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Clinical Genitourinary Cancer Oct 2022Patients with advanced renal cell carcinoma and poor performance status (PS≥2) are often deemed unsuitable for treatment. The Pazo2 trial aimed to assess tolerability...
A Study of Pazopanib Safety and Efficacy in Patients With Advanced Clear Cell Renal Cell Carcinoma and ECOG Performance Status 2 (Pazo2): An Open label, Multicentre, Single Arm, Phase II Trial.
AIM
Patients with advanced renal cell carcinoma and poor performance status (PS≥2) are often deemed unsuitable for treatment. The Pazo2 trial aimed to assess tolerability and efficacy of pazopanib as first-line treatment in renal cancer patients with ECOG PS2.
METHODS
Pazo2 was a prospective, single arm, open label, multicentre, phase II trial, conducted in 26 UK centres. Eligible patients were aged ≥18 years, with advanced or metastatic renal cancer and a clear cell component (aRCC), measurable disease as per RECIST Criteria 1.1, and ECOG PS2. Co-primary outcomes, assessed at 6-months after patients entered the trial, were tolerability, defined as the proportion of patients who did not develop "intolerable" adverse events, and efficacy, defined as the proportion of all patients who were progression-free and alive.
RESULTS
Between February 21, 2013 and August 12, 2016, 75 patients were registered. Median age was 68.6 years (IQR 64.6-76.0), 100% ECOG PS2, 62.7% 'poor risk' (International Metastatic Renal-Cell Carcinoma Database Consortium). Of the 65 evaluable patients, 70.8% (95% CI: 58.8, 80.4) did not develop "intolerable" adverse events and 56.9% (95% CI: 44.8, 68.2) were still alive and progression-free 6 months after starting pazopanib. Twenty-seven patients developed serious adverse events deemed to be related to pazopanib.
CONCLUSION
These data suggests that pazopanib is tolerated and effective in aRCC patients with PS2 and represents a treatment option for patients who cannot receive or tolerate immune checkpoint inhibitors.
Topics: Adolescent; Adult; Aged; Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Indazoles; Kidney Neoplasms; Prospective Studies; Pyrimidines; Sulfonamides
PubMed: 35803859
DOI: 10.1016/j.clgc.2022.06.012 -
Science Translational Medicine Apr 2021Acute lung injury (ALI) causes high mortality and lacks any pharmacological intervention. Here, we found that pazopanib ameliorated ALI manifestations and reduced...
Acute lung injury (ALI) causes high mortality and lacks any pharmacological intervention. Here, we found that pazopanib ameliorated ALI manifestations and reduced mortality in mouse ALI models and reduced edema in human lung transplantation recipients. Pazopanib inhibits mitogen-activated protein kinase kinase kinase 2 (MAP3K2)- and MAP3K3-mediated phosphorylation of NADPH oxidase 2 subunit p47 at Ser to increase reactive oxygen species (ROS) formation in myeloid cells. Genetic inactivation of MAP3K2 and MAP3K3 in myeloid cells or hematopoietic mutation of p47 Ser to alanine attenuated ALI manifestations and abrogates anti-ALI effects of pazopanib. This myeloid MAP3K2/MAP3K3-p47 pathway acted via paracrine HO to enhance pulmonary vasculature integrity and promote lung epithelial cell survival and proliferation, leading to increased pulmonary barrier function and resistance to ALI. Thus, pazopanib has the potential to be effective for treating ALI.
Topics: Acute Lung Injury; Animals; Humans; Hydrogen Peroxide; Indazoles; MAP Kinase Kinase Kinase 2; MAP Kinase Kinase Kinase 3; Mice; NADPH Oxidases; Phosphorylation; Pyrimidines; Reactive Oxygen Species; Sulfonamides
PubMed: 33910977
DOI: 10.1126/scitranslmed.abc2499 -
International Journal of Molecular... Jan 2023Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation...
Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib ( < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells ( < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.
Topics: Humans; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Vascular Endothelial Growth Factor A; Antineoplastic Agents
PubMed: 36768721
DOI: 10.3390/ijms24032398 -
Cancers Nov 2021There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is...
There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149-200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib ( = 0.41, = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells ( > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.
PubMed: 34830931
DOI: 10.3390/cancers13225780 -
International Journal of Molecular... Oct 2018Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in... (Review)
Review
Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented.
Topics: Anilides; Carcinoma, Neuroendocrine; Cardiotoxicity; Humans; Hypertension; Indazoles; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Sulfonamides; Thyroid Neoplasms
PubMed: 30347815
DOI: 10.3390/ijms19103258 -
PharmacoEconomics Mar 2019The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011. (Review)
Review
BACKGROUND
The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011.
OBJECTIVE
The objective of this study was to perform an updated review by synthesizing economic studies related to the treatment of RCC that have been published since the previous review.
METHODS
We performed a literature search in PubMed, EMBASE, and the Cochrane Library, covering English-language studies published between June 2010 and August 2018. We categorized these articles by type of analyses [cost-effectiveness analysis (CEA), cost analysis, and cost of illness (COI)] and treatment setting (cancer status and treatment), discussed findings from these articles, and synthesized information from each article in summary tables.
