{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T08:52:23Z","timestamp":1770886343682,"version":"3.50.1"},"reference-count":24,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T00:00:00Z","timestamp":1694822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Oral cabozantinib (25\u00a0mg\/m<jats:sup>2<\/jats:sup>) was administered daily for 21 (dose level 1) or 14 (dose level \u22121B) days. Topotecan (0.75\u00a0mg\/m<jats:sup>2<\/jats:sup>) and cyclophosphamide (250\u00a0mg\/m<jats:sup>2<\/jats:sup>) were administered intravenously (IV) on days 1\u20135. A modified 3+3 design based upon first cycle dose\u2010limiting toxicities (DLT) was used for dose escalation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twelve patients with a median age of 15 (12.9\u201333.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level \u22121B (interrupted cabozantinib, given days 8\u201321), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The recommended phase 2 doses and schedules for this combination are topotecan 0.75\u00a0mg\/m<jats:sup>2<\/jats:sup> IV days 1\u20135, cyclophosphamide 250\u00a0mg\/m<jats:sup>2<\/jats:sup> IV days 1\u20135, and cabozantinib 25\u00a0mg\/m<jats:sup>2<\/jats:sup> days 8\u201321. Non\u2010concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.30681","type":"journal-article","created":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T13:14:05Z","timestamp":1694870045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Phase 1 study of cabozantinib in combination with topotecan\u2013cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1826-4277","authenticated-orcid":false,"given":"Kevin","family":"Campbell","sequence":"first","affiliation":[{"name":"Dana\u2010Farber\/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School  Boston Massachusetts 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Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6000-3594","authenticated-orcid":false,"given":"Katherine A.","family":"Janeway","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber\/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5994-2604","authenticated-orcid":false,"given":"David S.","family":"Shulman","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber\/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne","family":"George","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber Cancer Institute and Harvard Medical School  Boston Massachusetts 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0882-738X","authenticated-orcid":false,"given":"Steven G.","family":"DuBois","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber\/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,9,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23040"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.05.105"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdg457"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21618"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.65.5381"},{"key":"e_1_2_10_7_1","volume-title":"Exelixis, Investigator's Brochure for Cabozantinib 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