BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is 
elevated in most tenosynovial giant-cell tumors. This observation has led to the 
discovery and clinical development of therapy targeting the CSF1 receptor 
(CSF1R).
METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we 
generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in 
the autoinhibited conformation. We then conducted a multicenter, phase 1 trial 
in two parts to analyze this compound. In the first part, we evaluated 
escalations in the dose of PLX3397 that was administered orally in patients with 
solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 
at the chosen phase 2 dose in an extension cohort of patients with tenosynovial 
giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the 
enrolled patients were assessed, and CSF1 in situ hybridization was performed to 
confirm the mechanism of action of PLX3397 and that the pattern of CSF1 
expression was consistent with the pathological features of tenosynovial 
giant-cell tumor.
RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and 
an additional 23 patients were enrolled in the extension study. The chosen phase 
2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with 
tenosynovial giant-cell tumors had a partial response and 7 patients had stable 
disease. Responses usually occurred within the first 4 months of treatment, and 
the median duration of response exceeded 8 months. The most common adverse 
events included fatigue, change in hair color, nausea, dysgeusia, and 
periorbital edema; adverse events rarely led to discontinuation of treatment.
CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted 
in a prolonged regression in tumor volume in most patients. (Funded by 
Plexxikon; ClinicalTrials.gov number, NCT01004861.).