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Pazopanib Versus Placebo in Patients With Soft Tissue Sarcoma Whose Disease Has Progressed During or Following Prior Therapy (PALETTE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00753688
First received: September 12, 2008
Last updated: August 15, 2013
Last verified: August 2013
Results First Received: November 17, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Sarcoma, Soft Tissue
Interventions: Drug: PAZOPANIB
Drug: Placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Participant Flow:   Overall Study
    Placebo   Pazopanib
STARTED   123   246 
Ongoing - in Follow-up   15   31 
COMPLETED   0   0 
NOT COMPLETED   123   246 
Death                102                203 
Missing                4                9 
Participant Withdrew Consent                2                2 
Ongoing - in Follow-up                15                31 
Adverse Event                0                1 



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Total Total of all reporting groups

Baseline Measures
   Placebo   Pazopanib   Total 
Overall Participants Analyzed 
[Units: Participants]
 123   246   369 
Age 
[Units: Years]
Mean (Standard Deviation)
 51.7  (13.77)   54.0  (14.92)   53.2  (14.57) 
Gender 
[Units: Participants]
     
Female   69   147   216 
Male   54   99   153 
Race/Ethnicity, Customized 
[Units: Participants]
     
African American/African Heritage   2   4   6 
American Indian or Alaska Native   0   1   1 
Asian - Central/South Asian Heritage   2   0   2 
Asian - East Asian Heritage   7   24   31 
Asian - Japanese Heritage   16   31   47 
Asian - South East Asian Heritage   2   2   4 
White - Arabic/North African Heritage   2   1   3 
White - White/Caucasian/European Heritage   89   174   263 
Mixed Race   1   0   1 
Unknown   2   9   11 
Number of participants in the indicated soft tissue sarcoma (STS) subgroups at Baseline [1] 
[Units: Participants]
     
Leiomyosarcoma   49   109   158 
Synovial sarcoma   13   25   38 
Other STS histologies   61   112   173 
[1] Participants were categorized in the following histology subgroups of STS (as per the World Health Organization [WHO] classification, 2008): leiomyosarcoma, defined as malignant cancer of smooth muscle; synovial sarcoma, defined as cancer near the joints of the arm or leg; and other STS, defined as sarcoma without the tumor type of leiomyosarcoma or synovial sarcoma.


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Progression-free Survival (PFS)   [ Time Frame: From the date of randomization until the date of the first documented radiological progression or date of death from any cause, whichever came first (assessed for an average of 10 months) ]

Measure Type Primary
Measure Title Progression-free Survival (PFS)
Measure Description PFS was defined as the time interval between the date of randomization and the earliest date of either disease progression or death due to any cause. The diagnosis of progression was based on tumor measurements, according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 criteria, by independent radiologic assessment. The Kaplan-Meier method was used for PFS estimates.
Time Frame From the date of randomization until the date of the first documented radiological progression or date of death from any cause, whichever came first (assessed for an average of 10 months)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat (ITT) Population: all randomized participants analyzed in the treatment arm they were allocated by randomization.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 123   246 
Progression-free Survival (PFS) 
[Units: Weeks]
Median (95% Confidence Interval)
 7.0 
 (4.4 to 8.1) 
 20.0 
 (17.9 to 21.3) 


Statistical Analysis 1 for Progression-free Survival (PFS)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] <0.001
Hazard Ratio (HR) [5] 0.35
95% Confidence Interval 0.26 to 0.48
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified two-sided log rank p-value
[5] Other relevant estimation information:
  The HR was adjusted for World Health Organization (WHO) performance status scale (0 versus 1 at Baseline) and number of prior lines of systemic treatment for advanced disease (0/1 versus 2+).



