pazopanib and Sarcoma

Pazopanib, an oral multi-targeted tyrosine kinase inhibitor, is associated with improved outcomes in patients with unresectable or metastatic soft tissue sarcoma. Pazopanib may cause cardiotoxicity such as heart failure.. A 50-year-old female patient with no cardiovascular risk factors other than the previous treatment with adriamycin had a baseline left ventricular ejection fraction of 60%. She was receiving pazopanib 800 mg once daily for advanced leiomyosarcoma of the presacral area. On the 60th day of treatment, she presented with fatigue, palpitation, and exertional dyspnea for several days. Echocardiography was performed, and left ventricular ejection fraction was measured as 25%. Pazopanib-induced heart failure was considered and all other possible preliminary diagnoses were excluded.. Pazopanib was stopped immediately. Bisoprolol fumarate 5 mg orally once daily, spironolactone 100 mg orally once daily, furosemide 40 mg orally once daily, and ramipril 2.5 mg orally once daily were started. The patient's symptoms partially improved. Second echocardiography was performed after 15 days, and left ventricular ejection fraction was measured as 35%. But, despite pazopanib was not resumed and cardiac support treatment was administered, she died four weeks after discontinuation of pazopanib due to heart failure.. Pazopanib-induced heart failure may be fatal. Physicians and patients should be aware of the cardiotoxicity risk when managing the use of pazopanib in soft tissue sarcoma.

Topics: Doxorubicin; Dyspnea; Female; Heart Failure; Humans; Indazoles; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Stroke Volume; Sulfonamides; Ventricular Function, Left

Topics: Drug Resistance, Neoplasm; Humans; Indazoles; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sarcoma; Sulfonamides

Due to the rarity and heterogeneity of bone and soft-tissue sarcomas, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and establishment of surgical procedures have improved the outcomes of patients with sarcoma, the curative rate of recurrent and metastatic sarcomas is still not satisfactory. Recent basic science research has revealed some of the mechanisms of progression and metastasis of malignancies including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and regulation of antitumor immune systems. Based on these basic studies, new anticancer drugs, including pazopanib, trabectedin, eribulin, and immune checkpoint inhibitors have been developed and the efficacies and safety of the new drugs have been assessed by clinical trials. This review summarizes new molecular therapeutic targets and advances in the treatment for bone and soft tissue sarcomas.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Neoplasms; Drug Therapy; Furans; Humans; Immunotherapy, Adoptive; Indazoles; Ipilimumab; Ketones; Nivolumab; Osteosarcoma; Progression-Free Survival; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sorafenib; Sulfonamides; Trabectedin

Overall survival is the true endpoint for most randomized controlled trials (RCTs) of malignant tumors, whereas progression-free survival (PFS) is considered the most reliable surrogate endpoint for overall survival (OS). The present study aimed to evaluate the correlation between surrogate endpoints and OS in randomized trials of first-line chemotherapy with doxorubicin (DOX), the standard treatment for advanced and metastatic soft tissue sarcomas (ASTS), using a meta-analytic approach.. In a systematic review, we identified RCTs of first-line chemotherapy for ASTS that compared single-agent doxorubicin (DOX) with other chemotherapy regimens, and were published in English during January 1974-December 2017. A meta-analysis was performed to evaluate the efficacy of first-line treatments for ASTS. Surrogacy of the intermediate endpoints for OS was investigated using weighted linear regression analysis. Correlation strength was examined using the coefficient of determination (R. Twenty-seven randomized trials, comprising 6156 patients (3371 patients in the experimental arm and 2785 patients in the DOX arm) were identified. The hazard ratios for OS and PFS showed that the efficacy of treatment for ASTS was not significantly different between standard DOX and experimental treatments. The median OS was significantly prolonged in RCTs published after 2012 when pazopanib was approved for treating ASTS. The median PFS, however, did not differ significantly. The correlation between PFS and OS was moderate (R. The trial-level correlation between PFS and OS was only modest; it tended to be better in RCTs published after 2012. While the effective lines of chemotherapy and the introduction of new drugs prolonged OS but not PFS, PFS is a better surrogate than other intermediate endpoints in the first-line ASTS trials even in the post-pazopanib era. Although this does not negate the need for more reliable surrogate endpoints for OS.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Biomarkers; Doxorubicin; Female; Humans; Indazoles; Male; Neoplasm Metastasis; Neoplasm Staging; Odds Ratio; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides; Treatment Outcome

Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by acute neurological symptoms such as severe headache, seizures, and visual disturbance, and by typical reversible lesion on brain magnetic resonance (MR) images. Since PRES is thought to be caused by vascular endothelial injury due to cytotoxic agents or acute systemic hypertension, the number of reports on PRES associated with angiogenesis inhibitors has been increasing. Although five cases that developed PRES due to pazopanib for renal cell carcinoma have already been reported, none of PRES due to pazopanib for soft-tissue sarcoma has been reported thus far. We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800 mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection was immediately started to control her blood pressure and pazopanib was discontinued. Her symptoms gradually improved and disappeared on the fifth hospital day. After 2 weeks, hyper-intense signals on a FLAIR sequence disappeared completely. She restarted a low dose of pazopanib under good blood pressure control and experienced no subsequent recurrence of PRES.

Topics: Brain; Fatal Outcome; Female; Humans; Indazoles; Magnetic Resonance Imaging; Middle Aged; Posterior Leukoencephalopathy Syndrome; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Sulfonamides

In the last decade the limited treatment options for patients with metastatic soft tissue sarcoma have expanded considerably. With the addition of olaratumab to first-line treatment with doxorubicin, the introduction of several new agents in second-line treatment and beyond and other promising agents in the pipeline, perspectives of patients with metastatic soft tissue sarcoma are improving. Due to increasing insight into the biology of the different soft tissue sarcoma subtypes, choice of treatment has become much more histology-driven, although more prognostic and predictive factors are needed to further personalise therapy. This report summarises the current state of the art and discusses the promising developments in the treatment of patients with metastatic soft tissue sarcoma.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Dioxoles; Doxorubicin; Drug Therapy; Forecasting; Humans; Indazoles; Neoplasm Metastasis; Pyrimidines; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin

Soft tissue sarcomas (STS) are a heterogeneous group of over 100 histologically and genetically distinct mesenchymal tumors. Standard of care for metastatic STS has historically relied on anthracycline-based chemotherapy regimens. Although effective for some patients, conventional chemotherapeutic agents used in STS are associated with substantial toxicity and also are not equally effective in all histologic subtypes of sarcoma. Pazopanib is an orally active antiangiogenic drug that is approved for non-adipogenic sarcomas after failure of at least one line of previous chemotherapy, and has a relatively favorable toxicity profile. Earlier use of pazopanib may be a better choice for patients with subtypes of sarcoma that do not respond well to conventional chemotherapy or those who are unlikely to tolerate chemotherapy. Here we review the evidence for the activity and toxicity profile of pazopanib and consider potential histologic, clinical, and genetic predictive factors that can help to guide treatment choices. Further prospective studies validating these observations may lead to refinement of a precision medicine approach to match ideal sarcoma patients to earlier treatment with pazopanib over traditional chemotherapy.

Topics: Humans; Indazoles; Precision Medicine; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cardiovascular Diseases; Cardiovascular System; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Risk Assessment; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome

Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs-pazopanib, trabectedin, and eribulin-have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs.. Eisai Co., Ltd.

Topics: Antineoplastic Agents, Alkylating; Dioxoles; Furans; Humans; Indazoles; Japan; Ketones; Pyrimidines; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin

Immune checkpoint inhibitors have shown promising results in several cancers and are now put to the test in sarcomas. This brief summary presents data regarding the previously approved and newer agents for more common sarcomas and focuses on specific sarcoma histologic subtypes or novel approaches for which there is particular optimism. Approaches involving epigenetic agents, metabolic therapy, and modulators of the tumor microenvironment represent other ways the field of sarcoma medical oncology will progress in 2016 and beyond.. A recent series of successful randomized trials provides new systemic therapy options for patients with metastatic soft-tissue sarcomas in the United States, after a gap of more than 10 years in which no new drugs were approved. The agents with most recent approval include pazopanib, trabectedin, and eribulin. As a sign that progress is not linear, 2 cousins of ifosfamide failed to show benefit in phase 3 trials, despite prior positive results of randomized phase 2 trials.. The biological features of each sarcoma subtype are associated with specific sensitivity patterns to chemotherapy, and despite their rarity, future trials will need to emphasize specific histologic subtypes (many with well-defined genetic alterations) to best fit diagnosis to therapy.

Topics: Adult; Antineoplastic Agents; Dioxoles; Furans; Humans; Indazoles; Ketones; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Tumor Microenvironment

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

Both the soft tissue sarcomas and the neuroendocrine tumors are rare diseases. Therefore the recruiting of these patients was more difficult than other cancer species, and the development of the new therapy for these diseases did not readily advance. However, the identification of driver molecules for each sub-type enabled us to the development of the molecular targeted drugs. As for the GIST, several TKIs are used, but in late years it is found that susceptibility of TKIs varies according to difference in second mutation. In this chapter, the molecular target drug for the soft tissue sarcoma and the neuroendocrine tumor is reviewed.

Topics: Antibodies, Monoclonal, Humanized; Benzamides; Denosumab; Drug Discovery; Everolimus; Gastrointestinal Neoplasms; Humans; Imatinib Mesylate; Indazoles; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Niacinamide; Phenylurea Compounds; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Sarcoma; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Soft tissue sarcomas (STS) are a rare and difficult to treat malignancy. Efforts to utilize targeted therapy have been ongoing for the last decade and have resulted in the approval of pazopanib for treatment of advanced disease. Although several other agents have been investigated, the inability to predict responses remains a limiting factor to the incorporation of these agents into treatment.. The authors summarize recent clinical findings from studies focused on targeted agents in STS. The authors also discuss the potential approaches and ongoing clinical trials with novel agents.. A major challenge in the treatment of advanced STS remains a lack of predictive biomarkers to guide therapy and the heterogeneity of response among different histologies of sarcoma. Incorporation of predictive biomarker analysis into clinical trials is warranted. Additionally, mechanisms of treatment resistance and parallel pathways of tumor growth pose challenges in how we treat these tumors. An active area of research in STS is the use of novel combinations of agents, such as chemotherapy combined with multi-targeted agents. The potential of immune check point inhibitors is being explored in advanced STS and is hoped to further expand our treatment armamentarium.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Biomarkers, Tumor; Drug Design; Humans; Indazoles; Molecular Targeted Therapy; Pyrimidines; Sarcoma; Sulfonamides

Soft tissue sarcomas (STS) are rare tumors with mesenchymal origin, accounting for 1% of all human cancer. Local control of STS can be obtained through the use of surgery and radiotherapy. In about 40% of these patients, disease will recur at distant sites, and of these more than 90% will die because of this aggressive malignancy. In advanced and/or metastatic STS patients treated with anthracycline-based regimen the median overall survival is about 12 months, and it has remained unchanged during the last 20 years. Clearly, this strongly suggests the need for discover more active compounds in STS, such as imatinib in GIST or dermatofibrosarcoma patients. In this paper we describe the crucial role of angiogenesis mechanisms in sarcomas development and progression. Consequentially, we focus on pazopanib, a novel multitargeted tyrosine kinase inhibitor with anti-angiogenic activity, mainly due to VEGFR2 pathway interference. We also analyze principal completed trials leading pazopanib approval in sarcomas pretreated patients.

Topics: Angiogenesis Inhibitors; Animals; Humans; Indazoles; Molecular Targeted Therapy; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Signal Transduction; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bevacizumab; Everolimus; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sarcoma, Synovial; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases

Sarcomas are a group of rare solid tumours arising from mesenchymal or connective tissue. This review focuses on soft tissue sarcoma and covers general topics such as the epidemiology, age distribution, site of disease, histogenesis, histological subtypes, prognosis and outcome of treatment. In more detail, the article reviews current systemic treatment standards and selected adverse events of agents such as doxorubicin, ifosfamide, trabectedin and pazopanib, and briefly highlights some drugs that are used off-label in specific subtypes of sarcoma.

