{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T22:34:23Z","timestamp":1789857263975,"version":"4.0.1"},"reference-count":28,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2015,7,15]],"date-time":"2015-07-15T00:00:00Z","timestamp":1436918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"funder":[{"name":"ProEd Communications, Inc."},{"DOI":"10.13039\/100006436","name":"Celgene Corporation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006436","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1\/mTORC2 inhibitor CC\u2010223 in patients with advanced cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5\u201060 mg of CC\u2010223, followed by oral daily dosing in 28\u2010day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Twenty\u2010eight patients were enrolled and received \u22651 dose of CC\u2010223. The most common treatment\u2010related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose\u2010limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg\/d was determined to be the MTD. The pharmacokinetics of CC\u2010223 demonstrated a mean terminal half\u2010life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng\/mL in patients who received CC\u2010223 \u226545 mg\/d. Phosphorylation of mTORC1\/mTORC2 pathway biomarkers in blood cells was inhibited by CC\u2010223 \u226530 mg\/d with an exposure\u2010response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30\u2010mg\/d cohort), stable disease (8 patients across \u226515 mg\/d cohorts; response duration range, 36\u2010168 days), and progressive disease (12 patients). The disease control rate was 32%.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>CC\u2010223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1\/mTORC2 pathway inhibition were observed. <jats:bold><jats:italic>Cancer<\/jats:italic> 2015;121:3435\u201343.<\/jats:bold> \u00a9 <jats:italic>2015 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.29422","type":"journal-article","created":{"date-parts":[[2015,7,15]],"date-time":"2015-07-15T10:27:29Z","timestamp":1436956049000},"page":"3481-3490","source":"Crossref","is-referenced-by-count":69,"title":["A phase I dose\u2010escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1\/mTORC2 kinase inhibitor CC\u2010223 in patients with advanced solid tumors or multiple myeloma"],"prefix":"10.1002","volume":"121","author":[{"given":"Johanna C.","family":"Bendell","sequence":"first","affiliation":[{"name":"Sarah Cannon Research Institute Nashville 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California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoo","family":"Matsutani","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, University of California at San Diego La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichan","family":"Xu","sequence":"additional","affiliation":[{"name":"Celgene Corporation San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilly","family":"Wong","sequence":"additional","affiliation":[{"name":"Celgene Corporation San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Celgene Corporation Summit New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Wu","sequence":"additional","affiliation":[{"name":"Celgene Corporation Berkeley Heights New 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