2.  Secondary:   Overall Survival (OS)   [ Time Frame: From the date of randomization until 215 deaths (assessed for an average of 12 months) ]

Measure Type Secondary
Measure Title Overall Survival (OS)
Measure Description OS was defined as the time from the date of randomization to the date of death due to any cause. The length of this interval was calculated as the date of death minus the date of randomization plus 1 day. Participants who were alive at the time of analysis were censored at the date of last follow-up. The interim OS analysis was conducted when 215 (77 percent [%]) of the 279 required death events had occurred in the study. The Kaplan-Meier method was used for OS estimates.
Time Frame From the date of randomization until 215 deaths (assessed for an average of 12 months)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 123   246 
Overall Survival (OS) 
[Units: Months]
Median (95% Confidence Interval)
 10.7 
 (9.0 to 13.1) 
 12.6 
 (10.9 to 14.9) 


Statistical Analysis 1 for Overall Survival (OS)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.256
Hazard Ratio (HR) [5] 0.86
95% Confidence Interval 0.67 to 1.12
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified two-sided log rank p-value
[5] Other relevant estimation information:
  The HR was adjusted for World Health Organization (WHO) performance status scale (0 versus 1 at Baseline) and number of prior lines of systemic treatment for advanced disease (0/1 versus 2+).



3.  Secondary:   Number of Participants in the Indicated Categories for Overall Response Assessed by an Independent Radiologist and the Investigator   [ Time Frame: From the start of treatment until disease progression (assessed for an average of 10 months) ]

Measure Type Secondary
Measure Title Number of Participants in the Indicated Categories for Overall Response Assessed by an Independent Radiologist and the Investigator
Measure Description Overall response is defined as the number of participants who had a complete response (CR) or a partial response (PR). According to RECIST, Version 1.0: CR, disappearance of all lesions; PR, a >=30% decrease in the sum of the longest dimensions (LD) of the target lesions (TLs) taking as a reference the baseline sum LD; Progressive disease (PD), a >=20% increase in the sum of the LD of TLs, or the appearance of >=1 new lesion; Stable Disease (SD), neither PR nor PD, persistence of >=1 non-TL. Participants with no follow-up radiological disease assessment were categorized as not evaluable (NE).
Time Frame From the start of treatment until disease progression (assessed for an average of 10 months)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 123   246 
Number of Participants in the Indicated Categories for Overall Response Assessed by an Independent Radiologist and the Investigator 
[Units: Participants]
   
CR, Independent radiologist assessed   0   0 
PR, Independent radiologist assessed   0   11 
SD, Independent radiologist assessed   33   134 
PD, Independent radiologist assessed   76   66 
NE, Independent radiologist assessed   14   35 
CR, Investigator assessed   0   0 
PR, Investigator assessed   0   23 
SD, Investigator assessed   36   138 
PD, Investigator assessed   83   70 
NE, Investigator assessed   4   15 

No statistical analysis provided for Number of Participants in the Indicated Categories for Overall Response Assessed by an Independent Radiologist and the Investigator



4.  Secondary:   Time to Response Assessed by an Independent Radiologist and the Investigator   [ Time Frame: From the date of randomization until the date of the first documented evidence of CR or PR (assessed for an average of 10 months) ]

Measure Type Secondary
Measure Title Time to Response Assessed by an Independent Radiologist and the Investigator
Measure Description Time to response was defined as the time from the date of randomization until the date of first documented evidence of CR or PR (whichever status was recorded first). The Kaplan-Meier method was used for time to response estimates.
Time Frame From the date of randomization until the date of the first documented evidence of CR or PR (assessed for an average of 10 months)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Only participants who achieved a confirmed CR or PR, as determined independently by the Independent Radiologist and the Investigator, were analyzed. Only results for the pazopanib arm are given because there was no response in the placebo arm.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 0   23 
Time to Response Assessed by an Independent Radiologist and the Investigator 
[Units: Weeks]
Median (95% Confidence Interval)
   
Independent radiologist assessed, n=0, 11      8.4 
 (4.7 to 19.1) 
Investigator assessed, n=0, 23      8.1 
 (4.6 to 11.7) 

No statistical analysis provided for Time to Response Assessed by an Independent Radiologist and the Investigator



5.  Secondary:   Duration of Response Assessed by the Independent Radiologist and the Investigator   [ Time Frame: From the date of randomization until the date of the first documented evidence of CR or PR (assessed for an average of 10 months) ]

