Kieran, MW;
Geoerger, B;
Dunkel, IJ;
Broniscer, A;
Hargrave, DR;
Hingorani, P;
Aerts, I;
... Whitlock, J; + view all
(2019)
A Phase 1 and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients With Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors.
Clinical Cancer Research
, 25
(24)
pp. 7294-7302.
10.1158/1078-0432.CCR-17-3572.
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Abstract
PURPOSE: The 2-part, phase 1/2a, 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. EXPERIMENTAL DESIGN: This phase 1 dose-finding part treated patients aged 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3-5.25 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 2 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 2 component is also closed and will be reported separately.
| Type: | Article |
|---|---|
| Title: | A Phase 1 and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients With Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1158/1078-0432.CCR-17-3572 |
| Publisher version: | https://doi.org/10.1158/1078-0432.CCR-17-3572 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10082104 |
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