A phase I and pharmacokinetic study of oral dabrafenib in children and adolescent patients with recurrent or refractory BRAF V600 mutation–positive solid tumors

Mark W. Kieran, Birgit Geoerger, Ira J. Dunkel, Alberto Broniscer, Darren Hargrave, Pooja Hingorani, Isabelle Aerts, Anne Isabelle Bertozzi, Kenneth J. Cohen, Trent R. Hummel, Violet Shen, Eric Bouffet, Christine A. Pratilas, Andrew D.J. Pearson, Lillian Tseng, Noelia Nebot, Steven Green, Mark W. Russo, James A. Whitlock

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Patients and Methods: 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. Results: 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 AUC012 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)7294-7302
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number24
DOIs
StatePublished - Dec 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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