Measure Type Secondary
Measure Title Duration of Response Assessed by the Independent Radiologist and the Investigator
Measure Description Duration of response was defined as the time from the date of the first documented evidence of CR or PR until the date of either the first documented sign of PD or death due to any cause. Participants who neither died nor progressed were censored at the date of the last adequate radiologic assessment. The Kaplan-Meier method was used for duration of response estimates.
Time Frame From the date of randomization until the date of the first documented evidence of CR or PR (assessed for an average of 10 months)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Only participants who achieved a confirmed CR or PR, as determined independently by the Independent Radiologist and the Investigator, were analyzed. Only results for the pazopanib arm are given because there was no response in the placebo arm.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 0   23 
Duration of Response Assessed by the Independent Radiologist and the Investigator 
[Units: Weeks]
Median (95% Confidence Interval)
   
Independent radiologist assessed, n=0, 11      38.9 
 (16.7 to 40.0) 
Investigator assessed, n=0, 23      32.1 
 (22.6 to 44.0) 

No statistical analysis provided for Duration of Response Assessed by the Independent Radiologist and the Investigator



6.  Secondary:   PFS in the Indicated Histology Subgroups of Soft Tissue Sarcoma (STS)   [ Time Frame: From the date of randomization until the date of the first documented progression or the date of death from any cause, whichever came first (assessed for an average of 10 months) ]

Measure Type Secondary
Measure Title PFS in the Indicated Histology Subgroups of Soft Tissue Sarcoma (STS)
Measure Description PFS was defined as the time interval between the date of randomization and the earliest date of either disease progression or death due to any cause. Participants were analyzed for PFS in histology subgroups of STS (as per the World Health Organization [WHO] classification, 2008): leiomyosarcoma (malignant cancer of smooth muscle), synovial sarcoma (cancer near the joints of the arm or leg), and other STS (without the tumor type of leiomyosarcoma or synovial sarcoma), based on independent review.The Kaplan-Meier method was used for PFS estimates.
Time Frame From the date of randomization until the date of the first documented progression or the date of death from any cause, whichever came first (assessed for an average of 10 months)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. The "n"s in the category titles represent the number of participants in each treatment arm with the indicated STS.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 123   246 
PFS in the Indicated Histology Subgroups of Soft Tissue Sarcoma (STS) 
[Units: Weeks]
Median (95% Confidence Interval)
   
Leiomyosarcoma, n=49, 109   8.1 
 (7.6 to 9.3) 
 20.1 
 (13.3 to 23.1) 
Synovial sarcoma, n=13, 25   4.1 
 (3.7 to 8.9) 
 17.9 
 (8.9 to 27.1) 
Other STS, n=61, 112   4.3 
 (4.0 to 7.9) 
 20.1 
 (13.0 to 27.1) 


Statistical Analysis 1 for PFS in the Indicated Histology Subgroups of Soft Tissue Sarcoma (STS)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] <0.001
Hazard Ratio (HR) [5] 0.37
95% Confidence Interval 0.23 to 0.60
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified two-sided log rank p-value for leiomyosarcoma
[5] Other relevant estimation information:
  The HR was adjusted for World Health Organization (WHO) performance status scale (0 versus 1 at Baseline) and number of prior lines of systemic treatment for advanced disease (0/1 versus 2+).

Statistical Analysis 2 for PFS in the Indicated Histology Subgroups of Soft Tissue Sarcoma (STS)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.005
Hazard Ratio (HR) [5] 0.43
95% Confidence Interval 0.19 to 0.98
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified two-sided log rank p-value for synovial sarcoma
[5] Other relevant estimation information:
  The HR was adjusted for World Health Organization (WHO) performance status scale (0 versus 1 at Baseline) and number of prior lines of systemic treatment for advanced disease (0/1 versus 2+).

Statistical Analysis 3 for PFS in the Indicated Histology Subgroups of Soft Tissue Sarcoma (STS)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] <0.001
Hazard Ratio (HR) [5] 0.39
95% Confidence Interval 0.25 to 0.60
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified two-sided log rank p-value for other STS histologies
[5] Other relevant estimation information:
  The HR was adjusted for World Health Organization (WHO) performance status scale (0 versus 1 at Baseline) and number of prior lines of systemic treatment for advanced disease (0/1 versus 2+).



