***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: BACKGROUND Focal adhesion kinase ( FAK ) is important in cancer growth , survival , invasion , and migration . The purpose of this study was to determine the maximum tolerated dose ( MTD ) , safety , pharmacokinetics ( PK ) , and pharmacodynamics ( PD ) of the FAK inhibitor , GSK2256098 , in cancer patients . PATIENTS AND METHODS The dose of GSK2256098 was escalated , in cohorts of patients with advanced cancer , from 80 to 1500 mg , oral twice daily ( BID ) , until the MTD was determined . Serial blood sample s were obtained from all patients , and the PK was determined . Paired tumor biopsies were obtained in select patients , and the level of phospho-FAK ( pFAK ) was determined . RESULTS Sixty-two patients ( 39 males , 23 females ; median age 61 y.o . , range 21 - 84 ) received GSK2256098 . Dose-limiting toxicities of grade 2 proteinuria ( 1000 mg BID ) , grade 2 fatigue , nausea , vomiting ( 1250 mg BID ) , and grade 3 asthenia and grade 2 fatigue ( 1500 mg BID ) were reported with the MTD identified as 1000 mg BID . The most frequent adverse events ( AEs ) were nausea ( 76 % ) , diarrhea ( 65 % ) , vomiting ( 58 % ) , and decreased appetite ( 47 % ) with the majority of AEs being grade s 1 - 2 . The PK was generally dose proportional with a geometric mean elimination half-life range of 4 - 9 h. At the 750 , 1000 , and 1500 mg BID dose levels evaluated , the pFAK , Y397 autophosphorylation site , was reduced by ∼80 % from baseline . Minor responses were observed in a patient with melanoma ( -26 % ) and three patients with mesothelioma ( -13 % , -15 % , and -17 % ) . In the 29 patients with recurrent mesothelioma , the median progression-free survival was 12 weeks with 95 % CI 9.1 , 23.4 weeks ( 23.4 weeks merlin negative , n = 14 ; 11.4 weeks merlin positive , n = 9 ; 10.9 weeks merlin status unknown , n = 6 ) . CONCLUSIONS GSK2256098 has an acceptable safety profile , has evidence of target engagement at doses at or below the MTD , and has clinical activity in patients with mesothelioma , particularly those with merlin loss Summary Objective VS-6063 ( also known as defactinib or PF-04554878 ) is a second-generation inhibitor of focal adhesion kinase ( FAK ) and proline-rich tyrosine kinase-2 ( Pyk2 ) . This phase I dose-escalation study was conducted in patients with advanced solid malignancies . Methods Using a traditional 3 + 3 design , VS-6063 was administered orally twice daily ( b.i.d . ) in 21-day cycles to cohorts of three to six patients . In cycle 1 , a lead-in dose was administered to assess single-dose pharmacokinetics ; steady-state pharmacokinetics was assessed after 15 days of continuous dosing . Dose escalation was performed in the fasted state , and repeated in two additional cohorts in the fed state . Results Forty-six patients were treated across nine dose levels ( 12.5–750 mg b.i.d . ) . Dose-limiting toxicities , comprising headache ( n = 1 ) , fatigue ( n = 1 ) and unconjugated hyperbilirubinemia ( n = 3 ) , occurred at the 300- or 425-mg b.i.d . dose level and were reversible . Frequent adverse events included nausea ( 37 % ) , fatigue ( 33 % ) , vomiting ( 28 % ) , diarrhea ( 22 % ) and headache ( 22 % ) . A maximum-tolerated dose was not defined . Dose escalation was stopped at the 750-mg b.i.d . dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups . Food delayed the time to peak serum concentration without affecting serum drug exposure . No radiographic responses were reported . Disease stabilization at ~12 weeks occurred in six of 37 ( 16 % ) patients receiving doses ≥100 mg b.i.d . Conclusions VS-6063 has an acceptable safety profile . Treatment-related adverse events were mild to moderate , and reversible . The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d PURPOSE PF-00562271 is a novel inhibitor of focal adhesion kinase ( FAK ) . The objectives of this study were to identify the recommended phase II dose ( RP2D ) and assess safety and tolerability , pharmacokinetics ( PK ) , pharmacodynamics ( PD ) , and antitumor activity of PF-00562271 . PATIENTS AND METHODS Part 1 was a dose escalation without and with food . Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients . RESULTS Ninety-nine patients ( median age , 60 years ; 98 % with Eastern Cooperative Oncology Group performance status of 0 or 1 ) were treated in 12 fasting and three fed cohorts . The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose ( MTD ) and RP2D . Grade 3 dose-limiting toxicities included headache , nausea/vomiting , dehydration , and edema . Nausea was the most frequently observed toxicity ( 60 % of patients , all grade s 1 or 2 at RP2D ) .  PF-00562271 exposure increased with increasing dose ; serum concentration-time profiles showed characteristic nonlinear disposition . Steady-state exposures were reached within 1 week . On coadministration , geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60 % and more than two-fold , respectively . Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission  tomography in the expansion cohorts , seven metabolic responses were observed . With conventional imaging , 31 patients had stable disease at first restaging scans , and 15 of these remained stable for six or more cycles . CONCLUSION The MTD and RP2D of PF-00562271 is 125 mg twice per day with food . PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor . This first-in-class study supports further investigation of FAK as a promising therapeutic target Abstract Purpose VS-6063 ( also known as defactinib or PF-04554878 ) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2 . This phase 1 study evaluated the safety and tolerability , pharmacokinetics , and clinical activity of VS-6063  in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting . Methods VS-6063 was administered orally twice daily ( b.i.d . ) in 21-day cycles to cohorts of three subjects each with a st and ard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity . Blood sample s for pharmacokinetics were collected on Day 1 and 15 . The assessment s were performed using CTCAE v4.0 for adverse events ( AEs ) , and the Response Evaluation Criteria In Solid Tumors , version v1.1 ( RECIST v1.1 ) for tumor response . Results Nine patients were treated across three dose levels ( 200–600 mg BID ) . No dose-limiting toxicities were observed at any dose level . Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia , fatigue , decreased appetite , and diarrhea . Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia . PK analyses confirmed that the exposure at the recommended Phase 2 dose ( RP2D ) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects . Durable stable disease of approximately 24 weeks was confirmed in two subjects ( malignant mesothelioma and rectal cancer ) . Conclusions VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study . These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies PURPOSE Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein ( merlin ) . On this basis , we design ed a r and omized , phase II trial to investigate whether defactinib as maintenance therapy after st and ard first-line chemotherapy could improve progression-free survival ( PFS ) in patients with malignant pleural mesothelioma ( MPM ) . METHODS This global , double-blind , r and omized , placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy . Patients were stratified for merlin and then r and omly assigned ( in a 1:1 fashion ) to receive either oral defactinib or placebo until disease progression , unacceptable toxicity , or withdrawal occurred . The co primary end points were PFS and overall survival ( OS ) . Quality of life ( QoL ) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool . RESULTS Three hundred forty-four patients were r and omly assigned to receive either defactinib ( n = 173 ) or placebo ( n = 171 ) . The median PFS was 4.1 months ( 95 % CI , 2.9 to 5.6 months ) for defactinib versus 4.0 months ( 95 % CI , 2.9 to 4.2 months ) for placebo . The median OS was 12.7 months ( 95 % CI , 9.1 to 21 months ) for defactinib versus 13.6 months ( 95 % CI , 9.6 to 21.2 months ) for placebo ( hazard ratio , 1.0 ; 95 % CI , 0.7 to 1.4 ) . Although shorter survival for both defactinib- and placebo-treated patients was observed , in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM , there were no statistical differences in response rate , PFS , OS , or QoL between the treatment groups . The most common grade 3 or worse adverse events were nausea , diarrhea , fatigue , dyspnea , and decreased appetite . CONCLUSION Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM . Defactinib can not be recommended as maintenance therapy for advanced MPM OBJECTIVES KRAS mutations , which occur in approximately 25 % of lung adenocarcinoma cases , represent a major unmet clinical need in thoracic oncology . Pre clinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A ( INK4A/ARF ) loci are sensitive to focal adhesion kinase ( FAK ) inhibition . Defactinib ( VS-6063 ) is a selective oral inhibitor of FAK . MATERIAL S AND METHODS Patients with previously treated advanced KRAS mutant NSCLC were prospect ively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity . The primary endpoint was progression-free survival ( PFS ) at 12 weeks . RESULTS Fifty-five patients were enrolled . Mean age was 62 years ; 51 % were female . The median number of prior lines of therapy was 4 ( range 1 - 8 ) . Fifteen ( 28 % ) patients met the 12-week PFS endpoint , with one patient achieving a partial response . Median PFS was 45 days . Clinical efficacy did not correlate with TP53 or CDKN2A status . The most common adverse events were fatigue , gastrointestinal , and increased bilirubin , and were generally grade 1 or 2 in severity . CONCLUSION In heavily pretreated patients with KRAS mutant NSCLC , defactinib monotherapy demonstrated modest clinical activity . Efficacy was not associated with TP53 and CDKN2A status . Defactinib was generally well tolerated 
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Expert opinion : The FAK inhibitors examined in clinical trials thus far have been shown to have manageable toxicity profiles and have demonstrated cytostatic effects as single agents , extending progression-free survival without producing a clinical or radiographic response .