Pazopanib In Patients Research Articles

A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib

Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib. Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2-7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5-37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6-5.2), and the median OS was 10.7 months (95% CI 3.9-NR). Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.

Risk of gastrointestinal events with sorafenib, sunitinib and pazopanib in patients with solid tumors: A systematic review and meta‐analysis of clinical trials

Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) in patients with cancer treated with these agents. PubMed databases were searched for articles published till May 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 6,447 patients were available for the meta-analysis; 2,260 had renal cell carcinoma (RCC) and 4,187, 1,691 non-small cell lung cancers, 599 hepatocellular cancers, 1,066 breast cancers, 165 neuroendocrine tumors, 304 gastrointestinal stromal tumors and 362 soft tissue sarcomas. Diarrhea was the most common GI event. When stratified by tumor type (RCC vs. non-RCC), the difference among the incidences of GI events was significant for diarrhea (p < 0.001) and vomiting (p = 0.006), that resulted higher in RCC patients. In RCC patients, sorafenib registered the lower incidence and RR of all grades GI events. The difference was statistically significant for sorafenib versus sunitinib-related all and high-grade events (p < 0.001) and for sorafenib versus pazopanib all grades GI events (p < 0.001) and high-grade anorexia (p < 0.001). Treatment with VEGFR TKIs sorafenib, sunitinib and pazopanib is associated with a significant increase in the risk of GI events in patients with cancer, and frequent clinical monitoring should be emphasized when managing these three and newer VEGFR TKIs.

A Phase II Safety and Efficacy Study of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Patients With Metastatic Urothelial Cancer

BackgroundVascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. MethodsPatients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. ResultsNineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. ConclusionsPazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies.

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.

Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors

The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites. In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day. Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration-time curve 24 h post-dose (AUC(0-24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0-24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0-24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased. Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.

A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update

BackgroundIn this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. MethodsTreatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. FindingsThe difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71–1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315–0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215–1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. InterpretationAlthough no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Advanced medullary thyroid cancer treated with Sorafenib: A case report

Background: Medullary thyroid carcinoma (MTC) accounts for 5% of all thyroid carcinomas. As no effective systemic therapy exists, surgery is the only curative treatment for MTC. In the last few years, several clinical trials have tested the efficacy of new multi-targeted agents such as sorafenib, vandetanib, motesanib, sunitinib and pazopanib in patients with metastatic MTC. Summary: In June 2010, a 38-year-old male patient complained on pain on swallowing and coughs. Physical examination detected a hard nodule of 2 cm on the left side of his neck. A fine-needle aspiration of it yielded evidence of carcinoma. A computed tomography scan showed multiple lyphadenopathies. In August 2010, the patient underwent an incomplete thyroidectomy and received radiotherapy. In spite of that, he was still unable to swallow either solids or liquids, and suffered dyspnoea on moderate exertion. In May 2011, the patient started receiving sorafenib and levothyroxine. After 20 days, his clinical symptoms were less severe and palpable lymphadenopathies shrank by 50%. After 5 months, the patient still had no dysphagia or dyspnoea, but developed fatigue and elevated transaminases. Sorafenib was discontinued and the liver was examined by ultrasonography with no abnormal findings. After a two-week rest period, the patient resumed sorafenib from November 2011 to December 2012, achieving a clinical, biochemical and radiological response. Conclusion: This case provides limited evidence for a potential role for sunitinib in the treatment of patients with metastatic MTC.

Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis

To gain a better understanding of the overall incidence and risk of hypertension in cancer patients who receive pazopanib and to compare the differences in incidence among sorafenib, sunitinib, and pazopanib. Several databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned single drug pazopanib 800 mg/day with data on hypertension available. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials. A total of 1,651 patients with a variety of solid tumors from 13 clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hypertension in cancer patients were 35.9 % (95 % CI 31.5-40.6 %) and 6.5 % (95 % CI 5.2-8.0 %), respectively. The use of pazopanib was associated with an increased risk of developing all-grade (RR 4.97, 95 % CI 3.38-7.30, p < 0.001) and high-grade hypertension (RR 2.87, 95 % CI 1.16-7.12, p = 0.023). Additionally, there was no significant difference in the incidence of all-grade (RR 1.21, 95 % CI 0.96-1.53, p = 0.11) and high-grade hypertension (RR 1.29, 95 % CI 0.80-2.07, p = 0.30) between RCC and non-RCC patients. Interestingly, the risk of all-grade hypertension with pazopanib was substantially higher than sorafenib (RR 1.99; 95 % CI 1.73-2.29, p = 0.00) and sunitinib (RR 2.20; 95 % CI 1.92-2.52, p = 0.00), while the risk of pazopanib-induced high-grade hypertension was similar to sorafenib (RR 0.98; 95 % CI 0.75-1.30, p = 0.90) and sunitinib (RR 0.81; 95 % CI 0.62-1.06, p = 0.12). The use of pazopanib is associated with a significantly increased risk of developing hypertension. Close monitoring and appropriate managements are recommended during the therapy. Future studies are still needed to investigate the risk reduction and possible use of pazopanib in selected patients.

Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma.2. In this two-part study, we investigated the metabolism, disposition of [14C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer.3. In part A, three men each received a single oral dose of [14C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose).4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5–28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

Pazopanib

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.

PALETTE: Final overall survival (OS) data and predictive factors for OS of EORTC 62072/GSK VEG110727, a randomized double-blind phase III trial of pazopanib versus placebo in advanced soft tissue sarcoma (STS) patients.

10009 Background: At ASCO 2011 we presented an increase in median progression-free survival (PFS) of pazopanib of 13 weeks (median 7 to 20 weeks; HR 0.31) in a randomized double-blind, placebo-controlled phase III trial in advanced non-adipocytic STS patients pretreated with chemotherapy. Now we present final OS data and predictive factors for OS, such as ethnicity, ancestry and well-known prognostic and predictive factors in STS patients treated with chemotherapy. Methods: At clinical cut-off median follow-up was 25 months. Comparison of both treatments for OS was performed using a two-sided log rank test stratified for number of prior lines of systemic therapy for advanced disease and WHO performance status (PS). HR was calculated with a 2-sided CI. A Kaplan-Meier OS curve was used. Baseline characteristics as potential predictive factors for OS were: PS (0 vs 1), number of lines of prior therapy for advanced disease (0-1 vs 2+), age (≤55 yrs vs &gt; 55 yrs), gender, ethnicity (Hispano or Latino vs other), geographic ancestry (White Caucasian, Asian, other), tumour grade (1-2 vs 3), histology (leiomyosarcoma vs synovial sarcoma vs other). A Cox model was fitted with the investigated factor, treatment arm and associated interaction factor. Data of all 369 randomized patients (123 placebo, 246 pazopanib) were used for the analyses. Results: Median OS (95% CI) was 10.7 (8.7-12.8) in the placebo versus 12.5 (10.6-14.8) months in the pazopanib group, HR: 0.86 (0.67-1.1). Post study protocol systemic treatment was administered in 63% of placebo, and in 49% of pazopanib treated patients. None of the investigated factors showed any statistical significant predictive value for OS. Conclusions: Although pazopanib demonstrated a statically significant increase in PFS compared to placebo, final OS analysis, which showed a trend in favor of pazopanib in patients with metastatic non-adipocytic STS, did not reach statistical significance. The factors studied were not predictive for OS.

A phase I study of BMS-936558 plus sunitinib or pazopanib in patients with metastatic renal cell carcinoma.

