Trial Outcomes & Findings for Safety and Efficacy of GW786034 (Pazopanib) In Metastatic Renal Cell Carcinoma (NCT NCT00334282)

Last Updated: 2016-02-05

Results Overview

Progression-free survival (PFS) is defined as the interval between the date of randomization and the earliest date of disease progression or death due to any cause. Assessments of progression and non-progression were made by an independent imaging review committee (IRC) for the primary analysis.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

435 participants

Primary outcome timeframe

Randomization until progression (up to 2 years)

Results posted on

2016-02-05

Participant Flow

Participant milestones

Participant milestones
Measure	Pazopanib 800 mg Pazopanib 800 mg (tablets) administered orally once a day	Placebo Matching Placebo administered orally once a day
Overall Study STARTED	290	145
Overall Study COMPLETED	68	37
Overall Study NOT COMPLETED	222	108

Reasons for withdrawal

Reasons for withdrawal
Measure	Pazopanib 800 mg Pazopanib 800 mg (tablets) administered orally once a day	Placebo Matching Placebo administered orally once a day
Overall Study Lost to Follow-up	11	5
Overall Study Withdrawal by Subject	17	3
Overall Study Death	194	100

Baseline Characteristics

Safety and Efficacy of GW786034 (Pazopanib) In Metastatic Renal Cell Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pazopanib 800 mg n=290 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 Participants Matching Placebo administered once a day	Total n=435 Participants Total of all reporting groups
Age, Continuous	59.1 years STANDARD_DEVIATION 10.06 • n=5 Participants	59.6 years STANDARD_DEVIATION 11.04 • n=7 Participants	59.3 years STANDARD_DEVIATION 10.38 • n=5 Participants
Sex: Female, Male Female	92 Participants n=5 Participants	36 Participants n=7 Participants	128 Participants n=5 Participants
Sex: Female, Male Male	198 Participants n=5 Participants	109 Participants n=7 Participants	307 Participants n=5 Participants
Race/Ethnicity, Customized White	252 participants n=5 Participants	122 participants n=7 Participants	374 participants n=5 Participants
Race/Ethnicity, Customized Asian	36 participants n=5 Participants	23 participants n=7 Participants	59 participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization until progression (up to 2 years)

Population: Intent-to-Treat (ITT) Population: all randomized participants

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=290 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 Participants Matching Placebo administered once a day
Progression-free Survival	9.2 months Interval 7.4 to 12.9	4.2 months Interval 2.8 to 5.6

SECONDARY outcome

Timeframe: Randomization until death (up to 2 years)

Population: ITT Population

Overall survival is defined as the time from randomization until death. The length of this interval was estimated as the date of death minus the date of randomization plus 1 day. Participants who were still alive at the time of analysis were censored.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=290 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 Participants Matching Placebo administered once a day
Overall Survival	22.9 months Interval 19.9 to 25.4	20.5 months Interval 15.6 to 27.6

SECONDARY outcome

Timeframe: Baseline until either response or progression (up to 2 years)

Population: ITT Population

Overall response is the number of participants who had a complete response (CR) or a partial response (PR). Per RECIST: CR, all detectable tumor has disappeared; PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the Baseline sum, no worsening of non-TLs, and no new lesions; Progressive disease (PD), a \>=20% increase in TLs, clearly worsening of non-TLs, or emergence of new lesions; Stable Disease, small changes that do not meet previously given criteria. IRC, independent review committee.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=290 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 Participants Matching Placebo administered once a day
Overall Response Unknown, IRC assessed	41 participants	23 participants
Overall Response Unknown, Investigator assessed	23 participants	9 participants
Overall Response Complete Response, IRC assessed	1 participants	0 participants
Overall Response Partial Response, IRC assessed	87 participants	5 participants
Overall Response Stable Disease, IRC assessed	110 participants	59 participants
Overall Response Progressive Disease, IRC assessed	51 participants	58 participants
Overall Response Complete Response, Investigator assessed	4 participants	0 participants
Overall Response Partial Response, Investigator assessed	99 participants	9 participants
Overall Response Stable Disease, Investigator assessed	118 participants	62 participants
Overall Response Progressive Disease, Investigator assessed	46 participants	65 participants

