Last updated: 11/04/2018 13:24:31
This product has been transferred to Novartis. GSK Clinical Study Register is no longer maintained for this study. The most up to date information is available on clinicaltrials.gov.
Safety and Efficacy of GW786034 (Pazopanib) In Metastatic Renal Cell Carcinoma
EudraCT ID
EU CT Number
Not applicable
Trial status
No longer a GSK study
No longer a GSK study
Trial overview
Official title: A Randomised, Double-blind, Placebo controlled, Multi-center Phase III Study to Evaluate the Efficacy and Safety of Pazopanib (GW786034) Compared to Placebo in Patients with Locally Advanced and/or Metastatic Renal Cell Carcinoma
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:
Progression-free survival
Timeframe: Randomization until progression (up to 2 years)
Secondary outcomes:
Overall Survival
Timeframe: Randomization until death (up to 2 years)
Overall Response
Timeframe: Baseline until either response or progression (up to 2 years)
Participants with complete response, partial response, or 6 months of stable disease
Timeframe: Baseline until 6 months post-Baseline or progressive disease
Duration of response
Timeframe: Time from response until progression (up to 2 years)
Time to response as assessed by an Independent Review Committee (IRC) and the Investigator
Timeframe: Randomization until CR or PR (assessed for up to 2 years)
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
Timeframe: Baseline and Weeks 6, 12, 18, 24, and 48
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
Timeframe: Baseline and Weeks 6, 12, 18, 24, and 48
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
Timeframe: Baseline and Weeks 6, 12, 18, 24, and 48
Plasma pazopanib concentrations before dosing and at 2, 4, and 8 hours after dosing on Day 1 and Week 3
Timeframe: Day 1 and Week 3
Baseline expression levels of the indicated target proteins in pazopanib- and placebo-treated participants
Timeframe: Baseline
Interventions:
Drug: Pazopanib
Drug: placebo
Enrollment:
435
Observational study model:
Not applicable
Primary completion date:
2008-23-05
Time perspective:
Not applicable
Clinical publications:
Bonate PL, Suttle B. Modeling Tumor Growth Kinetics After Treatment With Pazopanib or Placebo in Patients with Renal Cell Carcinoma. Cancer Chemother Pharmacol. 2013;72(1):231-40.
Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;8(August 13):827-37.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OAKavina A, Zarbá JJ, Chen M, McCann L, Pandite L,Roychowdhury D,Hawkins RE. Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial . J Clin Oncol. 2010;28(6):1061-1068.
Maitland ML, Wu K, Sharma MR, et al. Estimation of renal cell carcinoma treatment effects from disease progression modeling. Clin Pharmacol Ther. 2013;93(4):345-351.
Xu CF, Reck BH, Goodman VL, Xue Z, Huang L, Barnes M, Spraggs CF, Mooser VE, Cardon LR, Pandite L. Association of the Hemochromatosis Gene With Pazopanib-Induced Transaminase Elevation in Renal Cell Carcinoma. J Hepatol. 2011;54(6):1237-43.
Xu C-f, Reck BH, Xue Z, Huang L, Baker K, Chen M, Chen EP, Ellens HE, Mooser V, Cardon LR, Spraggs C, Pandite L. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer. 2010;102(9):1371-1377.
Sternberg CN, Hawkins RE, Davis ID, et al. A Randomized Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma: Final Overall Survival and Safety Update. Eur J Cancer. 2013;49(6):1287-96.
Choueiri T, Figueroa D, Fay A, et al.Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial.Clin Cancer Res.2014;21(5):1071-7
Maitland ML, Wu K, Sharma MR, Jin Y, Kang SP, Stadler WM, Karrison TG, Ratain MJ, Bies RR. Estimation of renal cell carcinoma treatment effects from disease progression modeling. Clin Pharmacol Ther. 2013;93(4):345-351.
Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. J Clin Oncol. 2010;28(6):1061-1068.
Tran HT, Liu Y, Zurita AJ, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;13(8):827-37.
Xu C-F, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer. 2010;102(9):1371-1377.
Xu CF, Reck BH, Goodman VL, et al. Association of the Hemochromatosis Gene With Pazopanib-Induced Transaminase Elevation in Renal Cell Carcinoma. J Hepatol. 2011;54(6):1237-43.
Medical condition
Carcinoma, Renal Cell
Product
pazopanib
Collaborators
Not applicable
Study date(s)
April 2006 to December 2014
Type
Interventional
Phase
3
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- A patient will be considered for inclusion in this study only if all of the following criteria apply:
- Signed written informed consent.
- A patient will not be eligible for inclusion in this study if any of the following criteria apply:
- Pregnant or lactating female.
Inclusion and exclusion criteria
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).
Trial location(s)
Location
GSK Investigational Site
Viña del Mar, Valparaíso, Chile, 254-0364
Status
Study Complete
Location
GSK Investigational Site
Orbassano (TO), Piemonte, Italy, 10043
Status
Study Complete
Location
GSK Investigational Site
Porto Alegre, Rio Grande Do Sul, Brazil, 90610 000
Status
Study Complete
Location
GSK Investigational Site
Rosario, Santa Fe, Argentina, S2000KZE
Status
Study Complete
Location
GSK Investigational Site
Bebington, Wirral, United Kingdom, CH63 4JY
Status
Study Complete
Location
GSK Investigational Site
Belfast, United Kingdom, BT9 7AB
Status
Terminated/Withdrawn
Location
GSK Investigational Site
songpa-gu, Seoul, South Korea, 138-736
Status
Study Complete
Location
GSK Investigational Site
Wodonga, Victoria, Australia, 3690
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Newtown, Wellington, New Zealand, 6002
Status
Study Complete
Location
GSK Investigational Site
Casalpusterlengo (LO), Lombardia, Italy, 26841
Status
Study Complete
Location
GSK Investigational Site
Santiago, Región Metro De Santiago, Chile, 7500921
Status
Study Complete
Location
GSK Investigational Site
Capital Federal, Buenos Aires, Argentina, C1405CUB
Status
Study Complete
Location
GSK Investigational Site
Belo Horizonte, Minas Gerais, Brazil, 30150-270
Status
Study Complete
Location
GSK Investigational Site
Manchester, Lancashire, United Kingdom, M20 4BX
Status
Study Complete
Location
GSK Investigational Site
Tuen Mun, New Territories, Hong Kong
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Jaú, São Paulo, Brazil, 17210-120
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Guadalajara, Jalisco, Mexico, CP44280
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Waratah, New South Wales, Australia, 2298
Status
Study Complete
Location
GSK Investigational Site
St Leonards, New South Wales, Australia, 2065
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Exeter, Devon, United Kingdom, EX2 5DW
Status
Study Complete
Location
GSK Investigational Site
Ostrava - Poruba, Czech Republic, 708 52
Status
Study Complete
Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
No longer a GSK study
Actual primary completion date
2008-23-05
Actual study completion date
2014-29-12
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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