***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 This study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma ( RCC ) who were previously treated with sunitinib . MATERIAL S AND METHODS This open-label , multicentre , phase 2 trial of oral linifanib 0.25 mg/kg/day enrolled patients who had prior nephrectomy and adequate organ function . The primary end-point was objective response rate ( ORR ) per response evaluation criteria in solid tumors ( RECIST ) by central imaging . Secondary end-points were progression-free survival ( PFS ) , overall survival ( OS ) and time to progression ( TTP ) . Safety was also assessed . RESULTS Fifty-three patients , median age 61 years ( range 40 - 80 ) were enrolled ( August 2007 to October 2008 ) across 12 North-American centres . Median number of prior therapies was 2 ( range 1 - 4 ) ; 43 patients ( 81 % ) had clear-cell histology .  ORR was 13.2 % , median PFS was 5.4 months ( 95 % Confidence Interval ( CI ) : 3.6 , 6.0 ) and TTP was the same ; median OS was 14.5 months ( 95 % CI : 10.8 , 24.1 ) . The most common treatment-related adverse events ( AEs ) were diarrhoea ( 74 % ) , fatigue ( 74 % ) and hypertension ( 66 % ) , and the most common treatment-related Grade 3/4 AE was hypertension ( 40 % ) . CONCLUSIONS Linifanib demonstrated clinical ly meaningful activity in patients with advanced RCC after sunitinib failure . At 0.25 mg/kg/day , significant dose modifications were required . An alternative , fixed-dosing strategy is being evaluated in other trials INTRODUCTION Malignant mesothelioma ( MM ) is an aggressive disease with limited therapeutic options . In pre clinical models , vascular endothelial growth factor ( VEGF ) stimulates MM proliferation . In MM patients , higher plasma VEGF levels correlate inversely with survival . Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1 , -2 , and -3 . METHODS We conducted a multi-center phase II trial of cediranib in patients with unresectable , histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy . The primary endpoint was objective response rate . Initial cediranib dosing was 45 mg daily during a 28-day cycle . Due to substantial toxicity , the starting dose was subsequently lowered to 30 mg daily . RESULTS Fifty-one patients enrolled at 9 centers ; 50 were evaluable for response .  Partial responses were observed in 10 % of patients ; stable disease was seen in 34 % . Disease control ( PR+SD ) was higher at the 45 mg cediranib dose level ( 67 % vs. 34 % , p=0.04 ) . Median progression-free survival was 1.8 months ( 95 % CI 0.1 , 14.2 ) ; median overall survival ( OS ) was 4.4 months ( 95 % CI 0.9 , 41.7 ) . The 1-year survival rate was 15 % . Grade 3/4 toxicities were more frequent in the 45 mg dose level group ( 87 % vs. 43 % , p=0.002 ) . These included fatigue , hypertension , pulmonary embolism , angioedema , and reversible posterior leukoencephalopathy . Median OS was superior in patients who developed ≥ grade 3 hypertension ( 8.5 vs. 4.1 months , p=0.024 ) . CONCLUSION This trial did not meet its pre-specified response endpoint . A higher cediranib dose level was associated with improved disease control , but this dose was poorly tolerated PURPOSE The antitumor activity and safety of tivozanib , which is a potent and selective vascular endothelial growth factor receptor-1 , -2 , and -3 inhibitor , was assessed in patients with advanced/metastatic renal cell carcinoma ( RCC ) . PATIENTS AND METHODS In this phase II , r and omized discontinuation trial , 272 patients received open-label tivozanib 1.5 mg/d ( one cycle equaled three treatment weeks followed by a 1-week break ) orally for 16 weeks . Thereafter , 78 patients who demonstrated ≥ 25 % tumor shrinkage continued to take tivozanib , and 118 patients with less than 25 % tumor change were r and omly assigned to receive tivozanib or a placebo in a double-blind manner ; patients with ≥ 25 % tumor growth were discontinued . Primary end points included safety , the objective response rate ( ORR ) at 16 weeks , and the percentage of r and omly assigned patients who remained progression free after 12 weeks of double-blind treatment ; secondary end points included progression-free survival ( PFS ) . RESULTS Of 272 patients enrolled onto the study , 83 % of patients had clear-cell histology , 73 % of patients had undergone nephrectomy , and 54 % of patients were treatment naive .  The ORR after 16 weeks of tivozanib treatment was 18 % ( 95 % CI , 14 % to 23 % ) . Of the 118 r and omized patients , significantly more patients who were r and omly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo ( 49 % v 21 % ; P = .001 ) . Throughout the study , the ORR was 24 % ( 95 % CI , 19 % to 30 % ) , and the median PFS was 11.7 months ( 95 % CI , 8.3 to 14.3 months ) in the overall study population . The most common grade 3 and 4 treatment-related adverse event was hypertension ( 12 % ) . CONCLUSION Tivozanib was active and well tolerated in patients with advanced RCC . These data support additional development of tivozanib in advanced RCC BACKGROUND & AIMS Sorafenib , a multi-kinase inhibitor with anti-angiogenic activity , was recently approved for the treatment of advanced hepatocellular carcinoma ( HCC ) .  Metronomic chemotherapy using tegafur/uracil ( 4:1 molar ratio ) , an oral fluoropyrimidine , has been shown to enhance the anti-tumor effect of anti-angiogenic agents in pre clinical models . This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC . METHODS Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib ( 400 mg twice daily ) and tegafur/uracil ( 125 mg/m(2 ) based on tegafur twice daily ) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies . The primary endpoint was progression-free survival ( PFS ) . RESULTS The study enrolled 53 patients . Thirty-eight patients ( 72 % ) were hepatitis B surface antigen-positive . The median PFS was 3.7 months ( 95 % C.I. , 1.9 - 5.5 ) and the median overall survival was 7.4 months ( 95 % C.I. , 3.4 - 11.4 ) . According to RECIST criteria , 4 patients ( 8 % ) had a partial response and 26 patients ( 49 % ) had a stable disease . Major grade 3/4 toxicities included fatigue ( 15 % ) , abnormal liver function ( 13 % ) , elevated serum lipase ( 10 % ) h and -foot skin reaction ( HFSR ) ( 9 % ) , and bleeding ( 8 % ) . HFSR was the major adverse event result ing in dose reduction ( 19 % ) or treatment delay ( 21 % ) . CONCLUSIONS Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients PURPOSE This r and omized , multicenter , blinded , placebo-controlled phase III trial tested the efficacy and safety of bevacizumab ( BV ) with gemcitabine and carboplatin ( GC ) compared with GC in platinum-sensitive recurrent ovarian , primary peritoneal , or fallopian tube cancer ( ROC ) . PATIENTS AND METHODS Patients with platinum-sensitive ROC ( recurrence ≥ 6 months after front-line platinum-based therapy ) and measurable disease were r and omly assigned to GC plus either BV or placebo ( PL ) for six to 10 cycles . BV or PL , respectively , was then continued until disease progression . The primary end point was progression-free survival ( PFS ) by RECIST ; secondary end points were objective response rate , duration of response ( DOR ) , overall survival , and safety . RESULTS Overall , 484 patients were r and omly assigned . PFS for the BV arm was superior to that for the PL arm ( hazard ratio [ HR ] , 0.484 ; 95 % CI , 0.388 to 0.605 ; log-rank P < .0001 ) ; median PFS was 12.4 v 8.4 months , respectively . The objective response rate ( 78.5 % v 57.4 % ; P < .0001 ) and DOR ( 10.4 v 7.4 months ; HR , 0.534 ; 95 % CI , 0.408 to 0.698 ) were significantly improved with the addition of BV . No new safety concerns were noted . Grade 3 or higher hypertension ( 17.4 % v < 1 % ) and proteinuria ( 8.5 % v < 1 % ) occurred more frequently in the BV arm . The rates of neutropenia and febrile neutropenia were similar in both arms . Two patients in the BV arm experienced GI perforation after study treatment discontinuation . CONCLUSION GC plus BV followed by BV until progression result ed in a statistically significant improvement in PFS compared with GC plus PL in platinum-sensitive ROC BACKGROUND Cediranib is a highly potent vascular endothelial growth factor ( VEGF ) signalling inhibitor with activity against VEGF receptors 1 , 2 and 3 . This Phase II , r and omised , double-blind , parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor . METHODS Patients were r and omised ( 3:1 ) to cediranib 45 mg/day or placebo .  The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy . Secondary objectives included response rate and duration , progression-free survival ( PFS ) and safety and tolerability . Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed . This study has been completed and is registered with Clinical Trials.gov , number NCT00423332 . FINDINGS Patients ( n=71 ) were r and omised to receive cediranib ( n=53 ) or placebo ( n=18 ) . The primary study outcome revealed that , after 12weeks of therapy , there was a significant difference in mean percentage change from baseline in tumour size between the cediranib ( -20 % ) and placebo ( + 20 % ) arms ( p<0.0001 ) . Eighteen patients ( 34 % ) on cediranib achieved a partial response and 25 ( 47 % ) experienced stable disease .  Cediranib treatment prolonged PFS significantly compared with placebo ( hazard ratio (HR)=0.45 , 90%confidence interval : 0.26 - 0.76 , p=0.017 ; median PFS 12.1 versus 2.8 months ) . The most common adverse events in patients receiving cediranib were diarrhoea ( 74 % ) , hypertension ( 64 % ) , fatigue ( 58 % ) and dysphonia ( 58 % ) . INTERPRETATION Cediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma . The adverse event profile was consistent with previous studies of cediranib 45 mg Summary Background Sorafenib , an inhibitor of B-raf , VEGFR2 , and PDGFR-β , has activity against pancreatic cancer in pre clinical models . In a phase I trial of gemcitabine plus sorafenib , 57 % of pancreatic cancer patients achieved stable disease . Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologically-confirmed , advanced pancreatic cancer . Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2 on days 1 , 8 and 15 of a 28 day cycle . Results Seventeen patients enrolled at 4 centers ; 13 were evaluable for response . There were no objective responses ; 18 % had stable disease . Median overall survival was 4.0 months ( 95 % CI : 3.4 , 
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Conclusions The use of VEGFR-TKIs is associated with a significant increased risk of developing proteinuria .