Topics: Antineoplastic Agents; Dioxoles; Doxorubicin; Evidence-Based Medicine; Humans; Ifosfamide; Indazoles; Pyrimidines; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Treatment Outcome

The role of angiogenesis in the physiopathology of renal cell carcinoma is fundamental. Strategies targeting angiogenesis have been developed including VEGF and VEGFR inhibitors for the treatment of metastatic renal cell carcinoma (mRCC), in first and second line. Pazopanib is an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor and c-KIT receptor. This treatment is a treatment option recommended for patients with mRCC, would be in first line or after cytokines failure. Pazopanib has been recently approved for patients with metastatic soft tissue sarcoma, after failure of at least one line of chemotherapy.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sarcoma; Sulfonamides

Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cell Cycle; Cell Survival; Chemotherapy, Adjuvant; Cyclin-Dependent Kinase 4; Humans; Indazoles; Indoles; Ipilimumab; Molecular Targeted Therapy; Niacinamide; Nivolumab; Phenylurea Compounds; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Pyrroles; Radiotherapy, Adjuvant; Sarcoma; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib; Tumor Microenvironment

Pazopanib (GW786034, Votrient®) is a vascular endothelial growth factor receptor-focused multi-tyrosine kinase inhibitor involved in inhibiting the angiogenesis pathway. The agent was recently registered for use in soft tissue sarcomas, a group of diseases with a major unmet medical need.. The relevance of angiogenesis in soft tissue sarcomas is discussed. These data were the basis to decide on the development of pazopanib in these diseases. The clinical pharmacology of pazopanib, as far as practically relevant, is summarized. After the first observations of possible activity in soft tissue sarcomas in the Phase I study, a Phase II and subsequent randomized placebo-controlled Phase III study were performed and are being put into perspective in this review.. Pazopanib is an active drug for the treatment of chemotherapy-failing nonadipocytic soft tissue sarcomas. It almost triples progression-free survival significantly from 1.6 to 4.6 months in this heavily pretreated population. The safety profile is manageable, exemplified by the high dose intensity that can be achieved over time. Pazopanib can be considered as part of the standard of care for patients with soft tissue sarcomas.

Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Disease-Free Survival; Humans; Indazoles; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sulfonamides

After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year. Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials?. Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression-free survival by 3 months relative to placebo. Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit.. Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit.

Topics: Angiogenesis Inhibitors; Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Indazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides

Current guidelines recommend anthracycline-based chemotherapy primarily with doxorubicin either as monotherapy or in combination with ifosfamide as the first-line treatment for most advanced STS subtypes. Therapeutic options after failure of doxorubicin and/or ifosfamide are limited. This study aimed to comprehensively review available data on the activity and safety of interventions in second- or later-line treatment of advanced STS.. Electronic literature databases (Embase®, MEDLINE®, MEDLINE® In-Process, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) were searched from 1980 to 01 March 2012 to identify randomised controlled trials (RCTs) and non-randomised studies (both prospective and retrospective) evaluating pharmacological interventions in patients with advanced STS pre-treated with anthracycline- and/or ifosfamide-based therapy.. The review identified six RCTs (one phase III and five phase II trials) and 94 non-randomised studies. Based on the primary trial endpoints, RCTs demonstrated favourable efficacy for pazopanib over placebo (PFS: 4.6 months vs. 1.6 months), gemcitabine plus dacarbazine over dacarbazine monotherapy (3-month PFS rate: 54.2% vs. 35.2%), and trabectedin 3-weekly schedule over weekly schedule (TTP: 3.7 months vs. 2.3 months. The non-randomised studies demonstrated heterogeneity in efficacy and safety results.. Across the RCTs, pazopanib over placebo, gemcitabine-dacarbazine over dacarbazine, and trabectedin 3-weekly over weekly regimen clearly demonstrated a PFS advantage in the second- and later-line treatment of advanced STS. With only one phase III trial in this setting, there is a clear need for additional comparative trials to better understand the risk: benefit ratios of available agents and combinations.

Topics: Antineoplastic Agents; Dacarbazine; Deoxycytidine; Dioxoles; Gemcitabine; Humans; Indazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Treatment Failure

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Indazoles; Mice; Proto-Oncogene Proteins c-kit; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome

Patients with advanced metastatic soft tissue sarcoma (STS) have a poor prognosis, and in the last two decades of the 20th century their overall survival has remained unchanged. Improved treatments are needed for these patients and for preventing metastases in earlier stages of disease. Numerous novel agents and new combination regimens are undergoing clinical testing in STS. Some of these agents show promising activity. Pazopanib is one such agent that has undergone Phase II and III evaluations in advanced STS. Pazopanib is a multi-tyrosine kinase inhibitor, blocking various signaling pathways, thereby preventing angiogenesis and metastasis, and inhibiting tumor cell growth and survival. In a Phase II study, pazopanib demonstrated activity in patients with advanced leiomyosarcomas, synovial sarcomas and other eligible STSs. This activity was confirmed in a Phase III trial, where pazopanib significantly extended the median progression-free survival versus placebo in a variety of STS subtypes.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Humans; Indazoles; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Gemcitabine; Humans; Hyperthermia, Induced; Indazoles; Multimodal Imaging; Neoadjuvant Therapy; Positron-Emission Tomography; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sirolimus; Soft Tissue Neoplasms; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Soft-tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. Although outcome varies by histology, adults with disseminated metastatic STS have a poor prognosis despite current treatment options. The authors reviewed commonly used clinical end points for STS and discussed which end points may be appropriate for evaluating the clinical benefit of novel targeted therapies. In sarcoma, surrogates for both overall survival, the gold standard end point, and the objective response rate, measured by Response Evaluation Criteria in Solid Tumors, are commonly used. More appropriate end points for evaluating newly targeted agents include progression-free survival and clinical benefit rate. Results from recently completed Phase III trials of two targeted therapies in advanced STS, the mTOR inhibitor ridaforolimus and the multikinase inhibitor pazopanib, should shed light on whether progression-free survival and clinical benefit rate are appropriate end points in advanced STS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Drug Substitution; Drugs, Investigational; Endpoint Determination; Humans; Indazoles; Molecular Targeted Therapy; Neoplasm Metastasis; Outcome and Process Assessment, Health Care; Prognosis; Pyrimidines; Sarcoma; Sirolimus; Sulfonamides; Survival Rate; TOR Serine-Threonine Kinases; Treatment Outcome

Angiogenesis is an essential prerequisite in the growth and dissemination of soft tissue sarcoma. The understanding of the VEGF and VEGFR pathway implication in the development of non GIST soft tissue sarcoma and the discovery of the antitumoral activity of drugs that inhibit this pathway in other solid tumors, led to the development of antiangiogenic drugs anti VEGF in soft tissue sarcoma, as monoclonal antibody (bevacuzimab) or as small molecules (tyrosine-kinase inhibitors anti VEGFR). This manuscript presents the results of the first clinical trials that have evaluated the efficacy and safety of some angiogenesis inhibitors in soft tissue sarcomas.

Topics: Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Doxorubicin; Humans; Indazoles; Indoles; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Soft Tissue Neoplasms; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

The EPAZ study (NCT01861951) showed recently that pazopanib was non-inferior to doxorubicin in patients ≥60 years treated in first line for advanced soft tissue sarcoma . The current post-hoc analysis aimed to assess the prognostic impact of frailty.. Geriatric assessments were evaluated at baseline. Age >75 years, liposarcoma, ECOG = 2, G8 ≤14, instrumental activities of daily living (IADL) ≥1 and Charlson Comorbidity Index ≥2 were tested for their impact on progression-free survival (PFS), overall survival (OS), CTCAE grade 3/4 adverse events (AEs) or serious AEs (SAEs), using univariate and multivariate analysis models.. univariate analysis showed an increased risk of grade 3/4 AEs and SAEs for ECOG = 2, G8 score ≤14 or IADL ≥1, independent of treatment. The multivariate analysis exhibited for pazopanib a significantly reduced risk for grade 3/4 AEs (HR 0.53; p = 0.033), and in patients with G8 ≤14 an increased risk for SAEs (HR 2.67; p = 0.011). In the multivariate analysis, G8 ≤14 was a negative prognostic factor for PFS (HR 1.82; p = 0.009) and IADL ≥1 for OS (HR 2.02; p = 0.007). ECOG = 2 was the strongest negative predictor for PFS (HR 4.39; p = 0.001) and OS (HR 3.74; p = 0.004). Neither age nor Charlson Comorbidity Index showed any impact on PFS, OS, incidence of grade 3/4 AEs or SAEs.. This post hoc analysis demonstrated that age is not a denominator for outcome or toxicity in elderly patients with soft tissue sarcoma . Instead, geriatric and functional assessments should be used to counsel patients and tailor therapy to individual needs. Moreover, pazopanib has a reduced risk for grade 3/4 AEs compared to doxorubicin.

Topics: Activities of Daily Living; Aged; Doxorubicin; Humans; Indazoles; Sarcoma; Soft Tissue Neoplasms

The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma.. Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy.. Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites.. The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

Topics: Child; Humans; Neoadjuvant Therapy; Postoperative Complications; Pyrimidines; Sarcoma; Soft Tissue Neoplasms

A prior phase I study showed that the neo-adjuvant combination of pazopanib and radiotherapy was well tolerated, and induced promising pathological responses in soft-tissue sarcoma patients. Results of the subsequent prospective, multicenter phase II, PASART-2 trial are presented here, further investigating the efficacy and safety of this combination.. Patients with high-risk, localized soft-tissue sarcoma received neo-adjuvant radiotherapy, 50 Gy in 25 fractions (PASART-2A) or with a subsequent dose de-escalation to 36 Gy in 18 fractions (PASART-2B). This was combined with 800 mg once daily pazopanib, which started one week before radiotherapy and finished simultaneously. After an interval of 4-8 weeks, surgical resection was performed. The primary endpoint was the rate of pathological complete responses (pCR), defined as ≤5% viable cells.. 25 patients were registered in the study, 21 in PASART-2A and 4 in PASART-2B. After central pathology review, the combination treatment led to a pCR in 5 patients (20%). 17 patients (68%) experienced grade 3+ toxicities during neo-adjuvant treatment, of which the most common were alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST) elevation, and hypertension, all asymptomatic. Grade 3+ acute post-operative toxicities occurred in 5 patients (20%), of which the most common was wound infection. All patients completed the full radiotherapy regimen and underwent surgery. Pazopanib was discontinued before completion in 9 patients (36%), due to elevated ALT and/or AST, and shortly interrupted in 2 patients (8%), due to hypertension.. Apart from asymptomatic hepatotoxicity, the study regimen was well tolerated. Although the pre-specified efficacy endpoint (30% pCR) was not met, a more than doubling of historical pCR rates after neo-adjuvant radiotherapy alone was observed, which warrants further investigation.

Topics: Humans; Indazoles; Neoadjuvant Therapy; Prospective Studies; Pyrimidines; Sarcoma; Sulfonamides

Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required.. To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone.. This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020.. Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B).. The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates.. A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological.. This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma).. German Clinical Trials Identifier: DRKS00003139.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Gemcitabine; Humans; Ifosfamide; Indazoles; Middle Aged; Pyrimidines; Quality of Life; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult

Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.. This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.. 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients.. In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Prospective Studies; Pyrimidines; Sarcoma; Sulfonamides; Topotecan; Treatment Outcome; Young Adult

Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib.. This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743).. From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0).. The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Chest Pain; Cross-Over Studies; Diarrhea; Disease Progression; Double-Blind Method; Female; Humans; Indazoles; Kaplan-Meier Estimate; Leukopenia; Male; Middle Aged; Phenylurea Compounds; Pyridines; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single-arm, multicenter, investigator-initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end-point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow-up period was 22.2 (range, 4.9-24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult

Cytotoxic chemotherapy remains the standard of care first-line treatment for advanced and metastatic soft-tissue sarcomas (STSs). Certain patients may not be chemotherapy candidates based upon age or co-morbidities, leaving limited treatment options. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic STS after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy.. Eligible patients were at least 18 years old, not candidates for chemotherapyand were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ≥35% against an unfavourable CBR of ≤20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers.. Fifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62-7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265-0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I-II events were diarrhoea, nausea and fatigue. The most common grade III-IV events were hypertension and liver function test abnormalities.. These data suggest that there is a benefit to front-line pazopanib in patients with STS who are not candidates for cytotoxic chemotherapy.

Topics: Aged; Female; Humans; Indazoles; Male; Neoplasm Metastasis; Progression-Free Survival; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity.. Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m. Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72;. Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.

