BACKGROUND: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive 
neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard 
with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 
receptor inhibitor, in patients with TGCT to provide them with a viable systemic 
treatment option, especially in cases that are not amenable to surgical 
resection.
METHODS: This phase 3 randomised trial had two parts. Part one was a 
double-blind study in which patients with symptomatic, advanced TGCT for whom 
surgery was not recommended were randomly assigned via an integrated web 
response system (1:1) to the pexidartinib or placebo group. Individuals in the 
pexidartinib group received a loading dose of 1000 mg pexidartinib per day 
orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 
mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study 
of pexidartinib for all patients. The primary endpoint, assessed in all 
intention-to-treat patients, was overall response at week 25, and was centrally 
reviewed by RECIST, version 1.1. Safety was analysed in all patients who 
received at least one dose of the study drug. This study is registered with 
ClinicalTrials.gov, number NCT02371369.
FINDINGS: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for 
eligibility, 120 patients were randomly assigned to, and received, pexidartinib 
(n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine 
in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity 
caused the data monitoring committee to stop enrolment six patients short of 
target. The proportion of patients who achieved overall response was higher for 
pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; 
absolute difference 39% [95% CI 27-53]; p<0·0001). Serious adverse events 
occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 
59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), 
aspartate aminotransferase increase (39%), nausea (38%), alanine 
aminotransferase increase (28%), and dysgeusia (25%) were the most frequent 
pexidartinib-associated adverse events. Three patients given pexidartinib had 
aminotransferase elevations three or more times the upper limit of normal with 
total bilirubin and alkaline phosphatase two or more times the upper limit of 
normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months 
and confirmed by biopsy.
INTERPRETATION: Pexidartinib is the first systemic therapy to show a robust 
tumour response in TGCT with improved patient symptoms and functional outcomes; 
mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be 
considered as a potential treatment for TGCT associated with severe morbidity or 
functional limitations in cases not amenable to improvement with surgery.
FUNDING: Daiichi Sankyo.