***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 : BIBF 1120 is an oral , potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors , platelet-derived growth factors , and fibroblast growth factors . This phase I , accelerated titration study assessed the maximum tolerated dose , safety , pharmacokinetics , and pharmacodynamic effects of BIBF 1120 . Patients and Methods : Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts . Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout . Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients . Results : Most frequent BIBF 1120–related  adverse events were mostly mild to moderate ( Common Toxicity Criteria grade 1 - 2 ) nausea ( 68.9 % ) , vomiting ( 45.9 % ) , and diarrhea ( 44.3 % ) . The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations . The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing . BIBF 1120 was absorbed moderately fast ( tmax = 1 - 3 hours at steady state ) , with no deviation from dose linearity and no decrease of exposure over time . The gMean terminal half-life was from 13 to 19 hours . One complete and two partial responses occurred in patients with renal cell cancer ( n = 2 ) and colorectal cancer ( n = 1 ) . Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55 % of evaluable patients . Conclusions : BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile , and first efficacy signals were observed . Twice daily dosing permitted increased drug exposure without additional toxicity . Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies . Clin Cancer Res ; 16(1 ) ; PURPOSE Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer . We investigated the efficacy and safety of a novel agent , BIBF 1120 , a triple angiokinase inhibitor , after chemotherapy for relapsed disease . PATIENTS AND METHODS We conducted a r and omized , double-blind , controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer , with evidence of response , but at high risk of further early recurrence . The patients were r and omly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo , twice per day , continuously for 36 weeks . End points were progression-free survival ( PFS ) , toxicity , and overall survival . RESULTS Thirty-six-week PFS rates were 16.3 % and 5.0 % in the BIBF 1120 and placebo groups , respectively ( hazard ratio , 0.65 ; 95 % CI , 0.42 to 1.02 ; P = .06 ) . Four patients continued on BIBF 1120 , including two patients for another year or more . The proportion of patients with any grade 3 or 4 adverse events was similar between the groups ( 34.9 % for BIBF 1120 v 27.5 % for placebo ; P = .49 ; mostly grade 3 ) . However , more patients on BIBF 1120 experienced diarrhea , nausea , or vomiting ( mainly grade 1 or 2 and no grade 4 ) . There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 ( 51.2 % ) compared with patients on placebo ( 7.5 % ; P < .001 ) , but this was rarely of clinical significance , and patients continued with the trial treatment . A single-level dose reduction to 150 mg was made in 15 patients , all on active drug . CONCLUSION BIBF 1120 is well tolerated and associated with a potential improvement in PFS . The observed treatment effect is sufficient to justify further study within a large phase III trial Nintedanib , a triple angiokinase inhibitor , has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis .  Nintedanib ( Vargatef ® ) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma non-small cell lung cancer ( NSCLC ) after first-line chemotherapy , and as monotherapy ( Ofev ® ) in the United States and EU for the treatment of patients with idiopathic pulmonary fibrosis . Pharmacokinetics ( PK ) of nintedanib after oral single and multiple doses and intravenous ( IV ) administration were assessed using 3 data sets : ( 1 ) an absolute bioavailability trial that enrolled 30 healthy volunteers ; ( 2 ) a pooled data analysis of 4 studies that enrolled a total of 107 healthy volunteers ; and ( 3 ) a pooled data analysis of 4 studies that enrolled a total of 149 patients with advanced cancer . In the absolute bioavailability trial of healthy volunteers , nintedanib showed a high total clearance ( geometric mean 1390 mL/min ) and a high volume of distribution at steady state ( Vss = 1050 L ) . Urinary excretion of IV nintedanib  was about 1 % of dose ; renal clearance was about 20 mL/min and therefore negligible . There was no deviation from dose proportionality after IV administration in the dose range tested . Absolute bioavailability of oral nintedanib ( 100 mg capsule ) relative to IV dosing ( 4-hour infusion , 6 mg ) was slightly below 5 % . Nintedanib was quickly absorbed after oral administration . It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics . In advanced cancer patients , steady state was reached at the latest at 7 days for twice-daily dosing . Nintedanib 's PK was time-independent ; accumulation after repeated administration was negligible Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to st and ard chemotherapy , with the greatest effect in patients at high risk of disease progression . We report the final overall survival results of the trial . Methods ICON7 was an international , phase 3 , open-label , r and omised trial undertaken at 263 centres in 11 countries across Europe , Canada , Australia and New Zeal and . Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease ( International Federation of Gynecology and Obstetrics [ FIGO ] stage I – IIa , grade 3 or clear cell histology ) or more advanced disease ( FIGO stage IIb – IV ) , with an Eastern Cooperative Oncology Group performance status of 0–2 , were enrolled and r and omly assigned in a 1:1 ratio to st and ard chemotherapy ( six 3-weekly cycles of intravenous carboplatin [ AUC 5 or 6 ] and paclitaxel 175 mg/m2 of body surface area ) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks , given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy . R and omisation was done by a minimisation algorithm stratified by FIGO stage , residual disease , interval between surgery and chemotherapy , and Gynecologic Cancer InterGroup group . The primary endpoint was progression-free survival ; the study was also powered to detect a difference in overall survival . Analysis was by intention to treat . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N91273375 . Findings Between Dec 18 , 2006 , and Feb 16 , 2009 , 1528 women were enrolled and r and omly assigned to receive chemotherapy ( n=764 ) or chemotherapy plus bevacizumab ( n=764 ) . Median follow-up at the end of the trial on March 31 , 2013 , was 48·9 months ( IQR 26·6–56·2 ) , at which point 714 patients had died ( 352 in the chemotherapy group and 362 in the bevacizumab group ) . Our results showed evidence of non-proportional hazards , so we used the difference in restricted mean survival time as the primary estimate of effect . No overall survival benefit of bevacizumab was recorded ( restricted mean survival time 44·6 months [ 95 % CI 43·2–45·9 ] in the st and ard chemotherapy group vs 45·5 months [ 44·2–46·7 ] in the bevacizumab group ; log-rank p=0·85 ) . In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease , 332 ( 66 % ) died ( 174 in the st and ard chemotherapy group and 158 in the bevacizumab group ) , and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone ( restricted mean survival time 34·5 months [ 95 % CI 32·0–37·0 ] with st and ard chemotherapy vs 39·3 months [ 37·0–41·7 ] with bevacizumab ; log-rank p=0·03 ) . However , in non-high-risk patients , the restricted mean survival time did not differ significantly between the two treatment groups ( 49·7 months [ 95 % CI 48·3–51·1 ] ) in the st and ard chemotherapy group vs 48·4 months [ 47·0–49·9 ] in the bevacizumab group ; p=0·20 ) . An up date d analysis of progression-free survival showed no difference between treatment groups . During extended follow-up , one further treatment-related grade 3 event ( gastrointestinal fistula in a bevacizumab-treated patient ) , three grade 2 treatment-related events ( cardiac failure , sarcoidosis , and foot fracture , all in bevacizumab-treated patients ) , and one grade 1 treatment-related event ( vaginal haemorrhage , in a patient treated with st and ard chemotherapy ) were reported . Interpretation Bevacizumab , added to platinum-based chemotherapy , did not increase overall survival in the study population as a whole . However , an overall survival benefit was recorded in poor-prognosis patients , which is concordant with the progression-free survival results from ICON7 and GOG-218 , and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer . Funding The National Institute for Health Research through the UK National Cancer Research Network , the Medical Research Council , and Roche BIBF 1120 is an oral multitargeted tyrosine kinase inhibitor that blocks the activity of vascular endothelial growth factor ( VEGF ) and other growth factor receptors . We have done a phase I study to evaluate the safety , pharmacokinetics , and pharmacodynamic biomarkers of BIBF 1120 .  Patients with advanced refractory solid tumors were treated with BIBF 1120 at oral doses of 150 to 250 mg twice daily . Drug safety and pharmacokinetics were evaluated , as were baseline and post-treatment levels of circulating CD117-positive bone marrow – derived progenitor cells and plasma soluble VEGF receptor 2 as potential biomarkers for BIBF 1120 . Twenty-one patients were treated at BIBF 1120 doses of 150 ( n = 3 ) , 200 ( n = 12 ) , or 250 mg twice daily ( n = 6 ) . Dose-limiting toxicities of reversible grade 3 or 4 elevations of liver enzymes occurred in 3 of 12 patients at 200 mg twice daily and 3 of 6 patients at 250 mg twice daily . Stable disease was achieved in 16 ( 76.2 % ) patients , and median progression-free survival was 113 days ( 95 % confidence interval , 77 - 119 d ) . Pharmacokinetic analysis indicated that the maximum plasma concentration and area under the curve for BIBF 1120 increased with the dose within the dose range tested . Levels of CD117-positive bone marrow – derived progenitors and soluble VEGF receptor 2 decreased significantly during treatment over all BIBF 1120 dose cohorts . In conclusion , the maximum tolerated dose of BIBF 1120 in the current study was determined to be 200 mg twice daily , and our biomarker analysis indicated that this angiokinase inhibitor is biologically active . Mol Cancer Ther ; 9(10 ) ; 2825–33 . © 2010 AACR LBA8011 Background : Nintedanib ( N ) inhibits VEGFRs , PDGFRs , and FGFRs . LUME Lung 1 is a placebo ( P ) controlled phase III trial of N + docet 
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Results : Although in early phase clinical trials , Nintedanib has demonstrated anticancer activity and tolerability as monotherapy or in combination with carboplatin and paclitaxel .
In the phase III trial AGO-OVAR 12 , it obtained a modest improvement in progression-free survival ( PFS ) as first-line combination therapy for patients with advanced EOC .
Interestingly , a PFS increase was observed in patients with non-high progression risk or low tumor burden .