RESULTS
We identified 52 studies from 2317 abstracts/titles deemed relevant from the initial search, including 21 CEA, 23 cost analysis, and 8 COI studies. For localized RCC, costs were found to be positively associated with the aggressiveness of the local treatment. For metastatic RCC (mRCC), pazopanib was reported to be cost effective in the first-line setting. We also found that the economic burden of RCC has increased over time.
CONCLUSION
RCC continues to impose a substantial economic burden to the healthcare system. Despite the large number of treatment alternatives now available for advanced RCC, the cost effectiveness and budgetary impact of many new agents remain unknown and warrant greater attention in future research.
Topics: Carcinoma, Renal Cell; Cost of Illness; Cost-Benefit Analysis; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Time Factors
PubMed: 30467701
DOI: 10.1007/s40273-018-0746-y -
Frontiers in Endocrinology 2023In recent years, the potential toxicities of different pharmaceuticals toward the thyroid system have received increasing attention. In this study, we aim to evaluate...
INTRODUCTION
In recent years, the potential toxicities of different pharmaceuticals toward the thyroid system have received increasing attention. In this study, we aim to evaluate the toxic effects of pazopanib and axitinib, two anti-tumor drugs with widespread clinical use, on thyroid function in the zebrafish model.
METHODS
We measured levels of thyroid-related hormones using the commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit. Whole-mount in situ hybridization (WISH) analysis was employed to detect target gene expression changes. Morphology of the thyroid were evaluated by using transgenic Tg (: EGFP) fish line under a confocal microscope. The relative mRNA expression of key genes was verified through quantitative real-time polymerase chain reaction (RT‒qPCR). The size and number of the follicles was quantified whereby Hematoxylin-Eosin (H & E) staining under a light microscope.
RESULTS
The results revealed that fertilized zebrafish embryos were incubated in pazopanib or axitinib for 96 hours, development and survival were significantly affected, which was accompanied by significant disturbances in thyroid endocrine system (e.g., increased thyroid-stimulating hormone (TSH) content and decreased triiodothyronine (T3) and thyroxine (T4) content, as well as transcription changes of genes associated with the hypothalamus-pituitary-thyroid (HPT) axis. Moreover, based on whole-mount in situ hybridization staining of tg and histopathological examination of zebrafish embryos treated with pazopanib and axitinib, we observed a significantly abnormal development of thyroid follicles in the Tg (: EGFP) zebrafish transgenic line.
CONCLUSION
Collectively, these findings indicate that pazopanib and axitinib may have toxic effects on thyroid development and function, at least partially, by influencing the regulation of the HPT axis. Thus, we believe that the potential thyroid toxicities of pazopanib and axitinib in their clinical applications should receive greater attention.
Topics: Animals; Axitinib; Zebrafish; Thyroid Gland; Larva; Antineoplastic Agents; Animals, Genetically Modified
PubMed: 37600710
DOI: 10.3389/fendo.2023.1204678 -
Pharmaceuticals (Basel, Switzerland) Sep 2021Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of...
Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L. However, routine monitoring of trough plasma concentrations at fixed hours is difficult in daily practice. Herein, we aimed to characterize the pharmacokinetic (PK) profile of pazopanib and to identify a target area under the curve (AUC) more easily extrapolated from blood samples obtained at various timings after drug intake. A population pharmacokinetic (popPK) model was constructed to analyze pazopanib PK and to estimate the pazopanib clearance of a patient regardless of the time of sampling. Data from the therapeutic drug monitoring (TDM) of patients with cancer at Institute Gustave Roussy and a clinical study (phase I/II) that evaluates the tolerance to pazopanib were used. From the individual clearance, it is then possible to obtain the patient's AUC. A target AUC for maximum efficacy and minimum side effects of 750 mg·h·L was determined. The comparison of the estimated AUC with the target AUC would enable us to determine whether plasma exposure is adequate or whether it would be necessary to propose therapeutic adjustments.
PubMed: 34577627
DOI: 10.3390/ph14090927 -
Frontiers in Oncology 2019The purpose of this study was to examine pazopanib/topotecan combination activity vs. pazopanib monotherapy on anaplastic thyroid cancer (ATC) cells. Proliferation...
The purpose of this study was to examine pazopanib/topotecan combination activity vs. pazopanib monotherapy on anaplastic thyroid cancer (ATC) cells. Proliferation analyses were performed on ATC cell lines administered for 72 h with pazopanib and topotecan alone and to their simultaneous combination. Pazopanib and topotecan produced a strong synergism on ATC cells, calculated by the combination index, increasing the intracellular concentrations of topotecan lactone measured by high-performance liquid chromatography. Furthermore, a significantly decrease of the gene expression of α α, and was presented in combination-treated ATC cells by real time PCR tests. In summary, the simultaneous association of pazopanib and topotecan established a highly synergistic ATC antiproliferative effect, suggesting a new possibility to translate this schedule into clinical trials.
PubMed: 31799182
DOI: 10.3389/fonc.2019.01202 -
Scientific Reports Feb 2023The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough...
The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.
Topics: Humans; Carcinoma, Renal Cell; East Asian People; Sarcoma; Indazoles; Soft Tissue Neoplasms; Kidney Neoplasms; Angiogenesis Inhibitors
PubMed: 36746987
DOI: 10.1038/s41598-023-28688-9