{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T09:57:26Z","timestamp":1791021446839,"version":"4.1.0"},"reference-count":36,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"3","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2023,1,20]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> BRAF V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I\/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAF V600\u2013mutant LGG; other cohorts will be reported elsewhere. <\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p> This is a four-part, phase I\/II study (ClinicalTrials.gov identifier: NCT02124772 ) in patients age &lt; 18 years with relapsed\/refractory malignancies: trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib + trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steady-state pharmacokinetics. Disease-specific efficacy and safety (across parts A-D) were secondary objectives. <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> Overall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in &gt; 1 patient (part A) included mucosal inflammation (n = 3) and hyponatremia (n = 2). There were no dose-limiting toxicities with combination therapy (part C). The recommended phase II dose of trametinib, with or without dabrafenib, was 0.032 mg\/kg once daily for patients age &lt; 6 years and 0.025 mg\/kg once daily for patients age \u2265 6 years; dabrafenib dosing in the combination was as previously identified for monotherapy. In 49 patients with BRAF V600\u2013mutant glioma (LGG, n = 47) across all four study parts, independently assessed objective response rates were 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Adverse event\u2013related treatment discontinuations were more common with monotherapy (54% v 22%). <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> The trial design provided efficient evaluation of pediatric dosing, safety, and efficacy of single-agent and combination targeted therapy. Age-based and weight-based dosing of trametinib with or without dabrafenib achieved target concentrations with manageable safety and demonstrated clinical efficacy and tolerability in BRAF V600\u2013mutant LGG. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.22.01000","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T20:59:25Z","timestamp":1668459565000},"page":"664-674","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":185,"title":["Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric <i>BRAF<\/i> V600\u2013Mutant Low-Grade Glioma"],"prefix":"10.1200","volume":"41","clinical-trial-number":[{"clinical-trial-number":"nct02124772","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6832-6539","authenticated-orcid":false,"given":"Eric","family":"Bouffet","sequence":"first","affiliation":[{"name":"Department of Paediatrics, 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