TPS2614 Background: Standard treatments for metastatic renal cell carcinoma (mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib, pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus, everolimus). However, most patients (pts) develop resistance and complete responses are rare. Upregulation of programmed death-1 (PD-1) in tumor infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for mRCC. In preliminary results of a phase I trial, the anti-PD-1 monoclonal antibody BMS-936558 had antitumor activity in pts with advanced tumors, including objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a phase I study planned to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of BMS-936558, when combined with sunitinib or pazopanib in pts with mRCC. Methods: This open-label study will have two parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558 plus pazopanib) conducted in two parts (dose escalation and dose expansion). Pts must have received ≥1 prior systemic therapy to be eligible for dose escalation. Only treatment-naïve pts will be eligible for dose expansion. Up to 36 pts (18 per arm) will be treated in the dose-escalation phase. After determining the MTD of BMS-936558, treatment-naïve pts will be enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed on Days 1 and 22 and sunitinib or pazopanib given according to product label. Adverse events will be graded according to NCI CTCAE v4.0. Disease will be assessed every 6 weeks for the first four assessments and then every 12 weeks until disease progression. Pts will be treated until unacceptable toxicity, disease progression, or withdrawal of consent. The safety profile in pts treated at the MTD will be used to determine the recommended phase II study dose of BMS-936558 in each combination arm. Secondary objectives will include OR rate and duration of response based on RECIST 1.1. Exploratory analyses will investigate predictive biomarkers of BMS-936558.

Abstract 5571: Inflammatory response as a novel prognostic parameter in patients with metastatic renal cell carcinoma treated with pazopanib

Abstract Over sixty thousand patients were diagnosed with metastatic renal cell carcinoma (mRCC) in 2010, yet no tumor markers have been identified. Standard prognostic systems only measure characteristics at baseline and do not assess the potential benefit of therapeutic intervention. The introduction of receptor tyrosine kinase inhibitors has significantly changed the management of mRCC. Pazopanib, a selective, multi-targeted, receptor tyrosine kinase inhibitor, was approved for mRCC in 2009. The modified Glasgow Prognostic Score (mGPS), a prognostic system based on inflammatory biomarkers (serum C-reactive protein (CRP) and albumin), has been validated in the pre-treatment setting for mRCC treated with surgery or cytokines. In this study, we present data demonstrating the correlation of serial mGPS measurements with objective responses to targeted therapy with pazopanib in patients with mRCC. We conducted a retrospective chart review of patients seen at the Winship Cancer Institute for whom serial CRP and albumin measurements as well as imaging studies were available while taking pazopanib. In these patients we assessed the correlation of pre- and post-treatment mGPS scores to objective responses by imaging. Twenty patients met inclusion criteria. Of these patients, 12 (60%) had progressive disease, and 8 (40%) had clinical benefit response (defined as stable disease, partial response, or complete response) by imaging. An elevated pre-treatment mGPS score had 75% sensitivity (95% confidence interval 35.5%-95.5%; P&amp;lt;0.01) and 83.3% specificity (95% confidence interval 50.9%-97.1%; P&amp;lt;0.01) for disease progression at the end of treatment. On the other hand, an elevated post-treatment mGPS score had 100% sensitivity (95% confidence interval 59.8%-100%; P&amp;lt;0.01) and 100% specificity (95% confidence interval 69.9%-100%; P&amp;lt;0.01) for disease progression at the end of treatment. Although these data require prospective validation, they suggest that serial measurements of serum inflammatory biomarkers may improve the sensitivity and specificity of mGPS for response to therapy. If confirmed, inflammatory response rates based on mGPS may become a valuable and cost effective tool to guide patient care and drug development for mRCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5571. doi:1538-7445.AM2012-5571

Treatment selection in metastatic renal cell carcinoma: expert consensus

In metastatic renal cell carcinoma (mRCC), many factors influence clinical decisions, including histology, tumour burden, prognostic factors, comorbidities, and the ability of the patient to tolerate treatment. Progression-free survival (PFS) durations reported from randomized trials of targeted therapies vary considerably, in part because of differences in patient characteristics. For first-line therapy, an estimate of PFS with sunitinib, bevacizumab plus interferon, or sorafenib in a 'general' population is 8-9 months, but each regimen is suitable for different patient categories. For example, sunitinib is suitable for all-prognosis groups, particularly younger, fitter patients; pazopanib for patients with a good or intermediate prognosis; bevacizumab plus interferon for good-prognosis patients or those with indolent disease; and sorafenib for patients at all prognostic risk levels, particularly the elderly and those with comorbidities. Sequential therapy with targeted agents provides significant benefit, and should be considered in all patients who can tolerate such treatment. Level 1 evidence supports sequential use of tyrosine kinase inhibitors, as well as these agents followed by everolimus. We consider how patient characteristics have influenced the results of studies of first-line therapy, and we provide expert opinion on the most appropriate treatment choices for particular patient groups receiving first-line and second-line therapy.

