{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:51:05Z","timestamp":1790470265865,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T00:00:00Z","timestamp":1517788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Dermatology"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with <jats:italic>BRAF<\/jats:italic> V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>) and preliminary efficacy of dabrafenib 150\u00a0mg b.i.d. plus trametinib 2\u00a0mg q.d. in Japanese patients with <jats:italic>BRAF<\/jats:italic> V600E\/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (<jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>), and the primary end\u2010point in phase 2 was to assess confirmed overall response rate (<jats:styled-content style=\"fixed-case\">ORR<\/jats:styled-content>). The secondary end\u2010points in phase 1 included <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>, confirmed\/unconfirmed <jats:styled-content style=\"fixed-case\">ORR<\/jats:styled-content> and duration of response (<jats:styled-content style=\"fixed-case\">DOR<\/jats:styled-content>). The secondary end\u2010points in phase 2 were <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>, unconfirmed <jats:styled-content style=\"fixed-case\">ORR<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> DOR<\/jats:styled-content>, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content> (\u226550.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator\u2010assessed <jats:styled-content style=\"fixed-case\">ORR<\/jats:styled-content> was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9\u201399.6; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content> properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.<\/jats:p>","DOI":"10.1111\/1346-8138.14210","type":"journal-article","created":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T06:04:38Z","timestamp":1517810678000},"page":"397-407","source":"Crossref","is-referenced-by-count":23,"title":["Phase 1\/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with <i><scp>BRAF<\/scp><\/i> V600 mutation\u2010positive advanced cutaneous melanoma"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9638-0428","authenticated-orcid":false,"given":"Naoya","family":"Yamazaki","sequence":"first","affiliation":[{"name":"Department of Dermatologic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arata","family":"Tsutsumida","sequence":"additional","affiliation":[{"name":"Department of Dermatologic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Dermatologic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Namikawa","sequence":"additional","affiliation":[{"name":"Department of Dermatologic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusuke","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Dermatology Division Shizuoka Cancer Center Hospital Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Kondo","sequence":"additional","affiliation":[{"name":"Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihira","family":"Mukaiyama","sequence":"additional","affiliation":[{"name":"Development Department Novartis Pharma K.K. 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