CINXE.COM

<!DOCTYPE html> <html xmlns="http://www.w3.org/1999/xhtml" lang="en" xml:lang="en" itemscope itemtype="http://schema.org/Article" class="no-js"> <head prefix="og: http://ogp.me/ns#"> <link rel="stylesheet" href="/resource/css/screen.css?79f248ebefa43b7800a14562e5049ab4"/>   <link rel="stylesheet" type="text/css" href="https://fonts.googleapis.com/css?family=Open+Sans:400,400i,600"> <link media="print" rel="stylesheet" type="text/css" href="/resource/css/print.css"/> <script type="text/javascript"> var siteUrlPrefix = "/plosone/"; </script> <script src="/resource/js/vendor/modernizr-v2.7.1.js" type="text/javascript"></script> <script src="/resource/js/vendor/detectizr.min.js" type="text/javascript"></script> <link rel="shortcut icon" href="/resource/img/favicon.ico" type="image/x-icon"/> <meta http-equiv="Content-Type" content="text/html; charset=utf-8"/> <link rel="canonical" href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090353" /> <meta name="description" content="Background In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks). Conclusions GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Trial Registration Clinicaltrials.gov NCT00356460" /> <meta name="citation_abstract" content="Background In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks). Conclusions GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Trial Registration Clinicaltrials.gov NCT00356460"> <meta name="citation_doi" content="10.1371/journal.pone.0090353"/> <meta name="citation_title" content="Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma"/> <meta itemprop="name" content="Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma"/> <meta name="citation_journal_title" content="PLOS ONE"/> <meta name="citation_journal_abbrev" content="PLOS ONE"/> <meta name="citation_date" content="Mar 11, 2014"/> <meta name="citation_firstpage" content="e90353"/> <meta name="citation_issue" content="3"/> <meta name="citation_volume" content="9"/> <meta name="citation_issn" content="1932-6203"/> <meta name="citation_publisher" content="Public Library of Science"/> <meta name="citation_article_type" content="Research Article"> <meta name="dc.identifier" content="10.1371/journal.pone.0090353" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:site" content="plosone"/> <meta name="twitter:title" content="Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma" /> <meta property="twitter:description" content="Background In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks). Conclusions GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Trial Registration Clinicaltrials.gov NCT00356460" /> <meta property="twitter:image" content="https://journals.plos.org/plosone/article/figure/image?id=10.1371/journal.pone.0090353.g001&size=inline" /> <meta property="og:type" content="article" /> <meta property="og:url" content="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090353"/> <meta property="og:title" content="Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma"/> <meta property="og:description" content="Background In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks). Conclusions GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Trial Registration Clinicaltrials.gov NCT00356460"/> <meta property="og:image" content="https://journals.plos.org/plosone/article/figure/image?id=10.1371/journal.pone.0090353.g001&size=inline"/>  <script type='text/javascript'> var googletag = googletag || {}; googletag.cmd = googletag.cmd || []; (function() { var gads = document.createElement('script'); gads.async = true; gads.type = 'text/javascript'; var useSSL = 'https:' == document.location.protocol; gads.src = (useSSL ? 'https:' : 'http:') + '//www.googletagservices.com/tag/js/gpt.js'; var node = document.getElementsByTagName('script')[0]; node.parentNode.insertBefore(gads, node); })(); </script>  <script id="doubleClickSetupScript" type='text/javascript'> googletag.cmd.push(function() { googletag.defineSlot('/75507958/PONE_728x90_ATF', [728, 90], 'div-gpt-ad-1458247671871-0').addService(googletag.pubads()); googletag.defineSlot('/75507958/PONE_160x600_BTF', [160, 600], 'div-gpt-ad-1458247671871-1').addService(googletag.pubads()); var personalizedAds = window.plosCookieConsent && window.plosCookieConsent.hasConsented('advertising'); googletag.pubads().setRequestNonPersonalizedAds(personalizedAds ? 0 : 1); googletag.pubads().enableSingleRequest(); googletag.enableServices(); }); </script> <script type="text/javascript"> var WombatConfig = WombatConfig || {}; WombatConfig.journalKey = "PLoSONE"; WombatConfig.journalName = "PLOS ONE"; WombatConfig.figurePath = "/plosone/article/figure/image"; WombatConfig.figShareInstitutionString = "plos"; WombatConfig.doiResolverPrefix = "https://dx.plos.org/"; </script> <script type="text/javascript"> var WombatConfig = WombatConfig || {}; WombatConfig.metrics = WombatConfig.metrics || {}; WombatConfig.metrics.referenceUrl = "http://lagotto.io/plos"; WombatConfig.metrics.googleScholarUrl = "https://scholar.google.com/scholar"; WombatConfig.metrics.googleScholarCitationUrl = WombatConfig.metrics.googleScholarUrl + "?hl=en&lr=&q="; WombatConfig.metrics.crossrefUrl = "https://www.crossref.org"; </script> <script defer="defer" src="/resource/js/defer.js?13928eb59791c3cc61cf"></script><script src="/resource/js/sync.js?13928eb59791c3cc61cf"></script> <script src="/resource/js/vendor/jquery.min.js" type="text/javascript"></script> <script type="text/javascript" src="https://widgets.figshare.com/static/figshare.js"></script> <script src="/resource/js/vendor/fastclick/lib/fastclick.js" type="text/javascript"></script> <script src="/resource/js/vendor/foundation/foundation.js" type="text/javascript"></script> <script src="/resource/js/vendor/underscore-min.js" type="text/javascript"></script> <script src="/resource/js/vendor/underscore.string.min.js" type="text/javascript"></script> <script src="/resource/js/vendor/moment.js" type="text/javascript"></script> <script src="/resource/js/vendor/jquery-ui-effects.min.js" type="text/javascript"></script> <script