Topics: Age Factors; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Chemotherapy-Induced Febrile Neutropenia; Doxorubicin; Drug Administration Schedule; Female; Humans; Indazoles; Male; Middle Aged; Neutropenia; Patient Reported Outcome Measures; Progression-Free Survival; Pyrimidines; Quality of Life; Sarcoma; Sulfonamides

Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects.. The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients.. Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99;. Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Gastric Acid; Humans; Indazoles; Male; Middle Aged; Neoplasm Grading; Prognosis; Pyrimidines; Sarcoma; Sulfonamides; Survival Analysis; Treatment Outcome

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Interactions; Female; Gastric Acid; Humans; Hydrogen-Ion Concentration; Indazoles; Male; Protein Kinase Inhibitors; Proton Pump Inhibitors; Pyrimidines; Sarcoma; Sulfonamides

Preoperative devascularization might improve local control and thus the outcome of patients with soft tissue sarcoma (STS). The multikinase inhibitor pazopanib has antiangiogenic effects and is approved for treating metastatic STS. We conducted a trial of preoperative pazopanib therapy in high-risk STS.. Although this study showed that preoperative pazopanib is not effective for unselected high-risk STS patients, relevant treatment effects were observed in a single patient. Future research needs to better define subgroups potentially benefiting from preoperative pazopanib treatment. CLINICALTRIALS.. NCT01543802.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Female; Follow-Up Studies; Germany; Humans; Indazoles; Male; Middle Aged; Neoadjuvant Therapy; Preoperative Care; Prognosis; Pyrimidines; Risk Factors; Sarcoma; Sulfonamides

For resectable soft tissue sarcoma (STS), radical surgery, usually combined with radiotherapy, is the mainstay of treatment and the only potentially curative modality. Since surgery is often complicated by large tumour size and extensive tumour vasculature, preoperative treatment strategies with the aim of devitalising the tumour are being explored. One option is treatment with antiangiogenic drugs. The multikinase inhibitor pazopanib, which possesses pronounced antiangiogenic effects, has shown activity in metastatic and unresectable STS, but has so far not been tested in the preoperative setting.. This open-label, multicentre phase II window-of-opportunity trial assesses pazopanib as preoperative treatment of resectable STS. Participants receive a 21-day course of pazopanib 800 mg daily during wait time for surgery. Major eligibility criteria are resectable, high-risk adult STS of any location, or metachronous solitary STS metastasis for which resection is planned, and adequate organ function and performance status. The trial uses an exact single-stage design. The primary end point is metabolic response rate (MRR), that is, the proportion of patients with >50% reduction of the mean standardised uptake value (SUVmean) in post-treatment compared to pre-treatment fluorodeoxyglucose positron emission tomography CT. The MRR below which the treatment is considered ineffective is 0.2. The MRR above which the treatment warrants further exploration is 0.4. With a type I error of 5% and a power of 80%, the sample size is 35 evaluable patients, with 12 or more responders as threshold. Main secondary end points are histopathological and MRI response, resectability, toxicity, recurrence-free and overall survival. In a translational substudy, endothelial progenitor cells and vascular epithelial growth factor receptor are analysed as potential prognostic and predictive markers.. Approval by the ethics committee II, University of Heidelberg, Germany (2012-019F-MA), German Federal Institute for Drugs and Medical Devices (61-3910-4038155) and German Federal Institute for Radiation Protection (Z5-22463/2-2012-007).. NCT01543802, EudraCT: 2011-003745-18; Pre-results.

Topics: Angiogenesis Inhibitors; Chemotherapy, Adjuvant; Disease-Free Survival; Endothelial Progenitor Cells; Germany; Humans; Indazoles; Neoplasm Recurrence, Local; Prognosis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Risk; Sarcoma; Sulfonamides

This analysis of the Japanese subpopulation of the PALETTE Phase III, randomized, placebo-controlled study investigated efficacy and safety of pazopanib in patients with metastatic soft tissue sarcoma after failure of standard chemotherapy.. Patients were randomly assigned in a 2:1 ratio to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Primary endpoint was progression-free survival. Secondary endpoints included overall survival and overall response rate. Efficacy analysis was by intent-to-treat. Safety was also investigated.. Forty-seven patients received either pazopanib (n = 31) or placebo (n = 16). Median progression-free survival was 7.0 weeks (95% confidence interval: 4.0-11.7) for placebo and 24.7 weeks (95% confidence interval: 8.6-28.1) for pazopanib (hazard ratio = 0.41 [95% confidence interval: 0.19-0.90]; P = 0.002). Median overall survival was 14.9 months (95% confidence interval: 6.8-not calculable) for placebo and 15.4 months (95% confidence interval: 7.9-28.8) for pazopanib (hazard ratio = 0.87 [95% confidence interval: 0.41-1.83]; P = 0.687). More patients receiving pazopanib experienced best response of stable disease versus placebo. Adverse events were similar to the global population; those leading to dose reduction were more common and mean daily dose was lower in the Japanese population versus the global population (45 vs. 32% and 624.4 vs. 700.4 mg, respectively).. The efficacy and safety of pazopanib observed in the Japanese subpopulation of PALETTE were similar to those in the global population. Pazopanib is a new treatment option for Japanese patients with metastatic non-adipocytic soft tissue sarcoma after chemotherapy.. NCT00753688; GSK study ID: VEG110727; http://www.gsk-clinicalstudyregister.com/study/VEG110727#ps.

Topics: Adult; Aged; Angiogenesis Inhibitors; Disease-Free Survival; Double-Blind Method; Female; Humans; Indazoles; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Odds Ratio; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome; Vascular Endothelial Growth Factor A

Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas.. Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared.. Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having ≥2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352).. Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Indazoles; Leiomyosarcoma; Middle Aged; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Survival Rate; Uterine Neoplasms; Young Adult

Anthracycline-based treatment remains the backbone of chemotherapy for nonresectable soft tissue sarcomas (STS). More than 30 % of patients with STS are aged 60 years or older, limiting the choice of treatment to single-agent approaches for this elderly population. Hematological toxicity is frequent during doxorubicin monotherapy, grade 4 neutropenia is reported in 34 %, with a febrile neutropenia rate of 9 % in STS. We assume that comorbidities in the elderly population may limit tolerability of doxorubicin, and novel agents may improve tolerability and health-related quality of life while maintaining efficacy. We therefore investigated whether the tyrosine kinase inhibitor pazopanib exerts such a clinical benefit in elderly patients with STS (pazopanib for elderly [the EPAZ study]).. This study is a randomized, controlled, open-label, multicenter, phase II noninferiority trial in which pazopanib 800 mg once daily is being compared six cycles of intravenous doxorubicin 75 mg/m(2) as first-line treatment in elderly patients (≥60 years) with metastatic or advanced STS. A total of 120 patients will be randomized 1:2 to receive doxorubicin or pazopanib, stratified by Eastern Cooperative Oncology Group performance status (0-1 vs. 2) and liposarcoma histology (yes vs. no). The primary endpoint is progression-free survival based on local tumor assessment according to Response Evaluation Criteria in Solid Tumors criteria. Secondary endpoints include grade 4 neutropenia and febrile neutropenia in hierarchical order, as well as overall survival, objective response rate, health-related quality of life, and geriatric assessments.. Pazopanib is associated with promising tolerability according to previous studies and may offer a significant clinical advantage in first-line treatment of STS compared with doxorubicin. The elderly population seems especially appealing for such an approach, since these patients are not suitable for aggressive combination therapy. The EPAZ study will confirm whether pazopanib may be an alternative to toxic chemotherapy for elderly patients with STS.. ClinicalTrials.gov NCT01861951 ; registered on 11 April 2013. EudraCT 2011-004168-30; registered on 4 June 2012.

Topics: Age Factors; Aged; Antibiotics, Antineoplastic; Belgium; Clinical Protocols; Disease Progression; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Geriatric Assessment; Germany; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Research Design; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Time Factors; Treatment Outcome

Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting.. Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5-7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II).. A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24-78 years, median tumor size 9 cm, range 5-15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases.. Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies.

Topics: Adult; Aged; Angiogenesis Inhibitors; Chemoradiotherapy, Adjuvant; Extremities; Female; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoadjuvant Therapy; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Young Adult

Health-related quality of life (HRQoL) was an exploratory endpoint in the PALETTE trial, a global, double-blind, randomized, phase 3 trial of pazopanib 800 mg versus placebo as second-line or later treatment for patients with advanced soft tissue sarcoma (N = 369). In that trial, progression-free survival was significantly improved in the pazopanib arm (median, 4.6 vs 1.6 months; hazard ratio, 0.31; P < .001), and toxicity of pazopanib consisted mainly of fatigue, diarrhea, nausea, weight loss, and hypertension.. HRQoL was assessed using the 30-item core European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline and at weeks 4, 8, and 12 in patients who received treatment on protocol. The primary HRQoL endpoint was the EORTC QLQ-C30 global health status scale.. Compliance with HRQoL assessments was good, ranging from 94% at baseline to 81% at week 12. Differences in scores on the EORTC QLQ-C30 global health status subscale between the 2 treatment arms were not statistically significant and did not exceed the predetermined, minimal clinically important difference of 10 points (P = .291; maximum difference, 3.8 points). Among the other subscales, the pazopanib arm reported significantly worse symptom scores for diarrhea (P < .001) loss of appetite (P < .001), nausea/vomiting (P < .001), and fatigue (P = .012). In general, HRQoL scores tended to decline over time in both arms.. HRQoL did not improve with the receipt of pazopanib. However, the observed improvement in progression-free survival without impairment of HRQoL was considered a meaningful result. The toxicity profile of pazopanib was reflected in the patients' self-reported symptoms but did not translate into significantly worse overall global health status during treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Disease-Free Survival; Double-Blind Method; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Pyrimidines; Quality of Life; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult

Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.. For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS.. Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response.. The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed.. GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Docetaxel; Female; Gemcitabine; Humans; Indazoles; Male; Middle Aged; Neoadjuvant Therapy; Pyrimidines; Sarcoma; Sulfonamides; Taxoids; Treatment Outcome

Pazopanib recently received approval for the treatment of certain soft tissue sarcoma (STS) subtypes. We conducted a retrospective analysis on pooled data from two EORTC trials on pazopanib in STS in order to characterize long-term responders and survivors.. Selected patients were treated with pazopanib in phase II (n = 118) and phase III study (PALETTE) (n = 226). Combined median progression-free survival (PFS) was 4.4 months; the median overall survival (OS) was 11.7 months. Thirty-six percent of patients had a PFS ≥ 6 months and were defined as long-term responders; 34% of patients survived ≥18 months, defined as long-term survivors. Patient characteristics were studied for their association with long-term outcomes.. The median follow-up was 2.3 years. Patient characteristics were compared among four subgroups based on short-/long-term PFS and OS, respectively. Seventy-six patients (22.1%) were both long-term responders and long-term survivors. The analysis confirmed the importance of known prognostic factors in metastatic STS patients treated with systemic treatment, such as performance status and tumor grading, and additionally hemoglobin at baseline as new prognostic factor. We identified 12 patients (3.5%) remaining on pazopanib for more than 2 years: nine aged younger than 50 years, nine females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. The median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years.. Thirty-six percent and 34% of all STS patients who received pazopanib in these studies had a long PFS and/or OS, respectively. For more than 2 years, 3.5% of patients remained progression free under pazopanib. Good performance status, low/intermediate grade of the primary tumor and a normal hemoglobin level at baseline were advantageous for long-term outcome. NCT00297258 (phase II) and NCT00753688 (phase III, PALETTE).

Topics: Adult; Aged; Angiogenesis Inhibitors; Disease-Free Survival; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Placebos; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sarcoma; Sulfonamides; Treatment Outcome

Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors.. Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD.. Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41).. Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Topics: Adolescent; Adult; Angiogenesis Inhibitors; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Indazoles; Male; Neoplasms; Pyrimidines; Sarcoma; Sulfonamides; Young Adult

Soft-tissue sarcomas are rare tumours of mesenchymal origin. Patients with metastatic disease have a median survival of about 10 months. Doxorubicin, an anthracycline, is often used to reduce tumour volume, but it does not prolong overall survival. Pazopanib, a multiple tyrosine kinase inhibitor already marketed for kidney cancer, is now licensed for the treatment of certain metastatic soft-tissue sarcomas when chemotherapy fails or when the disease progresses despite adjuvant or neoadjuvant therapy. Clinical evaluation of pazopanib in this setting is based on a double-blind, randomised, placebo-controlled trial in 369 patients whose tumours had progressed despite at least one line of chemotherapy, based on an anthracycline. In this trial, pazopanib did not provide a statistically significant increase in overall survival. The median survival time was about 12 months. A statistically significant increase in median progression-free survival was observed (4.6 versus 1.6 months, an increase of 3 months), based mainly on radiological criteria. Pazopanib did not improve quality of life. The adverse effect profile includes cardiovascular, gastrointestinal and hepatic disorders, and palmoplantar erythrodysaesthesia. Serious adverse effects are frequent. Other life-threatening adverse effects observed in patients with soft-tissue sarcoma include pneumothorax (especially in case of pulmonary metastasis), heart failure, venous thrombosis, pulmonary embolism and hypothyroidism. In practice, given its lack of any proven impact on overall survival and its excessive toxicity, the use of pazopanib is not justified. It is better to focus on appropriate symptomatic care in order to preserve these patients' quality of life.

Topics: Angiogenesis Inhibitors; Double-Blind Method; Heart Failure; Humans; Indazoles; Liver; Pneumothorax; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Sarcoma; Sulfonamides

Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy.. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688.. 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib.. Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy.. GlaxoSmithKline.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cross-Over Studies; Disease-Free Survival; Double-Blind Method; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome; Young Adult

Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome.. Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated.. At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05).. Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Cytokines; Disease-Free Survival; Female; Humans; Indazoles; Interleukin-12 Subunit p40; Male; Membrane Proteins; Middle Aged; Placenta Growth Factor; Polycomb-Group Proteins; Pregnancy Proteins; Pyrimidines; Repressor Proteins; Sarcoma; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Young Adult

PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.

