Carcinoma, Renal Cell
Conditions
Keywords
Metastatic, Anti-angiogenesis, GW786034, Pazopanib
Brief summary
To evaluate efficacy and safety of pazopanib compared to placebo in patients with locally advanced and/ or metastatic renal cell carcinoma (RCC). Approximately 350-400 eligible patients will be stratified and randomized in a 2:1 ratio to receive either 800 mg pazopanib once daily or matching placebo. The study treatment will continue until patients experience disease progression, unacceptable toxicity or death. Primary objective of the study is to evaluate and compare the two treatment arms for progression-free survival. Principal secondary objective is to evaluate and compare the two treatment arms with respect to overall survival. Other objectives are overall response rate \[complete response (CR) + partial response (PR)\], rate of CR + PR + 6 months stable disease, and the incidence, severity and causality of adverse events and serious adverse events. Safety and efficacy assessments will be regularly performed on all patients. An Independent Data Monitoring Committee will be established to monitor safety during the course of the study and to evaluate interim efficacy data on overall survival.
Interventions
DRUGPazopanib
Oral pazopanib tablet 800 mg once daily continuously
DRUGplacebo
matching placebo (800 mg tablet) once daily
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A patient will be considered for inclusion in this study only if all of the following criteria apply: * Signed written informed consent. * Diagnosis of clear cell RCC that is predominantly clear cell histology. Note: cytology cannot be the only pathologic criteria to confirm clear cell RCC. Patients with tumor types that are interpreted as non-clear cell, e.g. papillary, are excluded. * Locally advanced RCC (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to American Joint Committee on Cancer (AJCC) staging. * Note: If the metastatic disease is restricted to a solitary lesion, its neoplastic nature must be confirmed by histology or cytology. Cytology cannot be the only pathologic criteria to confirm clear cell RCC, but can be used in a patient with histologically confirmed clear cell RCC to confirm that metastatic disease is neoplastic in nature. * Must have measurable disease, i.e. presenting with at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST). A measurable lesion is defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques, or ≥ 10 mm with spiral CT scan. * Note: Patient should be excluded if all baseline measurable lesions are within previously irradiated areas. * Note: A patient must complete all the baseline disease assessments in order to be eligible. Baseline head, chest, abdominal and pelvic CT or MRI scans must be performed within 2 weeks prior to the first dose of study medication; baseline bone scan must be performed within 3 weeks of the first dose of study medication. * Patients who have received only one prior systemic treatment for locally advanced or metastatic RCC with documented disease progression or documented treatment discontinuation due to unacceptable toxicity. This first-line systemic treatment must be cytokine based. * Note: The first-line cytokine-based treatment can be interleukin-2 (IL-2) or interferon-α (INFα) monotherapy, IL-2 in combination with INF-α, IL-2 and/or INF-α in combination with chemotherapy, hormonal or other therapies excluding agents targeting angiogenesis pathways. Agents in a combination regimen can be given sequentially if the treatment sequence is pre-determined and the patient does not fail one agent prior to starting another. * Note: Prior adjuvant or neo-adjuvant therapies are permitted excluding any agents that target vascular endothelial growth factor (VEGF) or VEGF receptors. The adjuvant/neo-adjuvant therapies should not be considered as first-line systemic treatment for advanced RCC. Or, * Patients who have received no prior systemic therapy for advanced/metastatic RCC can be enrolled if under any of the following circumstances: * Patients who live in countries or regions where there is no established standard first-line therapy for advanced/metastatic RCC or where there are barriers to the access of established therapies such as sunitinib, sorafenib, IFNα or IL-2. * Patients who live in countries or regions where IL-2 or INF-α has been approved for the treatment of advanced/metastatic RCC, however, these agents are generally not recognized by the local clinical community as a standard treatment for advanced/metastatic RCC, or where the physician and the patient have determined that the available cytokine therapies are not an acceptable therapeutic option. * Patients who have recurred following prior adjuvant or neo-adjuvant cytokine therapy for RCC are eligible to participate without receiving a first-line systemic treatment for locally advanced or metastatic RCC. These patients should be stratified as the first-line population. * Male or female ≥ 18 years of age. * A woman is eligible to participate in the study if she is of: * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who: * Has had a hysterectomy, * Has had a bilateral oophorectomy (ovariectomy), * Has had 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 of the first dose of study medication, 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 patient'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 clinical trial, 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). * Oral contraceptives are not reliable due to the potential for drug-drug interactions. * A man with a female partner of childbearing potential is eligible