7.  Secondary:   Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)   [ Time Frame: Baseline, Day 8, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 88, 96, and 104 ]

Measure Type Secondary
Measure Title Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Measure Description Change from baseline in on-therapy SBP and DBP was calculated as the values at the indicated time points (Day 8 and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 88, 96, and 104) minus the value at baseline.
Time Frame Baseline, Day 8, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 88, 96, and 104  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population: all participants who had started their allocated treatment (at least one dose of the study drug). Data were analyzed for participants who were on-therapy and provided data at the indicated time point.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 120   235 
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
[Units: Millimeters of mercury]
Mean (Standard Deviation)
   
SBP, Day 8, n=120, 235   -0.6  (13.37)   10.3  (15.96) 
SBP, Week 4, n=106, 224   -0.2  (12.83)   10.9  (19.47) 
SBP, Week 8, n=71, 180   0.0  (13.60)   7.2  (17.46) 
SBP, Week 12, n=31, 115   -3.1  (15.82)   4.9  (18.21) 
SBP, Week 16, n=35, 136   -0.6  (15.91)   4.9  (18.49) 
SBP, Week 20, n=14, 66   -2.6  (14.89)   3.9  (19.84) 
SBP, Week 24, n=22, 107   -3.8  (16.71)   2.7  (20.24) 
SBP, Week 28, n=9, 41   0.2  (22.82)   0.9  (15.70) 
SBP, Week 32, n=12, 76   2.8  (12.50)   3.2  (18.89) 
SBP, Week 36, n=5, 24   3.6  (10.71)   1.9  (17.71) 
SBP, Week 40, n=5, 62   6.8  (15.47)   3.2  (19.75) 
SBP, Week 44, n=3, 16   6.0  (19.31)   1.2  (19.45) 
SBP, Week 48, n=3, 37   -1.7  (14.05)   -1.7  (16.90) 
SBP, Week 52, n=1, 6   -4.0  (0)   9.8  (18.28) 
SBP, Week 56, n=1, 27   16.0  (0)   1.4  (20.86) 
SBP, Week 60, n=0, 6   0  (0)   7.0  (18.60) 
SBP, Week 64, n=1, 15   20.0  (0)   -3.0  (19.26) 
SBP, Week 68, n=0, 2   0  (0)   14.5  (3.54) 
SBP, Week 72, n=1, 9   8.0  (0)   -1.1  (15.83) 
SBP, Week 76, n=0, 1   0  (0)   16.0  (0) 
SBP, Week 80, n=1, 5   19.0  (0)   -0.9  (22.66) 
SBP, Week 88, n=1, 3   3.0  (0)   3.9  (22.90) 
SBP, Week 96, n=1, 2   13.0  (0)   -3.0  (14.14) 
SBP, Week 104, n=1, 1   18.0  (0)   6.0  (0) 
DBP, Day 8, n=120, 235   -0.2  (9.53)   7.2  (10.68) 
DBP, Week 4, n=106, 224   -0.2  (9.51)   8.2  (11.37) 
DBP, Week 8, n=71, 180   -0.3  (9.24)   6.6  (12.18) 
DBP, Week 12, n=31, 115   -0.1  (10.81)   3.9  (11.31) 
DBP, Week 16, n=35, 136   0.8  (10.46)   5.3  (12.12) 
DBP, Week 20, n=14, 66   -0.3  (8.61)   4.5  (12.22) 
DBP, Week 24, n=22, 107   -1.6  (11.78)   3.7  (14.44) 
DBP, Week 28, n=9, 41   -1.9  (12.33)   3.7  (11.28) 
DBP, Week 32, n=12, 76   -2.0  (7.30)   3.9  (11.59) 
DBP, Week 36, n=5, 24   -6.6  (9.63)   4.1  (13.28) 
DBP, Week 40, n=5, 62   3.4  (9.24)   2.9  (13.34) 
DBP, Week 44, n=3, 16   4.7  (5.03)   1.7  (12.48) 
DBP, Week 48, n=3, 37   2.0  (4.36)   3.7  (12.01) 
DBP, Week 52, n=1, 6   1.0  (0)   12.0  (15.06) 
DBP, Week 56, n=1, 27   12.0  (0)   4.4  (12.28) 
DBP, Week 60, n=0, 6   0  (0)   12.7  (14.39) 
DBP, Week 64, n=1, 15   10.0  (0)   -2.2  (14.21) 
DBP, Week 68, n=0, 2   0  (0)   17.0  (25.46) 
DBP, Week 72, n=1, 9   13.0  (0)   0.8  (12.88) 
DBP, Week 76, n=0, 1   0  (0)   4.0  (0) 
DBP, Week 80, n=1, 5   14.0  (0)   -3.3  (15.15) 
DBP, Week 88, n=1, 3   9.0  (0)   5.2  (3.87) 
DBP, Week 96, n=1, 2   6.0  (0)   7.0  (5.66) 
DBP, Week 104, n=1, 1   12.0  (0)   12.0  (0) 

No statistical analysis provided for Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)



8.  Secondary:   Change From Baseline in Heart Rate   [ Time Frame: Baseline, Day 8, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 88, 96, and 104 ]

Measure Type Secondary
Measure Title Change From Baseline in Heart Rate
Measure Description Change from baseline in on-therapy heart rate was calculated as the value at the indicated time points (Day 8 and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 88, 96, and 104) minus the value at baseline.
Time Frame Baseline, Day 8, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 88, 96, and 104  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population. Data were analyzed for participants who were on-therapy and provided data at the indicated time point.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 113   225 
Change From Baseline in Heart Rate 
[Units: Beats per minute]
Mean (Standard Deviation)
   
Day 8, n=113, 225   1.6  (12.61)   -4.4  (11.24) 
Week 4, n=98, 208   3.1  (13.06)   -2.7  (13.51) 
Week 8, n=66, 171   2.1  (15.03)   -1.6  (14.31) 
Week 12, n=29, 103   1.1  (17.32)   -2.4  (11.67) 
Week 16, n=31, 127   6.0  (16.78)   -3.7  (12.76) 
Week 20, n=12, 57   0.6  (22.95)   -3.4  (11.71) 
Week 24, n=21, 94   4.5  (18.14)   -5.0  (12.83) 
Week 28, n=7, 37   -1.1  (27.99)   -3.8  (13.68) 
Week 32, n=12, 72   -1.7  (18.38)   -2.7  (12.63) 
Week 36, n=5, 24   -11.8  (32.57)   0.9  (13.37) 
Week 40, n=5, 58   -8.2  (30.19)   -2.4  (12.84) 
Week 44, n=3, 15   7.0  (16.09)   -0.9  (14.02) 
Week 48, n=3, 33   9.0  (18.00)   1.9  (14.38) 
Week 52, n=1, 5   -8.0  (0)   -3.4  (16.96) 
Week 56, n=1, 24   31.0  (0)   -0.4  (15.14) 
Week 60, n=0, 6   0  (0)   4.3  (15.13) 
Week 64, n=1, 13   36.0  (0)   -1.5  (13.56) 
Week 68, n=0, 2   0  (0)   9.5  (0.71) 
Week 72, n=1, 8   14.0  (0)   2.6  (12.60) 
Week 76, n=0, 1   0  (0)   5.0  (0) 
Week 80, n=1, 5   24.0  (0)   2.8  (16.08) 
Week 88, n=1, 3   9.0  (0)   -3.0  (10.58) 
Week 96, n=1, 2   17.0  (0)   -5.0  (4.24) 
Week 104, n=1, 1   30.0  (0)   1.0  (0) 

No statistical analysis provided for Change From Baseline in Heart Rate



9.  Secondary:   Number of Participants With the Indicated Grade Shifts From Baseline Grade for Hemoglobin Level, Lymphocyte Count, White Blood Cell Count, Neutrophil Count, and Platelet Count   [ Time Frame: From baseline (Day 1) until study drug discontinuation or end of treatment (assessed for an average of 20 weeks) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Grade Shifts From Baseline Grade for Hemoglobin Level, Lymphocyte Count, White Blood Cell Count, Neutrophil Count, and Platelet Count
Measure Description Shifts in hematology values by grade were summarized based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Version 3.0). Grade refers to the severity of the AE. The CTCAE Version 3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline. Participants with a missing baseline grade were assumed to have a baseline Grade of 0. Any increase in grade from baseline and shifts to Grade 3 (severe AE) and 4 (life-threatening or disabling AE) at any point in the study after baseline are reported.
Time Frame From baseline (Day 1) until study drug discontinuation or end of treatment (assessed for an average of 20 weeks)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population. Data were analyzed for participants who were on-therapy and provided data at the indicated time point.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 123   239 
Number of Participants With the Indicated Grade Shifts From Baseline Grade for Hemoglobin Level, Lymphocyte Count, White Blood Cell Count, Neutrophil Count, and Platelet Count 
[Units: Participants]
   
