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Journal of Oncology Pharmacy Practice :... Apr 2022Soft tissue sarcoma(STS) is a rare and heterogeneous group of disorders with dismal outcomes in metastatic setting. Pazopanib and oral metronomic chemotherapy (OMT) have...
INTRODUCTION
Soft tissue sarcoma(STS) is a rare and heterogeneous group of disorders with dismal outcomes in metastatic setting. Pazopanib and oral metronomic chemotherapy (OMT) have been evaluated as therapeutic options in this cohort.
MATERIALS AND METHODS
We conducted a retrospective, single center study evaluating 45 patients with unresectable and/or metastatic STS, who received pazopanib or oral metronomic regimen as per instituitonal protocol between January 2013 and December 2019. An informal cost minimisation analysis was conducted for both OMT and pazopanib arms, considering equivalent outcomes for both (PFS and OS).
RESULTS
Median PFS in OMT and Pazopanib groups was 4.13 months and 3.53 months,respectively (HR1.31, 95% CI:0.68-2.51, p = 0.41) Only one patient in the OMT group achieved an objective response (partial response) and no objective response was noted in the pazopanib group. The incidence of grade III/IVtoxicities was higher with pazopanib than with OMT (p = 0.08). There were no toxicity related deaths noted in either arm.
CONCLUSIONS
Our study demonstrates that OMT have a similar progression free survival (PFS) and overall survival (OS) in metastatic STS. This study raises the possibility that OMT might be an equally efficacious and less toxic alternative to pazopanib, without compromising survival outcome especially in LMIC.
Topics: Cost-Benefit Analysis; Humans; Indazoles; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides
PubMed: 33719725
DOI: 10.1177/10781552211000113 -
Molecular Diversity Oct 2022Angiogenesis is an important and interesting scientific subject in the area of malignant tumours. Current research importance and interest are directed in connection to... (Review)
Review
A patent review on efficient strategies for the total synthesis of pazopanib, regorafenib and lenvatinib as novel anti-angiogenesis receptor tyrosine kinase inhibitors for cancer therapy.
Angiogenesis is an important and interesting scientific subject in the area of malignant tumours. Current research importance and interest are directed in connection to blood microvessels in cancer cell proliferation, tumour growth, and metastasis. Tyrosine kinases have been intensely implicated as therapeutic targets that affect the angiogenic process in tumour growth. In the last decades, targeting angiogenesis has led to achievements in the therapy of different carcinomas by different mechanisms, such as the utilization of anti-angiogenic small molecule receptor tyrosine kinase inhibitors. In the current review, we aim to track the advancements in the total synthesis of three receptor tyrosine kinase inhibitors (pazopanib, regorafenib and lenvatinib). This review surveys different synthetic routes for these three approved drugs (pazopanib, regorafenib and lenvatinib) which were previously published as patents (2014-2021). The purity of medicines is a very important factor during manufacturing so we have decided to review the purification process of these anticancer medicines as well. It should be noted that the different patents may have reported some procedures with different yields and purities for the synthesis of desired drug and their intermediates. In order to simplify the understanding of the contents of this review article, only the best results reported in each of these patents are reported for the synthesis of desired drug and their intermediates.
Topics: Humans; Indazoles; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinolines; Sulfonamides; Tyrosine
PubMed: 35235141
DOI: 10.1007/s11030-022-10406-8 -
Clinical Genitourinary Cancer Aug 2017Pazopanib is a standard first-line treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Very few data on its activity in non-clear-cell renal cell carcinoma...
INTRODUCTION
Pazopanib is a standard first-line treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Very few data on its activity in non-clear-cell renal cell carcinoma (nccRCC) are currently available. The aim of this study was to retrospectively analyze efficacy and toxicity of pazopanib in nccRCC patients.
PATIENTS AND METHODS
Records from advanced nccRCC patients (consecutive sample) treated with first-line pazopanib between 2010 and 2015 at 17 Italian centers were reviewed. Response rate, progression-free survival (PFS), and overall survival (OS) were evaluated. Univariate and descriptive analyses were performed.