Topics: Adult; Aged; Angiogenesis Inhibitors; Disease-Free Survival; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Recurrence, Local; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.. We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.. Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10-4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker.. Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Topics: Humans; Indazoles; Pyrimidines; Sarcoma; Sulfonamides

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: Angiogenesis Inhibitors; Carcinoma, Renal Cell; East Asian People; Humans; Indazoles; Kidney Neoplasms; Sarcoma; Soft Tissue Neoplasms

Pazopanib, a receptor tyrosine kinase inhibitor, exhibits anti-tumor activity in adult bone and soft-tissue sarcomas (STS), but has not yet been approved for pediatric tumors. The primary objective was to evaluate pazopanib efficacy when used alone or in combination with topotecan. This real-world multicenter retrospective study included patients with solid tumors, aged 25 years or less at the time of initial diagnosis, treated with pazopanib outside of a clinical trial. Nineteen patients were eligible for efficacy analysis: 14 bone tumors and 5 STS. At pazopanib initiation, the median age was 16.9 years, 18 patients had metastatic disease with a median of 2 prior therapeutic lines. With 6.2 months of median follow-up, no objective response was observed, but 10 patients (52.6%) had stable disease at 8 weeks and the 6-month disease control rate was 26.3%. The median progression free (PFS) and overall survival (OS) were 3.0 months and 6.2 months, respectively. Multivariate analysis showed an inverse relationship between the number of prior treatment lines and PFS and OS (hazard ratio = 1.73 (

Topics: Adolescent; Adult; Child; Humans; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

Description of patient characteristics, effectiveness and safety in Turkish patients treated with pazopanib for metastatic soft tissue sarcoma (STS).. 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.. 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.. 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; Female; Humans; Indazoles; Leiomyosarcoma; Male; Middle Aged; Neoplasms, Second Primary; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Soft Tissue Neoplasms; Turkey

Radiation recall reaction is an acute inflammatory reaction confined to previously irradiated areas that are most commonly triggered by the administration of anti-cancer agents after radiotherapy. Radiation recall myositis is a relatively rare form of radiation recall reaction.. Here we report a 29-year-old female patient who suffered from metastatic monophasic synovial sarcoma. 8.5 months after post-operative radiotherapy of the right thigh region, the patient suffered pain, edema, redness, and increased temperature locally on the right thigh. Physical exam showed red fixed skin, rigidity and severe tenderness of region, and thigh magnetic resonance imaging revealed dense edema areas at the addiction, semimembranous-semitendinous muscle, and superior part of the biceps femoris and vastus lateralis isointense on T1AG, hyperintense T2AG images. Based on these findings, the patient was diagnosed with pazopanib-induced radiation recall myositis.. Pazopanib was stopped and pentoxifylline (2  × 400 mg), Vitamin E (3  × 400 mg), and methylprednisolone (2  × 8 mg) were prescribed. After 1 month, complete relief of thigh pain and marked recovery of rigidity, as well as erythema, were achieved and no recurrence of radiation recall reaction-related symptoms was observed after the pazopanib rechallenge.. Myositis is a relatively rare presentation of radiation recall reaction and physicians must be aware of the symptoms of the patients who are treated by radiotherapy and pazopanib.

Topics: Adult; Female; Humans; Myositis; Pain; Radiodermatitis; Sarcoma

Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison.. We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy).. Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma.. In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.

Topics: Dacarbazine; Deoxycytidine; Gemcitabine; Humans; Ifosfamide; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms

Tumor lysis syndrome (TLS) is recognized as an oncologic disorder with a variable incidence. TLS can cause the rapid destruction of tumor cells in response to oncologic therapy and is characterized by multiple electrolyte disturbances as well as its secondary complications, including death. This disease is common among patients with hematologic neoplasms, but very rare among those with solid tumors, as is the case with sarcomas. Such patients have a poor prognosis and increased risk of mortality. In the patient's particular case, this occurred after initiating third-line systemic therapy with gemcitabine associated with pazopanib, an event not previously described in the literature.. We report the case of a patient with a history of high-grade sarcoma of the left lower limb T4N1M0 stage IIIB undergoing surgical management and exhibiting tumor progression with the need for third-line systemic therapy with pazopanib and gemcitabine. The patient presented with pain at the amputation site, inflammatory changes, and a tumor mass of large components on admission. They later developed electrolyte imbalance and acute renal injury compatible with TLS after systemic therapy was initiated. Pharmacological therapy, including rasburicase, was initiated based on the clinical and laboratory findings. Due to the progression of renal involvement, it was necessary to initiate haemodialysis, and during her hospital stay, the patient presented febrile syndrome associated with pancytopenia. The patient showed a favourable clinical response to the proposed antibiotic therapy and recovery of renal function, for which reason therapy was restarted with pazopanib and gemcitabine, the latter with a 20% reduction for the following cycles. Outpatient follow-up continued, completing eight cycles of treatment with good tolerance and partial clinical response; the patient died of respiratory complications eight months after discharge.. There is limited evidence for TLS in patients with high-grade sarcoma in the literature related to the oncologic therapy used; this indicates that early risk evaluation along with prompt initiation of effective therapies is required to prevent the appearance of this type of complications in the short and long term.

Topics: Electrolytes; Female; Gemcitabine; Humans; Sarcoma; Tumor Lysis Syndrome

The goal of this study was to evaluate the predictive and prognostic importance of the lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (DNLR), and systemic immune inflammation index (SSI) in STS cases treated with pazopanib.. Thirty STS patients treated with pazopanib were included in this study. SSI, DNLR, LMR, and NLR values were calculated at baseline and in the first month. Median values of these predictors in these patients (SSI (944), DNLR (1.8), LMR (2.7), and NLR (3.0)) were taken as cutoff values. The associations between the survival time (both overall survival (OS) and progression-free survival (PFS)) and cutoff values were evaluated using Kaplan Meier curves and Cox regression models.. Patients with low SSI, NLR, and DNLR values at pretreatment and after the initial response had longer OS (for OS - p = 0.024, p = 0.015, and p = 0.041, respectively). Longer OS was also found in patients who showed increasing LMR and decreasing NLR after one month of therapy (for ΔLMR, p = 0.016; for ΔNLR, p = 0.016). Pa-tients with low SSI and NLR values at pretreatment and after the initial response had longer PFS (for PFS, p = 0.014, p = 0.04, p ˂ 0.001, respectively). In terms of initial responses to treatment, SSI, NLR, DNLR, and increased LMR were detected as independent risk factors in univariate analysis, but initial response was found to be the only independent risk factor for PFS in multivariate analysis.. Low values of SSI, NLR, and DNLR at pretreatment and at initial response may predict long-term survival rates. After one month of treatment with pazopanib, decreased NLR and increased LMR are predictive of favorable outcomes in these cases.

Topics: Humans; Indazoles; Lymphocytes; Neutrophils; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides

The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.. We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.. Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.. A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Topics: Gene Expression; Humans; Indazoles; Prospective Studies; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Young Adult

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.. 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).. 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.. 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

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.. 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.. 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.. 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

A 72-year-old man who underwent pazopanib therapy for soft-tissue sarcoma in the left leg was referred to our department because of elevated levels of liver enzymes. Laboratory tests showed high alanine aminotransferase, alkaline phosphatase, and total bilirubin levels. He was treated with intravenous methylprednisolone (mPSL) therapy (125 mg/day) followed by oral prednisolone and ursodeoxycholic acid therapy, but his liver enzyme abnormality deteriorated and he presented with jaundice. The intravenous mPSL (250 mg/day) treatment was effective and the abnormal levels of liver enzymes and jaundice were improved. He does not carry the UGT1A1*28 mutant allele. Based on our findings, patients presenting with markedly increased liver enzyme levels and jaundice after pazopanib may require steroid therapy.

Topics: Aged; Humans; Indazoles; Liver; Male; Mutation; Pyrimidines; Sarcoma; Sulfonamides

Our objective is to report on a case of posterior reversible encephalopathy syndrome associated with pazopanib.. A 64-year-old patient with uterine sarcoma developed PRES 3 days after pazopanib was initiated. After the discontinuation of pazopanib, the symptoms of PRES improved.. The first report worldwide to describe a patient with uterine sarcoma experiencing PRES caused by pazopanib. Patients with uterine sarcoma may experience PRES, even in the early phase of pazopanib therapy.

Topics: Angiogenesis Inhibitors; Diagnosis, Differential; Female; Humans; Indazoles; Magnetic Resonance Imaging; Middle Aged; Posterior Leukoencephalopathy Syndrome; Pyrimidines; Sarcoma; Sulfonamides; Uterine Neoplasms

This study evaluated the safety and efficacy of pazopanib in patients with metastatic soft tissue sarcoma in routine clinical use in Japan.. It was a multicentre, centrally registered and uncontrolled observational study in patients who received pazopanib for metastatic soft tissue sarcoma, with an observation period of 1 year after the start of drug administration. The study was conducted at 378 investigational sites in Japan from September 2012 to September 2019. Progression-free survival (PFS) and overall survival (OS) were the efficacy endpoints of the study.. A total of 1970 patients were enrolled. Of these, 680 with finalized study forms were included in the analysis. Overall, 649 patients were included in the safety analysis set, and 569 were included in the efficacy analysis set. Most of the patients (81.97%) experienced at least one adverse drug reaction (ADR); 22.34% of patients reported serious ADRs and 34.98% of patients experienced grade ≥ 3 ADRs in the safety set. Hypertension (40.37%) and hepatic dysfunction (26.50%) were the two most common ADRs. A total of 262 deaths were reported, of which 12 were due to ADRs. The median PFS was 3.09 months, whereas the median OS was not reached at the end of the 1-year observation period.. The safety and efficacy profiles in this postmarketing observational study were consistent with prior data and registration clinical trials. No new safety signals were observed while treating patients with metastatic soft tissue sarcoma with pazopanib.

Topics: Adolescent; Adult; Aged; Female; Humans; Incidence; Indazoles; Japan; Male; Middle Aged; Product Surveillance, Postmarketing; Progression-Free Survival; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome; Young Adult

Limited data are available on the real-world effectiveness and safety of systemic therapies for advanced (surgically unresectable and/or metastatic) epithelioid sarcoma (ES).. A retrospective medical records review was conducted in patients with advanced ES who were initiating first-line or ≥2 lines of systemic therapy (2000-2017) at 5 US cancer centers. The real-world overall response rate (rwORR), the duration of response (rwDOR), the disease control rate (rwDCR) (defined as stable disease for ≥32 weeks or any duration of response), and progression-free survival (rwPFS) were assessed by radiology reports. Overall survival (OS), rwDOR, and rwPFS were estimated from the time therapy was initiated using the Kaplan-Meier method. Serious adverse events were assessed.. Of 74 patients (median age at diagnosis, 33 years; range, 10.6-76.3 years), 72% were male, and 85% had metastatic disease. The median number of lines of therapy was 2 (range, 1-7 lines of therapy), and 46 patients (62%) received ≥2 lines of systemic therapy. First-line regimens were usually anthracycline-based (54%) or gemcitabine-based (24%). For patients receiving first-line systemic therapy, the rwORR was 15%, the rwDCR was 20%, the median rwDOR was 3.3 months (95% CI, 2.1-5.2 months), the median rwPFS was 2.5 months (95% CI, 1.7, 6.9 months), and the median OS was 15.2 months (95% CI, 11.4-21.7 months). For those who received ≥2 lines of systemic therapy, the rwORR was 9%, the rwDCR was 20%, the median rwDOR was 4.5 months (95% CI, 0.7-5.6 months), and the median rwPFS was 6.0 months (95% CI, 3.2-7.4 months). Over one-half of patients (51.4%) experienced an adverse event, most frequently febrile neutropenia (14%), pain (10%), anemia, dyspnea, fever, thrombocytopenia, or transaminitis (5% each).. Systemic therapies demonstrate limited efficacy in patients with advanced ES and have associated toxicities.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Deoxycytidine; Female; Gemcitabine; Health Records, Personal; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Treatment Outcome; United States; Young Adult

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.. 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.. 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.. 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

Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy.. Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%.. Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006).. We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Topics: Adult; Aged; Angiogenesis Inhibitors; B7-H1 Antigen; Female; Humans; Indazoles; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides

Pazopanib is an anti-angiogenic multi-targeted tyrosine kinase inhibitor used for treating soft tissue sarcomas and renal cell carcinoma. Although the occurrence of pneumothorax during pazopanib treatment has been recognized as an adverse event, there have been no reports of pneumothorax in patients treated with pazopanib. Here, we present the case of a 71- year-old male patient who developed pneumothorax during adjuvant pazopanib therapy after surgery for metastasized renal cell carcinoma. Left hilar and mediastinal lymph node swelling was detected in the postoperative surveillance after surgery, and radiological findings showed lymph node metastasis from renal cell carcinoma. Consequently, left upper lobectomy and mediastinal lymph node dissection were performed, and subsequent pathological examination confirmed the aforementioned diagnosis. Pazopanib was administered as an adjuvant therapy. However, the patient developed left pneumothorax on day 101. Although chest tube drainage was performed, massive air leak continued. A surgery was performed to repair the persistent air leak. This case demonstrates that pneumothorax should be recognized as an adverse event of pazopanib.

