Inclusion Criteria:

• Age ≥ 18 years.
• A diagnosis of PVNS or GCT-TS (i) that has been histologically confirmed either by a pathologist at the treating institution or a central pathologist, and (ii) where surgical resection would be associated with potentially worsening functional limitation or severe morbidity (locally advanced disease), with morbidity determined consensually by qualified personnel (eg, two surgeons or a multi-disciplinary tumor board).
• Measurable disease of at least 2 cm and otherwise based on RECIST 1.1, assessed from MRI scans by a central radiologist.
• Symptomatic disease
• Stable analgesic regimen during the 2 weeks prior to randomization.
• During the week prior to randomization, at least 4 days of BPI Worst Pain NRS items and Worst Stiffness NRS items completed correctly.
• Males and females of childbearing potential are permitted in the study as long as they consent to avoid getting their partner pregnant or becoming pregnant, respectively, by using a highly effective contraception method, as described below, throughout the study and for up to 90 days after completion. Highly effective methods of contraception include: hormonal methods associated with inhibition of ovulation, intra-uterine device; surgical sterilization (including partner's vasectomy) or sexual abstinence. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Women who have documentation of at least 12 months of spontaneous amenorrhea and have an follicle stimulating hormone (FSH) level >40 milli-international units per milliliter (mIU/mL) will be considered postmenopausal.
• Adequate hematologic, hepatic, and renal function, defined by:
  • Absolute neutrophil count ≥ 1.5 × 109/L
  • Ratio between the concentrations of the enzymes aspartate transaminase (AST) and alanine transaminase (ALT) in the blood (AST/ALT) ≤ 1.5 × the upper limit of normal (ULN)
  • Hemoglobin > 10 g/dL • Total bilirubin ≤ 1.5 × ULN
  • Platelet count ≥ 100 × 109/L • Serum creatinine ≤ 1.5 × ULN
• Willingness and ability to complete the BPI Worst Pain NRS item, Worst Stiffness NRS item, PROMIS Physical Function Scale, and other self-assessment instruments throughout the study.
• Willingness and ability to use an electronic diary.
• Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.

Exclusion Criteria:

• Investigational drug use within 28 days of randomization.
• Previous use of PLX3397 or any biologic treatment targeting Colony Stimulating Factor 1 (CSF1) or the Colony Stimulating Factor 1 Receptor (CSF1R); previous use of oral tyrosine kinase inhibitors, eg, imatinib or nilotinib, are allowed.
• Active cancer (either concurrent or within the last year of starting study treatment) that requires non-surgical therapy (eg, chemotherapy or radiation therapy), with the exception of PVNS/GCT-TS, surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix. Prostate and breast cancer in remission (not receiving active therapy) for > 5 years will be allowed.
• Known metastatic PVNS/GCT-TS.
• Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus or known active or chronic infection with human immunodeficiency virus.
• Known active tuberculosis.
• Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history that, in the investigator's opinion, would likely interfere with the person's study participation or the interpretation of his or her results.
• Women who are breastfeeding.
• A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women).
• MRI contraindications.