src="/resource/js/vendor/foundation/foundation.tooltip.js" type="text/javascript"></script> <script src="/resource/js/vendor/foundation/foundation.dropdown.js" type="text/javascript"></script> <script src="/resource/js/vendor/foundation/foundation.tab.js" type="text/javascript"></script> <script src="/resource/js/vendor/foundation/foundation.reveal.js" type="text/javascript"></script> <script src="/resource/js/vendor/foundation/foundation.slider.js" type="text/javascript"></script> <script src="/resource/js/util/utils.js" type="text/javascript"></script> <script src="/resource/js/components/toggle.js" type="text/javascript"></script> <script src="/resource/js/components/truncate_elem.js" type="text/javascript"></script> <script src="/resource/js/components/tooltip_hover.js" type="text/javascript"></script> <script src="/resource/js/vendor/jquery.dotdotdot.js" type="text/javascript"></script>  <script> dataLayer = [{ 'mobileSite': 'false', 'desktopSite': 'true' }]; </script> <title>Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma | PLOS ONE</title> </head> <body class="article plosone">  <noscript><iframe src="//www.googletagmanager.com/ns.html?id=GTM-TP26BH" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript> <script> (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= '//www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-TP26BH'); </script> <noscript><iframe src="//www.googletagmanager.com/ns.html?id=GTM-MQQMGF" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript> <script>(function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= '//www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MQQMGF');</script>   <script type="text/javascript"> ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; window.NREUM||(NREUM={}),__nr_require=function(t,e,n){function r(n){if(!e[n]){var o=e[n]={exports:{}};t[n][0].call(o.exports,function(e){var o=t[n][1][e];return r(o||e)},o,o.exports)}return e[n].exports}if("function"==typeof __nr_require)return __nr_require;for(var o=0;o<n.length;o++)r(n[o]);return r}({1:[function(t,e,n){function r(t){try{s.console&&console.log(t)}catch(e){}}var o,i=t("ee"),a=t(32),s={};try{o=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(s.console=!0,o.indexOf("dev")!==-1&&(s.dev=!0),o.indexOf("nr_dev")!==-1&&(s.nrDev=!0))}catch(c){}s.nrDev&&i.on("internal-error",function(t){r(t.stack)}),s.dev&&i.on("fn-err",function(t,e,n){r(n.stack)}),s.dev&&(r("NR AGENT IN DEVELOPMENT MODE"),r("flags: "+a(s,function(t,e){return t}).join(", ")))},{}],2:[function(t,e,n){function r(t,e,n,r,s){try{l?l-=1:o(s||new UncaughtException(t,e,n),!0)}catch(f){try{i("ierr",[f,c.now(),!0])}catch(d){}}return"function"==typeof u&&u.apply(this,a(arguments))}function UncaughtException(t,e,n){this.message=t||"Uncaught error with no additional information",this.sourceURL=e,this.line=n}function o(t,e){var n=e?null:c.now();i("err",[t,n])}var i=t("handle"),a=t(33),s=t("ee"),c=t("loader"),f=t("gos"),u=window.onerror,d=!1,p="nr@seenError";if(!c.disabled){var l=0;c.features.err=!0,t(1),window.onerror=r;try{throw new Error}catch(h){"stack"in h&&(t(14),t(13),"addEventListener"in window&&t(7),c.xhrWrappable&&t(15),d=!0)}s.on("fn-start",function(t,e,n){d&&(l+=1)}),s.on("fn-err",function(t,e,n){d&&!n[p]&&(f(n,p,function(){return!0}),this.thrown=!0,o(n))}),s.on("fn-end",function(){d&&!this.thrown&&l>0&&(l-=1)}),s.on("internal-error",function(t){i("ierr",[t,c.now(),!0])})}},{}],3:[function(t,e,n){var r=t("loader");r.disabled||(r.features.ins=!0)},{}],4:[function(t,e,n){function r(){U++,L=g.hash,this[u]=y.now()}function o(){U--,g.hash!==L&&i(0,!0);var t=y.now();this[h]=~~this[h]+t-this[u],this[d]=t}function i(t,e){E.emit("newURL",[""+g,e])}function a(t,e){t.on(e,function(){this[e]=y.now()})}var s="-start",c="-end",f="-body",u="fn"+s,d="fn"+c,p="cb"+s,l="cb"+c,h="jsTime",m="fetch",v="addEventListener",w=window,g=w.location,y=t("loader");if(w[v]&&y.xhrWrappable&&!y.disabled){var x=t(11),b=t(12),E=t(9),R=t(7),O=t(14),T=t(8),P=t(15),S=t(10),M=t("ee"),N=M.get("tracer"),C=t(23);t(17),y.features.spa=!0;var L,U=0;M.on(u,r),b.on(p,r),S.on(p,r),M.on(d,o),b.on(l,o),S.on(l,o),M.buffer([u,d,"xhr-resolved"]),R.buffer([u]),O.buffer(["setTimeout"+c,"clearTimeout"+s,u]),P.buffer([u,"new-xhr","send-xhr"+s]),T.buffer([m+s,m+"-done",m+f+s,m+f+c]),E.buffer(["newURL"]),x.buffer([u]),b.buffer(["propagate",p,l,"executor-err","resolve"+s]),N.buffer([u,"no-"+u]),S.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"]),a(T,m+s),a(T,m+"-done"),a(S,"new-jsonp"),a(S,"jsonp-end"),a(S,"cb-start"),E.on("pushState-end",i),E.on("replaceState-end",i),w[v]("hashchange",i,C(!0)),w[v]("load",i,C(!0)),w[v]("popstate",function(){i(0,U>1)},C(!0))}},{}],5:[function(t,e,n){function r(){var t=new PerformanceObserver(function(t,e){var n=t.getEntries();s(v,[n])});try{t.observe({entryTypes:["resource"]})}catch(e){}}function o(t){if(s(v,[window.performance.getEntriesByType(w)]),window.performance["c"+p])try{window.performance[h](m,o,!1)}catch(t){}else try{window.performance[h]("webkit"+m,o,!1)}catch(t){}}function i(t){}if(window.performance&&window.performance.timing&&window.performance.getEntriesByType){var a=t("ee"),s=t("handle"),c=t(14),f=t(13),u=t(6),d=t(23),p="learResourceTimings",l="addEventListener",h="removeEventListener",m="resourcetimingbufferfull",v="bstResource",w="resource",g="-start",y="-end",x="fn"+g,b="fn"+y,E="bstTimer",R="pushState",O=t("loader");if(!O.disabled){O.features.stn=!0,t(9),"addEventListener"in window&&t(7);var T=NREUM.o.EV;a.on(x,function(t,e){var n=t[0];n instanceof T&&(this.bstStart=O.now())}),a.on(b,function(t,e){var n=t[0];n instanceof T&&s("bst",[n,e,this.bstStart,O.now()])}),c.on(x,function(t,e,n){this.bstStart=O.now(),this.bstType=n}),c.on(b,function(t,e){s(E,[e,this.bstStart,O.now(),this.bstType])}),f.on(x,function(){this.bstStart=O.now()}),f.on(b,function(t,e){s(E,[e,this.bstStart,O.now(),"requestAnimationFrame"])}),a.on(R+g,function(t){this.time=O.now(),this.startPath=location.pathname+location.hash}),a.on(R+y,function(t){s("bstHist",[location.pathname+location.hash,this.startPath,this.time])}),u()?