Topics: Aged; Humans; Indazoles; Kidney Neoplasms; Male; Pneumothorax; Pyrimidines; Sarcoma; Sulfonamides

Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS.. Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method.. Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively.. This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Deoxycytidine; Female; Gemcitabine; Heart Neoplasms; Humans; Indazoles; Male; Middle Aged; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome; Tunica Intima

Tenosynovial giant cell tumour (TGCT) is a group of rare soft tissues neoplasia affecting synovial joints, bursae and tendon sheaths and is classified as localized type or diffuse type. The diffuse type (TGCT-D), also known as 'pigmented villonodular (teno)synovitis' is characterized by local aggressivity, with invasion and destruction of adjacent soft-tissue structures, and high local recurrence rate. Radical surgery remains the standard therapy while adjuvant radiotherapy may help to control local spread. Malignant TGCT is characterized by high rate of local recurrences and distant metastasis. Few cases of malignant TGCT and very few evidences on systemic therapies are described in the literature, so, to date, no systemic treatment is approved for this rare disease. We report the case of a malignant TGCT patient treated with many different systemic therapies, including chemotherapy and tyrosine-kinase inhibitors, and performed a review of the literature on the systemic treatment options of this rare tumour.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Giant Cell Tumor of Tendon Sheath; Humans; Imatinib Mesylate; Indazoles; Pyrimidines; Radiotherapy, Adjuvant; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Soft tissue sarcomas are a heterogeneous and rare group of cancers with a short median overall survival despite the chemotherapy. Pazopanib has approval for the treatment of advanced soft tissue sarcoma. We aimed to investigate the clinical outcomes of Turkish patients with advanced soft tissue sarcoma who received pazopanib.. This was a retrospective study. The inclusion criteria were: ≥18 years of age, having histologically proven advanced soft tissue sarcoma and receiving pazopanib at least one day.. A total of 79 patients were assessed in this study. The median age was 49.6 years. The average dose intensity of pazopanib was 767 mg (400-800). The median duration of pazopanib treatment was 6.11 months. Fourteen patients (17.7%) used pazopanib at first line for advanced soft tissue sarcomas. The most common cause of discontinuation of pazopanib was the progression of the disease (89.6%). Pazopanib was well tolerated. The most common grade ≥3 side effect was anemia. The most common grade ≤2 side effects were anemia and hyperbilirubinemia. The median progression-free survival, overall survival, and follow-up were 3.97 months, 11.40 months, and 32.72 months, respectively. Female gender, good performance status, and the presence of pazopanib-induced hypothyroidism were associated with longer progression-free survival. Also, good performance status and being a responder to first-line treatment were associated with longer overall survival.. We showed that pazopanib was well tolerated and had clinical benefit in patients with advanced soft tissue sarcoma in a Turkish cohort. This is the first study that suggests pazopanib-induced hypothyroidism may act as a predictive marker for better outcomes in patients with advanced soft tissue sarcoma.

Topics: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Young Adult

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

Pazopanib, a targeted molecular drug, has been proposed as an effective treatment for soft tissue tumour and as a novel adjuvant therapy. There has been a paradoxical concern that wound healing could be inhibited by its anti-angiogenic properties, especially in reconstructive surgery. This paper reports on a 28-year-old woman who underwent flap surgery due to a skin and soft tissue injury after an effective treatment with pazopanib for refractory epithelioid sarcoma. The flap survived without any complication in off-periods of pazopanib for four weeks before and after the surgery, although it is only recommended that the washout periods of pazopanib commence at least seven days before scheduled surgery.

Topics: Adult; Angiogenesis Inhibitors; Buttocks; Combined Modality Therapy; Female; Humans; Indazoles; Magnetic Resonance Imaging; Myocutaneous Flap; Pyrimidines; Quadriceps Muscle; Sarcoma; Sulfonamides; Treatment Outcome; Wound Healing

Soft-tissue sarcomas are a rare group of malignant tumors that usually are treated with surgical excision and radiation therapy, but recently, pazopanib, an oral tyrosine kinase inhibitor, has been used in patients with metastases who do not respond to standard chemotherapy regimens. Based on patients with advanced soft-tissue sarcomas who had received prior chemotherapy, several clinical studies have reported the survival and sensitivity (approximately 5% to 10% sensitive) of patients with soft-tissue sarcomas treated with pazopanib. Recently, next-generation sequencing (NGS) technologies have been used to provide a wide genetic information and to develop personalized medicine in cancer treatment. However, there are few reports and no genetic analyses of patients with soft-tissue sarcomas who had a complete response (CR) to pazopanib.. We described the clinicopathologic features of a patient with a rare, advanced soft-tissue sarcoma who achieved a CR to pazopanib treatment. Furthermore, integrative analyses using NGS and arrays were performed to elucidate characteristic alterations, including gene mutations, copy number changes, and protein expression that were associated with response to pazopanib. Additionally, functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified alterations were associated with oncogenic abilities and drug responses.. In a sample from a 70-year-old woman with an advanced soft-tissue sarcoma treated for 1 month with 800 mg of oral pazopanib daily, CT scans demonstrated a CR to treatment. To our knowledge, there have been no patients with soft-tissue sarcomas among several clinical trials of pazopanib that have achieved a CR and therefore, our patient is considered to be extremely rare. We performed an integrative analysis including whole-exome sequencing, transcriptome sequencing, and phosphorylation profiling of receptor tyrosine kinases (RTK) using tumor samples from a patient with a CR matched to normal samples. From here on we will refer to this patient as having a CR, although a short term high-grade partial response may be more accurate. These analyses were performed using NGS and the phosphoreceptor tyrosine kinase (phospho-RTK) array. As a validation study, we also performed target sequencing using three samples from patients with long-term stable disease and two samples from patients with progressive disease who responded to pazopanib treatment. In addition, characteristic gene alterations that were identified according to the response to pazopanib in one patient with a CR, in three patients with long-term stable disease, and in 27 patients with high-grade soft-tissue sarcomas with different histologic subtypes and different responses to pazopanib were verified by quantitative real-time polymerase chain reaction. We conducted a focus formation assay to evaluate the transforming activities of these genomic alterations.. In the patient with a CR to pazopanib, we identified several somatic mutations including Fms related receptor tyrosine kinase 1 (FLT1) p.G38S, platelet-derived growth factor receptor alpha (PDGFRA) p.T83S, and platelet-derived growth factor receptor beta (PDGFRB) exon 13 skipping. Amplification at chromosome 12q13-14 encompassing GLI family zinc finger 1 (GLI1) and cyclin-dependent kinase-4 (CDK4) was also detected. Furthermore, an elevated PDGFRB phosphorylation level was observed in the tumor. In target sequencing analyses in five patients, one of three patients with long-term stable disease had 12q13-14 amplification. The mRNA expression of GLI1, CDK4, and pazopanib targets including PDGFRA, PDGFRB, vascular endothelial growth factor receptor (VEGFR)1-3, and stem cell factor receptor (KIT) in samples from the patient with a CR, and 27 patients with high-grade soft-tissue sarcomas was verified. The expression of GLI1 was characteristically increased in the patient with a CR and in those with long-term stable disease relative to other patients with soft-tissue sarcomas. Overexpression of GLI1 showed strong transforming potential in 3T3 cells. Moreover, the overexpression of GLI1 upregulated the expression of the PDGFRB protein and promoted phosphorylation, which was dose-dependently inhibited by pazopanib. However, inhibition of GLI1-induced transformation by pazopanib was limited in the focus formation assay; therefore, mechanisms other than PDGFRB activation may contribute to transformation.. We identified several gene alterations that might be associated with a CR and long-term stable disease in patients who received pazopanib for advanced soft-tissue sarcomas. We therefore believe that this distinct molecular profile warrants further investigation to identify predictive biomarkers of the response to pazopanib.. Our findings identify molecular mechanisms that possibly explain the high sensitivity of soft-tissue sarcomas to pazopanib and may lead to the development of predictive biomarkers and novel therapies in patients with this and other types of soft-tissue sarcomas.

Topics: Adult; Aged; Angiogenesis Inhibitors; Biomarkers; Exome Sequencing; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides

Topics: Biomarkers; Humans; Indazoles; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Pazopanib is the only tyrosine kinase inhibitor approved for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy, but there have been limited real-world data on pazopanib for the treatment of advanced STS.. We aimed to evaluate clinical outcomes of pazopanib in patients with multiple histologic STS types in real-world settings.. We retrospectively analyzed clinical data of Korean patients with advanced STS treated with pazopanib between 2008 and 2019. Outcomes of interest included treatment response, survival according to histologic subtypes, and adverse events.. The analysis included 347 STS patients. The disease control rate for all pazopanib-treated patients was 54.8% (95% confidence interval (CI) 49.5-60.0); 54 patients (15.6%) achieved a partial response and 136 (39.2%) had stable disease. Patients with alveolar soft-part sarcoma (ASPS; 90%), solitary fibrous tumor (SFT; 88.2%), synovial sarcoma (66.7%), leiomyosarcoma (61.1%), and undifferentiated pleomorphic sarcoma (59.6%) showed higher disease control rates than those with other STS subtypes. Overall, median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% CI 4.5-6.0) and 12 months (95% CI 10-14), respectively. Noticeable survival outcomes occurred in patients with ASPS and SFT, with a median PFS of 24.5 (95% CI 2.5-30.0) and 13.0 (95% CI 3.0-21.3) months, respectively. The median OS of patients with ASPS and SFT was 48 (95% CI 17-52) and 32 (95% CI 19-66) months, respectively. Adverse drug reactions occurred in 170 patients (49.0%) but were not life-threatening.. This real-world data analysis showed acceptable efficacy and tolerability of pazopanib in patients pretreated with cytotoxic chemotherapy for advanced STS, with favorable treatment outcomes for ASPS and SFT.

Topics: Angiogenesis Inhibitors; Cohort Studies; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Republic of Korea; Retrospective Studies; Sarcoma; Sulfonamides; Survival Analysis

Topics: Benzazepines; Humans; Indazoles; Pyrimidines; Sarcoma; Sulfonamides

The median survival time of patients with advanced soft tissue sarcoma (STS) is typically <12 months. Since 2012, physicians were able to administer second- and/or third-line treatment easily in Japan, following the approval of new drugs, namely, pazopanib, eribulin, and trabectedin. We investigated the real-life experience of adults with advanced STS who received systemic therapy after the approval of the aforementioned new drugs.. We retrospectively evaluated 34 patients (median age: 66 years) with primary STS arising at the extremities/trunk or unresectable local and/or metastatic STS between 2012 and 2019. We evaluated the tumor response and patient survival after initial systemic treatment.. As first-line treatment, doxorubicin and ifosfamide and other drugs were administered to 7 and 27 patients, respectively. Of 31 patients with an evaluable tumor response, partial response was observed in 2 (6.5%) patients, and 16 (52%) patients showed stable disease at 8 weeks. The 1- and 2-year survival rates were 51.4% and 28.4%, respectively. The median overall survival (OS) time was 12.6 months. Tumor response to first-line therapy was related to patient prognosis.. New drugs may be beneficial for patients with advanced STS. When patients cannot receive anthracycline-based chemotherapy because of a high risk of side effects, we believe that the aforementioned drugs may be administered as the first-line treatment.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Female; Furans; Humans; Indazoles; Japan; Kaplan-Meier Estimate; Ketones; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Analysis; Trabectedin; Treatment Outcome

PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS.. PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory.. A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities.. Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity.. NCT00753688 , first posted September 16, 2008 (registered prospectively).

