***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 Lenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects . The aim of this study was to assess the feasibility of combining lenalidomide with the st and ard treatment gemcitabine in pancreatic cancer patients with advanced disease . Patients and Methods Eligible patients had locally advanced or metastatic adenocarcinoma of the pancreas . Patients received lenalidomide days 1–21 orally and gemcitabine 1000 mg/m2 intravenously ( days 1 , 8 and 15 ) , each 28 day cycle . Three cohorts of lenalidomide were examined ( Cohort I = 15 mg , Cohort II = 20 mg and Cohort III = 25 mg daily ) . The maximum tolerated dose ( MTD ) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four ( 25 % ) subjects experiences a dose-limiting toxicity ( DLT ) . Patients should also be able to receive daily low molecular weight heparin ( LMWH ) ( e.g. dalteparin 5000 IU s.c . daily ) as a prophylactic anticoagulant for venous thromboembolic events ( VTEs ) . Twelve patients ( n = 4 , n = 3 and n = 5 in cohort I , II and III , respectively ) were enrolled in this study . Results Median duration of treatment was 11 weeks ( range 1–66 ) , and median number of treatment cycles were three ( range 1–14 ) . The only DLT was a cardiac failure grade 3 in cohort III . Frequent treatment-related adverse events ( AEs ) ( all grade s ) included neutropenia , leucopenia and fatigue ( 83 % each , but there was no febrile neutropenia ) ; thrombocytopenia ( 75 % ) ; dermatological toxicity ( 75 % ) ; diarrhea and nausea ( 42 % each ) ; and neuropathy ( 42 % ) . Discussion This phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer . The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1–21 with st and ard dosing of gemcitabine and merits further evaluation in a phase II trial . Trial Registration Clinical Trials.gov Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer . In this study , the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer . Methods A multi-national , open-label , controlled , r and omized , parallel-group , phase II pilot study was conducted in 20 centers in 7 countries .  Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle . The planned treatment period was 6 four-week cycles . The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival ( PFS ) , response rate , quality of life ( QoL ) , effects on biological markers of disease ( CA 19.9 ) and angiogenesis ( vascular endothelial growth factor and basic fibroblast growth factor ) , and safety . An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients . Results Eighty-nine patients were r and omized . The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone . The median PFS times were 3.6 months and 3.8 months , respectively . The overall response rates were 17 % and 14 % , and the tumor growth control rates were 54 % and 56 % , respectively . Changes in the levels of CA 19.9 went in line with the clinical course of the disease , but no apparent relationships were seen with the biological markers of angiogenesis . QoL and safety evaluations were comparable between treatment groups . Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa . Conclusion There were no clinical ly important differences observed regarding efficacy , safety and QoL between the groups . The observations lay in the range of other clinical studies in this setting . The combination regimen was well tolerated with no adverse effects on the safety , tolerability and pharmacokinetics of either agent PURPOSE To define the safety , efficacy , and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy ( CRT ) in locally advanced pancreatic cancer . METHODS AND MATERIAL S Patients received gemcitabine 1000 mg/m(2 ) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT . Weekly gemcitabine 600 mg/m(2 ) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions . Sorafenib was dosed orally 400 mg twice daily until progression , except during CRT when it was escalated from 200 mg to 400 mg daily , and 400 mg twice daily . The maximum tolerated dose cohort was exp and ed to 15 patients . Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms ( VEGF-A and VEGF-R2 single nucleotide polymorphisms ) . RESULTS Twenty-seven patients were enrolled . No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT . The most common grade 3/4 toxicities were fatigue , hematologic , and gastrointestinal . The maximum tolerated dose was sorafenib 400 mg twice daily . The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months , respectively . The median overall survival for patients with VEGF-A -2578 AA , -1498 CC , and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months . Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans ) in responding patients . CONCLUSIONS Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer . Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival Objectives : Evaluate toxicity of two treatment arms , A ( cetuximab ) and B ( bevacizumab ) , when combined with gemcitabine , and chemoradiation in patients with completely resected pancreatic carcinoma . Secondary objectives included overall survival ( OS ) and disease-free survival ( DFS ) . Methods : Patients with R0/R1 resection were r and omized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine  for two treatment cycles . Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation , followed by one cycle of cetuximab/bevacizumab . Cycles 7 - 12 included cetuximab/bevacizumab with gemcitabine . Cycles were 2 weeks . Frequency of specific toxicities was summarized for each treatment arm at two times during the study , after chemotherapy but prior to chemoradiation and after all therapy . Results : A total of 127 patients were r and omized ( A , n = 65 ; B , n = 62 ) . Prior to chemoradiation , the overall rate for toxicities of interest was 10 % for arm A and 2 % for arm B. After all therapy , the overall rates for toxicities of interest were 30 and 25 % for arms A and B , respectively . Overall median OS and DFS were 17 and 11 months , respectively , which is not a significant improvement over expected survival rates for historical controls . Conclusions : Both treatments were tolerable with manageable toxicities , and were safe enough for a phase III trial had this been indicated Background : Hyaluronan accumulation in tumour stroma is associated with reduced survival in pre clinical cancer models . PEGPH20 de grade s hyaluronan to facilitate tumour access for cancer therapies . Our objective was to assess safety and antitumour activity of PEGPH20 in patients with advanced solid tumours . Methods : In HALO-109 - 101 ( N=14 ) , PEGPH20 was administered intravenously once or twice weekly ( 0.5 or 50 μg kg−1 ) or once every 3 weeks ( 0.5–1.5 μg kg−1 ) . In HALO-109 - 102 ( N=27 )  , PEGPH20 was administered once or twice weekly ( 0.5–5.0 μg kg−1 ) , with dexamethasone predose and postdose . Results : Dose-limiting toxicities included grade ⩾3 myalgia , arthralgia , and muscle spasms ; the maximum tolerated dose was 3.0 μg kg−1 twice weekly . Plasma hyaluronan increased in a dose-dependent manner , achieving steady state by Day 8 in multidose studies . A decrease in tumour hyaluronan level was observed in 5 of the 6 patients with pretreatment and posttreatment tumour biopsies . Exploratory imaging showed changes in tumour perfusion and decreased tumour metabolic activity , consistent with observations in animal models . Conclusions : The tumour stroma has emerging importance in the development of cancer therapeutics . PEGPH20 3.0 μg kg−1 administered twice weekly is feasible in patients with advanced cancers ; exploratory analyses indicate antitumour activity supporting further evaluation of PEGPH20 in solid tumours Objectives In mouse models of pancreatic cancer , IPI-926 , an oral Hedgehog inhibitor , increases chemotherapy delivery by depleting tumor-associated stroma . This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX ( 5-fluorouracil , leucovorin , irinotecan , oxaliplatin ) in patients with advanced pancreatic cancer . Methods Patients were treated with once-daily IPI-926 plus FOLFIRINOX . A 3 + 3 dose escalation design was used , with cohort expansion at the maximum tolerated dose . A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion . Results The maximum tolerated dose was identified 1 dose level below st and ard FOLFIRINOX . Common treatment-related adverse events included liver function test abnormalities , neuropathy , nausea/vomiting , and diarrhea . Objective response rate was high ( 67 % ) , and patients receiving IPI-926 maintenance showed further declines in CA19 - 9 levels even after FOLFIRINOX discontinuation . Treatment did not result in consistent increases in tumor perfusion . The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination . Conclusions This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design . Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen , future development of Hedgehog inhibitors in pancreatic cancer seems unlikely Purpose Sorafenib , an oral inhibitor of B-raf , VEGFR2 , and PDGFR2-beta , acts against pancreatic cancer in pre clinical models . Due to the radio-sensitization activity of both sorafenib and gemcitabine , we design ed a multicenter , phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy . Methods Patients with biopsy-proven , unresectable pancreatic adenocarcinoma ( based on vascular invasion detected by computed tomography ) were treated with gemcitabine ( 300 mg/m2 i.v . weekly ×5 weeks ) concurrently with radiation therapy ( 45 Gy in 25 fractions ) and sorafenib ( escalated doses in a 3 + 3 design , from 200 to 800 mg/day ) . Radiation portals included the primary tumor but not the regional lymph nodes . Patients with planning target volumes ( PTV ) over 500 cc were excluded . Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression . Results Twelve patients were included . Three patients received 200 mg/day , 6 received 400 mg/day , and 3 received 800 mg/day ; PTVs ranged from 105 to 500 cc . No dose-limiting toxicities occurred . The most common grade 2 toxicities were fatigue , neutropenia , nausea , and raised serum transaminases . Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy . There were no treatment-related deaths . Conclusion The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma . A dose of 800 mg/day is recommended for phase II evaluation . Trial Registration EudraCT 20 
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In conclusion , we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel .