherapy Lapatinib	Drug: lapatinib (GW572016)
Active Comparator: Pazopanib monotherapy Pazopanib	Drug: pazopanib (GW786034)

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) in Interim Analysis [From randomization until at least 35 PFS events in pairwise comparison of the three treatment arms (Interim Analysis; up to 52.14 weeks)]

   PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. The study was designed to test Combination vs. Lapatinib first. The result indicated that Combination would not show improvement over Lapatinib even if followed until the final analysis and the Combination arm was terminated. The monotherapy arms continued to the final analysis. Data shown here are from this interim analysis.

2. Progression-free Survival (PFS) in Final Analysis [From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)]

   PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. This study began as a 3-arm study. The combination arm was terminated at the interim analysis. The monotherapy arms continued to final analysis. Data shown here are from the final analysis.

Secondary Outcome Measures

1. Overall Survival [From Randomization (11 December 2006) until approximately 78% overall survival events at the time of the second overall survival update (3 March 2010) (up to 168.29 weeks)]

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

2. Clinical Benefit Response [From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)]

   Clinical benefit response is defined as the number of participants with evidence of complete (CR) or partial (PR) tumor response or stable disease (SD) for at least 6 months (183 days). Per Response Evaluation Criteria In Solid Tumors (RECIST): CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum; Stable Disease, small changes that do not meet previously given criteria. Confirmation requires at least 2 assessments of CR/PR with at least 4 weeks between assessments.

3. Response [From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)]

   Response is defined as the number of participants achieving either a complete or partial tumor response per RECIST criteria. CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum.

4. Time to Response [From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)]

   For the subset of participants who showed a confirmed CR or PR, time to response was defined as the time from randomization until the first documented evidence of CR or PR (whichever status was recorded first). CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum.

5. Duration of Response [From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)]

   For participants who had a CR or PR, the duration of response was defined as the time from first documented evidence of PR or CR until the first documented sign of disease progression or death. CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum.

6. Safety and Tolerability of Pazopanib, Lapatinib and the Combination of Pazopanib and Lapatinib [From Randomization (11 December 2006) until last participant had last visit (28 July 2011) in combined population of two monotherapy arms (up to 241.43 weeks)]

   Safety was assessed as the number of participants experiencing a serious adverse event (SAE) or an adverse event (AE). See the adverse event module for safety data.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• A subject will be eligible for inclusion in this study only if all of the following criteria are met:

• Signed, written informed consent prior to performing any study-related procedures

• Female subjects ≥18 years of age

• FIGO Stage IVB, or recurrent or persistent cervical cancer

• Life expectancy of at least 12 weeks

• ECOG status of 0 or 1.

• Histologically confirmed FIGO Stage IVB, or recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy

• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20 mm when measured by conventional techniques, including palpitation, plain x-ray, CT and MRI, or ≥10 mm when measured by spiral CT.

• At least one "target lesion" to be used to assess response as defined by Response Evaluation Criteria in Solid Tumors (RECIST; Terasse, 2000). Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.

• Received 0 or 1 prior chemotherapy regimen for metastatic disease.

• Note: Chemotherapy given in combination with radiation therapy as a radiosensitizer does not count toward this prior therapy limit

• Recovered from the effects of surgery or chemotherapy. At least three weeks must have elapsed from the last administration of chemotherapy.

• Adequate organ and bone marrow function as defined in Table 1.

• Table 1:(Definitions for Adequate Organ Function)

• System:(Laboratory Values)

• Hematologic: Absolute neutrophil count (ANC)(≥ 1.5 X 109/L)Hemoglobin1(≥9 g/dL)Platelets(≥100 X 109/L)

• Hepatic: Total bilirubin (≤1.5 X ULN)AST and ALT (≤2.5 X ULN)

• Renal: Calculated creatinine clearance2 (≥50 mL/min)

• Urine protein3 (Negative, trace or +1 by dipstick urinalysis or <1.0 gram determined by 24 hour urine protein analysis.)

• Subjects may not have had a transfusion within 7 days of screening assessment.

• Calculated by Cockcroft Gault formula See Appendix 7: Renal Function Tests

• A patient should first be screened with dipstick urinalysis. If urine protein by dipstick analysis is ≥2+, then a 24-hour urine protein must be assessed and 24 hour urine protein must be <1 g protein to be eligible.

• Ability to swallow and retain oral medication.

• A female is eligible to enter and participate in this study if she is of:

• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:

• A hysterectomy

• A bilateral oophorectomy (ovariectomy)

• A bilateral tubal ligation

• Is post-menopausal (total cessation of menses for ≥ 1 year)

• Childbearing potential, has a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:

• An intrauterine device with a documented failure rate of less than 1% per year.

• Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female.

• Complete abstinence from sexual intercourse for 14 days before exposure to investigation product, through the dosing period, and for at least 21 days after the last dose of investigational product.

• Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

Note: Oral contraceptives are not reliable due to potential drug-drug interactions.

• Subjects must provide written informed consent prior to performance of study specific procedures or assessments, and must be willing to comply with treatment and follow-up as outlined in the protocol. Procedures conducted as apart of routine clinical management of the patient (e.g., blood count, imaging study) and obtained prior to signed informed consent may be utilized for screening purposes provided these tests are obtained as specified in the protocol

Exclusion Criteria:

• A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Neuroendocrine or small cell carcinoma of the cervix.

• Prior use of any biologic therapy with VEGF, VEGFR, or ErbB1/ErbB2 inhibitors.

• Concurrent cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, and tumor embolization).

• Concurrent treatment with an investigational agent or participation in another clinical trial.

• Use of an investigational anti-cancer drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.

• Has taken or is taking prohibited medications listed in the protocol.

• Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with patient's safety, obtaining informed consent or compliance to the study.

• History of another malignancy. Note: Patients who have had another malignancy and have been disease-free for 5 years, or patients with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.

• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. Routine screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated.

• Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel.

• Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to beginning therapy.

• Presence of uncontrolled infection.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib.

• Corrected QT interval (QTc) prolongation defined as QTc interval > 470 msecs.

• History of any one of the following cardiac conditions within the past 6 months:

• Cardiac angioplasty or stenting

• Myocardial infarction

• Unstable angina

• History of cerebrovascular accident or pulmonary embolus within the past 6 months.

• Has Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (See Appendix 6)

• Poorly controlled hypertension (systolic blood pressure (SBP) of ≥ 140mmHg, or diastolic blood pressure (DBP) of ≥ 90mmHg).

• Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. The blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP/DBP values from both BP assessments must be < 140/90mmHg in order for a subject to be eligible for the study.

• History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf vein thrombosis).

• Note: Patients with recent DVT who are treated with therapeutic anti-coagulant agents (excluding therapeutic warfarin) for at least 6 weeks are eligible.

• Presence of any non-healing, non-tumor related wound, fracture, or ulcer, or the presence of symptomatic peripheral vascular disease.

• Subjects with bilateral hydronephrosis which cannot be alleviated by ureteral stents or percutaneous drainage.

• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded.

• Unable to swallow and retain orally administered medication.

• Pregnant or lactating female.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Los Angeles	California	United States	90033
2	GSK Investigational Site	Orange	California	United States	92868
3	GSK Investigational Site	Stanford	California	United States	94305-5317
4	GSK Investigational Site	Augusta	Georgia	United States	30912
5	GSK Investigational Site	Boston	Massachusetts	United States	02115
6	GSK Investigational Site	Albuquerque	New Mexico	United States	87131-5276
7	GSK Investigational Site	New York	New York	United States	10016
8	GSK Investigational Site	Cleveland	Ohio	United States	44106
9	GSK Investigational Site	Columbus	Ohio	United States	43214
10	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73104
11	GSK Investigational Site	Chattanooga	Tennessee	United States	37403
12	GSK Investigational Site	Dallas	Texas	United States	75390
13	GSK Investigational Site	Capital Federal	Buenos Aires	Argentina	C1405CUB
14	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1185AAT
15	GSK Investigational Site	Neuquen	Neuquén	Argentina	Q8300HDH
16	GSK Investigational Site	Rosario	Santa Fe	Argentina	S2000KZE
17	GSK Investigational Site	Tucuman	Tucumán.	Argentina	4000
18	GSK Investigational Site	Quilmes		Argentina	1878
19	GSK Investigational Site	Santa Fe		Argentina	3000
20	GSK Investigational Site	Brussel		Belgium	1000
21	GSK Investigational Site	Bruxelles		Belgium	1200
22	GSK Investigational Site	Gent		Belgium	9000
23	GSK Investigational Site	Leuven		Belgium	3000
24	GSK Investigational Site	Roeselare		Belgium	8800
25	GSK Investigational Site	Calgary	Alberta	Canada	T2N 4N2
26	GSK Investigational Site	Vancouver	British Columbia	Canada	V5Z 4E6
27	GSK Investigational Site	Hamilton	Ontario	Canada	L8V 5C2
28	GSK Investigational Site	Toronto	Ontario	Canada	M5G 2M9
29	GSK Investigational Site	Montréal	Quebec	Canada	H2L 4M1
30	GSK Investigational Site	Tallinn		Estonia	11619
31	GSK Investigational Site	Tartu		Estonia	51003
32	GSK Investigational Site	Bordeaux		France	33076
33	GSK Investigational Site	Caen Cedex		France	14076
34	GSK Investigational Site	Lille Cedex		France	59020
35	GSK Investigational Site	Marseille Cedex 09		France	13273
36	GSK Investigational Site	Strasbourg		France	67085
37	GSK Investigational Site	Villejuif		France	94805
38	GSK Investigational Site	Muenchen	Bayern	Germany	80337
39	GSK Investigational Site	Saarbruecken	Saarland	Germany	66113
40	GSK Investigational Site	Halle	Sachsen-Anhalt	Germany	06120
41	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39108
42	GSK Investigational Site	Berlin		Germany	10117
43	GSK Investigational Site	Berlin		Germany	10367
44	GSK Investigational Site	Ahemdabad		India	380016
45	GSK Investigational Site	Mangalore		India	575001
46	GSK Investigational Site	New Delhi		India	110096
47	GSK Investigational Site	Trivandrum		India	695011
48	GSK Investigational Site	Cork		Ireland
49	GSK Investigational Site	Dublin		Ireland	7
50	GSK Investigational Site	Napoli	Campania	Italy	80131
51	GSK Investigational Site	Milano	Lombardia	Italy	20141
52	GSK Investigational Site	Campobasso	Molise	Italy	86100
53	GSK Investigational Site	Bari	Puglia	Italy	70124
54	GSK Investigational Site	Mexico City		Mexico	CP 14080
55	GSK Investigational Site	Barcelona		Spain	08036
56	GSK Investigational Site	Barcelona		Spain	08907
57	GSK Investigational Site	La Laguna (Santa Cruz de Tenerife)		Spain	38320
58	GSK Investigational Site	Madrid		Spain	28007
59	GSK Investigational Site	Marid		Spain	28040
60	GSK Investigational Site	Pamplona		Spain	31008
61	GSK Investigational Site	Bangkok		Thailand	10330
62	GSK Investigational Site	Chiang Mai		Thailand	50200
63	GSK Investigational Site	Khon Kaen		Thailand	40002

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00430781
• Other Study ID Numbers: VEG105281
• First Posted: Feb 2, 2007
• Last Update Posted: May 8, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by GlaxoSmithKline: pazopanib; ErB1/ErB2; lapatinib; persistent; VEGF; recurrent; metastatic cervical cancer; advanced; FIGO Stage IVB
• Additional relevant MeSH terms: Uterine Cervical Neoplasms; Uterine Neoplasms; Lapatinib

Study Results

Participant Flow

Recruitment Details	Participants (par.) continued to be enrolled into all three treatment arms after clinical data cutoff for the interim analysis, but before the results were evaluated. Final total enrollment was 228 participants: 76 in the combination arm, 78 in the lapatinib monotherapy arm, and 74 in the pazopanib monotherapy arm.
Pre-assignment Detail	Study was initially designed and started as a randomized, three-arm, controlled trial. Participants were randomized to the combination of pazopanib plus lapatinib, pazopanib monotherapy, or lapatinib monotherapy. Based on results from a planned interim analysis, the combination group was terminated, but the monotherapy groups continued as planned.

Arm/Group Title	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	Lapatinib 1500 mg (6 x 250 mg tablets) and pazopanib 800 mg (2 x 400 mg tablets) daily	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Period Title: Interim Analysis; 11 February 2008
STARTED	59	58	60
Ongoing	23	20	25
COMPLETED	0	0	0
NOT COMPLETED	59	58	60
Period Title: Interim Analysis; 11 February 2008
STARTED	0	78	74
Ongoing	0	29	32
COMPLETED	0	39	26
NOT COMPLETED	0	39	48
Period Title: Interim Analysis; 11 February 2008
STARTED	77	77	74
COMPLETED	53	59	54
NOT COMPLETED	24	18	20

Baseline Characteristics

Arm/Group Title	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg	Lapatinib Monotherapy	Pazopanib Monotherapy	Total
Arm/Group Description	Lapatinib 1500 mg (6 x 250 mg tablets) and pazopanib 800 mg (2 x 400 mg tablets) daily	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily	Total of all reporting groups
Overall Participants	59	58	60	177
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.4 (11.04)	48.7 (11.47)	49.6 (10.34)	49.5 (10.91)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	NA (NA)	49.2 (11.27)	50.8 (10.93)	50 (11.1)
Sex: Female, Male (Count of Participants)
Female	59 100%	58 100%	60 100%	177 100%
Male	0 0%	0 0%	0 0%	0 0%
Gender (participants) [Number]
Female	NA NaN	78 134.5%	74 123.3%	152 85.9%
Male	NA NaN	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
African American	0 0%	1 1.7%	0 0%	1 0.6%
American Indian	10 16.9%	4 6.9%	12 20%	26 14.7%
Asian-South East	12 20.3%	10 17.2%	8 13.3%	30 16.9%
White	37 62.7%	43 74.1%	40 66.7%	120 67.8%
Race/Ethnicity, Customized (participants) [Number]
African American	NA NaN	1 1.7%	0 0%	1 0.6%
American Indian	NA NaN	10 17.2%	13 21.7%	23 13%
Asian-Central , South	NA NaN	2 3.4%	0 0%	2 1.1%
Asian-South East	NA NaN	13 22.4%	9 15%	22 12.4%
White	NA NaN	52 89.7%	52 86.7%	104 58.8%
Histology at diagnosis: Interim Analysis (participants) [Number]
Adenocarcinoma	15 25.4%	8 13.8%	8 13.3%	31 17.5%
Adenosquamous carcinoma	0 0%	4 6.9%	3 5%	7 4%
Squamous cell carcinoma	32 54.2%	38 65.5%	43 71.7%	113 63.8%
Other	10 16.9%	8 13.8%	5 8.3%	23 13%
Missing	2 3.4%	0 0%	1 1.7%	3 1.7%
Histology at diagnosis: Final Anaysis (participants) [Number]
Adenocarcinoma	NA NaN	11 19%	12 20%	23 13%
Adenosquamous carcinoma	NA NaN	4 6.9%	3 5%	7 4%
Squamous cell carcinoma	NA NaN	55 94.8%	53 88.3%	108 61%
Other	NA NaN	8 13.8%	6 10%	14 7.9%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) in Interim Analysis
Description	PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. The study was designed to test Combination vs. Lapatinib first. The result indicated that Combination would not show improvement over Lapatinib even if followed until the final analysis and the Combination arm was terminated. The monotherapy arms continued to the final analysis. Data shown here are from this interim analysis.
Time Frame	From randomization until at least 35 PFS events in pairwise comparison of the three treatment arms (Interim Analysis; up to 52.14 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all randomized participants

Arm/Group Title	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	Lapatinib 1500 mg (6 x 250 mg tablets) and pazopanib 800 mg (2 x 400 mg tablets) daily	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	59	58	60
Median (90% Confidence Interval) [Weeks]	12.6	12.6	17.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg, Lapatinib Monotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.535
	Comments	Stratified log-rank test with one-sided p-value. p<=0.0037 required for significance, and p>0.4956 indicated futility.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	() 90%; 0.65 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value is the hazard ratio comparing combination to lapatinib monotherapy

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from randomization until death due to any cause.
Time Frame	From Randomization (11 December 2006) until approximately 78% overall survival events at the time of the second overall survival update (3 March 2010) (up to 168.29 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	78	74
Median (90% Confidence Interval) [Weeks]	44.1	49.7

3. Secondary Outcome

Title	Clinical Benefit Response
Description	Clinical benefit response is defined as the number of participants with evidence of complete (CR) or partial (PR) tumor response or stable disease (SD) for at least 6 months (183 days). Per Response Evaluation Criteria In Solid Tumors (RECIST): CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum; Stable Disease, small changes that do not meet previously given criteria. Confirmation requires at least 2 assessments of CR/PR with at least 4 weeks between assessments.
Time Frame	From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	78	74
Number [participants]	7 11.9%	15 25.9%

4. Secondary Outcome

Title	Response
Description	Response is defined as the number of participants achieving either a complete or partial tumor response per RECIST criteria. CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum.
Time Frame	From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	78	74
Number [participants]	4 6.8%	7 12.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg, Lapatinib Monotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.237
	Comments	One-sided p-value.
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Time to Response
Description	For the subset of participants who showed a confirmed CR or PR, time to response was defined as the time from randomization until the first documented evidence of CR or PR (whichever status was recorded first). CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum.
Time Frame	From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	4	7
Mean (90% Confidence Interval) [weeks]	18.2	6.9

6. Secondary Outcome

Title	Duration of Response
Description	For participants who had a CR or PR, the duration of response was defined as the time from first documented evidence of PR or CR until the first documented sign of disease progression or death. CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum.
Time Frame	From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population. The median for lapatinib was not reached at the time of data cut-off. No formal analysis of this endpoint was conducted for this group due to a very small number of responding participants.

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	0	7
Mean (90% Confidence Interval) [weeks]	48.1

7. Secondary Outcome

Title	Safety and Tolerability of Pazopanib, Lapatinib and the Combination of Pazopanib and Lapatinib
Description	Safety was assessed as the number of participants experiencing a serious adverse event (SAE) or an adverse event (AE). See the adverse event module for safety data.
Time Frame	From Randomization (11 December 2006) until last participant had last visit (28 July 2011) in combined population of two monotherapy arms (up to 241.43 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least one dose of study drug

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily	Lapatinib 1500 mg (6 x 250 mg tablets) and pazopanib 800 mg (2 x 400 mg tablets) daily
Measure Participants	76	74	76
Serious adverse events	22 37.3%	28 48.3%	32 53.3%
Other adverse events with >5% occurrence	66 111.9%	69 119%	71 118.3%