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Sarcoma; Sulfonamides; Survival Analysis; Treatment Outcome

To analyze patterns of response in soft tissue sarcomas exposed to pazopanib using CT-morphologic and textural features and their suitability for evaluating therapeutic response.. Retrospective evaluation of CT response and texture patterns in 33 patients (23 female; mean age: 61.2 years, range, 30-85 years) with soft tissue sarcomas treated with pazopanib from October 2008 to July 2017. Response evaluation was based on modified (m)CHOI-criteria and RECISTv.1.1 and classified as partial response (PR), stable disease (SD), progressive disease (PD). The following CT-texture (CTTA)-parameters were calculated: mean, entropy and uniformity of intensity/average/skewness/entropy of co-occurrence matrix and contrast of neighboring-gray-level-dependence-matrix.. Following mCHOI-criteria, 12 patients achieved PR, 7 SD and 14 PD. As per RECISTv.1.1 9 patients obtained PR, 9 SD and 15 PD. Frequent patterns of response were tumor liquefaction and necrosis (n=4/33, 12.1% each). Further patterns included shrinkage and cavitation (n=2/33, 6.1% each). In responders, differences in mean heterogeneity (p=0.01), intensity (p=0.03), average (p=0.03) and entropy of skewness (p=0.01) were found at follow-up whereas in non-responders, CTTA-parameters did not change significantly. Baseline-CTTA-features differed between responders and non-responders in terms of uniformity of skewness (p=0.045). Baseline-CTTA-parameters did not correlate with any morphologic response pattern.. Most frequent patterns of response to pazopanib were tumor liquefaction and necrosis. Single CT-textural features show strong association with the response to pazopanib. Tumor liquefication and necrosis are important patterns of response to pazopanib. CT-texture analysis has limited associations with specific response patterns.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Soft-tissue sarcomas (STSs) are rare malignant tumors arising from tissues of mesenchymal origin throughout the body with poor prognosis in advanced disease. This commentary describes the current treatment landscape for patients with advanced STS undergoing chemotherapy as well as how pazopanib, a newer multitargeted tyrosine kinase inhibitor, has been incorporated into treatment for different subtypes of STS in our clinical practice.. PubMed was searched (2010-2015) for articles involving the treatment and management of advanced STS. Key search terms included "soft tissue sarcoma", "pazopanib", "chemotherapy", "doxorubicin", "ifosfamide", "trabectedin" and "gemcitabine". Additionally, ClinicalTrials.gov was searched to identify ongoing studies evaluating pazopanib in STS. Reference citations within relevant articles revealed further sources of value.. Standard treatment for advanced STS is single agent or combination systemic chemotherapy. The efficacy of these treatments varies widely, likely because of tumor heterogeneity and cellular mechanisms of chemoresistance, and adverse effects may be a limiting factor for combination therapy. Pazopanib, approved for the treatment of advanced STS in patients who received prior chemotherapy, has demonstrated clinical benefit in a variety of histologic types of advanced STS where the prognosis is often poor. While pazopanib has a favorable safety profile compared with commonly prescribed chemotherapies, it has several safety concerns and dose-limiting adverse effects. We share our best practice for managing adverse events to ensure patient tolerability.. Use of pazopanib increases the treatment options available to control advanced STS, with management of adverse events through close monitoring, patient education and treatment as necessary.

Topics: Deoxycytidine; Gemcitabine; Humans; Indazoles; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Twenty STS patients underwent FDG-PET scans at baseline, two- and eight-weeks following treatment with pazopanib. The FDG-PET scans were evaluated by quantitative PERCIST analysis and visually by an independent nuclear medicine physician and related to RECIST1.1 outcome at eight weeks.. After eight weeks of therapy, 14 out of 20 patients had discontinued pazopanib due to tumor progression identified radiologically ('non-responders' n=12) or toxicity (n=2). Quantitative FDG-PET scoring at two weeks, according to PERCIST guidelines, identified 25% (3 of 12) of the patients radiologically as non-responders versus 42% (5 of 12) identified by visual response analysis.. In this heterogeneous STS patients' cohort, early FDG-PET/CT identified a substantial part of pazopanib non-responders.

Topics: Adult; Aged; Angiogenesis Inhibitors; Feasibility Studies; Female; Fluorodeoxyglucose F18; Humans; Indazoles; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome

Topics: Humans; Indazoles; Patient Selection; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Topics: Antineoplastic Agents; Clinical Trials as Topic; Gastric Acid; Humans; Indazoles; Molecular Targeted Therapy; Precision Medicine; Pyrimidines; Sarcoma; Sulfonamides

Pazopanib (PAZ), a tyrosine kinase inhibitor used in the treatment of soft tissue sarcoma (STS), should not be administered with acid-suppressive medications (ASMs) due to decreased drug solubility. Common practice for patients requiring ASM with PAZ is to separate administration by 12 hours; however, there is little real-world evidence describing clinical outcomes using this strategy. The aim of this study was to determine whether concomitant ASM impacted efficacy and adverse event rates in patients with STS receiving PAZ. Medical records were retrospectively reviewed for patients with STS who received PAZ from June 2011 to July 2017. Patients were stratified into two groups, PAZ with or without ASM (PAZ + ASM or PAZ only). The primary objective was to determine whether progression-free survival (PFS) differed between groups. Secondary objectives were to determine overall survival (OS) and occurrence of grade 3/4 toxicities. Ninety-one patients were included in the study, 42 patients in the PAZ + ASM group and 49 in the PAZ only group. Median PFS was significantly shorter in the PAZ + ASM group than the PAZ only group (5.3 vs. 6.7 months). The PAZ + ASM group also had a 74% higher relative risk of progression or death than the PAZ only group, but there was no difference in OS. Regarding adverse events, the PAZ + ASM group trended toward lower levels of grade 3/4 hypertension (19% vs. 37%). These results suggest that ASM should be avoided in patients with STS receiving PAZ. Larger studies are needed to further elucidate the impact of ASM use with PAZ in clinical practice.

Topics: Aged; Female; Humans; Hypertension; Indazoles; Male; Middle Aged; Progression-Free Survival; Proton Pump Inhibitors; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome

Topics: Chondrosarcoma; Humans; Indazoles; Precision Medicine; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Pazopanib is a multi-tyrosine kinase inhibitor that is used to treat advanced soft-tissue sarcoma, and its efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. In other cancers, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the lymphocyte-to-monocyte ratio (LMR) are associated with chemotherapy response and prognosis. Therefore, we aimed to evaluate the associations of pazopanib response with NLR, PLR, and LMR among patients with advanced soft-tissue sarcoma.. Data regarding NLR, PLR, and LMR were obtained for 25 patients who received pazopanib for soft-tissue sarcoma. The patients were categorized according to their values for NLR (≥3.8 vs. <3.8), PLR (≥230 vs. <230), and LMR (≥2.4 vs. <2.4), and we evaluated the associations of these markers with progression-free survival and overall survival using Kaplan-Meier curves and Cox proportional models.. No significant differences in progression-free survival or overall survival were observed based on the pre-treatment NLR, PLR, and LMR values. However, decreased NLR values after treatment using pazopanib were independently associated with significantly prolonged progression-free survival (hazard ratio: 0.07, p = 0.001) and overall survival (hazard ratio: 0.17, p = 0.0006).. Decreased NLR values after treatment using pazopanib may predict high efficacy and favorable outcomes among patients with advanced soft-tissue sarcoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Blood Platelets; Cell Count; Disease-Free Survival; Female; Humans; Indazoles; Lymphocytes; Male; Middle Aged; Neutrophils; Prognosis; Proportional Hazards Models; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult

In the treatment of metastatic soft tissue sarcoma (STS), pazopanib is considered a standard treatment after failure of chemotherapy. We retrospectively investigated outcomes of pazopanib in patients with metastatic uterine STS.. A retrospective study was performed on 35 consecutive patients with uterine STS treated with oral pazopanib 800 mg daily as salvage therapy for metastatic disease between September 2013 and December 2015. Endpoints included response rate, survival, and safety.. Among 35 patients, 27 (77%) had a histologic diagnosis of leiomyosarcoma (LMS) and the median age was 57 years (range, 36-70). Median number of metastatic sites was one (range, 1-5) with lung as the most frequently involved site. Pazopanib was generally well-tolerated: the major hematologic toxicity was grade 1/2 anemia (14%). Among the non-hematologic toxicities, grade 1/2 stomatitis was most commonly observed (22%), followed by fatigue and hypertension. Objective response and stable disease were observed in 10 (29%) and 11 (31%) patients, respectively. However, most cases of clinical response were observed in patients with LMS: 33% for LMS, 20% for undifferentiated pleomorphic sarcoma, and 0% for endometrial stromal sarcoma. Median progression-free and overall survivals were 5.8 months (95% confidence interval [CI]=3.6-8.1) and 20.0 months (95% CI=11.6-28.4), respectively.. In this "real-world" retrospective study, salvage therapy with pazopanib demonstrated clinically relevant efficacy and tolerability in unselected patients with uterine STS. Although it is encouraging that outcomes for Korean patients with uterine STS were similar to those reported in the phase III trial, the clinical benefit was limited to LMS.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Female; Humans; Indazoles; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Salvage Therapy; Sarcoma; Sulfonamides; Survival Analysis; Uterine Neoplasms

Topics: Angiogenesis Inhibitors; Atrial Flutter; Carcinoma, Renal Cell; Electrocardiography; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides

Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease.. To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES.. Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria.. All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib.. Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines).. Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months.. This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Gemcitabine; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Pyrimidines; Remission Induction; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Sarcoma; Sulfonamides; Young Adult

Pazopanib is a multitargeted tyrosine kinase inhibitor used as a standard treatment for chemotherapy-refractory recurrent or metastatic soft tissue sarcoma. This study aimed to evaluate the efficacy and safety of pazopanib for treatment of metastatic soft tissue sarcoma in the Asian population.. Fifty patients with chemotherapy-refractory recurrent or metastatic soft tissue sarcoma, who had received pazopanib treatment between 2015 and 2016 were enrolled. We reviewed patients' clinical characteristics and studied survival outcomes following pazopanib treatment.. Median follow-up was 5.7 months. Seven patients were still on pazopanib by the end of this study and the disease had progressed in the other 43 patients, leading to 23 deaths. We found that despite treatment more than half the patients experienced disease progression (56% vs 14% partial response and 30% stable disease). The median progression-free survival and overall survival was 3.1 and 11.0 months, respectively. Multivariate analysis identified good Eastern Cooperative Oncology Group performance status (0 or 1) and occurrence of hand-foot skin reaction as independent factors associated with better outcome. Hand-foot skin reaction was 32% in our cohort and the median onset time was 4 (1.00-8.29) weeks. It had dose-dependent effect by clinical observation.. Our study showed that the incidence rate of hand-foot skin reaction in Taiwan is higher than western population, and it is an independent predictive factor for better treatment outcomes.

Topics: Adult; Aged; Asian People; Disease Progression; Disease-Free Survival; Female; Hand-Foot Syndrome; Humans; Indazoles; Male; Middle Aged; Predictive Value of Tests; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Taiwan; Treatment Outcome

Soft tissue sarcomas (STS) are a heterogeneous group of rare mesenchymal neoplasms, accounting for < 1% of all newly diagnosed malignancies. These tumors can occur in almost any anatomic site though they most frequently occur in the extremities. The objective of the study was to describe the epidemiology, treatment paradigm, and real-world outcomes in the clinical management of metastatic STS (mSTS) in the Middle East and North Africa (MEA) region.. MOON was an observational, multicenter, retrospective patient chart review study which included 200 patients with mSTS in the final analysis. The primary objective of the study is exploratory, so it is presented using descriptive statistics.. At the time of presentation, 62.0% patients had metastatic disease, 27.5% had received only their primary diagnosis and 10.0% had experienced a local recurrence. The most frequent STS localizations were lower extremities (74%), trunk (28.5%) and upper extremities (10.5%). Primary tumor was staged as T2b in the majority (60%) of patients. Surgical treatment was performed most often for the primary disease, whereas radiation therapy and chemotherapy were predominantly administered with palliative intent. A total of 38 patients received treatment with pazopanib. Thirteen adverse events (AEs) were attributed to pazopanib in eight patients.. Adult patients treated for STS have al most equal gender ratio and mostly are middle aged. The majority of patients have metastatic disease and disease progression, and half of the patients died from the disease during the period of evaluation. This study obtained real-life data on the clinical management of STS in MEA countries which could be shared with the medical community.

Topics: Adult; Africa, Northern; Aged; Aged, 80 and over; Drug Therapy; Female; Humans; Indazoles; Male; Middle Aged; Middle East; Neoplasm Metastasis; Pyrimidines; Radiotherapy; Retrospective Studies; Sarcoma; Sulfonamides; Surgical Procedures, Operative

The tyrosine kinase inhibitor pazopanib is used for treatment of sarcoma. Recent studies have suggested that the use of pazopanib may lead to the development of pneumothorax, an unexpected adverse effect in patients with sarcoma metastatic to the chest.. We conducted a retrospective case control study of patients with sarcoma with metastases to the chest with pneumothorax (cases) and without pneumothorax (controls). The control population was selected from tumor registry in a 1:4 (cases to controls) ratio. The primary outcome of interest was the association between pazopanib and pneumothorax risk in patients with sarcoma metastatic to the chest. Secondary objective was to evaluate risk factors for pneumothorax.. We identified 41 cases and 164 controls. Using purposeful selection method the odds of developing pneumothorax while being on pazopanib was not significant in univariate (p = .06) and multivariable analysis (p = .342). On univariate analysis risk factors of pneumothorax in patients with sarcoma were age, male sex, African American race, the presence of cavitary lung nodules/masses, and the presence of pleural-based nodules/masses. On multivariate analysis, only the presence of cavitary lung nodules/masses (P < .001) and the presence of pleural-based nodules/masses (P < .001) remained as risk factors for developing pneumothorax.. Pazopanib does not increase the risk of pneumothorax in patients with sarcoma and evidence of metastatic disease to the chest. Presence of cavitary lung nodules/masses and the presence of pleural-based nodules/masses were found to be risk factors for pneumothorax.