SECONDARY outcome

Timeframe: Baseline until 6 months post-Baseline or progressive disease

Population: ITT Population

This is similar to overall response rate, but also includes participants who had stable disease for at least 6 months. 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; Progressive Disease, a \>=20% increase in target lesions. IRC, independent review committee.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=290 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 Participants Matching Placebo administered once a day
Participants With Complete Response, Partial Response, or 6 Months of Stable Disease Complete Response, IRC assessed	1 participants	0 participants
Participants With Complete Response, Partial Response, or 6 Months of Stable Disease Partial Response, IRC assessed	87 participants	5 participants
Participants With Complete Response, Partial Response, or 6 Months of Stable Disease 6 Months Stable Disease, IRC assessed	48 participants	17 participants
Participants With Complete Response, Partial Response, or 6 Months of Stable Disease Progressive Disease, IRC assessed	92 participants	84 participants
Participants With Complete Response, Partial Response, or 6 Months of Stable Disease Unknown	62 participants	39 participants

SECONDARY outcome

Timeframe: Time from response until progression (up to 2 years)

Population: ITT Population. Only results for pazopanib are given because there were not enough placebo responders.

Duration of response is defined as the time from first observation of response until progression of disease or death.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=290 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo Matching Placebo administered once a day
Duration of Response	58.7 weeks Interval 52.1 to 68.1	—

SECONDARY outcome

Timeframe: Randomization until CR or PR (assessed for up to 2 years)

Population: ITT Population. Only participants with a complete or partial response were analyzed. Only results for pazopanib are given because there were not enough placebo responders. The different number of participants analyzed is due to differences in clinical judgement, measurement, and the selection of target lesions.

Time to response is defined as the time from randomization until the first documented evidence of complete response (all detectable tumor has disappeared) or partial response (a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the Baseline sum) (whichever status was recorded first).

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=103 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo Matching Placebo administered once a day
Time to Response as Assessed by an Independent Review Committee (IRC) and the Investigator IRC assessed, n=88	11.9 weeks Interval 9.4 to 12.3	—
Time to Response as Assessed by an Independent Review Committee (IRC) and the Investigator Investigator assessed, n=103	12.0 weeks Interval 11.6 to 12.3	—

SECONDARY outcome

Timeframe: Baseline and Weeks 6, 12, 18, 24, and 48

Population: Participants in the ITT Population who completed HRQOL assessments at Baseline and had at least one post-Baseline assessment are included. Only participants who were on treatment at the given time point were asked to complete the questionnaire, and only those who completed the questionnaire could be analyzed for each individual time point.

The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer participants. The analyses for EORTC QLQ-C30 were focused on global health status/Health-Related Quality of Life (HRQOL) scores on the questionnaire. The scores (from 1 \[very poor quality of life\] to 7 \[excellent quality of life\]) for these two questions were averaged and then transformed to a 0 - 100 scale (based on published methods) prior to analysis of change from Baseline.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=246 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=111 Participants Matching Placebo administered once a day
Adjusted Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ C-30) Score at Weeks 6, 12, 18, 24, and 48 Week 6, n=243, 110	-3.2 points on a scale Standard Deviation 19.66	-2.6 points on a scale Standard Deviation 19.18
Adjusted Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ C-30) Score at Weeks 6, 12, 18, 24, and 48 Week 12, n=219, 81	-3.6 points on a scale Standard Deviation 20.16	-0.5 points on a scale Standard Deviation 17.55
Adjusted Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ C-30) Score at Weeks 6, 12, 18, 24, and 48 Week 18, n=191, 61	-2.5 points on a scale Standard Deviation 21.70	-0.3 points on a scale Standard Deviation 18.13
Adjusted Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ C-30) Score at Weeks 6, 12, 18, 24, and 48 Week 24, n=164, 49	0.1 points on a scale Standard Deviation 19.81	-0.5 points on a scale Standard Deviation 18.67
Adjusted Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ C-30) Score at Weeks 6, 12, 18, 24, and 48 Week 48, n=96, 24	-0.3 points on a scale Standard Deviation 18.36	0.3 points on a scale Standard Deviation 15.63

