TY - JOUR
T1 - A phase I and pharmacokinetic study of oral dabrafenib in children and adolescent patients with recurrent or refractory BRAF V600 mutation–positive solid tumors
AU - Kieran, Mark W.
AU - Geoerger, Birgit
AU - Dunkel, Ira J.
AU - Broniscer, Alberto
AU - Hargrave, Darren
AU - Hingorani, Pooja
AU - Aerts, Isabelle
AU - Bertozzi, Anne Isabelle
AU - Cohen, Kenneth J.
AU - Hummel, Trent R.
AU - Shen, Violet
AU - Bouffet, Eric
AU - Pratilas, Christine A.
AU - Pearson, Andrew D.J.
AU - Tseng, Lillian
AU - Nebot, Noelia
AU - Green, Steven
AU - Russo, Mark W.
AU - Whitlock, James A.
N1 - Funding Information:
1Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. 2Department of Childhood and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France. 3Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York City, New York. 4Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. 5UCL Great Ormond Street Institute of Child Health, Pediatric Oncology Unit, London, United Kingdom. 6Phoenix Children's Hospital, Center for Cancer and Blood Disorders, Phoenix, Arizona. 7Institut Curie, PSL ResearchUniversity,OncologyCenterSIREDO,Paris,France.8CHUdeToulouse-Pôle Pédiatrique, Toulouse, France. 9The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. 10Cancer and Blood Disorder Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 11Children's Hospital of Orange County, Orange, California. 12The Hospital for Sick Children, University of Toronto, Department of Pediatrics, Toronto, Ontario. 13Paediatric Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research,
Funding Information:
The trial was sponsored by GlaxoSmithKline; dabrafenib and trametinib were designated as assets of Novartis on March 2, 2015, after which Novartis took sponsorship of the trial. The authors thank all participating patients, their families, and the treating clinical teams at the centers. The authors also thank Chris Barnes, PhD, and William Fazzone, PhD, of ArticulateScience, LLC, for editorial assistance. Editorial assistance was funded by Novartis Pharmaceuticals Corporation. They also acknowledge Bijoyesh Mookerjee, MD, of Novartis Pharmaceuticals Corporation for oversight and medical review. I. Dunkel is supported by the Memorial Sloan Kettering Cancer Center Support Grant/ Center Core Grant (P30 CA008748). D. Hargrave is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. J. Whitlock is supported by the Women's Auxiliary Millennium Chair in Haematology/Oncology at The Hospital for Sick Children. E. Bouffet and U. Tabori are supported by the Garron Family Chair in Childhood Cancer Research. M. Kieran was supported by the NCI of the NIH under Award Number P50CA165962. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-17-3572
DO - 10.1158/1078-0432.CCR-17-3572
M3 - Article
C2 - 31506385
AN - SCOPUS:85076502268
SN - 1078-0432
VL - 25
SP - 7294
EP - 7302
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -