***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose : To evaluate clinical activity and target modulation of v and etanib in women with recurrent ovarian cancer . Experimental Design : A phase II trial of orally administered v and etanib 300 mg daily was design ed to include analyses of target inhibition through paired biopsies and dynamic imaging . Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy . Biopsy sample s were subjected to reverse-phase protein lysate array endpoint analysis . Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma sample s. Results : Twelve patients entered the study , and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months . Adverse events included rash , diarrhea , and prolonged QT interval corrected for heart rate , but not hypertension . Exploratory analyses showed that epidermal growth factor receptor ( EGFR ) phosphorylation was reduced in the eight paired biopsy sets obtained ; vascular endothelial growth factor ( VEGF ) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters . Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed . Conclusions : V and etanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting . Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue , but only phosphorylated-EGFR was measurably inhibited by v and etanib . Clin Cancer Res ; 16(2 ) ; OBJECTIVE Sorafenib ( Nexavar ) is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis . This phase II study investigated efficacy , safety , and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma ( RCC ) . METHODS Nonr and omized , open-label study in Japanese patients with metastatic renal cell carcinoma who had received nephrectomy and failed > /=1 cytokine-containing therapy .  The primary endpoint was response rate . Patients received sorafenib 400 mg twice daily ( b.i.d . ) on a continuous dosing schedule . RESULTS A total of 129 patients ( median age 63 years ) were valid for intention-to-treat analyses . Confirmed partial responses were observed in 16 ( 12.4 % ) patients , and investigators assessed that 19 ( 14.7 % ) of the patients achieved a partial response . Stable disease was reported in 93 ( 72.1 % ) patients , and 103 ( 80.5 % ) patients had tumor shrinkage . Median progression-free survival was 224 days and the 25th percentile of overall survival was estimated at 288 days . The most frequently occurring drug-related adverse events ( any grade ) were elevated lipase ( 56 % ) , h and -foot skin reaction ( 55 % ) , alopecia ( 39 % ) , increased amylase ( 38 % ) , rash/desquamation ( 37 % ) , and diarrhea ( 34 % ) . A total of 14 ( 10.7 % ) patients had serious sorafenib-related adverse events , including one adverse event of worst grade 5 ( dyspnea occurred 35 days after the last dose of study medication ) . The C(trough , steady state ) values in RCC patients ( n = 63 ) receiving sorafenib 400 mg b.i.d . were similar to those obtained from a Japanese phase I study involving patients with mixed solid tumors . CONCLUSION Sorafenib showed encouraging efficacy and was well tolerated in Japanese patients with metastatic RCC The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib , a multi-targeted tyrosine kinase inhibitor , against vascular endothelial growth factor receptor (VEGFR)-1 , -2 , and -3 , platelet-derived growth factor receptor-alpha and -beta , and c-Kit , in recurrent glioblastoma . Patients with < or = 2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions . Brain magnetic resonance imaging and clinical re assessment were made every 8 weeks . The primary endpoint was efficacy as measured by 6-month progression-free survival ( PFS6 ) . Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued .  Grade 3/4 toxicities included leukopenia ( n = 1 ) , lymphopenia ( n = 2 ) , thrombocytopenia ( n = 1 ) , ALT elevation ( n = 3 ) , AST elevation ( n = 1 ) , CNS hemorrhage ( n = 1 ) , fatigue ( n = 1 ) , and thrombotic/embolic events ( n = 3 ) ; 8 patients required dose reduction . Two patients had a partial radiographic response by st and ard bidimensional measurements , whereas 9 patients ( 6 at the 8-week point and 3 only within the first month of treatment ) had decreased contrast enhancement , vasogenic edema , and mass effect but < 50 % reduction in tumor . The median PFS was 12 weeks ( 95 % confidence interval [ CI ] : 8 - 14 weeks ) and only 1 patient had a PFS time > or = 6 months ( PFS6 = 3 % ) . Thirty patients ( 86 % ) had died and median survival was 35 weeks ( 95 % CI : 24 - 47 weeks ) . Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents . Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses . Clinical Trials.gov identifier : NCT00459381 STUDY OBJECTIVE To determine if excretion of sorafenib in sweat is associated with h and -foot skin reaction in patients receiving sorafenib .  DESIGN Prospect i ve pilot study . SETTING Outpatient clinic of a cancer research institution . PATIENTS Two patients who were receiving sorafenib and developed a h and -foot skin reaction of at least grade 1 and two healthy subjects ( controls ) . INTERVENTION Sweat production was stimulated in both the patients with h and -foot skin reaction and the healthy subjects by means of pilocarpine iontophoresis . MEASUREMENTS AND MAIN RESULTS Sweat sample s were collected from the patients with h and -foot skin reaction and from the healthy subjects . Using liquid chromatography-t and em mass spectrometry ,  sorafenib concentrations were measured in the sweat sample s. Sweat sample s from the healthy subjects were spiked with known concentrations of sorafenib to determine the lower limit of quantification of the assay , which was determined to be 5 ng/ml .  Sorafenib concentrations in the sample s from the patients with h and -foot skin reaction were undetectable based on the assay 's sensitivity . CONCLUSION Our results suggest that h and -foot skin reaction in patients receiving sorafenib is not associated with excretion of sorafenib in sweat . Further studies are needed to underst and the mechanism of h and -foot skin reaction , a treatment-limiting adverse effect of multikinase inhibitors BACKGROUND We conducted a phase 3 , r and omized , double-blind , placebo-controlled trial of sorafenib , a multikinase inhibitor of tumor-cell proliferation and angiogenesis , in patients with advanced clear-cell renal-cell carcinoma . METHODS From November 2003 to March 2005 , we r and omly assigned 903 patients with renal-cell carcinoma that was resistant to st and ard therapy to receive either continuous treatment with oral sorafenib ( at a dose of 400 mg twice daily ) or placebo ;  451 patients received sorafenib and 452 received placebo .  The primary end point was overall survival . A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo . Consequently , crossover was permitted from placebo to sorafenib , beginning in May 2005 . RESULTS At the January 2005 cutoff , the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group ( hazard ratio for disease progression in the sorafenib group , 0.44 ; 95 % confidence interval [ CI ] , 0.35 to 0.55 ; P<0.01 ) . The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death , as compared with placebo ( hazard ratio , 0.72 ; 95 % CI , 0.54 to 0.94 ; P=0.02 ) , although this benefit was not statistically significant according to the O'Brien-Fleming threshold . Partial responses were reported as the best response in 10 % of patients receiving sorafenib and in 2 % of those receiving placebo ( P<0.001 ) . Diarrhea , rash , fatigue , and h and -foot skin reactions were the most common adverse events associated with sorafenib . Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo . CONCLUSIONS As compared with placebo , treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed ; however , treatment is associated with increased toxic effects . ( Clinical Trials.gov number , NCT00073307 [ Clinical Trials.gov ] . ) 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 grade s 1 to 2 . The most frequent grade s 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 PURPOSE Pazopanib and lapatinib are tyrosine kinase inhibitors that target vascular endothelial growth factor receptor , platelet-derived growth factor receptor , and c-Kit or epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor 2 ( HER2/neu ) , respectively . In cervical cancer , EGFR and HER2/neu overexpression and high microvascular density correlate with survival . PATIENTS AND METHODS Patients with measurable stage IVB persistent/recurrent cervical carcinoma not amenable to curative therapy and at least one prior regimen in the metastatic setting were r and omly assigned in a ratio of 1:1:1 to pazopanib at 800 mg once daily , lapatinib at 1,500 mg once daily , or lapatinib plus pazopanib combination therapy ( lapatinib at 1,000 mg plus pazopanib at 400 mg once daily or lapatinib at 1,500 mg plus pazopanib at 800 mg once daily ) . Therapy continued until progression or withdrawal because of adverse events ( AEs ) . Primary end point was progression-free survival ( PFS ) , and secondary end points were overall survival ( OS ) , response rate ( RR ) , and safety . The fut 
    Output:
    
Despite sharing the same spectrum of target receptors with sorafenib and sunitinib , pazopanib is associated with an unexpectedly low risk of HFSR .