8. Primary Outcome

Title	Progression-free Survival (PFS) in Final Analysis
Description	PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. This study began as a 3-arm study. The combination arm was terminated at the interim analysis. The monotherapy arms continued to final analysis. Data shown here are from the final analysis.
Time Frame	From Randomization until 105 total PFS events in combined population of two monotherapy arms (up to 85.57 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Monotherapy	Pazopanib Monotherapy
Arm/Group Description	1500 mg (6 x 250 mg tablets) of oral lapatinib daily	800 mg (2 x 400 mg tablets) of oral pazopanib daily
Measure Participants	78	74
Median (90% Confidence Interval) [Weeks]	17.1	18.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg, Lapatinib Monotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	Stratified log-rank test with one-sided p-value.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.66
	Confidence Interval	() 90%; 0.48 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	SAEs/AEs were assessed in par. receiving >=1 dose of study treatment at time of final PFS analysis (From Randomization [11 December 2006] until last par. had last visit [28 July 2011] in combined population of two monotherapy arms [up to 241.43 weeks])
Adverse Event Reporting Description	Serious adverse events (SAEs) and adverse events (AEs) are reported for the Safety Population (all participants who received at least one dose of study drug).
Arm/Group Title	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg		Lapatinib Monotherapy		Pazopanib Monotherapy
Arm/Group Description	Lapatinib 1500 mg (6 x 250 mg tablets) and pazopanib 800 mg (2 x 400 mg tablets) daily		1500 mg (6 x 250 mg tablets) of oral lapatinib daily		800 mg (2 x 400 mg tablets) of oral pazopanib daily
All Cause Mortality
	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg		Lapatinib Monotherapy		Pazopanib Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg		Lapatinib Monotherapy		Pazopanib Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/76 (42.1%)		22/76 (28.9%)		28/74 (37.8%)
Blood and lymphatic system disorders
Anaemia	4/76 (5.3%)		1/76 (1.3%)		2/74 (2.7%)
Febrile neutropenia	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Cardiac disorders
Cardiac arrest	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Tachycardia	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Myocardial infarction	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Gastrointestinal disorders
Diarrhoea	1/76 (1.3%)		4/76 (5.3%)		4/74 (5.4%)
Abdominal pain	3/76 (3.9%)		1/76 (1.3%)		4/74 (5.4%)
Intestinal obstruction	1/76 (1.3%)		2/76 (2.6%)		0/74 (0%)
Intestinal perforation	2/76 (2.6%)		0/76 (0%)		0/74 (0%)
Upper gastrointestinal haemorrhage	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Rectal haemorrhage	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Small intestinal obstruction	0/76 (0%)		0/76 (0%)		2/74 (2.7%)
Ascites	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Colitis	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Enteritis	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Enterovesical fistula	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Large intestine perforation	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Rectal ulcer	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Subileus	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Vomiting	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
General disorders
Pyrexia	0/76 (0%)		2/76 (2.6%)		0/74 (0%)
Chest pain	1/76 (1.3%)		1/76 (1.3%)		0/74 (0%)
Fatigue	1/76 (1.3%)		1/76 (1.3%)		0/74 (0%)
General physical health deterioration	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Pain	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Asthenia	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Performance status decreased	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Sudden death	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Hepatobiliary disorders
Jaundice	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Infections and infestations
Urinary tract infection	0/76 (0%)		1/76 (1.3%)		1/74 (1.4%)
