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Biomedicine & Pharmacotherapy =... Dec 2017Pazopanib is a relatively new compound to be introduced into the chemotherapy field. It is thought to have decent anti-angiogenic properties, which gives an additional... (Review)
Review
Pazopanib is a relatively new compound to be introduced into the chemotherapy field. It is thought to have decent anti-angiogenic properties, which gives an additional hope for the treatment of certain types of cancers. A systematic review solely discussing about pazopanib and its anti-angiogenic effect is yet to be published to date, despite several relevant clinical trials being conducted over the recent years. In this review, we aim to investigate the mechanism of pazopanib's anti-angiogenic effect and its effectiveness in treating several cancers. We have included, in this study, findings from electronically searchable data from randomized clinical trials, clinical studies, cohort studies and other relevant articles. A total of 352 studies were included in this review. From the studies, the effect of pazopanib in various cancers or models was observed and recorded. Study quality is indefinite, with a few decent quality articles. The most elaborately studied cancers include renal cell carcinoma, solid tumors, advanced solid tumors, soft tissue sarcoma, breast cancer and gynecological cancers. In addition, several less commonly studied cancers are included in the studies as well. Pazopanib had demonstrated its anti-angiogenic effect based on favorable results observed in cancers, which are caused by angiogenesis-related mechanisms, such as renal cell carcinoma, solid tumors, advanced solid tumors and soft tissue sarcoma. This review was conducted to study, analyze and review the anti-angiogenic properties of pazopanib in various cancers. The results obtained can provide a decent reference when considering treatment options for angiogenesis-related malignancies. Furthermore, the definite observations of the anti-angiogenic effects of pazopanib could provide newer insights leading to the future development of drugs of the same mechanism with increased efficiency and reduced adverse effects.
Topics: Angiogenesis Inhibitors; Humans; Indazoles; Neoplasms; Neovascularization, Pathologic; Pyrimidines; Sulfonamides
PubMed: 29054093
DOI: 10.1016/j.biopha.2017.10.058 -
Future Oncology (London, England) Oct 2022This study examined the efficacy/effectiveness of pazopanib and trabectedin in previously treated metastatic synovial sarcoma (mSS). A literature search identified... (Meta-Analysis)
Meta-Analysis Review
This study examined the efficacy/effectiveness of pazopanib and trabectedin in previously treated metastatic synovial sarcoma (mSS). A literature search identified studies (2002-2019) reporting outcomes of pazopanib and trabectedin in previously treated mSS, including median overall survival (mOS) and overall response rate (ORR). A meta-analysis was conducted and sensitivity analyses examined outcomes by agent (pazopanib/trabectedin), study type (clinical trial [CT] or real-world [RW]) and sample size. Sixteen studies were included (pazopanib: n = 7; trabectedin: n = 9). Pooled mOS was 10.4 months and was consistent across agents and in RW and CT (pazopanib: 10.3; trabectedin: 10.4; CT: 10.8; RW: 9.9). ORR results were more variable (pooled ORR: 14.7%). ORR was consistently higher for RW (17.7%) than for CT (9.5%) and for pazopanib (18.9%) compared with trabectedin (12.3%). Poor outcomes across agents and settings highlight a need for novel treatments with improved efficacy. This study serves as a benchmark for efficacy estimates in this rare disease.
Topics: Humans; Trabectedin; Sarcoma, Synovial; Sarcoma; Pyrimidines; Neoplasms, Second Primary; Tetrahydroisoquinolines; Dioxoles
PubMed: 36399116
DOI: 10.2217/fon-2022-0348 -
Journal of Cancer Research and Clinical... Sep 2023Description of patient characteristics, effectiveness and safety in Turkish patients treated with pazopanib for metastatic soft tissue sarcoma (STS).
AIM
Description of patient characteristics, effectiveness and safety in Turkish patients treated with pazopanib for metastatic soft tissue sarcoma (STS).