RESULTS
Thirty-seven patients with nccRCC were treated with first-line pazopanib; 51% had papillary histology, 24% chromophobe, 22% unclassified, and 3% had Xp11.2 translocation. Dose reductions/temporary interruptions for toxicity were required in 46% of cases. Grade (G) 3/4 toxicity was seen in 32%, G1/2 in 89% of cases; 81% achieved disease control, with 10 partial responses (27%) and 20 cases of stable disease (54%); 16% of patients had disease progression as best response. Median PFS and OS were 15.9 and 17.3 months, respectively. In univariate analysis, nephrectomy (P = .020), Memorial Sloan Kettering Cancer Center (MSKCC) score (P < .001), basal neutrophil/lymphocyte ratio (NLR; P = .009) and performance status (PS) (P = .001) were associated with PFS; MSKCC score (P < .001), International Metastatic Renal Cell Carcinoma Database Consortium score (P = .003), PS (P < .0001), nephrectomy (P = .002), histology (P = .035), dose reductions/interruptions (P = .039), best response to treatment (P < .001), and NLR (P = .008) were associated with OS.
CONCLUSION
In nccRCC patients, treatment with pazopanib was effective and feasible; dose reductions required for toxicity were similar as expected in ccRCC.
Topics: Aged; Aged, 80 and over; Disease-Free Survival; Female; Humans; Indazoles; Italy; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Analysis; Treatment Outcome
PubMed: 28108284
DOI: 10.1016/j.clgc.2016.12.024 -
Biological & Pharmaceutical Bulletin May 2020The currently approved dose of pazopanib (800 mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among... (Observational Study)
Observational Study
The currently approved dose of pazopanib (800 mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among starting or maintenance doses of pazopanib, estimated pazopanib C, and other clinical factors, including albumin and α-1 acid glycoprotein levels, in soft-tissue sarcoma and renal cell carcinoma. We also determined whether therapeutic drug monitoring of pazopanib concentrations may be used to improve its therapeutic efficacy and prevent adverse effects. Forty patients who received pazopanib for renal cancer or soft-tissue sarcoma at the Hokkaido Cancer Center were evaluated prospectively. C for pazopanib was calculated based on the measured values from the plasma samples. The efficacy and time to treatment failure were then assessed. The pazopanib maintenance doses were 200 (n = 4), 400 (n = 34), 600 (n = 4), and 800 mg (n = 1). Most patients (65%) who received a 400 mg dose had an effective pazopanib concentration (≧20 µg/mL), whereas 35% of patients who received the 400 mg dose had ineffective concentrations (<20 µg/mL). Logistic regression analysis revealed that only the albumin level was significantly associated with effective pazopanib concentrations (odds ratio: 1.37, p = 0.0234). In conclusion, a dose of 400 mg had been effective and well tolerated in more than half of patients in this study. However, therapeutic drug monitoring is necessary during pazopanib therapy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Asian People; Carcinoma, Renal Cell; Drug Monitoring; Female; Humans; Indazoles; Japan; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult
PubMed: 32115446
DOI: 10.1248/bpb.b19-00560 -
Experimental Animals May 2021Pazopanib is a tyrosine kinase inhibitor that is generally used for the treatment of metastatic renal cell cancer and advanced soft tissue sarcoma. It can cause various...
Pazopanib is a tyrosine kinase inhibitor that is generally used for the treatment of metastatic renal cell cancer and advanced soft tissue sarcoma. It can cause various degrees of hepatotoxicity. Our study aimed to investigate the effect of taxifolin on pazopanib-induced liver toxicity. A total of 18 rats were divided into three groups: the pazopanib (PP), pazopanib plus taxifolin (TPP), and control (C) group. Taxifolin was administered to the TPP (n=6) group with a dose of 50 mg/kg. Distilled water was orally admnistered to the C (n=6) and PP (n=6) groups as a solvent. Subsequently, pazopanib 200 mg/kg was administered to the TPP and PP groups via the stomach. This procedure was repeated once a day for four weeks. Then, all rats were sacrificed, and their livers were removed. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), and total antioxidant status (TAS) levels were evaluated. MDA and TOS levels were higher in the PP group compared with the levels of the other parameters (P<0.001). tGSH and TAS levels were lower in the PP group than in the TPP and C groups (P<0.001), and the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were higher. Furthermore, liver tissue damage, including hemorrhage, hydropic degeneration, and necrosis was observed in the PP group. Administration of taxifolin before pazopanib significantly improved degenerative changes. Our study demonstrated that the administration of taxifolin is significantly effective in preventing pazopanib-induced hepatotoxicity in rats.
Topics: Animals; Chemical and Drug Induced Liver Injury; Indazoles; Liver; Male; Protective Agents; Pyrimidines; Quercetin; Rats; Rats, Wistar; Sulfonamides
PubMed: 33239495
DOI: 10.1538/expanim.20-0103 -
Journal of Oncology Pharmacy Practice :... Apr 2021Pazopanib, a tyrosine kinase inhibitor (TKI), is a standard treatment for various tumours, including metastatic non-adipocytic soft-tissue sarcomas. In literature,... (Review)
Review
INTRODUCTION
Pazopanib, a tyrosine kinase inhibitor (TKI), is a standard treatment for various tumours, including metastatic non-adipocytic soft-tissue sarcomas. In literature, erythrocytosis has been described as a TKI-related condition.
CASE REPORT
A 59-year-old man underwent surgical removal of a sub-scapular mass consistent with myxofibrosarcoma. After distant relapse, he first started chemotherapy, and then Pazopanib. He was found to have increased levels of hemoglobin (Hb) and hematocrit (Hct). He was asymphtomatic, with no history of pulmonary disease nor smoking habit. Erythropoietin (EPO) level was higher than normal. A polycythemia vera was ruled out. The patient started a prophylactic therapy with lysine acetylsalicylate, and we observed a reduction of Hb, but not Hct. Due to disease progression, we interrupted Pazopanib. After a week from drug discontinuation, Hb levels got back to the normal range, Hct was lowering. We decided not to perform phlebotomy, considering the declining trend in Hb and Hct values and the absence of symptoms.
DISCUSSION
We postulated a Pazopanib-related secondary erythrocytosis, since Hb and Hct levels increased from baseline during treatment, then normalized when Pazopanib was discontinued. We used the Naranjo Nomogram to assess the correlation between the adverse effect and Pazopanib, the correlation was "Probable", a score of 5. To the best of our knowledge, this is the first case report of Pazopanib-related secondary polycythemia in a patient with sarcoma. It is important to pay attention to blood count and to any symptoms potentially related to erythrocytosis in patients treated with TKIs.
Topics: Angiogenesis Inhibitors; Fibroma; Fibrosarcoma; Humans; Indazoles; Male; Middle Aged; Polycythemia; Protein Kinase Inhibitors; Pyrimidines; Soft Tissue Neoplasms; Sulfonamides
PubMed: 32838682
DOI: 10.1177/1078155220950440 -
The Lancet. Oncology Oct 2018No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal...
BACKGROUND
No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of pazopanib in patients with von Hippel-Lindau disease.
METHODS
In this non-randomised, single-centre, open-label, phase 2 trial, adult patients with clinical manifestations of von Hippel-Lindau disease were recruited from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an option to continue treatment if desired by the patient and treating physician. Primary endpoints were the proportion of patients who achieved an objective response and safety in the per-protocol population. The objective response was measured for each patient and each lesion type. Radiographic assessments were done at baseline and every 12 weeks throughout the study. Activity and safety were assessed with continuous monitoring and a Bayesian design. This study is registered with ClinicalTrials.gov, number NCT01436227, and is closed to accrual.
