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Clin Cancer Res. 2019 Dec 15;25(24):7294-7302. doi: 10.1158/1078-0432.CCR-17-3572. Epub 2019 Sep 10.

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors.

Author information

1
Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Department of Childhood and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France. birgit.geoerger@gustaveroussy.fr.
3
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York.
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
5
UCL Great Ormond Street Institute of Child Health, Pediatric Oncology Unit, London, United Kingdom.
6
Phoenix Children's Hospital, Center for Cancer and Blood Disorders, Phoenix, Arizona.
7
Institut Curie, PSL Research University, Oncology Center SIREDO, Paris, France.
8
CHU de Toulouse - Pôle Pédiatrique, Toulouse, France.
9
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
10
Cancer and Blood Disorder Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
11
Children's Hospital of Orange County, Orange, California.
12
The Hospital for Sick Children, University of Toronto, Department of Pediatrics, Toronto, Ontario.
13
Paediatric Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research, Sutton, United Kingdom.
14
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
15
Novartis Pharma AG, Basel, Switzerland.
#
Contributed equally

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 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.

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.

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