Topics: Adult; Aged; Case-Control Studies; Female; Humans; Indazoles; Logistic Models; Lung Neoplasms; Male; Middle Aged; Pneumothorax; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sarcoma; Sulfonamides

Topics: Adult; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Heart Failure; Humans; Indazoles; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients.. Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation.. A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs.. The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.

Topics: Angiogenesis Inhibitors; Compassionate Use Trials; Disease-Free Survival; Female; Hemangiosarcoma; Humans; Indazoles; Leiomyosarcoma; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Solitary Fibrous Tumors; Sulfonamides; Survival Rate; Time Factors; Uterine Neoplasms

Sarcomas are rare, heterogeneous tumors for which prognosis remains dismal in patients with advanced disease. Pazopanib, a vascular endothelial growth factor receptor inhibitor, has shown modest efficacy in patients with soft tissue sarcoma who fail cytotoxic chemotherapy. The cytotoxic agent temozolomide has also demonstrated activity in patients with advanced sarcoma.. We performed a retrospective case series to evaluate the feasibility of adding temozolomide to pazopanib in advanced sarcoma patients following single-agent pazopanib failure.. Patients with recurrent, metastatic sarcomas who had progressed on single-agent pazopanib and continued on pazopanib with the addition of temozolomide were included in this retrospective analysis to examine the tolerability and responses associated with the treatment combination.. Nine patients with a range of sarcoma subtypes were identified (55% female; median age, 48 years; median number of therapies prior to pazopanib, 3). All patients received combination therapy. One patient was recently started on therapy and was excluded from the analysis (n = 8 evaluable patients). Median PFS for single-agent pazopanib was 7.5 months (range 2-19). For the eight evaluable patients (63% female), best response at 4 months with pazopanib plus temozolomide was partial response (n = 1), stable disease (n = 3) and progressive disease (n = 4), with a median PFS of 3.5 months (range 0-15). Median PFS with combination treatment in patients with stable disease or response was 8 months (range 5-15). All four patients who achieved clinical benefit remain on therapy and are tolerating the combination therapy with expected but manageable side effects.. In heavily pretreated patients with advanced sarcoma, the addition of temozolomide to pazopanib was found to be tolerable. Future prospective trials are required to deduce whether temozolomide extends the clinical benefit of pazopanib.

Topics: Adult; Aged; Antineoplastic Agents; Dacarbazine; Disease Progression; Female; High-Throughput Nucleotide Sequencing; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Temozolomide; Treatment Failure; Vascular Endothelial Growth Factor A; Young Adult

Pazopanib is US FDA approved for the treatment of advanced soft tissue sarcomas. All patients with this disease ultimately develop resistance to therapy. Mechanisms of resistance include activation of the mTOR, histone deacetylase (HDAC), MAPK, and ERBB4 pathways. We hypothesized that combining pazopanib with other targeted agents inhibiting these pathways would increase response rates. We retrospectively evaluated the safety and efficacy of pazopanib plus vorinostat, everolimus, lapatinib or trastuzumab, and MEK inhibitor in patients with advanced sarcoma. The Cancer Geneome Atlas (TCGA) data was analyzed for HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations from sarcoma TCGA. Of the 44 advanced sarcoma patients in these trials, 27 (61%) were male; 18 (41%) had bone sarcoma, and 26 (59%) had soft tissue sarcoma. Best response was partial response (PR) in four patients [(overall response rate (ORR) = 9%, 95% confidence interval [CI] 3% to 22%)]. The median progression-free survival (PFS) for all patients was 9.6 weeks (95% CI 8.0 to 15.7 weeks). Analysis of TCGA data revealed HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations in 112/243 (46%) of patients predominantly HDAC1-11 (41%) alterations. Pazopanib combinations did demonstrate safety in combination with other agents. TCGA data suggests further evaluation of epigenetic pathway inhibitors in sarcoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Histone Deacetylase Inhibitors; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Receptor, ErbB-2; Sarcoma; Signal Transduction; Sulfonamides; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Topics: Angiogenesis Inhibitors; Bronchial Fistula; Female; Humans; Indazoles; Lung Neoplasms; Middle Aged; Pleural Diseases; Pyrimidines; Sarcoma; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Etoposide; Humans; Ifosfamide; Indazoles; Infant; Male; Pyrimidines; Remission Induction; Sarcoma; Sulfonamides

The French EMS study prospectively collected exhaustive data from STS patients diagnosed in the Rhone-Alpes region from 2005 to 07.. The database included diagnosis/histology, surgery, radiotherapy, systemic treatments and treatment response. Treatment patterns and outcomes of patients with metastatic disease, excluding adipocytic sarcoma and GIST were analyzed.. Of 888 total patients, 145 were included based on having metastatic disease and appropriate subtypes. All patients received treatment with systemic therapy being most common (74%, n = 107), followed by radiotherapy (30%, n = 44) and surgery (23%, n = 33). Doxorubicin, alone or in combination, was the most common first line systemic therapy (65%, n = 46). Drugs without license in sarcoma were used in 38-83% of treatments depending on treatment line. 24% of frontline patients demonstrated an objective response, decreasing to 11% objective responses in second line but no responses were documented beyond second line, with median PFS declining with each additional line. Median PFS also declined in patients receiving surgery compared to those receiving no surgery (8-15 m vs 5 m). Median OS from metastatic diagnosis for patients receiving systemic therapy was double that of patients without systemic treatment (24 m vs 12 m, p = 0.007).. Outcomes in this population were poor and declined with successive treatment. However, results suggest that further anticancer therapies in recurrent sarcoma might be beneficial.

Topics: Aged; Antineoplastic Agents; Female; France; Humans; Indazoles; Male; Middle Aged; Prospective Studies; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome

To investigate whether TP53 DNA mutational status impacts progression-free survival (PFS) in patients with advanced sarcomas (soft tissue sarcoma) treated with vascular endothelial growth factor receptors (VEGFR) inhibition.. We retrospectively reviewed 19 cases of patients treated at the Ohio State James Comprehensive Cancer Center with advanced sarcoma treated with VEGFR inhibition who also had next-generation sequencing of their tumors (via FoundationOne Heme panel). We evaluated TP53 as well as mutations that were observed in at least 20% of patients and evaluated its contribution to PFS using the Kaplan-Meier survival analysis of available radiology end points.. Mutations that were observed in at least 20% of patients included TP53 and Rb1. Only TP53 was predictive of PFS in the context of VEGFR inhibition. The PFS of patients with TP53 mutations was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)].. Mutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with advanced sarcoma. Larger, prospective studies are necessary to confirm these findings.

Topics: Angiogenesis Inhibitors; Base Sequence; Disease-Free Survival; Female; Genetic Markers; High-Throughput Nucleotide Sequencing; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Retinoblastoma Protein; Retrospective Studies; Sarcoma; Sequence Analysis, DNA; Sulfonamides; Treatment Outcome; Tumor Suppressor Protein p53

A patient with a pleural epitheloid hemangio-endothelioma (EHE) who failed to respond to six cycles of initial chemotherapy with iphosphamide and epirubicine was treated with pazopanib in second-line. A significant subjective and objective metabolic response on (18)F-fluoro-deoxyglucose positron-emission tomography-computed tomography was noted. Based on this observation, the role of vasculoendothelial growth factor receptor inhibitors such as pazopanib (or other tyrosine kinase inhibitors), in the treatment of pleural EHE should be established through prospective collaborative studies as upfront medication and in combination with chemotherapy.

Topics: Adult; Disease-Free Survival; Hemangioendothelioma; Humans; Indazoles; Male; Pyrimidines; Sarcoma; Sulfonamides; Treatment Outcome

Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data.. Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS.. The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively.. There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408-16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Chemical and Drug Induced Liver Injury; Disease-Free Survival; Female; Fibrosarcoma; Humans; Hypertension; Indazoles; Japan; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Neoplasm Recurrence, Local; Neurilemmoma; Pneumothorax; Product Surveillance, Postmarketing; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Sulfonamides; Survival Analysis; Thrombocytopenia

Topics: Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Indazoles; Nurse's Role; Patient Education as Topic; Pyrimidines; Sarcoma; Sulfonamides

Topics: Humans; Indazoles; Pyrimidines; Sarcoma; Sulfonamides

Topics: Antineoplastic Agents; Chromosomal Proteins, Non-Histone; Dioxoles; Disease-Free Survival; DNA-Binding Proteins; Furans; Humans; Indazoles; Ketones; Molecular Targeted Therapy; Mutation; Pyrimidines; Sarcoma; SMARCB1 Protein; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Transcription Factors

A consensus has not been reached regarding the optimal pazopanib dosing schedule, which we determined in patients who received pazopanib at our Institution.. Twenty-five patients who were prescribed pazopanib between 2012 and 2015 were included in this retrospective analysis.. The median progression-free survival (PFS) time was 7.7 months. This time (various doses) was similar to that achieved by high-dose pazopanib in the PALETTE study. The log-rank test revealed no significant differences in the PFS times between the low- and high-dose pazopanib groups, with the majority of patients receiving a dose of 400 mg, indicating that controlling the side-effects might be more critical than administering higher doses.. Pazopanib should be started from a low dose with careful increase to avoid pazopanib-related side-effects, which is necessary to provide a balance between the life-prolonging effects of pazopanib and quality of life (QoL) of patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Female; Histiocytoma, Malignant Fibrous; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Quality of Life; Retrospective Studies; Sarcoma; Sulfonamides

To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib.. Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose.. Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17).. Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chondrosarcoma; Disease Progression; Drug Administration Schedule; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sarcoma; Sirolimus; Sulfonamides; Survival Analysis; Treatment Outcome; Young Adult

Soft tissue sarcomas are rare malignant tumors with a great variety of histological types and different response to multimodality treatment. Pazopanib has been recently introduced for the treatment of non-adipocytic metastatic soft tissue sarcomas which are resistant to conventional chemotherapy. Spontaneous pneumothorax is a rare but well recognized complication of this molecule and its treatment is quite challenging. The case reported herein describes the surgical management of a simultaneous bilateral spontaneous pneumothorax in a patient with pulmonary metastases treated with pazopanib. It underlines the fact that the main objective should be the maintenance of the treatment in patients who benefit from it. Close oncologic and surgical collaboration is crucial in order to deal with adverse effects due to the anti-angiogenic action of pazopanib.

Topics: Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Muscle Neoplasms; Pneumonectomy; Pneumothorax; Pyrimidines; Sarcoma; Sulfonamides

To assess the efficiency of pazopanib compared with trabectedin in the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) after chemotherapy failure.. The progression of STS was modeled using a partitioned survival analysis model. Survival curves for pazopanib and trabectedin were modeled using data from PALETTE phase III clinical trial and based on unadjusted indirect comparison. Effectiveness was measured in quality-adjusted life years (QALY). The Spanish National Health System perspective was considered over a 10-year time horizon, including direct health care costs (, 2014). A discount rate of 3% was applied to both costs and outcomes. The robustness of the results was evaluated using univariate and probabilistic sensitivity analyses (PSA).. Pazopanib was associated with better health outcomes than trabectedin (0.705 versus 0.686 QALY). Pazopanib also showed lower direct health care costs (21,861 versus 45,338), mainly due to lower cost of pharmacological treatment (13,762 versus 33,392), administration (57 versus 2,955) and AE management (658 versus 1,695) costs. PSA confirmed that pazopanib was a dominant option in 71% of the simulations performed.. In this analysis, and from a health economics perspective, pazopanib was the option of choice versus trabectedin in the treatment of adult patients with advanced soft-tissue sarcoma after chemotherapy failure.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Dioxoles; Disease Progression; Drug Costs; Humans; Indazoles; Probability; Pyrimidines; Quality-Adjusted Life Years; Sarcoma; Spain; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Treatment Outcome

