{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T03:41:56Z","timestamp":1781149316372,"version":"3.54.1"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,1,19]],"date-time":"2018-01-19T00:00:00Z","timestamp":1516320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007013","name":"F. Hoffmann-La Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc\/IV\n                      <jats:italic>BRAF V600<\/jats:italic>\n                      mutation\u2010positive melanoma. We conducted a phase I, open\u2010label, dose\u2010escalation study in pediatric patients aged 12\u201317 years with this tumor type (NCT01519323).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Procedure<\/jats:title>\n                    <jats:p>Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose\u2010limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety\/tolerability, tumor response, and pharmacokinetics were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Six patients were enrolled (720\u00a0mg twice daily [BID], n\u00a0=\u00a03; 960\u00a0mg BID [n\u00a0=\u00a03]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady\u2010state plasma concentrations of vemurafenib following 720\u00a0mg and 960\u00a0mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression\u2010free survival and overall survival were 4.4\u00a0months (95% confidence interval [CI]\u00a0=\u00a02.7\u20135.2) and 8.1 months (95% CI\u00a0=\u00a05.1\u201312.0), respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A recommended and effective dose of vemurafenib for patients aged 12\u201317 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pbc.26947","type":"journal-article","created":{"date-parts":[[2018,1,19]],"date-time":"2018-01-19T06:16:22Z","timestamp":1516342582000},"source":"Crossref","is-referenced-by-count":37,"title":["BRIM\u2010P: A phase I, open\u2010label, multicenter, dose\u2010escalation study of vemurafenib in pediatric patients with surgically incurable,\n                    <i>BRAF<\/i>\n                    mutation\u2010positive melanoma"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3479-7997","authenticated-orcid":false,"given":"Julia C.","family":"Chisholm","sequence":"first","affiliation":[{"name":"Children and Young People's Unit The Royal Marsden NHS Foundation Trust  Sutton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef","family":"Suvada","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Children's Teaching Hospital and St. Elizabeth University  Bratislava Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira J.","family":"Dunkel","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Casanova","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Roche Innovation Center  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Ritchie","sequence":"additional","affiliation":[{"name":"Roche Products Limited  Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YounJeong","family":"Choi","sequence":"additional","affiliation":[{"name":"Genentech  South San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Park","sequence":"additional","affiliation":[{"name":"Genentech  South San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghna","family":"Das Thakur","sequence":"additional","affiliation":[{"name":"Genentech  South San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Simko","sequence":"additional","affiliation":[{"name":"Genentech  South San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nga","family":"Wan Rachel Tam","sequence":"additional","affiliation":[{"name":"Genentech  South San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4724-0517","authenticated-orcid":false,"given":"Andrea","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,1,19]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975\u20131995","author":"Ries LAG","year":"1999"},{"key":"e_1_2_8_3_1","unstructured":"FerlayJ SoerjomataramI ErvikM et\u00a0al.GLOBOCAN 2012 v1.0 Cancer Incidence and Mortality Worldwide: IARC Cancer Base No.11. 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