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

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 mutationpositive 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 AUC 0-12 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.

Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002)

“…Our study found a high proportion of objective radiographic responses that were durable, with 1 CR, 5 PRs, and 13 SDs as the centrally-reviewed best responses on therapy. The recently reported phase I/IIa experience with the BRAF V600E inhibitor dabrafenib in children with recurrent pediatric low grade glioma reported 1 CR, 13 PR, 11 SD and two progressive diseases as best responses in a cohort of 32 patients [12,13]. This is of particular interest as both drugs have been shown to have poor CNS penetration in animal models [14].…”

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation

“…Novel therapeutic options are thus urgently needed. Recent studies have demonstrated safety and remarkable efficacy of BRAF [73–78] and MEK [78,79] inhibition in patients with BRAF ‐mutated or BRAF wildtype histiocytic neoplasms, respectively. Moreover, dramatic responses to selective inhibition of RET (Selpercatinib) or ALK (Crizotinib) have been observed in two patients with histiocytic neoplasms driven by rare rearrangements involving one of these genes [10], and high response rates have been described in ECD patients treated with the mTOR inhibitor Sirolimus [80].…”

Effectiveness and Safety of Dabrafenib in the Treatment of 20 Chinese Children with BRAFV600E-Mutated Langerhans Cell Histiocytosis

“…The dosage of dabrafenib was 2 mg/kg according to dose escalation and dose limiting toxicity (DLT) evaluation in a phase I/II study on dabrafenib in children with refractory/resistant BRAF V600E solid tumors [11], and for the treatment of pediatric BRAF V600E mutated high grade gliomas [12], dabrafenib was administered orally once every 12 hours. The general duration of the course of dabrafenib treatment was 6 months to 1 year, adjusted according to disease assessment and patient tolerance to the drug.…”

“…The most common adverse events of dabrafenib reported in the literature are skin-related toxic effects (including maculopapular rash, skin pain, and severe events, including squamous cell carcinoma and keratocanthoma), fever, fatigue, arthralgia, etc [11].…”