PATIENTS AND METHODS
This multicenter study is based on retrospective review of hospital medical records of patients (≥ 18 years) treated with pazopanib for non-adipocytic metastatic STS at 37 Oncology clinics across Turkey. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated with further analysis of data on the three most common histological subtypes (leiomyosarcoma [LMS], undifferentiated pleomorphic sarcoma [UPS], synovial sarcoma [SS]) in the cohort.
RESULTS
Data of 552 adults (57.6% women, median age: 52 years) were analyzed. DCR and ORR were 43.1% and 30.8%, respectively. Median PFS was 6.7 months and OS was 13.8 months. For LMS, UPS and SS, median PFSs were 6.1, 5.9 and 7.53 months and median OSs were 15.03, 12.87 and 12.27 months, respectively. ECOG ≥ 2 was associated with poor PFS and OS. Liver metastasis was only a factor for progression. Second-line use of pazopanib (vs. front-line) was associated with better PFS, its use beyond third line predicted worse OS. Adverse events (AE) occurred in 82.7% of patients. Most common AEs were fatigue (58.3%) and anorexia (52.3%) which were graded as ≥ 3 in 8.2% and 7.4% of patients, respectively.
CONCLUSION
Pazopanib is effective and well-tolerated in treatment of non-adipocytic metastatic STS. Its earlier use (at second-line), good performance status may result in better outcomes. Worldwide scientific collaborations are important to gain knowledge on rarer STS subtypes by conducting studies in larger patient populations.
Topics: Adult; Humans; Female; Middle Aged; Male; Retrospective Studies; Turkey; Sarcoma; Leiomyosarcoma; Indazoles; Sarcoma, Synovial; Soft Tissue Neoplasms; Neoplasms, Second Primary
PubMed: 37067546
DOI: 10.1007/s00432-023-04766-3 -
Investigational New Drugs Dec 2021The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies...
The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Hepatocyte Growth Factor; Humans; Indazoles; Maximum Tolerated Dose; Middle Aged; Neoplasms; Proto-Oncogene Proteins c-met; Pyrimidines; Pyrrolidinones; Quinolines; Sulfonamides; Vascular Endothelial Growth Factor A
PubMed: 34180036
DOI: 10.1007/s10637-021-01138-x -
Angiogenesis Feb 2022Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral...
Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treated on a predefined institutional pazopanib treatment pathway (with data collected retrospectively). The primary endpoint was achievement of transfusion independence. Secondary endpoints included hemoglobin, epistaxis severity score, RBC transfusion and iron infusion requirements, number of local hemostatic procedures, ferritin and transferrin saturation, compared using paired and repeated measures mean tests. Thirteen transfusion-dependent HHT patients received pazopanib [median (range) dose 150 (25-300) mg daily)] for a median of 22 months. All patients achieved transfusion independence. Compared with pretreatment, pazopanib increased mean hemoglobin by 4.8 (95% CI, 3.6-5.9) g/dL (7.8 vs. 12.7 g/dL, P < 0.0001) and decreased mean epistaxis severity score by 4.77 (3.11-6.44) points (7.20 vs. 2.43 points, P < 0.0001) after 12 months of treatment. Compared with 3 months of pretreatment, RBC transfusions decreased by 93% (median of 16.0 vs. 0.0 units, P < 0.0001) and elemental iron infusion decreased by 92% (median of 4500 vs. 0 mg, P = 0.005) during the first 3 months of treatment; improvements were maintained over time. Pazopanib was well-tolerated: hypertension, lymphocytopenia, and fatigue were the most common TEAEs. In conclusion, pazopanib was safe and effective to manage severe bleeding in HHT, liberating all patients from transfusion dependence and normalizing hematologic parameters at doses lower than used to treat malignancies. These findings require confirmation in a randomized trial.
Topics: Anemia; Epistaxis; Humans; Indazoles; Pyrimidines; Retrospective Studies; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic
PubMed: 34292451
DOI: 10.1007/s10456-021-09807-4 -
Clinical Cancer Research : An Official... Oct 2017
Topics: Angiogenesis Inhibitors; Humans; Indazoles; Pyrimidines; Sulfonamides
PubMed: 29030334
DOI: 10.1158/1078-0432.CCR-17-1873 -
British Journal of Clinical Pharmacology Feb 2020Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral... (Review)
Review
Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.
