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

Abstract

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.

• Authors: Lauren H Boal, John Glod, Melissa Spencer, Miki Kasai, Joanne Derdak, Eva Dombi, Mark Ahlman, Daniel W Beury, Melinda S Merchant, Christianne Persenaire, David J Liewehr, Seth M Steinberg, Brigitte C Widemann, Rosandra N Kaplan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 23 Pg. 6112-6121 (12 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32943455 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Intramural)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Aminopyridines
• Pyrroles
• pexidartinib

Topics

• Adolescent
• Adult
• Aminopyridines (pharmacokinetics, therapeutic use)
• Child
• Child, Preschool
• Drug Resistance, Neoplasm (drug effects)
• Female
• Follow-Up Studies
• Humans
• Male
• Maximum Tolerated Dose
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Neoplasms (drug therapy, pathology)
• Neurofibroma, Plexiform (drug therapy, pathology)
• Neurofibromatosis 1 (drug therapy, pathology)
• Prognosis
• Pyrroles (pharmacokinetics, therapeutic use)
• Salvage Therapy
• Tissue Distribution
• Young Adult