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|Ref Type||Journal Article|
|Authors||Kieran MW, Geoerger B, Dunkel IJ, Broniscer A, Hargrave D, Hingorani P, Aerts I, Bertozzi AI, Cohen KJ, Hummel TR, Shen V, Bouffet E, Pratilas CA, Pearson ADJ, Tseng L, Nebot N, Green S, Russo MW, Whitlock JA|
|Title||A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2019 Dec 15|
|Abstract Text||The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers.This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.|
|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||Advanced Solid Tumor||predicted - sensitive||Dabrafenib||Phase I||Actionable||In a Phase I trial (BRF116013), Tafinlar (dabrafenib) treatment was well tolerated and demonstrated preliminary efficacy, resulted in a median duration of treatment of 75.6 week in pediatric patients with BRAF V600-mutant advanced solid tumors, including low-grade (n=15) and high-grade (n=8) gliomas, Langerhans cell histiocytosis (n=2), neuroblastoma (n=1), and papillary thyroid cancer (n=1) (PMID: 31506385; NCT01677741).||31506385|