{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:04:00Z","timestamp":1753869840811,"version":"3.41.2"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,11,4]],"date-time":"2018-11-04T00:00:00Z","timestamp":1541289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000015","name":"Canadian Cancer Society Research Institute","doi-asserted-by":"publisher","award":["704970"],"award-info":[{"award-number":["704970"]}],"id":[{"id":"10.13039\/501100000015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>Patients\u00a0\u2265\u00a01 and\u00a0\u2264\u00a018 years with recurrent\/refractory solid or CNS tumors were eligible. Vinblastine (4\u00a0mg\/m<jats:sup>2<\/jats:sup>) and temsirolimus (15\u00a0mg\/m<jats:sup>2<\/jats:sup>) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seven patients with median age 12 years (range, 8\u201318 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose\u2010limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level \u22122 (temsirolimus 10\u00a0mg\/m<jats:sup>2<\/jats:sup>, vinblastine 4\u00a0mg\/m<jats:sup>2<\/jats:sup>) with no protocol\u2010related toxicity\u00a0&gt;\u00a0grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred\u2014an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)\u2014unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1\u20138.3 months).\n<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The combination of weekly temsirolimus (15\u00a0mg\/m<jats:sup>2<\/jats:sup>) and vinblastine (4\u00a0mg\/m<jats:sup>2<\/jats:sup>) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.27540","type":"journal-article","created":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T05:47:05Z","timestamp":1541396825000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3315-4383","authenticated-orcid":false,"given":"Rebecca J.","family":"Deyell","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology\/BMT University of British Columbia British Columbia Children's Hospital and Research Institute  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Toronto and New Agent and Innovative Therapy Program The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Rod","family":"Rassekh","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology\/BMT University of British Columbia British Columbia Children's Hospital and Research Institute  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongsheng","family":"Tu","sequence":"additional","affiliation":[{"name":"Canadian Cancer Trials Group and Queen's University  Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvan","family":"Samson","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Sainte\u2010Justine  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Fleming","sequence":"additional","affiliation":[{"name":"McMaster Children's Hospital at Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Bouffet","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Toronto and New Agent and Innovative Therapy Program The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqun","family":"Sun","sequence":"additional","affiliation":[{"name":"Canadian Cancer Trials Group and Queen's University  Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Powers","sequence":"additional","affiliation":[{"name":"Canadian Cancer Trials Group and Queen's University  Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley","family":"Seymour","sequence":"additional","affiliation":[{"name":"Canadian Cancer Trials Group and Queen's University  Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvain","family":"Baruchel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Toronto and New Agent and Innovative Therapy Program The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4859-1108","authenticated-orcid":false,"given":"Daniel A.","family":"Morgenstern","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Toronto and New Agent and Innovative Therapy Program The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,11,4]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"1758","article-title":"Biochemical correlates of mTOR inhibition by the rapamycin ester CCI\u2010779 and tumor growth inhibition","volume":"7","author":"Dudkin L","year":"2001","journal-title":"Clin Cancer Res"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-814153"},{"key":"e_1_2_8_4_1","first-page":"886","article-title":"Rapamycin causes poorly reversible inhibition of mTOR and induces p53\u2010independent apoptosis in human rhabdomyosarcoma cells","volume":"59","author":"Hosoi H","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210938"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.33.4649"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2011.09.021"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0361"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.03.024"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-02-137141"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.26768"},{"key":"e_1_2_8_12_1","article-title":"Improvement of tumor response by combined rapamycin and vinblastine treatment in neuroblastoma preclinical models","author":"Zhang L","year":"2009","journal-title":"AACR Meeting Abstracts"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24656"},{"key":"e_1_2_8_14_1","doi-asserted-by":"crossref","unstructured":"MascarenhasL MeyerWH LydenE et\u00a0al.Randomized phase 2 trial of bevacizumab and temsirolimus in combination with vinorelbine and cyclophosphamide for first relapse\/disease progression of rhabdomyosarcoma: a report from the Children's Oncology Group. 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