SECONDARY outcome

Timeframe: Baseline and Weeks 6, 12, 18, 24, and 48

Population: Participants in the ITT Population who completed HRQOL assessments at Baseline and had at least one post-baseline assessment are included. Only participants who were on treatment at the given time point were asked to complete the questionnaire, and only those who completed the questionnaire could be analyzed for each individual time point.

The EQ-5D is comprised of a 5-item health status measure and a visual analogue rating scale, and measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (no, moderate, and extreme problems). Scoring of the EQ-5D yields an index-based summary score (Index), through application of societal weights, and a VAS score (VAS). Index is interpreted on a continuum from 1.0 (best possible health) to 0 (represents dead), to some health sates being worse than dead (\<0).

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=253 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=125 Participants Matching Placebo administered once a day
Adjusted Mean Change From Baseline in the Index Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 6, n=253, 125	-0.014 points on a scale Standard Deviation 0.2203	-0.029 points on a scale Standard Deviation 0.2674
Adjusted Mean Change From Baseline in the Index Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 12, n=219, 86	-0.040 points on a scale Standard Deviation 0.2148	0.007 points on a scale Standard Deviation 0.1969
Adjusted Mean Change From Baseline in the Index Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 18, n=196, 62	-0.023 points on a scale Standard Deviation 0.2305	-0.006 points on a scale Standard Deviation 0.1466
Adjusted Mean Change From Baseline in the Index Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 24, n=166, 51	-0.025 points on a scale Standard Deviation 0.2420	-0.001 points on a scale Standard Deviation 0.2411
Adjusted Mean Change From Baseline in the Index Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 36, n=98, 24	0.030 points on a scale Standard Deviation 0.1961	-0.005 points on a scale Standard Deviation 0.2015

SECONDARY outcome

Timeframe: Baseline and Weeks 6, 12, 18, 24, and 48

The EQ-5D is comprised of a 5-item health status measure and a visual analogue rating scale, and measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (no, moderate, and extreme problems). Scoring of the EQ-5D yields an index-based summary score (Index) and a VAS score (VAS), obtained from participant's self-reports of their health on a VAS thermometer scale. The EQ-5D VAS ranges from 0% (worst imaginable health state) to 100% (best imaginable health state).

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=239 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=111 Participants Matching Placebo administered once a day
Adjusted Mean Change From Baseline in the Visual Analog Scale (VAS) Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 12, n=212, 80	-0.9 points on a scale Standard Deviation 21.07	-3.6 points on a scale Standard Deviation 23.04
Adjusted Mean Change From Baseline in the Visual Analog Scale (VAS) Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 6, n=239, 111	0.4 points on a scale Standard Deviation 22.55	0.2 points on a scale Standard Deviation 25.35
Adjusted Mean Change From Baseline in the Visual Analog Scale (VAS) Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 18, n=189, 60	0.1 points on a scale Standard Deviation 23.20	0.1 points on a scale Standard Deviation 19.35
Adjusted Mean Change From Baseline in the Visual Analog Scale (VAS) Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 24, n=161, 49	2.6 points on a scale Standard Deviation 22.16	5.4 points on a scale Standard Deviation 21.27
Adjusted Mean Change From Baseline in the Visual Analog Scale (VAS) Score of the EQ-5D (EuroQoL [Quality of Life]-5D) Questionnaire at Weeks 6, 12, 18, 24, and 48 Week 36, n=95, 23	2.4 points on a scale Standard Deviation 24.21	8.8 points on a scale Standard Deviation 23.96

SECONDARY outcome

Timeframe: Day 1 and Week 3

Population: Subgroup of enrolled participants who agreed to have blood samples collected for analysis of pazopanib in plasma. Data were missing or not collected at Week 3 for 8 participants for whom data were available on Day 1. No samples were collected at Week 3 from 2 participants.