FINDINGS
Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with genetically confirmed or clinical features consistent with von Hippel-Lindau disease, of whom 31 eligible patients were treated with pazopanib. The proportion of patients who achieved an objective response was 42% (13 of 31 patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment after 24 weeks. Four (13%) of 31 patients withdrew from the study because of grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because of treatment intolerance with multiple intercurrent grade 1-2 toxicities. Treatment-related serious adverse events included one case each of appendicitis and gastritis and one patient had a fatal CNS bleed.
INTERPRETATION
Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side-effect profile consistent with that seen in previous trials. Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients. The safety and activity of pazopanib in this setting warrants further investigation.
FUNDING
Novartis Inc and NIH National Cancer Institute core grant.
Topics: Adult; Angiogenesis Inhibitors; Female; Humans; Indazoles; Male; Prospective Studies; Pyrimidines; Sulfonamides; Texas; Time Factors; Treatment Outcome; von Hippel-Lindau Disease
PubMed: 30236511
DOI: 10.1016/S1470-2045(18)30487-X -
Pharmacology Research & Perspectives Dec 2019Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in patients over the age of 60 years. Choroidal neovascularization (CNV) is the...
Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in patients over the age of 60 years. Choroidal neovascularization (CNV) is the hallmark of neovascular AMD and vascular endothelial growth factor (VEGF) plays a causal role in the formation of CNV. Although regorafenib and pazopanib, small molecule VEGF receptor (VEGFR) inhibitors, were developed as eye-drops, their efficacies were insufficient in clinical. In this study, we evaluated ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib after ocular instillation in multiple animal species. In rats, both regorafenib and pazopanib showed high enough concentrations in the posterior eye tissues to inhibit VEGFR. In laser-induced rat CNV model, regorafenib showed clear reduction in CNV area. On the other hand, the concentrations of regorafenib and pazopanib in the posterior eye tissues were much lower after ocular instillation in rabbits and monkeys compared to those in rats. Pazopanib did not show any improvement in monkey model. Regorafenib was nano-crystalized to improve its drug delivery to the posterior eye tissues. The nano-crystalized formulation of regorafenib showed higher concentrations in the posterior segments in rabbits compared to its microcrystal suspension. From these studies, large interspecies differences were found in ocular delivery to the posterior segments after ocular instillation. Such large interspecies difference could be the reason for the insufficient efficacies of regorafenib and pazopanib in clinical studies. Nano-crystallization was suggested to be one of the effective ways to overcome this issue.
Topics: Angiogenesis Inhibitors; Animals; Choroidal Neovascularization; Crystallization; Disease Models, Animal; Drug Evaluation, Preclinical; Eye; Female; Humans; Indazoles; Macaca fascicularis; Macular Degeneration; Male; Nanoparticles; Ophthalmic Solutions; Particle Size; Phenylurea Compounds; Pyridines; Pyrimidines; Rabbits; Rats; Receptors, Vascular Endothelial Growth Factor; Species Specificity; Sulfonamides; Vascular Endothelial Growth Factor A
PubMed: 31763044
DOI: 10.1002/prp2.545 -
Chemotherapy 2018Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has...
Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p < 0.050 for all) but none in any other parameter (p > 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow-brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity.
Topics: Administration, Oral; Alkaline Phosphatase; Animals; Bilirubin; Blood Chemical Analysis; Blood Glucose; Chemical and Drug Induced Liver Injury; Fatty Liver; Hemosiderin; Indazoles; Kupffer Cells; Liver; Male; Pyrimidines; Rats; Rats, Wistar; Sulfonamides
PubMed: 29393107
DOI: 10.1159/000481795 -
Breast Cancer Research and Treatment Jan 2015This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant...
Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.
This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Indazoles; Lymph Nodes; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Pyrimidines; Receptor, ErbB-2; Sulfonamides
PubMed: 25542269
DOI: 10.1007/s10549-014-3221-2