(s(v,[window.performance.getEntriesByType("resource")]),r()):l in window.performance&&(window.performance["c"+p]?window.performance[l](m,o,d(!1)):window.performance[l]("webkit"+m,o,d(!1))),document[l]("scroll",i,d(!1)),document[l]("keypress",i,d(!1)),document[l]("click",i,d(!1))}}},{}],6:[function(t,e,n){e.exports=function(){return"PerformanceObserver"in window&&"function"==typeof window.PerformanceObserver}},{}],7:[function(t,e,n){function r(t){for(var e=t;e&&!e.hasOwnProperty(u);)e=Object.getPrototypeOf(e);e&&o(e)}function o(t){s.inPlace(t,[u,d],"-",i)}function i(t,e){return t[1]}var a=t("ee").get("events"),s=t("wrap-function")(a,!0),c=t("gos"),f=XMLHttpRequest,u="addEventListener",d="removeEventListener";e.exports=a,"getPrototypeOf"in Object?(r(document),r(window),r(f.prototype)):f.prototype.hasOwnProperty(u)&&(o(window),o(f.prototype)),a.on(u+"-start",function(t,e){var n=t[1];if(null!==n&&("function"==typeof n||"object"==typeof n)){var r=c(n,"nr@wrapped",function(){function t(){if("function"==typeof n.handleEvent)return n.handleEvent.apply(n,arguments)}var e={object:t,"function":n}[typeof n];return e?s(e,"fn-",null,e.name||"anonymous"):n});this.wrapped=t[1]=r}}),a.on(d+"-start",function(t){t[1]=this.wrapped||t[1]})},{}],8:[function(t,e,n){function r(t,e,n){var r=t[e];"function"==typeof r&&(t[e]=function(){var t=i(arguments),e={};o.emit(n+"before-start",[t],e);var a;e[m]&&e[m].dt&&(a=e[m].dt);var s=r.apply(this,t);return o.emit(n+"start",[t,a],s),s.then(function(t){return o.emit(n+"end",[null,t],s),t},function(t){throw o.emit(n+"end",[t],s),t})})}var o=t("ee").get("fetch"),i=t(33),a=t(32);e.exports=o;var s=window,c="fetch-",f=c+"body-",u=["arrayBuffer","blob","json","text","formData"],d=s.Request,p=s.Response,l=s.fetch,h="prototype",m="nr@context";d&&p&&l&&(a(u,function(t,e){r(d[h],e,f),r(p[h],e,f)}),r(s,"fetch",c),o.on(c+"end",function(t,e){var n=this;if(e){var r=e.headers.get("content-length");null!==r&&(n.rxSize=r),o.emit(c+"done",[null,e],n)}else o.emit(c+"done",[t],n)}))},{}],9:[function(t,e,n){var r=t("ee").get("history"),o=t("wrap-function")(r);e.exports=r;var i=window.history&&window.history.constructor&&window.history.constructor.prototype,a=window.history;i&&i.pushState&&i.replaceState&&(a=i),o.inPlace(a,["pushState","replaceState"],"-")},{}],10:[function(t,e,n){function r(t){function e(){f.emit("jsonp-end",[],l),t.removeEventListener("load",e,c(!1)),t.removeEventListener("error",n,c(!1))}function n(){f.emit("jsonp-error",[],l),f.emit("jsonp-end",[],l),t.removeEventListener("load",e,c(!1)),t.removeEventListener("error",n,c(!1))}var r=t&&"string"==typeof t.nodeName&&"script"===t.nodeName.toLowerCase();if(r){var o="function"==typeof t.addEventListener;if(o){var a=i(t.src);if(a){var d=s(a),p="function"==typeof d.parent[d.key];if(p){var l={};u.inPlace(d.parent,[d.key],"cb-",l),t.addEventListener("load",e,c(!1)),t.addEventListener("error",n,c(!1)),f.emit("new-jsonp",[t.src],l)}}}}}function o(){return"addEventListener"in window}function i(t){var e=t.match(d);return e?e[1]:null}function a(t,e){var n=t.match(l),r=n[1],o=n[3];return o?a(o,e[r]):e[r]}function s(t){var e=t.match(p);return e&&e.length>=3?{key:e[2],parent:a(e[1],window)}:{key:t,parent:window}}var c=t(23),f=t("ee").get("jsonp"),u=t("wrap-function")(f);if(e.exports=f,o()){var d=/[?&](?:callback|cb)=([^&#]+)/,p=/(.*)\.([^.]+)/,l=/^(\w+)(\.|$)(.*)$/,h=["appendChild","insertBefore","replaceChild"];Node&&Node.prototype&&Node.prototype.appendChild?u.inPlace(Node.prototype,h,"dom-"):(u.inPlace(HTMLElement.prototype,h,"dom-"),u.inPlace(HTMLHeadElement.prototype,h,"dom-"),u.inPlace(HTMLBodyElement.prototype,h,"dom-")),f.on("dom-start",function(t){r(t[0])})}},{}],11:[function(t,e,n){var r=t("ee").get("mutation"),o=t("wrap-function")(r),i=NREUM.o.MO;e.exports=r,i&&(window.MutationObserver=function(t){return this instanceof i?new i(o(t,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype)},{}],12:[function(t,e,n){function r(t){var e=i.context(),n=s(t,"executor-",e,null,!1),r=new f(n);return i.context(r).getCtx=function(){return e},r}var o=t("wrap-function"),i=t("ee").get("promise"),a=t("ee").getOrSetContext,s=o(i),c=t(32),f=NREUM.o.PR;e.exports=i,f&&(window.Promise=r,["all","race"].forEach(function(t){var e=f[t];f[t]=function(n){function r(t){return function(){i.emit("propagate",[null,!o],a,!1,!1),o=o||!t}}var o=!1;c(n,function(e,n){Promise.resolve(n).then(r("all"===t),r(!1))});var a=e.apply(f,arguments),s=f.resolve(a);return s}}),["resolve","reject"].forEach(function(t){var e=f[t];f[t]=function(t){var n=e.apply(f,arguments);return t!==n&&i.emit("propagate",[t,!0],n,!1,!1),n}}),f.prototype["catch"]=function(t){return this.then(null,t)},f.prototype=Object.create(f.prototype,{constructor:{value:r}}),c(Object.getOwnPropertyNames(f),function(t,e){try{r[e]=f[e]}catch(n){}}),o.wrapInPlace(f.prototype,"then",function(t){return function(){var e=this,n=o.argsToArray.apply(this,arguments),r=a(e);r.promise=e,n[0]=s(n[0],"cb-",r,null,!1),n[1]=s(n[1],"cb-",r,null,!1);var c=t.apply(this,n);return r.nextPromise=c,i.emit("propagate",[e,!0],c,!1,!1),c}}),i.on("executor-start",function(t){t[0]=s(t[0],"resolve-",this,null,!1),t[1]=s(t[1],"resolve-",this,null,!1)}),i.on("executor-err",function(t,e,n){t[1](n)}),i.on("cb-end",function(t,e,n){i.emit("propagate",[n,!0],this.nextPromise,!1,!1)}),i.on("propagate",function(t,e,n){this.getCtx&&!e||(this.getCtx=function(){if(t instanceof Promise)var e=i.context(t);return e&&e.getCtx?e.getCtx():this})}),r.toString=function(){return""+f})},{}],13:[function(t,e,n){var r=t("ee").get("raf"),o=t("wrap-function")(r),i="equestAnimationFrame";e.exports=r,o.inPlace(window,["r"+i,"mozR"+i,"webkitR"+i,"msR"+i],"raf-"),r.on("raf-start",function(t){t[0]=o(t[0],"fn-")})},{}],14:[function(t,e,n){function r(t,e,n){t[0]=a(t[0],"fn-",null,n)}function o(t,e,n){this.method=n,this.timerDuration=isNaN(t[1])?0:+t[1],t[0]=a(t[0],"fn-",this,n)}var i=t("ee").get("timer"),a=t("wrap-function")(i),s="setTimeout",c="setInterval",f="clearTimeout",u="-start",d="-";e.exports=i,a.inPlace(window,[s,"setImmediate"],s+d),a.inPlace(window,[c],c+d),a.inPlace(window,[f,"clearImmediate"],f+d),i.on(c+u,r),i.on(s+u,o)},{}],15:[function(t,e,n){function r(t,e){d.inPlace(e,["onreadystatechange"],"fn-",s)}function o(){var t=this,e=u.context(t);t.readyState>3&&!e.resolved&&(e.resolved=!0,u.emit("xhr-resolved",[],t)),d.inPlace(t,y,"fn-",s)}function i(t){x.push(t),m&&(E?E.then(a):w?w(a):(R=-R,O.data=R))}function a(){for(var t=0;t<x.length;t++)r([],x[t]);x.length&&(x=[])}function s(t,e){return e}function c(t,e){for(var n in t)e[n]=t[n];return e}t(7);var f=t("ee"),u=f.get("xhr"),d=t("wrap-function")(u),p=t(23),l=NREUM.o,h=l.XHR,m=l.MO,v=l.PR,w=l.SI,g="readystatechange",y=["onload","onerror","onabort","onloadstart","onloadend","onprogress","ontimeout"],x=[];e.exports=u;var b=window.XMLHttpRequest=function(t){var e=new h(t);try{u.emit("new-xhr",[e],e),e.addEventListener(g,o,p(!1))}catch(n){try{u.emit("internal-error",[n])}catch(r){}}return e};if(c(h,b),b.prototype=h.prototype,d.inPlace(b.prototype,["open","send"],"-xhr-",s),u.on("send-xhr-start",function(t,e){r(t,e),i(e)}),u.on("open-xhr-start",r),m){var E=v&&v.resolve();if(!w&&!v){var R=1,O=document.createTextNode(R);new m(a).observe(O,{characterData:!0})}}else f.on("fn-end",function(t){t[0]&&t[0].type===g||a()})},{}],16:[function(t,e,n){function r(t){if(!s(t))return null;var e=window.NREUM;if(!e.loader_config)return null;var n=(e.loader_config.accountID||"").toString()||null,r=(e.loader_config.agentID||"").toString()||null,f=(e.loader_config.trustKey||"").toString()||null;if(!n||!r)return null;var h=l.generateSpanId(),m=l.generateTraceId(),v=Date.now(),w={spanId:h,traceId:m,timestamp:v};return(t.sameOrigin||c(t)&&p())&&(w.traceContextParentHeader=o(h,m),w.traceContextStateHeader=i(h,v,n,r,f)),(t.sameOrigin&&!u()||!t.sameOrigin&&c(t)&&d())&&(w.newrelicHeader=a(h,m,v,n,r,f)),w}function o(t,e){return"00-"+e+"-"+t+"-01"}function i(t,e,n,r,o){var i=0,a="",s=1,c="",f="";return o+"@nr="+i+"-"+s+"-"+n+"-"+r+"-"+t+"-"+a+"-"+c+"-"+f+"-"+e}function a(t,e,n,r,o,i){var a="btoa"in window&&"function"==typeof window.btoa;if(!a)return null;var s={v:[0,1],d:{ty:"Browser",ac:r,ap:o,id:t,tr:e,ti:n}};return i&&r!==i&&(s.d.tk=i),btoa(JSON.stringify(s))}function s(t){return f()&&c(t)}function c(t){var e=!1,n={};if("init"in NREUM&&"distributed_tracing"in NREUM.init&&(n=NREUM.init.distributed_tracing),t.sameOrigin)e=!0;else if(n.allowed_origins instanceof Array)for(var r=0;r<n.allowed_origins.length;r++){var o=h(n.allowed_origins[r]);if(t.hostname===o.hostname&&t.protocol===o.protocol&&t.port===o.port){e=!0;break}}return e}function f(){return"init"in NREUM&&"distributed_tracing"in NREUM.init&&!!NREUM.init.distributed_tracing.enabled}function u(){return"init"in NREUM&&"distributed_tracing"in NREUM.init&&!!NREUM.init.distributed_tracing.exclude_newrelic_header}function d(){return"init"in NREUM&&"distributed_tracing"in NREUM.init&&NREUM.init.distributed_tracing.cors_use_newrelic_header!==!1}function p(){return"init"in NREUM&&"distributed_tracing"in NREUM.init&&!!NREUM.init.distributed_tracing.cors_use_tracecontext_headers}var l=t(29),h=t(18);e.exports={generateTracePayload:r,shouldGenerateTrace:s}},{}],17:[function(t,e,n){function r(t){var e=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var r=0;r<p;r++)t.removeEventListener(d[r],this.listener,!1);e.aborted||(n.duration=a.now()-this.startTime,this.loadCaptureCalled||4!==t.readyState?null==e.status&&(e.status=0):i(this,t),n.cbTime=this.cbTime,s("xhr",[e,n,this.startTime,this.endTime,"xhr"],this))}}function o(t,e){var n=c(e),r=t.params;r.hostname=n.hostname,r.port=n.port,r.protocol=n.protocol,r.host=n.hostname+":"+n.port,r.pathname=n.pathname,t.parsedOrigin=n,t.sameOrigin=n.sameOrigin}function i(t,e){t.params.status=e.status;var n=v(e,t.lastSize);if(n&&(t.metrics.rxSize=n),t.sameOrigin){var r=e.getResponseHeader("X-NewRelic-App-Data");r&&(t.params.cat=r.split(", ").pop())}t.loadCaptureCalled=!0}var a=t("loader");if(a.xhrWrappable&&!a.disabled){var s=t("handle"),c=t(18),f=t(16).generateTracePayload,u=t("ee"),d=["load","error","abort","timeout"],p=d.length,l=t("id"),h=t(24),m=t(22),v=t(19),w=t(23),g=NREUM.o.REQ,y=window.XMLHttpRequest;a.features.xhr=!0,t(15),t(8),u.on("new-xhr",function(t){var e=this;e.totalCbs=0,e.called=0,e.cbTime=0,e.end=r,e.ended=!1,e.xhrGuids={},e.lastSize=null,e.loadCaptureCalled=!1,e.params=this.params||{},e.metrics=this.metrics||{},t.addEventListener("load",function(n){i(e,t)},w(!1)),h&&(h>34||h<10)||t.addEventListener("progress",function(t){e.lastSize=t.loaded},w(!1))}),u.on("open-xhr-start",function(t){this.params={method:t[0]},o(this,t[1]),this.metrics={}}),u.on("open-xhr-end",function(t,e){"loader_config"in NREUM&&"xpid"in NREUM.loader_config&&this.sameOrigin&&e.setRequestHeader("X-NewRelic-ID",NREUM.loader_config.xpid);var n=f(this.parsedOrigin);if(n){var r=!1;n.newrelicHeader&&(e.setRequestHeader("newrelic",n.newrelicHeader),r=!0),n.traceContextParentHeader&&(e.setRequestHeader("traceparent",n.traceContextParentHeader),n.traceContextStateHeader&&e.setRequestHeader("tracestate",n.traceContextStateHeader),r=!0),r&&(this.dt=n)}}),u.on("send-xhr-start",function(t,e){var n=this.metrics,r=t[0],o=this;if(n&&r){var i=m(r);i&&(n.txSize=i)}this.startTime=a.now(),this.listener=function(t){try{"abort"!==t.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==t.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof e.onload))&&o.end(e)}catch(n){try{u.emit("internal-error",[n])}catch(r){}}};for(var s=0;s<p;s++)e.addEventListener(d[s],this.listener,w(!1))}),u.on("xhr-cb-time",function(t,e,n){this.cbTime+=t,e?this.onloadCalled=!0:this.called+=1,this.called!