The concentration of pazopanib in the plasma was measured.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=57 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo Matching Placebo administered once a day
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Day 1, before dosing, n=57	0 nanograms per milliliter Interval 0.0 to 846.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Week 3, before dosing, n=48	31851 nanograms per milliliter Interval 2634.0 to 61720.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Day 1, 2 hours after dosing, n=57	17270 nanograms per milliliter Interval 0.0 to 107454.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Week 3, 2 hours after dosing, n=49	42205 nanograms per milliliter Interval 4282.0 to 79977.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Day 1, 4 hours after dosing, n=57	24360 nanograms per milliliter Interval 2371.0 to 74606.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Week 3, 4 hours after dosing, n=49	42637 nanograms per milliliter Interval 3532.0 to 107972.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Day 1, 8 hours after dosing, n=57	19925 nanograms per milliliter Interval 3273.0 to 60974.0	—
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 Week 3, 8 hours after dosing, n=48	40177.5 nanograms per milliliter Interval 3760.0 to 96548.0	—

SECONDARY outcome

Timeframe: Baseline

Population: Subgroup of enrolled participants who agreed to have plasma samples collected for biomarker analyses.

Baseline plasma samples were obtained from participants and were tested for the indicated cytokine and angiogenesis factors. Protein levels were determined using the Searchlight multiplex system based on chemiluminescence.

Outcome measures

Outcome measures
Measure	Pazopanib 800 mg n=225 Participants Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=119 Participants Matching Placebo administered once a day
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants Interleukin-6	31.003 picograms per milliliter Standard Deviation 65.247	24.145 picograms per milliliter Standard Deviation 31.708
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants Interleukin-8	35.429 picograms per milliliter Standard Deviation 164.12	27.755 picograms per milliliter Standard Deviation 66.129
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants Vascular endothelial growth factor	308.61 picograms per milliliter Standard Deviation 365.19	273.15 picograms per milliliter Standard Deviation 350.91
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants Hepatocyte growth factor	383.55 picograms per milliliter Standard Deviation 308.89	522.94 picograms per milliliter Standard Deviation 1003.8
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants Tissue inhibitor of metalloproteinase 1	847464 picograms per milliliter Standard Deviation 690744	735915 picograms per milliliter Standard Deviation 423493
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants e-Selectin	41649.28 picograms per milliliter Standard Deviation 22389.04	41231.45 picograms per milliliter Standard Deviation 19825.7
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants Osteopotin	444343 picograms per milliliter Standard Deviation 707005	369317 picograms per milliliter Standard Deviation 490931

