Pexidartinib (PLX3397) (Synonyms: PLX3397)

Cell lines

LM8(RCB1450)、NFSa(RCB0282)、KUM5(RCB2322)、LAG(RCB2758)

Reaction Conditions

a 10mmol/L stock of pexidartinib was formulated in dimethyl sulfoxide (DMSO)

Applications

In vitro administration of pexidartinib suppressed pERK1/2 stimulation by CSF1 or TCM. CSF1R blockade in the in vitro TAM model resulted in reduced viability and chemotaxis of macrophages and polarization from M2-like to a more M1-like phenotype

Animal models

Two-month-old 5XFAD mice

Preparation Method

Treated two-month-old 5XFAD mice with pexidartinib, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, analyse the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze

Dosage form

290mg/kg formulated in standard chow，3 month

Applications

Early long-term treatment with the CSF1R inhibitor, pexidartinib significantly reduced intraneuronal amyloid, neuritic plaque formation, a reduced amount of toxic prefibrillar oligomers and improved cognitive function in particular associative learning in the contextual fear conditioning of 5XFAD mice.

human subjects

Eligible patients were 18 years old or older and have a histologically confirmed TGCT that was both unresectable and symptomatic

Preparation Method

The pooled analysis encompassed 3 groups of pexidartinib-treated patients with TGCT: 1) patients from a phase 1 extension study, 2) patients from ENLIVEN who were randomized to pexidartinib at 1000mg/d for 2 weeks and then 800mg/d, and 3) crossover patients from ENLIVEN receiving pexidartinib at 800mg/d.

Applications

One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months).

References:

[1].Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. Mol Cancer Ther. 2021;20(8):1388-1399.

[2].Sosna J, Philipp S, Albay R 3rd, et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener. 2018;13(1):11. Published 2018 Mar 1.

[3].Gelderblom H, Wagner AJ, Tap WD, et al. Long-term outcomes of pexidartinib in tenosynovial giant cell tumors. Cancer. 2021;127(6):884-893.