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Ref Type Journal Article
PMID (36375115)
Authors Bouffet E, Geoerger B, Moertel C, Whitlock JA, Aerts I, Hargrave D, Osterloh L, Tan E, Choi J, Russo M, Fox E
Title Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma.
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Abstract Text 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-mutant LGG; other cohorts will be reported elsewhere.This is a four-part, phase I/II study (ClinicalTrials.gov identifier: NCT02124772) in patients age < 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.Overall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in > 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 < 6 years and 0.025 mg/kg once daily for patients age ≥ 6 years; dabrafenib dosing in the combination was as previously identified for monotherapy. In 49 patients with BRAF V600-mutant 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-related treatment discontinuations were more common with monotherapy (54% v 22%).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-mutant LGG.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600X low grade glioma predicted - sensitive Trametinib Phase Ib/II Actionable In a Phase I/II trial, Mekinist (trametinib) treatment demonstrated a manageable safety profile in pediatric patients with BRAF V600-mutant low grade glioma, and resulted in an objective response rate of 15.4% (2/13, all partial responses), a clinical benefit rate of 61.5% (8/13), a median progression-free survival of 16.4 months, and median duration of response not reached (PMID: 36375115; NCT02124772). 36375115
BRAF V600X low grade glioma predicted - sensitive Dabrafenib + Trametinib Phase Ib/II Actionable In a Phase I/II trial, Mekinist (trametinib) and Tafinlar (dabrafenib) combination treatment demonstrated a manageable safety profile in pediatric patients with BRAF V600-mutant low-grade glioma, and resulted in an objective response rate of 25% (9/36, all partial responses), a clinical benefit rate of 88.9% (32/36), a median duration of response of 33.6 months, and a median progression-free survival of 36.9 months (PMID: 36375115; NCT02124772). 36375115