Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I related Plexiform Neurofibromas

Purpose: Simultaneously targeting the tumor and tumor microenvironment (TME) 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 (TGCT). A phase I trial was conducted in pediatric and young adult patients (pts) with refractory leukemias or solid tumors including neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PN).

Materials 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. PK and population PK were analyzed during C1.

Results: Twelve pts (4 per DL, 9 evaluable) enrolled on the dose escalation phase and four patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities (DLT) were observed. PK appeared linear over three DLs.. Two pts had stable disease and 1 pt with peritoneal mesothelioma (C49+) had a sustained partial response 67% RECIST reduction. PD markers included a rise in plasma macrophage colony stimulating factor levels and a decrease in absolute monocyte count.

Conclusions: Pexidartinib in pediatric pts was well tolerated at all DL tested, achieved target inhibition and resulted in a weight based RPD2 dose.