to enter and participate in the study if he is abstinent or uses a barrier method of contraception during the study. * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 * Adequate baseline organ function defined as: * Hematologic function: Absolute Neutrophil Count (ANC) ≥1 x 10\^9/L Hemoglobin ≥ 9 g/dL Platelet ≥75 x 10\^9/L * Hepatic function: Total bilirubin ≥ 1.5 x Upper Limit of Normal (ULN) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≥ 2 x ULN * Renal function: Calculated creatinine clearance≥30 mL/min \[See Section 14.6 Appendix 6\] and ≥Urine protein is 0, trace, or +1 determined by dipstick urinalysis, or \< 1.0 gram determined by 24-hour urine protein analysis. * Note: A patient should first be screened with dipstick urinalysis. If urine protein is ≥2+, then a 24-hour urine protein must be assessed and patient will be excluded if 24-hour urine protein is≥ 1.0 gram. * Corrected serum calcium level within normal range per local clinical laboratory standard. Note: Patients with hypercalcemia should be treated until the corrected serum calcium level reaches the normal range. * At least 4 weeks must have elapsed since the last surgery and 2 weeks must have elapsed since radiotherapy or the last systemic cytokine therapy. * Complete recovery from prior surgery, and/or reduction of all AEs to Grade 1 from prior systemic therapy or radiotherapy. * Note: In patients with prior radiotherapy, the steroid doses should be stable or decreasing for at least 2 weeks.
Exclusion criteria
A patient will not be eligible for inclusion in this study if any of the following criteria apply: * Pregnant or lactating female. * 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 presence of central nervous system (CNS) metastasis or leptomeningeal tumors as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. Note: A baseline brain CT or MRI scan must be obtained in all patients within 2 weeks of the first dose of study medication. * Malabsorption syndrome or disease that significantly affects gastrointestinal function, or major resection of the stomach or small bowel that could affect the absorption of pazopanib. * Unable to swallow and retain orally administered medication. * Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to beginning study treatment. * History of human immunodeficiency virus infection. * Presence of uncontrolled infection. * Corrected QT interval (QTc) prolongation defined as QTc interval \> 470 msecs. * History of Class III or IV congestive heart failure according to New York Heart Association (NYHA) classification. * History of any one of the following cardiac conditions within the past 6 months: * Cardiac angioplasty or stenting, or * Myocardial infarction, or * Unstable angina. * History of cerebrovascular accident within the past 6 months. * Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥140mmHg, or diastolic blood pressure (DBP) of ≥ 90mmHg\]. * Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. The blood pressure must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP / DBP values from both blood pressure assessments must be \< 140/90mmHg in order for a patient to be eligible for the study. * History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. a calf vein thrombosis that is not treated). Note: Patients with recent DVT who are treated with therapeutic anti-coagulating agents (excluding therapeutic warfarin) for at least 2 weeks are eligible. * Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease. * Evidence of bleeding diathesis or coagulopathy. * 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. * Has taken any prohibited medications within 14 days of the first dose of study medication. * Current or prior use of an investigational anti-cancer drug within 4 weeks of start of study. * Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors (eg. bevacizumab, sunitinib, sorafenib, etc).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Randomization until progression (up to 2 years) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | Baseline until either response or progression (up to 2 years) | 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. |
| Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Baseline until 6 months post-Baseline or progressive disease | 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. |
| Duration of Response | Time from response until progression (up to 2 years) | Duration of response is defined as the time from first observation of response until progression of disease or death. |
| Time to Response as Assessed by an Independent Review Committee (IRC) and the Investigator | Randomization until CR or PR (assessed for up to 2 years) | 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). |
| Overall Survival | Randomization until death (up to 2 years) | 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. |
| 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 | 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), 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). |
| 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 | 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). |
| Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3 | Day 1 and Week 3 | The concentration of pazopanib in the plasma was measured. |
| Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Baseline | 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. |
| 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 | Baseline and Weeks 6, 12, 18, 24, and 48 | 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. |
Countries
