PURPOSE: Simultaneously targeting the tumor and tumor microenvironment may hold 
promise in treating children with refractory solid tumors. Pexidartinib, an oral 
inhibitor of tyrosine kinases including colony stimulating factor 1 receptor 
(CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell 
tumor. A phase I trial was conducted in pediatric and young adult patients with 
refractory leukemias or solid tumors including neurofibromatosis type 1-related 
plexiform neurofibromas.
PATIENTS AND METHODS: A rolling six design with dose levels (DL) of 400 mg/m2, 
600 mg/m2, and 800 mg/m2 once daily for 28-day cycles (C) was used. Response was 
assessed at regular intervals. Pharmacokinetics and population pharmacokinetics 
were analyzed during C1.
RESULTS: Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation 
phase and 4 patients enrolled in the expansion cohort: median (lower, upper 
quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. 
Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and 
simulation determined a weight-based recommended phase II dose (RP2D). Two 
patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) 
had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers 
included a rise in plasma macrophage CSF (MCSF) levels and a decrease in 
absolute monocyte count.
CONCLUSIONS: Pexidartinib in pediatric patients was well tolerated at all DL 
tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.