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JAMA Oncology Sep 2018
Topics: Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Pyrimidines; Sulfonamides
PubMed: 29978183
DOI: 10.1001/jamaoncol.2018.1712 -
JAMA Oncology Sep 2018
Topics: Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Pyrimidines; Sulfonamides
PubMed: 29978181
DOI: 10.1001/jamaoncol.2018.1695 -
Journal of Oncology Pharmacy Practice :... Apr 2021Soft tissue sarcomas are associated with a poor prognosis and low chemotherapeutic efficiency. Pazopanib is an orally available multi-tyrosine kinase inhibitor that was...
PURPOSE
Soft tissue sarcomas are associated with a poor prognosis and low chemotherapeutic efficiency. Pazopanib is an orally available multi-tyrosine kinase inhibitor that was explored in patients with non-adipocytic advanced soft tissue sarcomas. The aim of this retrospective study was to evaluate the real life data of single-agent pazopanib efficacy and safety for soft tissue sarcomas in the Turkish population.
MATERIALS AND METHODS
We evaluated a total of 103 patients (41 males, 62 females) who received pazopanib for advanced non-adipocytic soft tissue sarcomas diagnosis in eight centers of Turkey, retrospectively. The pazopanib dose was 800 mg once daily. Progression-free survival, overall survival, and adverse events were analyzed.
RESULTS
The median age was 50 years (range, 38-58). Majority of the patients had leimyosarcoma (41%). Median progression-free survival was 4.3 months, and the median overall survival was 10.1 months. The main common toxicities were fatigue, anorexia, weight loss, nausea, hypertension, and grade ≥3 toxicities were fatigue, anorexia, weight loss, and liver disorder.
CONCLUSION
Pazopanib is an efficient and tolerable agent and is well tolerated in good performance status patients with relapsed, advanced non-adipocytic soft tissue sarcomas.
Topics: Adult; Female; Humans; Indazoles; Leiomyosarcoma; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Analysis
PubMed: 32419618
DOI: 10.1177/1078155220924075 -
Gynecologic Oncology Mar 2020Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin.
METHODS
Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use.
RESULTS
Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06).
CONCLUSIONS
It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cardiotoxicity; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Ovarian Neoplasms; Progression-Free Survival; Pyrimidines; Stilbenes; Sulfonamides; Survival Rate
PubMed: 31932108
DOI: 10.1016/j.ygyno.2020.01.005 -
Cancer Chemotherapy and Pharmacology Feb 2016A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in...
PURPOSE
A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in combination. Pharmacokinetic interactions were evaluated.
METHODS
Plasma pazopanib and ultrafilterable cisplatin concentrations were obtained in 32 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib and 60 or 75 mg/m(2) of cisplatin. Two sequences of treatment were performed in order to explore any interaction of cisplatin on pazopanib pharmacokinetics and inversely. Data were analyzed using the NONMEM program.
RESULTS
Maximum tolerated dose was 400 mg of pazopanib and 75 mg/m(2) of cisplatin. Mean (CV % for inter-individual variability) cisplatin clearance was 10.3 L/h (33.2 %) and appeared not to be influenced by pazopanib. However, pazopanib pharmacokinetics was significantly modified by the cisplatin regimen. Mean (CV %) of oral pazopanib clearance was 0.66 L/h (55 %) at Day 0 (before cisplatin administration), 24.8 % lower at Day 1 and 32.9 % lower at Day 2. The interaction is less likely to be due to cisplatin than to a competitive inhibition of pazopanib metabolism and efflux by aprepitant, an antiemetic drug systematically administered with cisplatin. The plasma pazopanib exposures observed at Day 0 with a 400 mg dose were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800 mg) during the first-in-man phase 1 study.
CONCLUSION
The observed pazopanib plasma overexposure probably contributed to the poor tolerance encountered during this phase 1 study.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Female; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Treatment Outcome
PubMed: 26779916
DOI: 10.1007/s00280-015-2953-y -
Thyroid : Official Journal of the... Oct 2021The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic...
The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib ( = 33), lenvatinib ( = 53), and pazopanib ( = 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Disease Progression; Disease-Free Survival; Female; Humans; Indazoles; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Quinolines; Radiopharmaceuticals; Retrospective Studies; Safety; Salvage Therapy; Sorafenib; Sulfonamides; Thyroid Neoplasms; Treatment Outcome; Young Adult
PubMed: 34405734
DOI: 10.1089/thy.2021.0091 -
BMC Urology Jul 2016The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include pazopanib as a second-line treatment option. It would therefore be of interest to determine the efficiency of pazopanib in this setting in terms of the partial response rate (PRR), disease control rate (DCR), and progression-free survival (PFS).