Argentina, Australia, Austria, Brazil, Chile, China, Czechia, Estonia, Greece, Hong Kong, India, Ireland, Italy, Latvia, Lithuania, Mexico, New Zealand, Pakistan, Poland, Russia, Slovakia, South Korea, Tunisia, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib 800 mg Pazopanib 800 mg (tablets) administered orally once a day | 290 |
| Placebo Matching Placebo administered once a day | 145 |
| Total | 435 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 194 | 100 |
| Overall Study | Lost to Follow-up | 11 | 5 |
| Overall Study | Withdrawal by Subject | 17 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Pazopanib 800 mg |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 11.04 | 59.3 years STANDARD_DEVIATION 10.38 | 59.1 years STANDARD_DEVIATION 10.06 |
| Race/Ethnicity, Customized African American/African Heritage | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 23 participants | 59 participants | 36 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 122 participants | 374 participants | 252 participants |
| Sex: Female, Male Female | 36 Participants | 128 Participants | 92 Participants |
| Sex: Female, Male Male | 109 Participants | 307 Participants | 198 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 258 / 290 | 87 / 145 |
| serious Total, serious adverse events | 79 / 290 | 28 / 145 |
Outcome results
Primary
Progression-free Survival
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.
Time frame: Randomization until progression (up to 2 years)
Population: Intent-to-Treat (ITT) Population: all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Progression-free Survival | 9.2 months |
| Placebo | Progression-free Survival | 4.2 months |
p-value: 1e-795% CI: [0.34, 0.62]Log Rank
Secondary
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
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 21.7 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Placebo | 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 15.63 |
| Placebo | 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 | -0.5 points on a scale | Standard Deviation 18.67 |
| Placebo | 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 | -0.5 points on a scale | Standard Deviation 17.55 |
| Placebo | 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 | -2.6 points on a scale | Standard Deviation 19.18 |
| Placebo | 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 | -0.3 points on a scale | Standard Deviation 18.13 |
Secondary
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
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 0.242 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Placebo | 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 | -0.005 points on a scale | Standard Deviation 0.2015 |
| Placebo | 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 | -0.029 points on a scale | Standard Deviation 0.2674 |
| Placebo | 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 | 0.007 points on a scale | Standard Deviation 0.1969 |
| Placebo | 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 | -0.006 points on a scale | Standard Deviation 0.1466 |
| Placebo | 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 | -0.001 points on a scale | Standard Deviation 0.2411 |
Secondary
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
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 23.2 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Placebo | 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 | 8.8 points on a scale | Standard Deviation 23.96 |
| Placebo | 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 | -3.6 points on a scale | Standard Deviation 23.04 |
| Placebo | 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 | 0.2 points on a scale | Standard Deviation 25.35 |
| Placebo | 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 19.35 |
| Placebo | 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 | 5.4 points on a scale | Standard Deviation 21.27 |
Secondary
Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants
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.
Time frame: Baseline
Population: Subgroup of enrolled participants who agreed to have plasma samples collected for biomarker analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Osteopotin | 444343 picograms per milliliter | Standard Deviation 707005 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | e-Selectin | 41231.45 picograms per milliliter | Standard Deviation 19825.7 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Vascular endothelial growth factor | 273.15 picograms per milliliter | Standard Deviation 350.91 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Osteopotin | 369317 picograms per milliliter | Standard Deviation 490931 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Tissue inhibitor of metalloproteinase 1 | 735915 picograms per milliliter | Standard Deviation 423493 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Interleukin-6 | 24.145 picograms per milliliter | Standard Deviation 31.708 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Hepatocyte growth factor | 522.94 picograms per milliliter | Standard Deviation 1003.8 |
| Placebo | Baseline Expression Levels of the Indicated Target Proteins in Pazopanib- and Placebo-treated Participants | Interleukin-8 | 27.755 picograms per milliliter | Standard Deviation 66.129 |
Secondary
Duration of Response
Duration of response is defined as the time from first observation of response until progression of disease or death.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Duration of Response | 58.7 weeks |
Secondary
Overall Response
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.
Time frame: Baseline until either response or progression (up to 2 years)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Overall Response | Progressive Disease, Investigator assessed | 46 participants |
| Pazopanib 800 mg | Overall Response | Partial Response, IRC assessed | 87 participants |
| Pazopanib 800 mg | Overall Response | Progressive Disease, IRC assessed | 51 participants |
| Pazopanib 800 mg | Overall Response | Complete Response, Investigator assessed | 4 participants |
| Pazopanib 800 mg | Overall Response | Stable Disease, IRC assessed | 110 participants |
| Pazopanib 800 mg | Overall Response | Partial Response, Investigator assessed | 99 participants |
| Pazopanib 800 mg | Overall Response | Unknown, IRC assessed | 41 participants |
| Pazopanib 800 mg | Overall Response | Complete Response, IRC assessed | 1 participants |
| Pazopanib 800 mg | Overall Response | Unknown, Investigator assessed | 23 participants |
| Pazopanib 800 mg | Overall Response | Stable Disease, Investigator assessed | 118 participants |
| Placebo | Overall Response | Unknown, Investigator assessed | 9 participants |
| Placebo | Overall Response | Stable Disease, Investigator assessed | 62 participants |
| Placebo | Overall Response | Partial Response, IRC assessed | 5 participants |
| Placebo | Overall Response | Stable Disease, IRC assessed | 59 participants |
| Placebo | Overall Response | Progressive Disease, IRC assessed | 58 participants |
| Placebo | Overall Response | Complete Response, IRC assessed | 0 participants |
| Placebo | Overall Response | Unknown, IRC assessed | 23 participants |
| Placebo | Overall Response | Complete Response, Investigator assessed | 0 participants |
| Placebo | Overall Response | Partial Response, Investigator assessed | 9 participants |
| Placebo | Overall Response | Progressive Disease, Investigator assessed | 65 participants |
Secondary
Overall Survival
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.
Time frame: Randomization until death (up to 2 years)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg | Overall Survival | 22.9 months |
| Placebo | Overall Survival | 20.5 months |
Secondary
Participants With Complete Response, Partial Response, or 6 Months of Stable Disease
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.
Time frame: Baseline until 6 months post-Baseline or progressive disease
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Partial Response, IRC assessed | 87 participants |
| Pazopanib 800 mg | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Progressive Disease, IRC assessed | 92 participants |
| Pazopanib 800 mg | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | 6 Months Stable Disease, IRC assessed | 48 participants |
| Pazopanib 800 mg | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Unknown | 62 participants |
| Pazopanib 800 mg | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Complete Response, IRC assessed | 1 participants |
| Placebo | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Unknown | 39 participants |
| Placebo | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Complete Response, IRC assessed | 0 participants |
| Placebo | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Partial Response, IRC assessed | 5 participants |
| Placebo | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | 6 Months Stable Disease, IRC assessed | 17 participants |
| Placebo | Participants With Complete Response, Partial Response, or 6 Months of Stable Disease | Progressive Disease, IRC assessed | 84 participants |
Secondary
Plasma Pazopanib Concentrations Before Dosing and at 2, 4, and 8 Hours After Dosing on Day 1 and Week 3
The concentration of pazopanib in the plasma was measured.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
| Pazopanib 800 mg | 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 |
Secondary
Time to Response as Assessed by an Independent Review Committee (IRC) and the Investigator
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pazopanib 800 mg | Time to Response as Assessed by an Independent Review Committee (IRC) and the Investigator | IRC assessed, n=88 | 11.9 weeks |
| Pazopanib 800 mg | Time to Response as Assessed by an Independent Review Committee (IRC) and the Investigator | Investigator assessed, n=103 | 12.0 weeks |