Topics: Antineoplastic Agents; Drug Monitoring; Humans; Imatinib Mesylate; Indazoles; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Sunitinib
PubMed: 31782166
DOI: 10.1111/bcp.14185 -
Cancer Treatment and Research... 2021Sarcomas are uncommon malignancies. No advances have been recently achieved despite multiple efforts. Pazopanib is a safe and effective tyrosine kinase inhibitor used in...
INTRODUCTION
Sarcomas are uncommon malignancies. No advances have been recently achieved despite multiple efforts. Pazopanib is a safe and effective tyrosine kinase inhibitor used in managing soft tissue sarcomas (STS) after chemotherapy failure. However, its use is limited in developing countries and no efficacy data exist from our region. We aimed to study the efficacy of pazopanib in our population, characterized by response rates of patients with chemotherapy-refractory advanced STS receiving pazopanib. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity profile.
MATERIALS AND METHODS
15 patients (age≥18 year) diagnosed with advanced STS, refractory to first-line chemotherapy, receiving pazopanib as ≥second-line therapy in one tertiary center in Lebanon were included between January 1st, 2014 and October 31st, 2018. Patient and disease characteristics, disease evaluation, as well as tolerance to treatment, were extracted from charts retrospectively. Statistical analysis was done using SPSS version 24.
RESULTS
The mean age was 48.6 [19-66] years. Eleven patients (73.3%) received pazopanib in second-line, whereas four patients (26.7%) received it in third-line. Thirteen patients (86.7%) progressed, and two patients (13.3%) had stable disease. The median PFS was three months [1-19] and the mean OS was 25.4 months [17.2-33.6]. Five patients required dose-reductions due to poor tolerance.
CONCLUSION
Conclusions cannot be drawn due to small patient numbers. However, given the 3-month PFS, 13% of patients maintaining stable disease, and tolerable safety profile, it is reasonable to incorporate pazopanib in STS treatment. More focused studies with larger patient populations need to be done in Lebanon.
Topics: Adult; Aged; Appetite; Fatigue; Female; Humans; Indazoles; Lebanon; Male; Middle Aged; Neoplasm Staging; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Tertiary Care Centers; Young Adult
PubMed: 33340905
DOI: 10.1016/j.ctarc.2020.100275 -
Pharmacogenetics and Genomics Aug 2017
Review
Topics: Antineoplastic Agents; Clinical Trials as Topic; Gene Regulatory Networks; Humans; Indazoles; Neoplasms; Pharmacogenomic Variants; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 28678138
DOI: 10.1097/FPC.0000000000000292 -
Expert Opinion on Drug Metabolism &... Dec 2016In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of... (Review)
Review
In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of compounds that suppressed vascular endothelial growth factor receptor-2 (VEGFR-2). As other tyrosine kinase inhibitors (TKI), pazopanib is not totally specific for one target since it also inhibits stem-cell factor receptor (cKIT), platelet-derived growth factor receptors (PDGFRα, β), VEGFR-1 and -3. Areas covered: Clinical pharmacology, drug-drug interactions and safety data published on pazopanib, between January 2006 and April 2016, are reviewed. Expert opinion: This new therapy has been shown to improve progression-free survival compared with previous approaches, in renal cell cancer and soft-tissue sarcoma. However, some specific sub-populations, such as elderly patients, patients with brain metastases or with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 or comorbidities, are poorly represented in pivotal pazopanib phase III studies. Pazopanib meets criteria defining therapies as candidates for therapeutic drug monitoring: large intra- and inter-patient pharmacokinetic variability, potential pharmacokinetic drug-drug interactions, pharmacokinetic/pharmacodynamic relationship and narrow therapeutic index. Knowledge of predictors that can be used to guide dosing regimens in the target population and in special populations needs to be improved.
Topics: Aged; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Interactions; Drug Monitoring; Humans; Indazoles; Kidney Neoplasms; Neoplasm Metastasis; Pyrimidines; Sarcoma; Sulfonamides
PubMed: 27556889
DOI: 10.1080/17425255.2016.1225038