==this.totalCbs||!this.onloadCalled&&"function"==typeof n.onload||this.end(n)}),u.on("xhr-load-added",function(t,e){var n=""+l(t)+!!e;this.xhrGuids&&!this.xhrGuids[n]&&(this.xhrGuids[n]=!0,this.totalCbs+=1)}),u.on("xhr-load-removed",function(t,e){var n=""+l(t)+!!e;this.xhrGuids&&this.xhrGuids[n]&&(delete this.xhrGuids[n],this.totalCbs-=1)}),u.on("xhr-resolved",function(){this.endTime=a.now()}),u.on("addEventListener-end",function(t,e){e instanceof y&&"load"===t[0]&&u.emit("xhr-load-added",[t[1],t[2]],e)}),u.on("removeEventListener-end",function(t,e){e instanceof y&&"load"===t[0]&&u.emit("xhr-load-removed",[t[1],t[2]],e)}),u.on("fn-start",function(t,e,n){e instanceof y&&("onload"===n&&(this.onload=!0),("load"===(t[0]&&t[0].type)||this.onload)&&(this.xhrCbStart=a.now()))}),u.on("fn-end",function(t,e){this.xhrCbStart&&u.emit("xhr-cb-time",[a.now()-this.xhrCbStart,this.onload,e],e)}),u.on("fetch-before-start",function(t){function e(t,e){var n=!1;return e.newrelicHeader&&(t.set("newrelic",e.newrelicHeader),n=!0),e.traceContextParentHeader&&(t.set("traceparent",e.traceContextParentHeader),e.traceContextStateHeader&&t.set("tracestate",e.traceContextStateHeader),n=!0),n}var n,r=t[1]||{};"string"==typeof t[0]?n=t[0]:t[0]&&t[0].url?n=t[0].url:window.URL&&t[0]&&t[0]instanceof URL&&(n=t[0].href),n&&(this.parsedOrigin=c(n),this.sameOrigin=this.parsedOrigin.sameOrigin);var o=f(this.parsedOrigin);if(o&&(o.newrelicHeader||o.traceContextParentHeader))if("string"==typeof t[0]||window.URL&&t[0]&&t[0]instanceof URL){var i={};for(var a in r)i[a]=r[a];i.headers=new Headers(r.headers||{}),e(i.headers,o)&&(this.dt=o),t.length>1?t[1]=i:t.push(i)}else t[0]&&t[0].headers&&e(t[0].headers,o)&&(this.dt=o)}),u.on("fetch-start",function(t,e){this.params={},this.metrics={},this.startTime=a.now(),this.dt=e,t.length>=1&&(this.target=t[0]),t.length>=2&&(this.opts=t[1]);var n,r=this.opts||{},i=this.target;"string"==typeof i?n=i:"object"==typeof i&&i instanceof g?n=i.url:window.URL&&"object"==typeof i&&i instanceof URL&&(n=i.href),o(this,n);var s=(""+(i&&i instanceof g&&i.method||r.method||"GET")).toUpperCase();this.params.method=s,this.txSize=m(r.body)||0}),u.on("fetch-done",function(t,e){this.endTime=a.now(),this.params||(this.params={}),this.params.status=e?e.status:0;var n;"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var r={txSize:this.txSize,rxSize:n,duration:a.now()-this.startTime};s("xhr",[this.params,r,this.startTime,this.endTime,"fetch"],this)})}},{}],18:[function(t,e,n){var r={};e.exports=function(t){if(t in r)return r[t];var e=document.createElement("a"),n=window.location,o={};e.href=t,o.port=e.port;var i=e.href.split("://");!o.port&&i[1]&&(o.port=i[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===i[0]?"443":"80"),o.hostname=e.hostname||n.hostname,o.pathname=e.pathname,o.protocol=i[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var a=!e.protocol||":"===e.protocol||e.protocol===n.protocol,s=e.hostname===document.domain&&e.port===n.port;return o.sameOrigin=a&&(!e.hostname||s),"/"===o.pathname&&(r[t]=o),o}},{}],19:[function(t,e,n){function r(t,e){var n=t.responseType;return"json"===n&&null!==e?e:"arraybuffer"===n||"blob"===n||"json"===n?o(t.response):"text"===n||""===n||void 0===n?o(t.responseText):void 0}var o=t(22);e.exports=r},{}],20:[function(t,e,n){function r(){}function o(t,e,n,r){return function(){return u.recordSupportability("API/"+e+"/called"),i(t+e,[f.now()].concat(s(arguments)),n?null:this,r),n?void 0:this}}var i=t("handle"),a=t(32),s=t(33),c=t("ee").get("tracer"),f=t("loader"),u=t(25),d=NREUM;"undefined"==typeof window.newrelic&&(newrelic=d);var p=["setPageViewName","setCustomAttribute","setErrorHandler","finished","addToTrace","inlineHit","addRelease"],l="api-",h=l+"ixn-";a(p,function(t,e){d[e]=o(l,e,!0,"api")}),d.addPageAction=o(l,"addPageAction",!0),d.setCurrentRouteName=o(l,"routeName",!0),e.exports=newrelic,d.interaction=function(){return(new r).get()};var m=r.prototype={createTracer:function(t,e){var n={},r=this,o="function"==typeof e;return i(h+"tracer",[f.now(),t,n],r),function(){if(c.emit((o?"":"no-")+"fn-start",[f.now(),r,o],n),o)try{return e.apply(this,arguments)}catch(t){throw c.emit("fn-err",[arguments,this,t],n),t}finally{c.emit("fn-end",[f.now()],n)}}}};a("actionText,setName,setAttribute,save,ignore,onEnd,getContext,end,get".split(","),function(t,e){m[e]=o(h,e)}),newrelic.noticeError=function(t,e){"string"==typeof t&&(t=new Error(t)),u.recordSupportability("API/noticeError/called"),i("err",[t,f.now(),!1,e])}},{}],21:[function(t,e,n){function r(t){if(NREUM.init){for(var e=NREUM.init,n=t.split("."),r=0;r<n.length-1;r++)if(e=e[n[r]],"object"!=typeof e)return;return e=e[n[n.length-1]]}}e.exports={getConfiguration:r}},{}],22:[function(t,e,n){e.exports=function(t){if("string"==typeof t&&t.length)return t.length;if("object"==typeof t){if("undefined"!=typeof ArrayBuffer&&t instanceof ArrayBuffer&&t.byteLength)return t.byteLength;if("undefined"!=typeof Blob&&t instanceof Blob&&t.size)return t.size;if(!("undefined"!=typeof FormData&&t instanceof FormData))try{return JSON.stringify(t).length}catch(e){return}}}},{}],23:[function(t,e,n){var r=!1;try{var o=Object.defineProperty({},"passive",{get:function(){r=!0}});window.addEventListener("testPassive",null,o),window.removeEventListener("testPassive",null,o)}catch(i){}e.exports=function(t){return r?{passive:!0,capture:!!t}:!!t}},{}],24:[function(t,e,n){var r=0,o=navigator.userAgent.match(/Firefox[\/\s](\d+\.\d+)/);o&&(r=+o[1]),e.exports=r},{}],25:[function(t,e,n){function r(t,e){var n=[a,t,{name:t},e];return i("storeMetric",n,null,"api"),n}function o(t,e){var n=[s,t,{name:t},e];return i("storeEventMetrics",n,null,"api"),n}var i=t("handle"),a="sm",s="cm";e.exports={constants:{SUPPORTABILITY_METRIC:a,CUSTOM_METRIC:s},recordSupportability:r,recordCustom:o}},{}],26:[function(t,e,n){function r(){return s.exists&&performance.now?Math.round(performance.now()):(i=Math.max((new Date).getTime(),i))-a}function o(){return i}var i=(new Date).getTime(),a=i,s=t(34);e.exports=r,e.exports.offset=a,e.exports.getLastTimestamp=o},{}],27:[function(t,e,n){function r(t){return!(!t||!t.protocol||"file:"===t.protocol)}e.exports=r},{}],28:[function(t,e,n){function r(t,e){var n=t.getEntries();n.forEach(function(t){"first-paint"===t.name?p("timing",["fp",Math.floor(t.startTime)]):"first-contentful-paint"===t.name&&p("timing",["fcp",Math.floor(t.startTime)])})}function o(t,e){var n=t.getEntries();if(n.length>0){var r=n[n.length-1];if(c&&c<r.startTime)return;p("lcp",[r])}}function i(t){t.getEntries().forEach(function(t){t.hadRecentInput||p("cls",[t])})}function a(t){if(t instanceof v&&!g){var e=Math.round(t.timeStamp),n={type:t.type};e<=l.now()?n.fid=l.now()-e:e>l.offset&&e<=Date.now()?