Gastroenteritis	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Pneumonia primary atypical	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Pyelonephritis	1/76 (1.3%)		0/76 (0%)		1/74 (1.4%)
Pyonephrosis	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Cellulitis	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Gangrene	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Pneumonia	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Septic Shock	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Injury, poisoning and procedural complications
Toxicity to various agents	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Wound	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Investigations
Ejection fraction decreased	2/76 (2.6%)		0/76 (0%)		0/74 (0%)
Forced expiratory volume decreased	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Metabolism and nutrition disorders
Decreased appetite	0/76 (0%)		1/76 (1.3%)		1/74 (1.4%)
Dehydration	2/76 (2.6%)		0/76 (0%)		1/74 (1.4%)
Failure to thrive	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Hypercalcaemia	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Hyperkalaemia	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Hypoglycaemia	1/76 (1.3%)		1/76 (1.3%)		0/74 (0%)
Hypokalaemia	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Hyponatraemia	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Musculoskeletal and connective tissue disorders
Bone pain	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Groin pain	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Intervertebral disc protrusion	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Muscular weakness	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Pain in extremity	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Osteonecrosis	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cardiac neoplasm unspecified	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Tumour haemorrhage	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Tumour pain	1/76 (1.3%)		1/76 (1.3%)		0/74 (0%)
Nervous system disorders
Convulsion	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Dizziness	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Spinal cord compression	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Peripheral sensory neuropathy	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Psychiatric disorders
Confusional state	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Insomnia	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Renal and urinary disorders
Proteinuria	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Renal failure	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Haematuria	2/76 (2.6%)		0/76 (0%)		0/74 (0%)
Renal failure acute	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Ureteric stenosis	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Urethral fistula	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Urinary bladder haemorrhage	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Urinary retention	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Reproductive system and breast disorders
Female genital tract fistula	4/76 (5.3%)		0/76 (0%)		2/74 (2.7%)
Pelvic pain	0/76 (0%)		1/76 (1.3%)		1/74 (1.4%)
Vaginal haemorrhage	2/76 (2.6%)		0/76 (0%)		1/74 (1.4%)
Cervix disorder	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Genital hemorrhage	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Respiratory, thoracic and mediastinal disorders
Cough	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Dyspnoea	1/76 (1.3%)		4/76 (5.3%)		0/74 (0%)
Pulmonary embolism	0/76 (0%)		1/76 (1.3%)		2/74 (2.7%)
Bronchial obstruction	0/76 (0%)		1/76 (1.3%)		0/74 (0%)
Epistaxis	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Pulmonary haemorrhage	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Respiratory distress	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Respiratory Failure	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Tachypnoea	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Vascular disorders
Deep vein thrombosis	0/76 (0%)		0/76 (0%)		2/74 (2.7%)
Hypertension	1/76 (1.3%)		0/76 (0%)		2/74 (2.7%)
