{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:44:53Z","timestamp":1790847893719,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,8,17]],"date-time":"2013-08-17T00:00:00Z","timestamp":1376697600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Solving Kids Cancer and the James Birrell Neuroblastoma Research Fund"},{"DOI":"10.13039\/501100006126","name":"Hospital for Sick Children","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006126","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro\u2010apoptotic and anti\u2010angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>Patients \u226421 years of age with recurrent\/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10\u201315\u2009ng\/ml, with weekly intravenous vinblastine (dose escalated 4\u20136\u2009mg\/m<jats:sup>2<\/jats:sup>\/dose according to 3\u2009+\u20093 phase I design).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fourteen patients were enrolled (median age 8.7 years; range 2.3\u201319) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose\u2010limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose\u2010adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50\u2009\u00b1\u20090.75\u2009ng\/ml\/mg vs. 2.25\u2009\u00b1\u20091.07\u2009ng\/ml\/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned. Pediatr Blood Cancer 2014;61:128\u2013133. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.24656","type":"journal-article","created":{"date-parts":[[2013,8,17]],"date-time":"2013-08-17T07:44:41Z","timestamp":1376725481000},"page":"128-133","source":"Crossref","is-referenced-by-count":33,"title":["Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors"],"prefix":"10.1002","volume":"61","author":[{"given":"Daniel A.","family":"Morgenstern","sequence":"first","affiliation":[{"name":"Department of Paediatrics University of Toronto and New Agent and Innovative Therapy Programme, The Hospital for Sick Children Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Marzouki","sequence":"additional","affiliation":[{"name":"CHU Sainte\u2010Justine Montr\u00e9al Quebec 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