***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 The r and omized controlled trial ( RCT ) is the gold st and ard for establishing new therapies in clinical oncology . Here we document changes with time in design , sponsorship , and outcomes of oncology RCTs . METHODS Reports of RCTs evaluating  systemic therapy for breast , colorectal ( CRC ) , and non-small-cell lung cancer ( NSCLC ) published 1975 to 2004 in six major journals were review ed . Two authors abstract ed data regarding trial design , results , and conclusions . Conclusions of authors were grade d using a 7-point Likert scale . For each study the effect size for the primary end point was converted to a summary measure . RESULTS A total of 321 eligible RCTs were included ( 48 % breast , 24 % CRC , 28 % NSCLC ) . Over time , the number and size of RCTs increased considerably . For-profit/mixed sponsorship increased substantially during the study period ( 4 % to 57 % ; P < .001 ) . There was increasing use of time-to-event measures ( 39 % to 78 % ) and decreasing use of response rate ( 54 % to 14 % ) as primary end point ( P < .001 ) . Effect size remained stable over the study period . Authors have become more likely to strongly endorse the experimental arm ( P = .017 ) . A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent ( odds ratio [ OR ] = 19.6 , 95 % CI , 8.9 to 43.1 , and OR = 3.5 , 95 % CI , 1.6 to 7.5 , respectively ) . CONCLUSION RCTs in oncology have become larger and are more likely to be sponsored by industry . Authors of modern RCTs are more likely to strongly endorse novel therapies . For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm PURPOSE Historical data from pilot , Phase II , and Phase III studies for patients with advanced-stage non-small cell lung cancer ( NSCLC ) were used to evaluate a statistical model developed to provide assistance in selecting regimens from pilot studies for subsequent use in larger Phase III r and omized studies . EXPERIMENTAL DESIGN Information from 33 Phase III trials for patients with advanced-stage NSCLC performed from 1973 and 1994 in the United States and Canada was collected . The data from antecedent pilot or Phase II and subsequent Phase III trials were analyzed using a predictive statistical model . This model uses the number of  patients in the pilot/Phase II study , the median survival of patients in the pilot , and the number of deaths observed , to estimate the statistical likelihood that the pilot regimen will be shown superior to st and ard therapy in a subsequent Phase III trial . RESULTS Ten pilot/Phase II studies were identified that preceded eleven subsequent Phase III studies . The three pilot regimens associated with Phase III trials , revealing statistically significant longer survival , had an expected power of 0.69 , 0.85 , and 0.94 respectively . The regimens from the seven other pilot studies for which the median power expected was 0.38 ( range , 0.07 - 0.80 ) showed no difference when compared with st and ard treatment in a Phase III trial . CONCLUSION The use of the expected power model provides an important enhancement to the screening of new therapies . Regimens with an expected power of > 0.55 may be good c and i date s for testing in Phase III trials BACKGROUND Non-small-cell lung cancer ( NSCLC ) harboring the anaplastic lymphoma kinase gene ( ALK ) rearrangement is sensitive to the ALK inhibitor crizotinib , but resistance invariably develops . Ceritinib ( LDK378 ) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in pre clinical studies . METHODS In this phase 1 study , we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK . In an expansion phase of the study , patients received the maximum tolerated dose . Patients were assessed to determine the safety , pharmacokinetic properties , and antitumor activity of ceritinib . Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib .  RESULTS A total of 59 patients were enrolled in the dose-escalation phase . The maximum tolerated dose of ceritinib was 750 mg once daily ; dose-limiting toxic events included diarrhea , vomiting , dehydration , elevated aminotransferase levels , and hypophosphatemia . This phase was followed by an expansion phase , in which an additional 71 patients were treated , for a total of 130 patients overall . Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day , the overall response rate was 58 % ( 95 % confidence interval [ CI ] , 48 to 67 ) . Among 80 patients who had received crizotinib  previously , the response rate was 56 % ( 95 % CI , 45 to 67 ) . Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations . Among patients with NSCLC who received at least 400 mg of ceritinib per day , the median progression-free survival was 7.0 months ( 95 % CI , 5.6 to 9.5 ) . CONCLUSIONS Ceritinib was highly active in patients with advanced , ALK-rearranged NSCLC , including those who had had disease progression during crizotinib treatment , regardless of the presence of resistance mutations in ALK . ( Funded by Novartis Pharmaceuticals and others ; Clinical Trials.gov number , NCT01283516 . ) Purpose : We hypothesized that chemotherapy synergizes with VEGF/VEGFR ( VEGF/R ) inhibitors in patients with advanced solid malignancies . Experimental Design : Patients treated on phase I protocol s between December 2004 and July 2013 ( n = 1,498 ) were included in this analysis . The primary outcome was clinical benefit , defined as stable disease ≥6 months , complete response , or partial response . Two odds ratios ( OR ) for achieving clinical benefit were calculated : one for patients treated with VEGF/R inhibitors ( OR with VEGF/R ) and another for patients treated without ( OR without VEGF/R ) . To compare these two ORs , an interaction term was included in the multivariate model : ( chemotherapy/factor of interest) × (VEGF/R ) . We took significant interaction terms ( Pinteraction < 0.05 ) to suggest effect modification ( either synergy or antagonism ) with VEGF/R inhibitors . Results : All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [ OR = 1.9 ; 95 % confidence interval ( CI ) , 1.5–2.4 ; P < 0.0001 ] . Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [ OR with VEGF/R = 1.6 ( 95 % CI , 1.1–2.5 ) vs. OR without VEGF/R = 0.4 ( 95 % CI , 0.3–0.6 ) , Pinteraction = 0.02 ] . Specifically , the antimetabolite class was associated with the greatest increase in OR for clinical benefit [ OR with VEGF/R = 2.7 ( 95 % CI , 1.5–4.7 ) vs. OR without VEGF/R = 0.2 ( 95 % CI 0.1–0.3 ) , Pinteraction = 0.004 ] . Conclusions : VEGF/R inhibitor was found to synergize with chemotherapeutics . This effect was most pronounced with the antimetabolite class . Clin Cancer Res ; 20(23 ) ; 5956–63 . © 2014 AACR BACKGROUND Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy ( DCMI ) . We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS An FORTIS-M trial was an international , multicenter , r and omized , double-blind comparison of talactoferrin ( 1.5 g p.o . BID ) versus placebo BID , in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens . Treatment was administered for a maximum of five 14-week cycles . The primary efficacy end point was overall survival ( OS ) ; secondary end points included 6- and 12-month survival , progression-free survival ( PFS ) , and disease control rate ( DCR ) . RESULTS Seven hundred and forty-two patients were r and omly assigned ( 2:1 ) to talactoferrin ( 497 ) or placebo ( 245 ) . The median OS in the intent-to-treat ( ITT ) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [ hazard ratio ( HR ) , 1.04 ; 95 % CI , 0.873 - 1.24 ; P = 0.6602 ] . The 6-month survival rates were 59.9 % ( 95 % CI , 53.4 % to 65.8 % ) and 55.7 % ( 95 % CI , 51.1 % to 59.9 % ) , respectively . The 12-month survival rates were 32.2 % ( 95 % CI , 26.3 % to 38.2 % ) and 30.9 % ( 95 % CI , 26.8 % to 35 % ) , respectively . The median PFS rates were 1.64 months and 1.68 months , respectively ( HR , 0.99 ; 95 % CI , 0.835 - 1.16 ; P = 0.8073 ) . The DCRs were 38.4 and 37.6 % , respectively [ stratified odds ratio ( OR ) , 0.96 ; 95 % CI , 0.698 - 1.33 ; P = 0.8336 ] . The safety profiles were comparable between arms . CONCLUSIONS There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens PURPOSE We conducted a phase III trial comparing intravenous ( IV ) diaziquone ( AZQ ) and carmustine ( BCNU ) as single agents in patients with cerebral anaplastic gliomas who had received surgery and radiotherapy . Its purpose was to compare the efficacy of AZQ with that of BCNU , the st and ard agent for brain tumor chemotherapy . PATIENTS AND METHODS R and omization between the two regimens occurred 8 weeks after completion of radiotherapy . A total of 251 patients were r and omized to receive either AZQ or BCNU , and there were no significant differences between the two treatment arms in any of the known prognostic variables , including age , histologic grade , and Karnofsky performance status ( KPS ) . RESULTS There was no significant difference in either time to tumor progression or survival between the two treatment arms . Age and histology were strong predictors of outcome , whereas KPS had relatively less effect . Three groups of patients with distinctly different outcomes could be identified : ( 1 ) older age ( 45 + ) and glioblastoma/gliosarcoma ( GBM/GS ) patients had a median survival of 37 weeks after r and omization ; ( 2 ) patients with either older age or GBM/GS had a median survival of 61 weeks ; and ( 3 ) younger age ( < 45 ) and non-GBM/GS ( usually anaplastic astrocytoma ) patients had a median survival of 147 weeks . Toxicity was primarily hematologic , although acute gastrointestinal toxicity and chronic pulmonary toxicity were more common with BCNU . Patients r and omized to AZQ who had significant hematologic toxicity that required dose reduction after the first treatment cycle had significantly longer time to tumor progression and survival than those who did not require dose reduction ( P = .011 and .016 , respectively ) . CONCLUSION There was no significant difference in efficacy between AZQ and BCNU in patients with anaplastic gliomas as tested in this study , although AZQ was somewhat better tolerated BACKGROUND Everolimus ( RAD001 ) is an orally administered inhibitor of the mammalian target of rapamycin ( mTOR ) , a therapeutic target for metastatic renal cell carcinoma . We did a phase III , r and omised , double-blind , placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy . METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib , sorafenib , or both , were r and omly assigned in a two to one ratio to receive everolimus 10 mg once daily ( n=272 )  or placebo  ( n=138 ) , in conjunction with best supportive care . R and omisation was done central ly via an interactive voice response system using a vali date d computer 
    Output:
    
For drugs that reached Phase III , lack of a biomarker-driven strategy and failure to attain proof of concept in phase II are potential risk factors for later discontinuation , especially for targeted agents