Venous thrombosis	0/76 (0%)		0/76 (0%)		1/74 (1.4%)
Arterial thrombosis limb	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Hypotension	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Iliac artery occlusion	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Shock haemorrhagic	1/76 (1.3%)		0/76 (0%)		0/74 (0%)
Other (Not Including Serious) Adverse Events
	Combination Therapy: Lapatinib 1500 mg and Pazopanib 800 mg		Lapatinib Monotherapy		Pazopanib Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/76 (93.4%)		66/76 (86.8%)		69/74 (93.2%)
Blood and lymphatic system disorders
Anaemia	12/76 (15.8%)		12/76 (15.8%)		8/74 (10.8%)
Neutropenia	3/76 (3.9%)		1/76 (1.3%)		9/74 (12.2%)
Leukopenia	6/76 (7.9%)		0/76 (0%)		5/74 (6.8%)
Lymphopenia	0/76 (0%)		3/76 (3.9%)		4/74 (5.4%)
Gastrointestinal disorders
Diarrhoea	58/76 (76.3%)		42/76 (55.3%)		40/74 (54.1%)
Nausea	28/76 (36.8%)		25/76 (32.9%)		28/74 (37.8%)
Vomiting	32/76 (42.1%)		18/76 (23.7%)		15/74 (20.3%)
Abdominal pain	15/76 (19.7%)		9/76 (11.8%)		14/74 (18.9%)
Constipation	8/76 (10.5%)		8/76 (10.5%)		17/74 (23%)
Abdominal pain upper	5/76 (6.6%)		7/76 (9.2%)		13/74 (17.6%)
Rectal haemorrhage	7/76 (9.2%)		3/76 (3.9%)		2/74 (2.7%)
Dyspepsia	4/76 (5.3%)		3/76 (3.9%)		2/74 (2.7%)
Stomatitis	4/76 (5.3%)		5/76 (6.6%)		2/74 (2.7%)
Dry mouth	3/76 (3.9%)		4/76 (5.3%)		2/74 (2.7%)
Flatulence	1/76 (1.3%)		4/76 (5.3%)		0/74 (0%)
General disorders
Asthenia	19/76 (25%)		17/76 (22.4%)		13/74 (17.6%)
Fatigue	14/76 (18.4%)		15/76 (19.7%)		10/74 (13.5%)
Oedema peripheral	5/76 (6.6%)		8/76 (10.5%)		6/74 (8.1%)
Pain	3/76 (3.9%)		1/76 (1.3%)		5/74 (6.8%)
Pyrexia	5/76 (6.6%)		6/76 (7.9%)		3/74 (4.1%)
Hepatobiliary disorders
Hyperbilirubinaemia	5/76 (6.6%)		1/76 (1.3%)		4/74 (5.4%)
Infections and infestations
Urinary tract infection	9/76 (11.8%)		10/76 (13.2%)		6/74 (8.1%)
Pharyngitis	0/76 (0%)		0/76 (0%)		4/74 (5.4%)
Investigations
Blood alkaline phosphatase increased	7/76 (9.2%)		5/76 (6.6%)		14/74 (18.9%)
Aspartate aminotransferase increased	9/76 (11.8%)		2/76 (2.6%)		11/74 (14.9%)
Alanine aminotransferase increased	5/76 (6.6%)		1/76 (1.3%)		11/74 (14.9%)
Blood lactate dehydrogenase increased	5/76 (6.6%)		1/76 (1.3%)		8/74 (10.8%)
Weight decreased	6/76 (7.9%)		4/76 (5.3%)		3/74 (4.1%)
Haemoglobin decreased	2/76 (2.6%)		1/76 (1.3%)		4/74 (5.4%)
Metabolism and nutrition disorders
Decreased appetite	29/76 (38.2%)		25/76 (32.9%)		20/74 (27%)
Musculoskeletal and connective tissue disorders
Back pain	8/76 (10.5%)		11/76 (14.5%)		9/74 (12.2%)
Pain in extremity	4/76 (5.3%)		7/76 (9.2%)		8/74 (10.8%)
Myalgia	5/76 (6.6%)		6/76 (7.9%)		5/74 (6.8%)
Arthralgia	5/76 (6.6%)		3/76 (3.9%)		4/74 (5.4%)
Nervous system disorders
Headache	10/76 (13.2%)		7/76 (9.2%)		20/74 (27%)
Dizziness	3/76 (3.9%)		5/76 (6.6%)		5/74 (6.8%)
Dysgeusia	11/76 (14.5%)		3/76 (3.9%)		5/74 (6.8%)
Somnolence	0/76 (0%)		4/76 (5.3%)		3/74 (4.1%)
Psychiatric disorders
Insomnia	3/76 (3.9%)		5/76 (6.6%)		5/74 (6.8%)
Renal and urinary disorders
Proteinuria	9/76 (11.8%)		11/76 (14.5%)		6/74 (8.1%)
Dysuria	5/76 (6.6%)		4/76 (5.3%)		3/74 (4.1%)
Haematuria	3/76 (3.9%)		5/76 (6.6%)		3/74 (4.1%)
Urinary incontinence	0/76 (0%)		5/76 (6.6%)		2/74 (2.7%)
Reproductive system and breast disorders
Pelvic pain	4/76 (5.3%)		5/76 (6.6%)		5/74 (6.8%)
Vaginal haemorrhage	8/76 (10.5%)		2/76 (2.6%)		5/74 (6.8%)
Respiratory, thoracic and mediastinal disorders
Cough	4/76 (5.3%)		7/76 (9.2%)		7/74 (9.5%)
Dyspnoea	9/76 (11.8%)		8/76 (10.5%)		3/74 (4.1%)
Epistaxis	6/76 (7.9%)		1/76 (1.3%)		2/74 (2.7%)
Skin and subcutaneous tissue disorders
Rash	12/76 (15.8%)		22/76 (28.9%)		4/74 (5.4%)
Hair colour changes	8/76 (10.5%)		0/76 (0%)		11/74 (14.9%)
Dry skin	3/76 (3.9%)		5/76 (6.6%)		5/74 (6.8%)
Alopecia	7/76 (9.2%)		1/76 (1.3%)		6/74 (8.1%)
Erythema	0/76 (0%)		3/76 (3.9%)		5/74 (6.8%)
Acne	6/76 (7.9%)		4/76 (5.3%)		0/74 (0%)
Skin hypopigmentation	4/76 (5.3%)		0/76 (0%)		2/74 (2.7%)
Pruritus	1/76 (1.3%)		8/76 (10.5%)		2/74 (2.7%)
Dermatitis acneiform	3/76 (3.9%)		5/76 (6.6%)		1/74 (1.4%)
Vascular disorders
Hypertension	24/76 (31.6%)		2/76 (2.6%)		23/74 (31.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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