In Japan, pazopanib has been made available to soft tissue sarcoma patients, also to patients histologically diagnosed as ineligible for the international Phase 3 study (PALETTE). However, clinical evidence for the use of pazopanib in PALETTE-ineligible patients is currently insufficient.. We retrospectively reviewed medical records of soft tissue sarcoma patients treated with pazopanib at our institute. By pathological review, the patients' eligibility for the PALETTE study was evaluated and the differences in their responses to pazopanib and incidences of adverse events were investigated.. From November 2012 to August 2014, a total of 47 patients received pazopanib, 38 (81%) of whom were histologically eligible for the PALETTE study, and 9 of whom (19%) were not. The median follow-up time was 7.5 months (range 1.4-20.3 months). An objective response was observed in both groups, but the patients' survival tended to be longer in the PALETTE-eligible patients; median progression-free survival was 4.5 months vs. 2.9 months (P = 0.15) and overall survival was 10.7 months vs. 7.8 months (P = 0.55), though these differences were not statistically significant. There were no significant differences in the incidence of adverse events by PALETTE eligibility, but dose skipping or dose reduction was more likely to be observed in PALETTE-ineligible patients.. Pazopanib is tolerable to soft tissue sarcoma patients ineligible for the PALETTE study and some of them respond to pazopanib, but the prognoses of patients ineligible for the PALETTE study might be worse than those of PALETTE-eligible patients. The indication of pazopanib for soft tissue sarcoma patients with PALETTE-ineligible histologies should be decided carefully.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Indazoles; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Patient Selection; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Treatment Outcome

We retrospectively reviewed outcomes of treatment with pazopanib, an oral multi-tyrosine kinase angiogenesis inhibitor, in patients with advanced soft tissue sarcoma, a rare and heterogeneous tumor group with limited treatment options.. Between 2009 and 2013, 43 patients with metastatic soft tissue sarcoma received pazopanib as salvage chemotherapy after one or more cytotoxic regimens. Response rate, progression-free survival, and overall survival were analyzed according to histological subtype, Eastern Cooperative Oncology Group performance status, and metastatic site.. Common histological subtypes included leiomyosarcoma (n = 9), angiosarcoma (n = 6), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (MFH/UPS, n = 5), malignant peripheral nerve sheath tumor (MPNST, n = 5), and synovial sarcoma (n = 4). Nineteen patients (44.2%) received more than two chemotherapy regimens before pazopanib. At the time of analysis, 208 treatment cycles of pazopanib had been administered (median, 4.8 cycles per patient), and no treatment-related mortality occurred. The disease control rate was 61.0% (95% confidence interval [CI], 46.1-75.9%), and the overall response rate was 17.1% (partial response, n = 7; complete response, n = 0). Partial response was achieved in two patients with synovial sarcoma, two with MFH/UPS, one with MPNST, one with leiomyosarcoma, and one with angiosarcoma. The median lengths of progression-free survival and overall survival were 5.0 months (95% CI, 3.6-6.4 months) and 8.2 months (95% CI, 5.8-10.6 months), respectively. Progression-free survival was shorter in the patients with liposarcoma and rhabdomyosarcoma (1.3 and 0.9 months, respectively) than in those with leiomyosarcoma, MPNST, MFH/UPS, and synovial sarcoma (5.6, 6.5, 7.1, and 7.7 months, respectively).. Pazopanib demonstrated acceptable antitumor activity in the Asian patients who had been heavily pretreated for sarcoma, with seemingly more favorable results in the patients with leiomyosarcoma, MPNST, MFH/UPS, and synovial sarcoma than in those with liposarcoma and rhabdomyosarcoma.

Topics: Adult; Aged; Disease-Free Survival; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides

Pazopanib was approved by the U.S. Food and Drug Administration for use in patients with soft tissue sarcoma (STS) in 2012. Because of the scarcity of effective treatments for advanced STS, pazopanib has become commonly prescribed.. The purpose of this study was to assess the knowledge level of nurses regarding the safe administration of pazopanib, as well as management of its side effects. The study was also intended to examine the consistency of patient education about pazopanib.. A 12-question online survey was completed by six nurses working in the outpatient sarcoma department of a National Cancer Institute-designated comprehensive cancer center. The survey included questions about patient education, including side-effect management and medication safety.. The survey revealed that most nurses were consistent with best practices surrounding pazopanib teaching and side-effect management. However, many differences were observed, and patient education regarding drug interactions and the safe administration of pazopanib is lacking. Further standardization of nursing practice in this regard would greatly benefit patients taking pazopanib.

Topics: Angiogenesis Inhibitors; Clinical Competence; Humans; Indazoles; New York; Patient Education as Topic; Practice Patterns, Nurses'; Pyrimidines; Sarcoma; Sulfonamides; Surveys and Questionnaires

Soft tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. The biology of STS causes high aggressiveness, poor prognosis due to early development of distant metastases and limited chemotherapeutic options due to tumor resistance. The paper considers the current principles of chemotherapy for early and metastatic disease. Results of own experience of advanced STS patients' treatment are presented and discussed.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dacarbazine; Deoxycytidine; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Ifosfamide; Indazoles; Indoles; Male; Molecular Targeted Therapy; Neoadjuvant Therapy; Niacinamide; Palliative Care; Phenylurea Compounds; Polyethylene Glycols; Pyrimidines; Pyrroles; Radiography; Sarcoma; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

A patient-derived nude-mouse model of soft-tissue sarcoma has been established and treated in the following groups: (1) untreated controls; (2) gemcitabine (GEM) (80 mg/kg, ip, weekly, 3 weeks); (3) Pazopanib (100 mg/kg, orally, daily, 3 weeks) and (4) Salmonella typhimurium A1-R (5 × 10(7) CFU/body, ip, weekly, 3 weeks). The sarcoma was resistant to GEM (p = 0.879). Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was no significant difference (p = 0.115). S. typhimurium A1-R significantly inhibited tumor growth compared to the untreated mice (p = 0.001). S. typhimurium A1-R was the only effective treatment for the soft-tissue sarcoma nude mouse model among all treatments including a newly approved multiple tyrosine kinase inhibitor; Pazopanib. These results suggest tumor-targeting S. typhimurium A1-R is a promising treatment for chemo-resistant soft-tissue sarcoma.

Topics: Animals; Antineoplastic Agents; Deoxycytidine; Disease Models, Animal; Gemcitabine; Indazoles; Mice; Mice, Nude; Pyrimidines; Salmonella Infections; Salmonella typhimurium; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Xenograft Model Antitumor Assays

Reliable biomarkers of pazopanib's efficacy in soft tissue sarcoma (STS) are lacking. Hypertension (HTN) is an on-target effect of vascular endothelial growth factor (VEGF)-receptor inhibitors such as pazopanib. We evaluated the association of pazopanib-induced HTN with antitumour efficacy in patients with metastatic non-adipocytic STS.. Associations between pazopanib-induced-HTN and antitumour efficacy were retrospectively assessed across 2 prospective studies (European Organisation for Research and Treatment of Cancer (EORTC) study 62043 and 62072) in metastatic STS patients who received pazopanib 800 mg daily. Only patients with baseline blood pressure (BP)<150/90 mmHg, were included. BP was measured monthly. HTN was reported according to National Cancer Institute-Common Toxicity Criteria Adverse Events (NCI-CTC AE) grading (v3.0), and as absolute differences compared to baseline. The effect of HTN developing in patients without baseline anti-hypertensive medication was assessed on progression-free (PFS) and overall survival (OS) using a landmark analysis stratified by study; univariately using the Kaplan-Meier method and a log-rank test, and in a multivariate Cox regression model after adjustment for important prognostic factors.. Of the 337 patients eligible for this analysis, 21.7% received anti-hypertensive medication at baseline and had a similar PFS and OS compared to those who did not. In patients without baseline anti-hypertensive medication, 38.6% developed HTN. As the majority of patients developing HTN did so within 5 weeks after initiation of pazopanib (68.6%), this time point was used as landmark. Univariately, there was no effect on PFS or OS from occurrence of HTN within 5 weeks of treatment expressed either in NCI-CTC AE criteria or as maximal differences from baseline in systolic and diastolic BP. Also in multivariate analysis, after adjusting for important prognostic factors, the occurrence of HTN expressed in the different parameters was not associated with PFS and OS.. In this retrospective analysis, pazopanib-induced HTN did not correlate with outcome in pazopanib-treated STS patients. The occurrence of HTN cannot serve as biomarker in this setting.

Topics: Adult; Aged; Blood Pressure; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Europe; Female; Follow-Up Studies; Humans; Hypertension; Indazoles; Male; Middle Aged; Outcome Assessment, Health Care; Proportional Hazards Models; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Sarcoma; Sulfonamides

Topics: Angiogenesis Inhibitors; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides; Tomography, X-Ray Computed

The present studies were to determine whether the multi-kinase inhibitor pazopanib interacted with histone deacetylase inhibitors (HDACI: valproate, vorinostat) to kill sarcoma cells. In multiple sarcoma cell lines, at clinically achievable doses, pazopanib and HDACI interacted in an additive to greater than additive fashion to cause tumor cell death. The drug combination increased the numbers of LC3-GFP and LC3-RFP vesicles. Knockdown of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, and to a lesser extent BCL-XL or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 was required to strongly suppress drug combination lethality. The drug combination inactivated mTOR and expression of activated mTOR strongly suppressed drug combination lethality. Treatment of animals carrying sarcoma tumors with pazopanib and valproate resulted in a greater than additive reduction in tumor volume compared with either drug individually. As both pazopanib and HDACIs are FDA-approved agents, our data argue for further determination as to whether this drug combination is a useful sarcoma therapy in the clinic.

Topics: Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Cell Line, Tumor; Drug Synergism; Female; Gene Knockdown Techniques; Histone Deacetylase Inhibitors; Indazoles; Membrane Proteins; Mice, Nude; Microtubule-Associated Proteins; Pyrimidines; Receptors, Death Domain; Sarcoma; Signal Transduction; Sulfonamides; Valproic Acid

Topics: Adult; Angiogenesis Inhibitors; Humans; Incidence; Indazoles; Male; Middle Aged; Pneumothorax; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Increasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).. We exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.. After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).. Anti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.

Topics: Aldehyde Dehydrogenase 1 Family; Angiogenesis Inhibitors; Animals; Antigens, CD; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Indazoles; Isoenzymes; Liver Neoplasms; Lung Neoplasms; Mice, Inbred NOD; Neoadjuvant Therapy; Neoplastic Stem Cells; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Retinal Dehydrogenase; Sarcoma; Sorafenib; Sulfonamides; Tissue Array Analysis; Xenograft Model Antitumor Assays

Topics: Adult; Bone Neoplasms; Female; Hair Diseases; Hip Joint; Humans; Indazoles; Pigmentation Disorders; Protein-Tyrosine Kinases; Pyrimidines; Sarcoma; Sulfonamides

Topics: Antineoplastic Agents; Female; Humans; Indazoles; Male; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Topics: Clinical Trials, Phase III as Topic; Humans; Indazoles; Molecular Targeted Therapy; Prognosis; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides; Survival Rate

Pazopanib inhibits multiple receptor tyrosine kinases, through which it mediates antiangiogenic and antitumour effects. The clinical efficacy of oral pazopanib in patients with metastatic soft tissue sarcoma (STS) was demonstrated in a randomized, double-blind, placebo-controlled, phase III trial (PALETTE), generally confirming the findings of an earlier, noncomparative phase II study. In the multicentre PALETTE trial, pazopanib 800 mg once daily significantly prolonged median progression-free survival (PFS; primary endpoint) ≈3-fold relative to placebo (4.6 vs 1.6 months) in adults with progressive metastatic STS following standard chemotherapy. According to subgroup analyses, pazopanib provided benefit over placebo in terms of PFS regardless of whether the tumour was low/intermediate or high grade and regardless of tumour histology (leiomyosarcoma, synovial sarcoma, other STS), although patients with adipocytic STS were among those excluded from the PALETTE trial, as sufficient benefit had not been shown with the drug in patients with adipocytic STS in the phase II study. At final analysis of the PALETTE trial, median overall survival was ≈2 months longer with pazopanib than with placebo, although this between-group difference was not statistically significant. Oral pazopanib generally had no detrimental effect on health-related quality of life and had an acceptable tolerability profile in patients with STS in the PALETTE trial, with adverse events generally being grade 1 or 2 in severity.

Topics: Adult; Angiogenesis Inhibitors; Humans; Indazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides; Treatment Outcome

Pazopanib (GW786034) is a novel, small-molecule tyrosine kinase inhibitor. The primary mechanism of action of pazopanib can be described through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of VEGF receptor (VEGFR) and PDGF receptor (PDGFR). It is an orally available angiogenesis inhibitor that targets VEGFR-1, -2 and -3, PDGFR-α and -β, and c-kit. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in that class. Phase I studies defined the recommended monotherapy dose of pazopanib as 800 mg once daily. In 2009, it was approved in the USA for the treatment of advanced and metastatic renal cell carcinoma, and subsequently approved in other countries and demonstrated clinically and statistically significant activity in Phase II and III studies in advanced soft tissue sarcoma patients. This article focuses on its emerging role in the treatment of advanced soft tissue sarcomas.

Topics: Antineoplastic Agents; Humans; Indazoles; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Sulfonamides