Hemoglobin, Any Increase, n=123, 239   28   65 
Hemoglobin, Increase to Grade 3, n=123, 239   1   11 
Hemoglobin, Increase to Grade 4, n=123, 239   1   4 
Lymphocytes, Any Increase, n=123, 238   44   102 
Lymphocytes, Increase to Grade 3, n=123, 238   11   23 
Lymphocytes, Increase to Grade 4, n=123, 238   2   0 
Neutrophils, Any Increase, n=123, 239   8   79 
Neutrophils, Increase to Grade 3, n=123, 239   0   10 
Neutrophils, Increase to Grade 4, n=123, 239   0   0 
Platelets, Any Increase, n=123, 239   7   86 
Platelets, Increase to Grade 3, n=123, 239   0   7 
Platelets, Increase to Grade 4, n=123, 239   0   2 
White Blood Cells, Any Increase, n=123, 239   18   106 
White Blood Cells, Increase to Grade 3, n=123, 239   0   3 
White Blood Cells, Increase to Grade , n=123, 239   0   0 

No statistical analysis provided for Number of Participants With the Indicated Grade Shifts From Baseline Grade for Hemoglobin Level, Lymphocyte Count, White Blood Cell Count, Neutrophil Count, and Platelet Count



10.  Secondary:   Number of Participants With the Indicated Grade Shifts From Baseline Grade for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Albumin, Creatinine, Hyper/Hypoglycemia, Hyper/Hypokalemia, Hyper/Hyponatremia, and Total Bilirubin   [ Time Frame: From baseline (Day 1) until study drug discontinuation or end of treatment (assessed for an average of 20 weeks) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Grade Shifts From Baseline Grade for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Albumin, Creatinine, Hyper/Hypoglycemia, Hyper/Hypokalemia, Hyper/Hyponatremia, and Total Bilirubin
Measure Description Shifts in clinical chemistry values by grade were summarized based on the NCI CTCAE Version 3.0. Participants with a missing baseline grade were assumed to have a baseline Grade of 0. Any increase in grade from baseline and shifts to Grade 3 and 4 at any point in the study after baseline are reported. alkaline phosphatase, ALKP; alanine aminotransferase, ALT; aspartate aminotransferase, AST. Hyper/hypoglycemia refers to high/low glucose; hyper/hypokalemia refers to high/low potassium; hyper/hyponatremia refers to high/low sodium.
Time Frame From baseline (Day 1) until study drug discontinuation or end of treatment (assessed for an average of 20 weeks)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population. Data were analyzed for participants who were on-therapy and provided data at the indicated time point.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 123   239 
Number of Participants With the Indicated Grade Shifts From Baseline Grade for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Albumin, Creatinine, Hyper/Hypoglycemia, Hyper/Hypokalemia, Hyper/Hyponatremia, and Total Bilirubin 
[Units: Participants]
   