(e-=l.offset,n.fid=l.now()-e):e=l.now(),g=!0,p("timing",["fi",e,n])}}function s(t){"hidden"===t&&(c=l.now(),p("pageHide",[c]))}if(!("init"in NREUM&&"page_view_timing"in NREUM.init&&"enabled"in NREUM.init.page_view_timing&&NREUM.init.page_view_timing.enabled===!1)){var c,f,u,d,p=t("handle"),l=t("loader"),h=t(31),m=t(23),v=NREUM.o.EV;if("PerformanceObserver"in window&&"function"==typeof window.PerformanceObserver){f=new PerformanceObserver(r);try{f.observe({entryTypes:["paint"]})}catch(w){}u=new PerformanceObserver(o);try{u.observe({entryTypes:["largest-contentful-paint"]})}catch(w){}d=new PerformanceObserver(i);try{d.observe({type:"layout-shift",buffered:!0})}catch(w){}}if("addEventListener"in document){var g=!1,y=["click","keydown","mousedown","pointerdown","touchstart"];y.forEach(function(t){document.addEventListener(t,a,m(!1))})}h(s)}},{}],29:[function(t,e,n){function r(){function t(){return e?15&e[n++]:16*Math.random()|0}var e=null,n=0,r=window.crypto||window.msCrypto;r&&r.getRandomValues&&(e=r.getRandomValues(new Uint8Array(31)));for(var o,i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx",a="",s=0;s<i.length;s++)o=i[s],"x"===o?a+=t().toString(16):"y"===o?(o=3&t()|8,a+=o.toString(16)):a+=o;return a}function o(){return a(16)}function i(){return a(32)}function a(t){function e(){return n?15&n[r++]:16*Math.random()|0}var n=null,r=0,o=window.crypto||window.msCrypto;o&&o.getRandomValues&&Uint8Array&&(n=o.getRandomValues(new Uint8Array(31)));for(var i=[],a=0;a<t;a++)i.push(e().toString(16));return i.join("")}e.exports={generateUuid:r,generateSpanId:o,generateTraceId:i}},{}],30:[function(t,e,n){function r(t,e){if(!o)return!1;if(t!==o)return!1;if(!e)return!0;if(!i)return!1;for(var n=i.split("."),r=e.split("."),a=0;a<r.length;a++)if(r[a]!==n[a])return!1;return!0}var o=null,i=null,a=/Version\/(\S+)\s+Safari/;if(navigator.userAgent){var s=navigator.userAgent,c=s.match(a);c&&s.indexOf("Chrome")===-1&&s.indexOf("Chromium")===-1&&(o="Safari",i=c[1])}e.exports={agent:o,version:i,match:r}},{}],31:[function(t,e,n){function r(t){function e(){t(s&&document[s]?document[s]:document[i]?"hidden":"visible")}"addEventListener"in document&&a&&document.addEventListener(a,e,o(!1))}var o=t(23);e.exports=r;var i,a,s;"undefined"!=typeof document.hidden?(i="hidden",a="visibilitychange",s="visibilityState"):"undefined"!=typeof document.msHidden?(i="msHidden",a="msvisibilitychange"):"undefined"!=typeof document.webkitHidden&&(i="webkitHidden",a="webkitvisibilitychange",s="webkitVisibilityState")},{}],32:[function(t,e,n){function r(t,e){var n=[],r="",i=0;for(r in t)o.call(t,r)&&(n[i]=e(r,t[r]),i+=1);return n}var o=Object.prototype.hasOwnProperty;e.exports=r},{}],33:[function(t,e,n){function r(t,e,n){e||(e=0),"undefined"==typeof n&&(n=t?t.length:0);for(var r=-1,o=n-e||0,i=Array(o<0?0:o);++r<o;)i[r]=t[e+r];return i}e.exports=r},{}],34:[function(t,e,n){e.exports={exists:"undefined"!=typeof window.performance&&window.performance.timing&&"undefined"!=typeof window.performance.timing.navigationStart}},{}],ee:[function(t,e,n){function r(){}function o(t){function e(t){return t&&t instanceof r?t:t?f(t,c,a):a()}function n(n,r,o,i,a){if(a!==!1&&(a=!0),!l.aborted||i){t&&a&&t(n,r,o);for(var s=e(o),c=m(n),f=c.length,u=0;u<f;u++)c[u].apply(s,r);var p=d[y[n]];return p&&p.push([x,n,r,s]),s}}function i(t,e){g[t]=m(t).concat(e)}function h(t,e){var n=g[t];if(n)for(var r=0;r<n.length;r++)n[r]===e&&n.splice(r,1)}function m(t){return g[t]||[]}function v(t){return p[t]=p[t]||o(n)}function w(t,e){l.aborted||u(t,function(t,n){e=e||"feature",y[n]=e,e in d||(d[e]=[])})}var g={},y={},x={on:i,addEventListener:i,removeEventListener:h,emit:n,get:v,listeners:m,context:e,buffer:w,abort:s,aborted:!1};return x}function i(t){return f(t,c,a)}function a(){return new r}function s(){(d.api||d.feature)&&(l.aborted=!0,d=l.backlog={})}var c="nr@context",f=t("gos"),u=t(32),d={},p={},l=e.exports=o();e.exports.getOrSetContext=i,l.backlog=d},{}],gos:[function(t,e,n){function r(t,e,n){if(o.call(t,e))return t[e];var r=n();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(t,e,{value:r,writable:!0,enumerable:!1}),r}catch(i){}return t[e]=r,r}var o=Object.prototype.hasOwnProperty;e.exports=r},{}],handle:[function(t,e,n){function r(t,e,n,r){o.buffer([t],r),o.emit(t,e,n)}var o=t("ee").get("handle");e.exports=r,r.ee=o},{}],id:[function(t,e,n){function r(t){var e=typeof t;return!t||"object"!==e&&"function"!==e?-1:t===window?0:a(t,i,function(){return o++})}var o=1,i="nr@id",a=t("gos");e.exports=r},{}],loader:[function(t,e,n){function r(){if(!P++){var t=T.info=NREUM.info,e=v.getElementsByTagName("script")[0];if(setTimeout(f.abort,3e4),!(t&&t.licenseKey&&t.applicationID&&e))return f.abort();c(R,function(e,n){t[e]||(t[e]=n)});var n=a();s("mark",["onload",n+T.offset],null,"api"),s("timing",["load",n]);var r=v.createElement("script");0===t.agent.indexOf("http://")||0===t.agent.indexOf("https://")?r.src=t.agent:r.src=h+"://"+t.agent,e.parentNode.insertBefore(r,e)}}function o(){"complete"===v.readyState&&i()}function i(){s("mark",["domContent",a()+T.offset],null,"api")}var a=t(26),s=t("handle"),c=t(32),f=t("ee"),u=t(30),d=t(27),p=t(21),l=t(23),h=p.getConfiguration("ssl")===!1?"http":"https",m=window,v=m.document,w="addEventListener",g="attachEvent",y=m.XMLHttpRequest,x=y&&y.prototype,b=!d(m.location);NREUM.o={ST:setTimeout,SI:m.setImmediate,CT:clearTimeout,XHR:y,REQ:m.Request,EV:m.Event,PR:m.Promise,MO:m.MutationObserver};var E=""+location,R={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",agent:"js-agent.newrelic.com/nr-spa-1212.min.js"},O=y&&x&&x[w]&&!/CriOS/.test(navigator.userAgent),T=e.exports={offset:a.getLastTimestamp(),now:a,origin:E,features:{},xhrWrappable:O,userAgent:u,disabled:b};if(!b){t(20),t(28),v[w]?