Phase 1 study of dabrafenib in pediatric patients (pts) with relapsed or refractory BRAF V600E high- and low-grade gliomas (HGG, LGG), Langerhans cell histiocytosis (LCH), and other solid tumors (OST)

10004 Background: Dabrafenib is an orally available, selective ATP-competitive inhibitor of BRAF V600E kinase, approved in unresectable or metastatic melanoma pts with the V600E mutation. This international study was designed to determine the recommended phase 2 dose (RP2D) in pts 12yrs and [≤] 12yrs. Doses of 3.0, 3.75, 4.5, and 5.25mg/kg/day were assessed by a rolling six design. When a dose level was filled and under assessment, additional pts could join the previous dose level deemed tolerable. Results: Enrollment for phase 1 completed at 27 pts, 15 male, median age 9yrs (range 1-17), with HGG n = 8, LGG n = 15, LCH n = 2, and OST n = 2. One pt had a dose-limiting toxicity (DLT) of grade 3 maculopapular rash (MR) at 4.5mg/kg/day, but is on study {approx}9mths after restarting dabrafenib at 3.75mg/kg/day. Serious adverse events judged related to dabrafenib included MR (1 pt); hypotension, disseminated intravascular coagulation, fever (1 pt, outside DLT period); and arthralgia (1 pt). Duration on study ranged from 9wks to 19mo (ongoing); 20 pts remain on treatment. The RP2D for pts > 12yrs is 4.5mg/kg/day (median AUC 5285) and 5.25mg/kg/day (median AUC 4384) for [≤] 12yrs. Investigator-assessed best radiographic responses included 3 complete response (CR), 3 partial response (PR) and 2 progressive disease (PD) in HGG; 8 PR, 6 stable disease (SD) and 1 PD in LGG; 2 CR in LCH; 1 SD and 1 PD in OST (source data verification ongoing). Conclusions: The RP2D of dabrafenib for children > 12yrs and for those [≤] 12 was determined based on the target AUC when taken twice daily. The drug was well-tolerated with manageable toxicity. A high proportion of pts demonstrated radiographic responses in this phase 1 trial in different BRAF V600E-positive tumors. The disease stratified phase 2 component of the study is underway (NCT01677741). Clinical trial information: NCT01677741.