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

• Published in: Clinical cancer research Vol. 26; no. 23; pp. 6112 - 6121
• Main Authors: Boal, Lauren H, Glod, John, Spencer, Melissa, Kasai, Miki, Derdak, Joanne, Dombi, Eva, Ahlman, Mark, Beury, Daniel W, Merchant, Melinda S, Persenaire, Christianne, Liewehr, David J, Steinberg, Seth M, Widemann, Brigitte C, Kaplan, Rosandra N
• Format: Journal Article
• Language: English
• Published: United States 01.12.2020
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-1696

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. A rolling six design with dose levels (DL) of 400 mg/m , 600 mg/m , and 800 mg/m once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1. 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. Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.