{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:53:48Z","timestamp":1790276028028,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T00:00:00Z","timestamp":1586908800000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH\/NCI Cancer Center Support Grant","award":["P30CA008748"],"award-info":[{"award-number":["P30CA008748"]}]},{"name":"NCI-Cancer Therapy Evaluation Program","award":["NIH\/NCI U01CA069856"],"award-info":[{"award-number":["NIH\/NCI U01CA069856"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K\/AKT\/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well\u2010tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti\u2010tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adults with recurrent MG, Karnofsky Performance Status\u00a0\u2265\u00a060 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3\u00a0+\u00a03 design from 15\u00a0mg to 170\u00a0mg administered once weekly. Perifosine was fixed as a 600\u00a0mg load on day 1 followed by 100\u00a0mg nightly (single agent MTD) until dose level 7 when the load increased to 900\u00a0mg.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose\u2010limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170\u00a0mg temsirolimus), and then two more at dose level 6 expansion (170\u00a0mg temsirolimus). DLTs included thrombocytopenia (<jats:italic>n<\/jats:italic>\u00a0=\u00a03), intracerebral hemorrhage (<jats:italic>n<\/jats:italic>\u00a0=\u00a01) and lung infection (<jats:italic>n<\/jats:italic>\u00a0=\u00a01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Combining the mTOR inhibitor temsirolimus dosed at 115\u00a0mg weekly and the AKT inhibitor perifosine dosed at 100\u00a0mg daily (following 600\u00a0mg load) is tolerable in heavily pretreated adults with recurrent MGs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51009","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T14:00:56Z","timestamp":1586959256000},"page":"429-436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2540-8518","authenticated-orcid":false,"given":"Thomas J.","family":"Kaley","sequence":"first","affiliation":[{"name":"Department of Neurology Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Brain Tumor Center Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Panageas","sequence":"additional","affiliation":[{"name":"Brain Tumor Center Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena I.","family":"Pentsova","sequence":"additional","affiliation":[{"name":"Department of Neurology Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Brain Tumor Center Memorial Sloan Kettering 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