Adverse Events

Pazopanib 800 mg

Serious events: 79 serious events

Other events: 258 other events

Deaths: 0 deaths

Placebo

Serious events: 28 serious events

Other events: 87 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Pazopanib 800 mg n=290 participants at risk Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 participants at risk Matching Placebo administered orally once a day
Gastrointestinal disorders Diarrhea	2.1% 6/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Vomiting	1.4% 4/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Abdominal pain	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Abdominal pain upper	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Intestinal obstruction	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Abdominal distension	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Constipation	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Enterocutaneous fistula	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Gastric haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Irritable bowel syndrome	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Nausea	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Oesophageal haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Peritonitis	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Rectal haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Retroperitoneal haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.1% 6/290 • Date of study entry until 28 days after the last dose.	2.1% 3/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.4% 4/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.0% 3/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Pneumonia	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Upper respiratory tract infection	0.00% 0/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Appendicitis	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Bronchitis	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Bronchopneumonia	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Ear infection	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Herpes zoster	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Infection	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Lower respiratory tract infection	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Blood and lymphatic system disorders Anaemia	2.1% 6/290 • Date of study entry until 28 days after the last dose.	2.8% 4/145 • Date of study entry until 28 days after the last dose.
Blood and lymphatic system disorders Leukopenia	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Hepatobiliary disorders Hepatic function abnormal	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Hepatobiliary disorders Hepatotoxicity	1.0% 3/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Hepatobiliary disorders Jaundice cholestatic	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Hepatobiliary disorders Hyperbilirubinaemia	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Metabolism and nutrition disorders Dehydration	0.69% 2/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Metabolism and nutrition disorders Decreased appetite	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Metabolism and nutrition disorders Hyperkalaemia	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Metabolism and nutrition disorders Cachexia	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Seizure	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Paraplegia	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Cerebrovascular insufficiency	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Coordination abnormal	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Dizziness	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Ischaemic stroke	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Myelitis	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Speech disorder	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Myocardial ischaemia	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Acute myocardial infarction	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Atrial fibrillation	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Bradycardia	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Cardiac arrest	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Cardiac failure	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Cardiac disorders Myocardial infarction	1.0% 3/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
General disorders Asthenia	0.00% 0/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
General disorders Chest pain	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
General disorders Fatigue	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
General disorders Hernia	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
General disorders Pain	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
General disorders Pyrexia	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
General disorders Sudden death	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Investigations Alanine aminotransferase increasead	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Investigations Blood creatinine increased	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Investigations Aspartate aminotransferase increased	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Investigations Blood bilirubin increased	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Investigations Blood urea increased	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Investigations Electrocardiogram QT prolonged	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Investigations Haemoglobin decreased	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Investigations Neutrophil count decreased	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Renal and urinary disorders Acute kidney injury	0.00% 0/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Renal and urinary disorders Haematuria	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Renal and urinary disorders Renal haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Renal and urinary disorders Renal vein thrombosis	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Renal and urinary disorders Urinary retention	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Vascular disorders Hypertension	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Vascular disorders Deep vein thrombosis	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Vascular disorders Hypertensive crisis	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Injury, poisoning and procedural complications Contusion	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Injury, poisoning and procedural complications Lower limb fracture	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Musculoskeletal and connective tissue disorders Back pain	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Skin and subcutaneous tissue disorders Rash	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Skin and subcutaneous tissue disorders Skin lesion	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Psychiatric disorders Confusional state	0.69% 2/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Ear and labyrinth disorders Vertigo	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Gastritis	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Transient ischaemic attack	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Injury, poisoning and procedural complications Skin graft failure	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm	0.00% 0/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Immune system disorders Anaphylactic reaction	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Anorectal varices haemorrhage	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Infections and infestations Septic shock	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Reproductive system and breast disorders Pelvic pain	0.34% 1/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.