ALKP, Any Increase, n=123, 237   28   77 
ALKP, Increase to Grade 3, n=123, 237   1   7 
ALKP, Increase to Grade 4, n=123, 237   0   0 
ALT, Any Increase, n=123, 237   22   110 
ALT, Increase to Grade 3, n=123, 237   3   18 
ALT, Increase to Grade 4, n=123, 237   1   5 
AST, Any Increase, n=123, 239   27   122 
AST, Increase to Grade 3, n=123, 239   2   13 
AST, Increase to Grade 4, n=123, 239   0   6 
Albumin, Any Increase, n=123, 239   26   81 
Albumin, Increase to Grade 3, n=123, 239   0   2 
Albumin, Increase to Grade 4, n=123, 239   0   0 
Creatinine, Any Increase, n=123, 239   9   28 
Creatinine, Increase to Grade 3, n=123, 239   0   1 
Creatinine, Increase to Grade 4, n=123, 239   0   0 
Hyperglycemia, Any Increase, n=122, 238   43   106 
Hyperglycemia, Increase to Grade 3, n=122, 238   2   1 
Hyperglycemia, Increase to Grade 4, n=122, 238   0   0 
Hyperkalemia, Any Increase, n=123, 238   13   37 
Hyperkalemia, Increase to Grade 3, n=123, 238   0   3 
Hyperkalemia, Increase to Grade 4, n=123, 238   0   0 
Hypernatremia, Any Increase, n=123, 238   3   10 
Hypernatremia, Increase to Grade 3, n=123, 238   0   0 
Hypernatremia, Increase to Grade 4, n=123, 238   0   0 
Hypoglycemia, Any Increase, n=122, 238   4   21 
Hypoglycemia, Increase to Grade 3, n=122, 238   0   1 
Hypoglycemia, Increase to Grade 4, n=122, 238   0   0 
Hypokalemia, Any Increase, n=123, 238   11   32 
Hypokalemia, Increase to Grade 3, n=123, 238   1   6 
Hypokalemia, Increase to Grade 4, n=123, 238   0   1 
Hyponatremia, Any Increase, n=123, 238   25   74 
Hyponatremia, Increase to Grade 3, n=123, 238   4   9 
Hyponatremia, Increase to Grade 4, n=123, 238   0   0 
Total Bilirubin, Any Increase, n=122, 237   9   68 
Total Bilirubin, Increase to Grade 3, n=122, 237   2   3 
Total Bilirubin, Increase to Grade 4, n=122, 237   0   0 

No statistical analysis provided for Number of Participants With the Indicated Grade Shifts From Baseline Grade for Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Albumin, Creatinine, Hyper/Hypoglycemia, Hyper/Hypokalemia, Hyper/Hyponatremia, and Total Bilirubin



11.  Secondary:   Number of Participants With the Indicated Absolute Percent Change From Baseline (BL) in Left Ventricular Ejection Fraction (LVEF) at Any Time Post-BL (Worst Case On-therapy)   [ Time Frame: Baseline (within 14 days of the first dose of study drug) and any time post-baseline until study drug discontinuation or end of treatment (assessed for an average of 20 weeks) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Absolute Percent Change From Baseline (BL) in Left Ventricular Ejection Fraction (LVEF) at Any Time Post-BL (Worst Case On-therapy)
Measure Description LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction and is used to determine cardiac function (based on the institutional lower limit of normal [LLN]). LVEF was assessed at BL, Week 12, and every second scheduled visit thereafter until study drug discontinuation and end of treatment or as clinically indicated by using multi-gated acquisition scan (MUGA) or echocardiogram (ECHO). Absolute change from BL was calculated as the on-study value minus the baseline value (LVEF is calculated as a percentage).
Time Frame Baseline (within 14 days of the first dose of study drug) and any time post-baseline until study drug discontinuation or end of treatment (assessed for an average of 20 weeks)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population. Data were analyzed for participants who were on-therapy and provided data at the indicated time point.

Reporting Groups
  Description
Placebo Matching placebo tablets administered orally once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent
Pazopanib Pazopanib 200 milligrams (mg) and 400 mg film-coated tablets (containing pazopanib monohydrochloride) administered orally at a dose of 800 mg once daily for a duration until participants experienced disease progression, death, unacceptable toxicity, or participants withdrew consent

Measured Values
   Placebo   Pazopanib 
Participants Analyzed 
[Units: Participants]
 39   140 
Number of Participants With the Indicated Absolute Percent Change From Baseline (BL) in Left Ventricular Ejection Fraction (LVEF) at Any Time Post-BL (Worst Case On-therapy) 
[Units: Participants]
   
Any Increase   15   39 
No Change   6   14 
0 to <10% Decrease   15   66 
10 to 19% Decrease   3   15 
>=20% Decrease   0   6 
>=10% Decrease and >= LLN   3   8 
>=10% Decrease and below LLN   0   13 
>=20% Decrease and >= LLN   0   1 
>=20% Decrease and below LLN   0   5 

No statistical analysis provided for Number of Participants With the Indicated Absolute Percent Change From Baseline (BL) in Left Ventricular Ejection Fraction (LVEF) at Any Time Post-BL (Worst Case On-therapy)




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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