METHODS
Peer-reviewed clinical reports without language restriction, both full papers and conference abstracts, which assessed the second-line use of pazopanib following failure of first-line non-cytokine-targeted therapy, were included. After the literature retrieval, we conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-compliant systematic review of the literature and meta-analysis of the size of the effect of each outcome measure (PRR, DCR, and PFS). The effect size and 95 % confidence interval (CI) were calculated using fixed-effect or random-effects models based on the heterogeneity represented by I(2) of selected studies. Meta-analysis forest plots with a fixed-effect model showing the PRR and DCR were created.
RESULTS
Our results show that there are no available comparative studies on pazopanib second-line treatment. Only phase II trials or retrospective analysis reports were retrievable. Six studies (comprising 217 patients) were included in the qualitative and quantitative analysis. Pazopanib as a second-line treatment resulted in a PRR of 23 % (95 % CI, 17-31 %; I(2) = 52.6 %) and a DCR of 73 % (95 % CI, 65-80 %; I(2) = 0.00 %). The meta-analysis with fixed-effect model revealed that PFS was 6.5 months (95 % CI, 5.6-7.5 months; I(2) = 86.2 %).
CONCLUSIONS
In conclusion, the effectiveness and indication of pazopanib for use in the second-line setting has not yet been examined in-depth; however, this meta-analysis has shown that the treatment effects in terms of PRR, DCR, and PFS may be similar to other well-studied second-line targeted therapies. Rigorous comparative phase III trials testing this hypothesis are required.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 27377922
DOI: 10.1186/s12894-016-0156-4 -
International Journal of Cancer Aug 2014Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the... (Meta-Analysis)
Meta-Analysis Review
Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) in patients with cancer treated with these agents. PubMed databases were searched for articles published till May 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 6,447 patients were available for the meta-analysis; 2,260 had renal cell carcinoma (RCC) and 4,187, 1,691 non-small cell lung cancers, 599 hepatocellular cancers, 1,066 breast cancers, 165 neuroendocrine tumors, 304 gastrointestinal stromal tumors and 362 soft tissue sarcomas. Diarrhea was the most common GI event. When stratified by tumor type (RCC vs. non-RCC), the difference among the incidences of GI events was significant for diarrhea (p < 0.001) and vomiting (p = 0.006), that resulted higher in RCC patients. In RCC patients, sorafenib registered the lower incidence and RR of all grades GI events. The difference was statistically significant for sorafenib versus sunitinib-related all and high-grade events (p < 0.001) and for sorafenib versus pazopanib all grades GI events (p < 0.001) and high-grade anorexia (p < 0.001). Treatment with VEGFR TKIs sorafenib, sunitinib and pazopanib is associated with a significant increase in the risk of GI events in patients with cancer, and frequent clinical monitoring should be emphasized when managing these three and newer VEGFR TKIs.
Topics: Adverse Drug Reaction Reporting Systems; Carcinoma, Renal Cell; Clinical Trials as Topic; Diarrhea; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Incidence; Indazoles; Indoles; Liver Neoplasms; Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vomiting
PubMed: 24127298
DOI: 10.1002/ijc.28544 -
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 -
Investigational New Drugs Feb 2022Herein, a novel series of dual histone deacetylase (HDAC) and vascular endothelial growth factor receptor (VEGFR) inhibitors were designed, synthesized and biologically...
Herein, a novel series of dual histone deacetylase (HDAC) and vascular endothelial growth factor receptor (VEGFR) inhibitors were designed, synthesized and biologically evaluated based on previously reported pazopanib-based HDAC and VEGFR dual inhibitors. Most target compounds showed significant HDAC1, HDAC6 and VEGFR2 inhibition, which contributed to their potent antiproliferative activities against multiple cancer cell lines and significant antiangiogenic potencies in both human umbilical vein endothelial cell (HUVEC) tube formation assays and rat thoracic aorta ring assays. Further HDAC selectivity evaluations indicated that hydroxamic acids 5 and 9e possessed HDAC isoform selectivity profiles similar to that of the approved HDAC inhibitor suberoylanilide hydroxamic acid(SAHA), while hydrazide12 presented an HDAC isoform selectivity profilesimilar to that of the clinical HDAC inhibitor MS-275. The VEGFR inhibition profiles of 5, 9e and 12 were similar to that of the approved VEGFR inhibitor pazopanib. The intracellular target engagements of Compounds 5 and 12 were confirmed by western blot analysis. The metabolic stabilities of 5, 9e and 12 in mouse liver microsomes were inferior to that of pazopanib. These dual HDAC and VEGFR inhibitors provide lead compounds for further structural optimization to obtainpolypharmacological anticancer agents.
Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Drug Design; Histone Deacetylase Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Hydroxamic Acids; Indazoles; Mice; Microsomes, Liver; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Vascular Endothelial Growth Factors; Vorinostat
PubMed: 34463890
DOI: 10.1007/s10637-021-01169-4