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Lancet (London, England) May 2012Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy.
METHODS
This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688.
FINDINGS
372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib.
INTERPRETATION
Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy.
FUNDING
GlaxoSmithKline.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cross-Over Studies; Disease-Free Survival; Double-Blind Method; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome; Young Adult
PubMed: 22595799
DOI: 10.1016/S0140-6736(12)60651-5 -
The New England Journal of Medicine Aug 2013Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.
METHODS
We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.
RESULTS
Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).
CONCLUSIONS
Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).
Topics: Adult; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Sunitinib
PubMed: 23964934
DOI: 10.1056/NEJMoa1303989 -
Japanese Journal of Clinical Oncology Jun 2018Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that primarily inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet... (Review)
Review
Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that primarily inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet endothelial growth factor receptor-α, and -β, and the stem-cell factor receptor c-kit. In preliminary experiments using angiogenesis models with mice and rabbits, pazopanib inhibited angiogenesis caused by combined vascular endothelial growth factor and basic fibroblast growth factor. Although pazopanib was developed as a therapeutic agent against various tumors, it is currently approved in many countries for advanced soft-tissue sarcoma and renal cell carcinoma. The importance of pazopanib has been acknowledged, with positive results demonstrated in large-scale clinical trials involving patients with soft-tissue sarcoma and renal cell carcinoma. However, adverse events such as liver dysfunction and hypertension are common, often necessitating treatment discontinuation. These adverse events are generally manageable, and from the perspective of health-related quality of life and cost-effectiveness, pazopanib provides an improvement in quality-adjusted life years and decreases the treatment cost compared with other alternatives. In this review, we present the results of clinical trials and discuss the pharmacological action of pazopanib, with the aim of evaluating its current state by examining various associated issues.
Topics: Animals; Clinical Trials as Topic; Humans; Indazoles; Neoplasms; Pyrimidines; Sulfonamides
PubMed: 29684209
DOI: 10.1093/jjco/hyy053 -
Expert Opinion on Investigational Drugs Jun 2019: Liposarcomas (LPS) are a heterogeneous group of adipocytic soft tissue sarcomas with limited treatment options in the advanced/metastatic setting. Pazopanib is a... (Review)
Review
: Liposarcomas (LPS) are a heterogeneous group of adipocytic soft tissue sarcomas with limited treatment options in the advanced/metastatic setting. Pazopanib is a multi-target tyrosine kinase inhibitor (TKI) with anti-angiogenic and antitumorigenic properties. Whilst targeted agents including TKIs have been extensively studied in other solid tumors and the sarcoma subtype gastrointestinal stromal tumor (GIST), we currently lack effective treatments for the liposarcoma subtype. Several phase II and III studies of oral TKIs in soft tissue sarcomas have excluded liposarcoma because of a reported lack of activity following the EORTC 62043 study. : We review the use of pazopanib in advanced intermediate and high-grade liposarcomas where complete surgical resection is not possible. : The current clinical and pharmacological data demonstrate the efficacy of pazopanib in soft tissue sarcomas, but new data suggest that anti-angiogenic agents may have limited activity in liposarcoma. Anti-angiogenic TKIs are generally well tolerated and liposarcomas vary in their response to systemic chemotherapy; hence, there is a role for further exploration of the efficacy of this treatment amongst the histological subtypes of liposarcoma. This affords further understanding of biomarkers which may be associated with response to pazopanib and other anti-angiogenic TKI treatments.
Topics: Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Humans; Indazoles; Liposarcoma; Neoplasm Grading; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 31010343
DOI: 10.1080/13543784.2019.1607291 -
Targeted Oncology Aug 2017Pazopanib (Votrient®), an orally administered multi-targeted tyrosine kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and... (Review)
Review
Pazopanib (Votrient®), an orally administered multi-targeted tyrosine kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β, and the stem cell factor receptor c-Kit, is approved in the EU, the USA and other countries for the treatment of advanced renal cell carcinoma (RCC). In randomized controlled trials in patients with advanced, predominantly clear-cell RCC, pazopanib significantly improved progression-free survival (PFS) compared with placebo in both treatment-naïve and cytokine-pretreated patients and, as a first-line therapy, was noninferior to intermittent sunitinib with respect to PFS. However, pazopanib had a tolerability profile that was distinguishable from that of sunitinib, based on lower incidences of most adverse events, particularly those associated with discomfort, such as fatigue, hand-foot syndrome and stomatitis. Consistent with this, health-related quality of life (HR-QOL) measures evaluating fatigue, hand/foot soreness and mouth/throat soreness significantly favoured pazopanib over sunitinib. In addition, significantly more patients expressed a preference for pazopanib over sunitinib, primarily because of better overall HR-QOL and less fatigue. Efficacy and tolerability findings from these prospective clinical trials have been substantiated by evidence from a number of retrospective studies evaluating unselected real-world patients with metastatic RCC who received pazopanib (or sunitinib) as a first-line therapy. Thus, data from clinical trials supplemented with that from clinical practice support the use of pazopanib as a standard or alternative first-line treatment for advanced or metastatic RCC.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Female; Humans; Indazoles; Male; Pyrimidines; Sulfonamides
PubMed: 28664385
DOI: 10.1007/s11523-017-0511-8 -
Journal of Cardiovascular Pharmacology... Sep 2018Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited... (Review)
Review
Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.
Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cardiovascular Diseases; Cardiovascular System; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Risk Assessment; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome
PubMed: 29706106
DOI: 10.1177/1074248418769612 -
Expert Review of Anticancer Therapy 2015The majority of women with ovarian cancer present with advanced disease, and ultimately relapse following primary surgery and platinum-taxane chemotherapy. Despite... (Review)
Review
The majority of women with ovarian cancer present with advanced disease, and ultimately relapse following primary surgery and platinum-taxane chemotherapy. Despite recent advances in the development of targeted agents in ovarian cancer, survival rates remain poor. The promising activity of bevacizumab, a VEGF receptor inhibitor, has stimulated research on the use of additional anti-angiogenic agents in ovarian cancer. Pazopanib, an oral tyrosine kinase inhibitor, targets VEGF receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β and c-kit; resulting in the inhibition of angiogenesis and tumor proliferation. Early phase studies have demonstrated promising efficacy and tolerability. To date, there has been one Phase III trial of pazopanib in ovarian cancer, demonstrating a progression-free survival benefit in women treated with maintenance pazopanib following primary surgery and systemic therapy. This article summarizes the preclinical and clinical data of pazopanib in ovarian cancer, highlighting future research options for this agent.
Topics: Angiogenesis Inhibitors; Animals; Disease-Free Survival; Female; Humans; Indazoles; Neovascularization, Pathologic; Ovarian Neoplasms; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides
PubMed: 26296187
DOI: 10.1586/14737140.2015.1081383 -
The Lancet. Oncology Feb 2023Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and... (Randomized Controlled Trial)
Randomized Controlled Trial
Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial.
BACKGROUND
Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population.
METHODS
Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete.
FINDINGS
The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group).
INTERPRETATION
To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated.
FUNDING
National Cancer Institute and Novartis.
Topics: Female; Humans; Male; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Paclitaxel; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Chemoradiotherapy
PubMed: 36681089
DOI: 10.1016/S1470-2045(22)00763-X -
Expert Opinion on Pharmacotherapy Dec 2009Pazopanib (Votrient, GW786034) is a potent pan-VEGF inhibitor in advanced clinical development. Like other orally available VEGFR inhibitors, pazopanib is clinically... (Review)
Review
Pazopanib (Votrient, GW786034) is a potent pan-VEGF inhibitor in advanced clinical development. Like other orally available VEGFR inhibitors, pazopanib is clinically efficacious and well tolerated. The recently reported Phase III clinical trial in metastatic renal cell carcinoma showed activity similar to approved agents with variations in toxicity which has led to its recent FDA approval. Given the growing number of agents in this category, differences not only in single-agent activity but also toxicity and combinatorial potency will probably distinguish pazopanib from other similar agents.
Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Indazoles; Kidney Neoplasms; Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Vascular Endothelial Growth Factors
PubMed: 19954277
DOI: 10.1517/14656560903436493 -
Expert Opinion on Investigational Drugs Feb 2012Several clinical trials have shown clinical benefit of angiogenesis inhibitors in the treatment of solid tumors. Pazopanib is a multitargeted tyrosine kinase inhibitor... (Review)
Review
INTRODUCTION
Several clinical trials have shown clinical benefit of angiogenesis inhibitors in the treatment of solid tumors. Pazopanib is a multitargeted tyrosine kinase inhibitor that is currently approved for the treatment of patients with advanced renal cell carcinoma (RCC).
AREAS COVERED
In this article, the clinical development of pazopanib as it relates to breast cancer is reviewed including its evaluation in clinical trials and side effect profile. Preclinical data show the anti-tumor activity of pazopanib in animal models. Several trials of pazopanib monotherapy and combination therapy in breast cancer have been completed or are underway.
EXPERT OPINION
The development of biomarkers predictive of response and toxicity to angiogenesis inhibitors remains a challenging endeavor and is necessary to help guide treatment decision.
Topics: Angiogenesis Inhibitors; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Indazoles; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides
PubMed: 22233389
DOI: 10.1517/13543784.2012.652304