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36-68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0-70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile.

Pazopanib in patients with metastatic renal cell carcinoma previously treated with sunitinib or bevacizumab: A Sarah Cannon Research Institute phase II trial.

4659 Background: Pazopanib, a multi-targeted inhibitor of VEGFR, PDGFR, and c-KIT, is an active first-line agent in the treatment of advanced renal cell carcinoma (RCC). The efficacy of pazopanib in patients (pts) who have progressed on other anti-angiogenesis agents, particularly sunitinib, is unclear. Methods: Pts with metastatic clear-cell RCC who had progressed on or were intolerant of first-line single-agent sunitinib or bevacizumab were eligible. Additional criteria: ECOG PS 0 or 1; measurable disease (RECIST); previous nephrectomy unless clinically inappropriate; no active CNS metastases; adequate bone marrow, kidney, liver function; no risk factors for anti-angiogenesis agents; informed consent. All pts received pazopanib 800mg PO daily. Response was assessed every 8 weeks until progression. Results: 44 pts have been treated with pazopanib (previous sunitinib – 32; previous bevacizumab – 12). Additional pt characteristics: male/female, 77%/23%; Motzer risk low/intermediate/high, 25%/43%/32%; previous nephrectomy, 93%. The median duration of treatment was 24 weeks (range 0 to 52 weeks). After a median follow-up of 9 months, efficacy is as follows (see table). 37 pts remain alive, and 13 are continuing treatment. Toxicity with pazopanib was similar to previous reports: frequent grade 3/4 toxicity included fatigue (14%), hypertension (11%), proteinuria (11%). Three pts discontinued treatment due to toxicity, and 13 required dose reductions. Conclusions: Pazopanib is active and well tolerated following treatment with either sunitinib or bevacizumab. All (N=44) Previous sunitinib (N=32) Previous bevacizumab (N=12) ORR 9 (20%) 5 (16%) 4 (33%) Disease control rate (CR+PR+SD) 31 (77%) 21 (66%) 10 (83%) Median PFS, mo. 9.23 (95% CI: 5.42, NA) 12.06 (95% CI: 6.14, NA) 8.05 (95% CI: 2.76, 11.93)

PAZONET: A phase II trial of pazopanib in patients with metastatic neuroendocrine tumors (NETs) who may have previously received antiangiogenic or mTOR treatment.

TPS171 Background: NETs are characterized by profuse vasculature, VEGF and VEGFR-2 are overexpressed in 60-84% of the carcinoids and pancreatic islet cells tumors. Other pro-angiogenic factors like...

Risk of high-grade liver toxicity with pazopanib in patients with cancer: A meta-analysis.

4595 Background: Pazopanib, as an oral receptor tyrosine kinase inhibitor, has been approved for the treatment of advanced renal cell cancer (RCC) and undergoing evaluation in other tumors. Hepatotoxicity is a concern for clinical application. This study was conducted to determine the risk of high-grade liver toxicity with pazopanib by a systematic review and meta-analysis of clinical trials. Methods: Databases from PubMed, Web of Science and abstracts presented at ASCO meetings up to December 2010 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which pazopanib was started at 800 mg daily as a monotherapy. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Results: A total of 1,155 patients with a variety of solid tumors from eight clinical trials were included for the analysis. The incidence of all-grade ALT el...

Pazopanib for the treatment of renal cancer

Introduction: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.Areas covered: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.Expert opinion: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents – sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) – have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.