Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma

Hutson, Thomas E.; Davis, Ian D.; Machiels, Jean‐Pascal; Souza, Paul L. de; Rottey, Sylvie; Hong, Bao; Epstein, Richard J.; Baker, Kristy Z.; McCann, Lauren; Crofts, T.; Pandite, Lini; Figlin, Robert A.

doi:10.1200/jco.2008.21.6994

Cited by 268 publications

(192 citation statements)

References 13 publications

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“…Clinical data were obtained from a multicenter, open‐label phase II study (NCT00244764) 16. We had access to a subset of 47 patients, aged 43 to 79 years, with advanced and/or metastatic RCC of predominantly clear‐cell histology and obviousness of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Ouerdani

Struemper

Suttle

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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The objective was to leverage tumor size data from preclinical experiments to propose a model of tumor growth and angiogenesis inhibition for the analysis of pazopanib efficacy in renal cell carcinoma (RCC) patients. We analyzed tumor data in mice with RCC CAKI‐2 cell line treated with pazopanib. Clinical tumor size data obtained in a subset of patients with RCC were also analyzed. A model accounting for the processes of tumor growth, angiogenesis, and drug effect was developed. The final tumor model was composed of two variables: the tumor and its vasculature. Our results show that, both in mice and in humans, pazopanib exhibits a dual mechanism of action, and parameter estimation values highlight the inherent difference between mice and humans on the time scale of tumor size response. We developed a semimechanistic tumor growth inhibition model that takes into account tumor angiogenesis in order to describe the effects of pazopanib in mice. Analyzing rich preclinical data with a semimechanistic model may be a relevant approach to facilitate the description of sparse clinical longitudinal tumor size data and to provide insights for the understanding of the drug mechanisms of action in patients.

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Section: Methodsmentioning

confidence: 99%

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Ouerdani

Struemper

Suttle

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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“…The phase II RCC study (VEG102616, Study 1) had 225 participants (Hutson et al, 2010) and the phase III RCC study (VEG105192, Study 2) had 435 participants (Sternberg et al, 2010). All patients from Study 1 and 290 patients from Study 2 received pazopanib (800 mg daily); the remaining 145 patients in Study 2 were randomised to the placebo arm.…”

Section: Patientsmentioning

confidence: 99%

“…It is currently under clinical development for the treatment of multiple tumour types (Altorki et al, 2008;Friedlander et al, 2008;Sleijfer et al, 2009;Taylor et al, 2009;Sternberg et al, 2010). Clinical meaningful efficacy was observed in pazopanib-treated patients with RCC (Hutson et al, 2010;Sternberg et al, 2010). The safety profile of pazopanib was generally acceptable and tolerable.…”

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confidence: 99%

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Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

Zhang

et al. 2010

Br J Cancer

113

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BACKGROUND: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. METHODS: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. RESULTS: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (Po0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 Â upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (X1.5 Â ULN), 32 (84%) were either TA7 homozygotes (n ¼ 18) or TA7 heterozygotes (n ¼ 14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3 -32.2) compared with other genotypes. CONCLUSIONS: The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

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“…Although pazopanib has been developed and is currently being clinically used as an anti-angiogenesis agent, 8,20 direct antitumor effects of pazopanib have been described in the published literature for several tumor cells, including, multiple myeloma, 10 HER2 þ breast cancer, 11 lung cancer, 12 and chronic lymphocytic leukemia cells. 13 The dose-effectiveness of pazopanib against synovial sarcoma cells in the present study was comparable to the results of these studies which showed an IC 50 value ranging between approximately 2 and 15 mg/ml.…”

Section: Discussionmentioning

confidence: 99%

A novel multi‐kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K‐AKT pathway

Hosaka

Horiuchi

Yoda

et al. 2012

Journal Orthopaedic Research

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Synovial sarcoma is an aggressive soft tissue sarcoma with only a modest response to conventional cytotoxic agents. In the present study, we evaluated the potential antitumor effects of a novel anti-angiogenesis agent, pazopanib, against synovial sarcoma cells. We found that pazopanib directly inhibited the growth of synovial sarcoma cells by inducing G1 arrest. Multiplex analyses revealed that the PI3K-AKT pathway was highly suppressed in pazopanib-sensitive synovial sarcoma cells. Furthermore, administration of pazopanib highly suppressed the tumor growth in a xenograft model. Taken Keywords: synovial sarcoma; pazopanib; PI3K-AKT pathway; molecular targeted therapy Synovial sarcoma accounts for approximately 5-10% of the soft tissue sarcoma in adults, and predominantly affects young adults in their third to fifth decade of life. 1 Typically, it is found as a slow-growing mass in the muscle of a limb or in the body wall. However, it is a clinically aggressive neoplasm, and patients suffering from this tumor have a relatively poor prognosis with a 5-year survival rate of 50-80%. 2,3 Past studies have accumulated a substantial amount of biological information on this neoplasm, including the characteristic chromosomal translocation, t(X;18)(p11.2;q11.2), which gives rise to a chimeric protein, SYT-SSX, 4 and extensive data on the gene expression profiling using cDNA microarrays. 5,6 Despite the progress in understanding the biology of synovial sarcoma, surgical removal still remains as the modality of choice, and other therapeutic approaches, including radiation and chemotherapy, have thus far not been shown to be highly curative. Therefore, there is much room for improvement of systemic therapy, especially given that the majority of patients who expire from synovial sarcoma die from metastatic disease.Pazopanib is a multi-kinase inhibitor which potently inhibits the activity of several receptor tyrosine kinases (RTKs), including vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1), VEGFR2, VEGFR3, platelet-derived growth factor (PDGF) receptor a (PDGFRa), PDGFRb, and c-Kit. 7 Since these RTKs are not only essential for tumor neoangiogenesis, but also for cell proliferation and survival in certain of tumors, treatment with pazopanib potentially has dimorphic effects in suppressing tumor growth in vivo. In accordance with these observations, pazopanib is currently being used in clinical practice to treat advanced renal cell carcinoma, which frequently produces high amounts of VEGF and PDGF from a loss of function of the von Hippel-Lindau tumor suppressor gene. 8 Although the clinical studies of pazopanib has mainly been focused on carcinoma patients, a recent phase II clinical study in which patients with intermediate to high-grade advanced soft tissue sarcoma were treated with pazopanib indicated the potential effectiveness of pazopanib against leiomyosarcoma and synovial sarcoma. 9 Based on this observation, a phase III clinical study is currently underway to further validate the antitumor eff...

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Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma

Abstract: Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of pazopanib in advanced RCC.

Cited by 268 publications

References 13 publications

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

A novel multi‐kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K‐AKT pathway

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