(v[w]("DOMContentLoaded",i,l(!1)),m[w]("load",r,l(!1))):(v[g]("onreadystatechange",o),m[g]("onload",r)),s("mark",["firstbyte",a.getLastTimestamp()],null,"api");var P=0}},{}],"wrap-function":[function(t,e,n){function r(t,e){function n(e,n,r,c,f){function nrWrapper(){var i,a,u,p;try{a=this,i=d(arguments),u="function"==typeof r?r(i,a):r||{}}catch(l){o([l,"",[i,a,c],u],t)}s(n+"start",[i,a,c],u,f);try{return p=e.apply(a,i)}catch(h){throw s(n+"err",[i,a,h],u,f),h}finally{s(n+"end",[i,a,p],u,f)}}return a(e)?e:(n||(n=""),nrWrapper[p]=e,i(e,nrWrapper,t),nrWrapper)}function r(t,e,r,o,i){r||(r="");var s,c,f,u="-"===r.charAt(0);for(f=0;f<e.length;f++)c=e[f],s=t[c],a(s)||(t[c]=n(s,u?c+r:r,o,c,i))}function s(n,r,i,a){if(!h||e){var s=h;h=!0;try{t.emit(n,r,i,e,a)}catch(c){o([c,n,r,i],t)}h=s}}return t||(t=u),n.inPlace=r,n.flag=p,n}function o(t,e){e||(e=u);try{e.emit("internal-error",t)}catch(n){}}function i(t,e,n){if(Object.defineProperty&&Object.keys)try{var r=Object.keys(t);return r.forEach(function(n){Object.defineProperty(e,n,{get:function(){return t[n]},set:function(e){return t[n]=e,e}})}),e}catch(i){o([i],n)}for(var a in t)l.call(t,a)&&(e[a]=t[a]);return e}function a(t){return!(t&&t instanceof Function&&t.apply&&!t[p])}function s(t,e){var n=e(t);return n[p]=t,i(t,n,u),n}function c(t,e,n){var r=t[e];t[e]=s(r,n)}function f(){for(var t=arguments.length,e=new Array(t),n=0;n<t;++n)e[n]=arguments[n];return e}var u=t("ee"),d=t(33),p="nr@original",l=Object.prototype.hasOwnProperty,h=!1;e.exports=r,e.exports.wrapFunction=s,e.exports.wrapInPlace=c,e.exports.argsToArray=f},{}]},{},["loader",2,17,5,3,4]); ;NREUM.loader_config={accountID:"804283",trustKey:"804283",agentID:"402703674",licenseKey:"cf99e8d2a3",applicationID:"402703674"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"cf99e8d2a3", // Modified this value from the generated script, to pass prod vs dev applicationID: window.location.hostname.includes('journals.plos.org') ? "402703674" : "402694889", sa:1} </script>  <header> <div id="topslot" class="head-top"> <a id="skip-to-content" tabindex="0" class="button" href="#main-content"> Skip to main content </a> <div class="center"> <div class="title">Advertisement</div>  <div class='advertisement' id='div-gpt-ad-1458247671871-0' style='width:728px; height:90px;'> <script type='text/javascript'> googletag.cmd.push(function() { googletag.display('div-gpt-ad-1458247671871-0'); }); </script> </div> </div> </div> <div id="user" class="nav" data-user-management-url="https://community.plos.org"> </div> <div id="pagehdr"> <nav class="nav-main"> <h1 class="logo"> <a href="/plosone/.">PLOS ONE</a> </h1> <section class="top-bar-section"> <ul class="nav-elements"> <li class="multi-col-parent menu-section-header has-dropdown" id="publish"> Publish <div class="dropdown mega "> <ul class="multi-col" id="publish-dropdown-list"> <li class="menu-section-header " id="submissions"> <span class="menu-section-header-title"> Submissions </span> <ul class="menu-section " id="submissions-dropdown-list"> <li> <a href="/plosone/s/getting-started" >Getting Started</a> </li> <li> <a href="/plosone/s/submission-guidelines" >Submission Guidelines</a> </li> <li> <a href="/plosone/s/figures" >Figures</a> </li> <li> <a href="/plosone/s/tables" >Tables</a> </li> <li> <a href="/plosone/s/supporting-information" >Supporting Information</a> </li> <li> <a href="/plosone/s/latex" >LaTeX</a> </li> <li> <a href="/plosone/s/what-we-publish" >What We Publish</a> </li> <li> <a href="/plosone/s/preprints" >Preprints</a> </li> <li> <a href="/plosone/s/revising-your-manuscript" >Revising Your Manuscript</a> </li> <li> <a href="/plosone/s/submit-now" >Submit Now</a> </li> <li> <a href="https://collections.plos.org/s/calls-for-papers" >Calls for Papers</a> </li> </ul> </li> <li class="menu-section-header " id="policies"> <span class="menu-section-header-title"> Policies </span> <ul class="menu-section " id="policies-dropdown-list"> <li> <a href="/plosone/s/best-practices-in-research-reporting" >Best Practices in Research Reporting</a> </li> <li> <a href="/plosone/s/human-subjects-research" >Human Subjects Research</a> </li> <li> <a href="/plosone/s/animal-research" >Animal Research</a> </li> <li> <a href="/plosone/s/competing-interests" >Competing Interests</a> </li> <li> <a href="/plosone/s/disclosure-of-funding-sources" >Disclosure of Funding Sources</a> </li> <li> <a href="/plosone/s/licenses-and-copyright" >Licenses and Copyright</a> </li> <li> <a href="/plosone/s/data-availability" >Data Availability</a> </li> <li> <a href="/plosone/s/complementary-research" >Complementary Research</a> </li> <li> <a href="/plosone/s/materials-software-and-code-sharing" >Materials, Software and Code Sharing</a> </li> <li> <a href="/plosone/s/ethical-publishing-practice" >Ethical Publishing Practice</a> </li> <li> <a href="/plosone/s/authorship" >Authorship</a> </li> <li> <a href="/plosone/s/corrections-expressions-of-concern-and-retractions" >Corrections, Expressions of Concern, and Retractions</a> </li> </ul> </li> <li class="menu-section-header " id="manuscript-review-and-publication"> <span class="menu-section-header-title"> Manuscript Review and Publication </span> <ul class="menu-section " id="manuscript-review-and-publication-dropdown-list"> <li> <a href="/plosone/s/criteria-for-publication" >Criteria for Publication</a> </li> <li> <a href="/plosone/s/editorial-and-peer-review-process" >Editorial and Peer Review Process</a> </li> <li> <a href="https://plos.org/resources/editor-center" >Editor Center</a> </li> <li> <a href="/plosone/s/resources-for-editors" >Resources for Editors</a> </li> <li> <a href="/plosone/s/reviewer-guidelines" >Guidelines for Reviewers</a> </li> <li> <a href="/plosone/s/accepted-manuscripts" >Accepted Manuscripts</a> </li> <li> <a href="/plosone/s/comments" >Comments</a> </li> </ul> </li> </ul> <div class="calloutcontainer"> <h3 class="callout-headline">Submit Your Manuscript</h3> <div class="action-contain"> <p class="callout-content"> Discover a faster, simpler path to publishing in a high-quality journal. <em>PLOS ONE</em> promises fair, rigorous peer review, broad scope, and wide readership – a perfect fit for your research every time. </p> <p class="button-contain special"> <a class="button button-default" href="/plosone/static/publish"> Learn More </a> <a class="button-link" href="https://www.editorialmanager.com/pone/default.asp"> Submit Now </a> </p> </div>  </div> </div> </li> <li class="menu-section-header has-dropdown " id="about"> <span class="menu-section-header-title"> About </span> <ul class="menu-section dropdown " id="about-dropdown-list"> <li> <a href="/plosone/static/publish" >Why Publish with PLOS ONE</a> </li> <li> <a href="/plosone/s/journal-information" >Journal Information</a> </li> <li> <a href="/plosone/s/staff-editors" >Staff Editors</a> </li> <li> <a href="/plosone/static/editorial-board" >Editorial Board</a> </li> <li> <a href="/plosone/s/section-editors" >Section Editors</a> </li> <li> <a href="/plosone/s/advisory-groups" >Advisory Groups</a> </li> <li> <a href="/plosone/s/find-and-read-articles" >Find and Read Articles</a> </li> <li> <a href="/plosone/s/publishing-information" >Publishing Information</a> </li> <li> <a href="https://plos.org/publication-fees" >Publication Fees</a> </li> <li> <a href="https://plos.org/press-and-media" >Press and Media</a> </li> <li> <a href="/plosone/s/contact" >Contact</a> </li> </ul> </li> <li data-js-tooltip-hover="trigger" class="subject-area menu-section-header"> Browse </li> <script src="/resource/js/vendor/jquery.hoverIntent.js" type="text/javascript"></script> <script src="/resource/js/components/menu_drop.js" type="text/javascript"></script> <script src="/resource/js/components/hover_delay.js" type="text/javascript"></script> <li id="navsearch" class="head-search"> <form name="searchForm" action="/plosone/search" method="get"> <fieldset> <legend>Search</legend> <label for="search">Search</label> <div class="search-contain"> <input id="search" type="text" name="q" placeholder="SEARCH" required/> <button id="headerSearchButton" type="submit" aria-label="Submit search"> <i title="Submit search" class="search-icon"></i> </button> </div> </fieldset> <input type="hidden" name="filterJournals" value="PLoSONE"/> </form> <a id="advSearch" href="/plosone/search"> advanced search </a> <script src="/resource/js/components/placeholder_style.js" type="text/javascript"></script> </li> </ul> </section> </nav> </div> </header> <section id="taxonomyContainer"> <script src="/resource/js/taxonomy-browser.js" type="text/javascript"></script> <div id="taxonomy-browser" class="areas" data-search-url="/plosone/browse"> <div class="wrapper"> <div class="taxonomy-header"> Browse Subject Areas <div id="subjInfo">?</div> <div id="subjInfoText"> <p>Click through the PLOS taxonomy to find articles in your field.</p> <p>For more information about PLOS Subject Areas, click <a href="https://github.com/PLOS/plos-thesaurus/blob/master/README.md" target="_blank" title="Link opens in new window">here</a>. </p> </div> </div> <div class="levels"> <div class="levels-container cf"> <div class="levels-position"></div> </div> <a href="#" class="prev"></a> <a href="#" class="next active"></a> </div> </div> <div class="taxonomy-browser-border-bottom"></div> </div> </section> <main id="main-content"> <div class="set-grid"> <section class="body-section"> <p> <a class="back" href="/plosone/article?id=10.1371/journal.pone.0090353"> < Back to Article </a> </p> <h1 id="artTitle"><?xml version="1.0" encoding="UTF-8"?>Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma</h1> <h2>Table 1</h2> <p> Patient Demographics. </p> <div> <img class="figure-img" src="/plosone/article/file?id=10.1371/journal.pone.0090353.t001&type=large" alt="Table 1"> </div> <p class="article-id"> doi: <a href="https://doi.org/10.1371/journal.pone.0090353.t001">https://doi.org/10.1371/journal.pone.0090353.t001</a> </p> </div> </section> </main> <footer id="pageftr"> <div class="row"> <div class="block x-small"> <ul class="nav nav-secondary"> <li class="ftr-header"><a href="https://plos.org/publications/journals/">Publications</a></li> <li><a href="/plosbiology/" id="ftr-bio">PLOS Biology</a></li> <li><a href="/climate/" id="ftr-climate">PLOS Climate</a></li> <li><a href="/complexsystems/" id="ftr-complex-systems">PLOS Complex Systems</a></li> <li><a href="/ploscompbiol/" id="ftr-compbio">PLOS Computational Biology</a></li> <li><a href="/digitalhealth/" id="ftr-digitalhealth">PLOS Digital Health</a></li> <li><a href="/plosgenetics/" id="ftr-gen">PLOS Genetics</a></li> <li><a href="/globalpublichealth/" id="ftr-globalpublichealth">PLOS Global Public Health</a></li> </ul> </div> <div class="block x-small"> <ul class="nav nav-secondary"> <li class="ftr-header"> </li> <li><a href="/plosmedicine/" id="ftr-med">PLOS Medicine</a></li> <li><a href="/mentalhealth/" id="ftr-mental-health">PLOS Mental Health</a></li> <li><a href="/plosntds/" id="ftr-ntds">PLOS Neglected Tropical Diseases</a></li> <li><a href="/plosone/" id="ftr-one">PLOS ONE</a></li> <li><a href="/plospathogens/" id="ftr-path">PLOS Pathogens</a></li> <li><a href="/sustainabilitytransformation/" id="ftr-sustainabilitytransformation">PLOS Sustainability and Transformation</a></li> <li><a href="/water/" id="ftr-water">PLOS Water</a></li> </ul> </div> <div class="block xx-small"> <ul class="nav nav-tertiary"> <li> <a href="https://plos.org" id="ftr-home">Home</a> </li> <li> <a href="https://blogs.plos.org" id="ftr-blog">Blogs</a> </li> <li> <a href="https://collections.plos.org/" id="ftr-collections">Collections</a> </li> <li> <a href="mailto:webmaster@plos.org" id="ftr-feedback">Give feedback</a> </li> <li> <a href="/plosone/lockss-manifest" id="ftr-lockss">LOCKSS</a> </li> </ul> </div> <div class="block xx-small"> <ul class="nav nav-primary"> <li><a href="https://plos.org/privacy-policy" id="ftr-privacy">Privacy Policy</a></li> <li><a href="https://plos.org/terms-of-use" id="ftr-terms">Terms of Use</a></li> <li><a href="https://plos.org/advertise/" id="ftr-advertise">Advertise</a></li> <li><a href="https://plos.org/media-inquiries" id="ftr-media">Media Inquiries</a></li> <li><a href="https://plos.org/contact" id="ftr-contact">Contact</a></li> </ul> </div> </div> <div class="row"> <p> <img src="/resource/img/logo-plos-footer.png" alt="PLOS" class="logo-footer"/> <span class="footer-non-profit-statement">PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US</span> </p> <div class="block"> </div> </div> <script src="/resource/js/global.js" type="text/javascript"></script> </footer> </body> </html>