Measure	Pazopanib 800 mg n=290 participants at risk Pazopanib 800 mg (tablets) administered orally once a day	Placebo n=145 participants at risk Matching Placebo administered orally once a day
Gastrointestinal disorders Diarrhoea	51.4% 149/290 • Date of study entry until 28 days after the last dose.	9.0% 13/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Nausea	25.9% 75/290 • Date of study entry until 28 days after the last dose.	9.0% 13/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Vomiting	20.3% 59/290 • Date of study entry until 28 days after the last dose.	8.3% 12/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Abdominal pain	11.0% 32/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Abdominal pain upper	8.3% 24/290 • Date of study entry until 28 days after the last dose.	5.5% 8/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Constipation	6.9% 20/290 • Date of study entry until 28 days after the last dose.	6.2% 9/145 • Date of study entry until 28 days after the last dose.
Skin and subcutaneous tissue disorders Hair colour changes	37.6% 109/290 • Date of study entry until 28 days after the last dose.	3.4% 5/145 • Date of study entry until 28 days after the last dose.
Skin and subcutaneous tissue disorders Rash	8.3% 24/290 • Date of study entry until 28 days after the last dose.	2.8% 4/145 • Date of study entry until 28 days after the last dose.
Skin and subcutaneous tissue disorders Alopecia	8.3% 24/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	5.9% 17/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
General disorders Fatigue	20.0% 58/290 • Date of study entry until 28 days after the last dose.	9.0% 13/145 • Date of study entry until 28 days after the last dose.
General disorders Asthenia	15.2% 44/290 • Date of study entry until 28 days after the last dose.	9.0% 13/145 • Date of study entry until 28 days after the last dose.
General disorders Pyrexia	4.8% 14/290 • Date of study entry until 28 days after the last dose.	6.2% 9/145 • Date of study entry until 28 days after the last dose.
Vascular disorders Hypertension	39.7% 115/290 • Date of study entry until 28 days after the last dose.	11.0% 16/145 • Date of study entry until 28 days after the last dose.
Investigations Alanine aminotransferase increased	18.6% 54/290 • Date of study entry until 28 days after the last dose.	2.8% 4/145 • Date of study entry until 28 days after the last dose.
Investigations Aspartate aminotransferase increased	15.9% 46/290 • Date of study entry until 28 days after the last dose.	3.4% 5/145 • Date of study entry until 28 days after the last dose.
Investigations Weight decreased	10.7% 31/290 • Date of study entry until 28 days after the last dose.	4.1% 6/145 • Date of study entry until 28 days after the last dose.
Metabolism and nutrition disorders Decreased appetite	24.1% 70/290 • Date of study entry until 28 days after the last dose.	11.7% 17/145 • Date of study entry until 28 days after the last dose.
Musculoskeletal and connective tissue disorders Back pain	7.9% 23/290 • Date of study entry until 28 days after the last dose.	11.7% 17/145 • Date of study entry until 28 days after the last dose.
Musculoskeletal and connective tissue disorders Arthralgia	8.6% 25/290 • Date of study entry until 28 days after the last dose.	9.7% 14/145 • Date of study entry until 28 days after the last dose.
Musculoskeletal and connective tissue disorders Pain in extremity	6.9% 20/290 • Date of study entry until 28 days after the last dose.	6.2% 9/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Headache	10.7% 31/290 • Date of study entry until 28 days after the last dose.	5.5% 8/145 • Date of study entry until 28 days after the last dose.
Nervous system disorders Dysgeusia	8.6% 25/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Cough	8.6% 25/290 • Date of study entry until 28 days after the last dose.	9.7% 14/145 • Date of study entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.6% 19/290 • Date of study entry until 28 days after the last dose.	5.5% 8/145 • Date of study entry until 28 days after the last dose.
Blood and lymphatic system disorders Thrombocytopenia	7.6% 22/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Renal and urinary disorders Proteinuria	10.3% 30/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Psychiatric disorders Insomnia	5.5% 16/290 • Date of study entry until 28 days after the last dose.	6.9% 10/145 • Date of study entry until 28 days after the last dose.
Endocrine disorders Hypothyroidism	6.9% 20/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Gastrointestinal disorders Dyspepsia	5.9% 17/290 • Date of study entry until 28 days after the last dose.	0.69% 1/145 • Date of study entry until 28 days after the last dose.
General disorders Chest pain	5.5% 16/290 • Date of study entry until 28 days after the last dose.	1.4% 2/145 • Date of study entry until 28 days after the last dose.
Blood and lymphatic system disorders Neutropenia	5.2% 15/290 • Date of study entry until 28 days after the last dose.	0.00% 0/145 • Date of study entry until 28 days after the last dose.
Blood and lymphatic system disorders Anaemia	6.6% 19/290 • Date of study entry until 28 days after the last dose.	4.8% 7/145 • Date of study entry until 28 days after the last dose.