A Double-blind, Randomized, Placebo-controlled Phase 3 Study of Orally Administered PLX3397 in Subjects with Pigmented Villonodular Synovitis or Giant Cell Tumor of the Tendon Sheath - ENLIVEN

Pigmented villonodular synovitis (PVNS) / giant cell tumor of the tendon sheath
(GCT-TS) are progressive diseases with no ideal or standardized treatments. No
systemic treatments and no treatments specifically directed to the recently
identified pathogenetic pathways have been approved for these diseases.
Although the standard of care is surgery, guidelines and evidence-based data
for the timing and extent of surgical intervention are lacking. Surgical
outcomes, even when curative, may result in marked patient morbidity as
reflected in post-operative pain, limitation in function, and cosmetic
disfigurement. In extreme or recurrent cases, the tumor may be aggressive and
require limb amputation. The use of Pexidartinib, a selective kinase inhibitor
that targets CSF1R (which is overexpressed in PVNS and GCT-TS), offers a
promising new therapeutic option for patients with PVNS or GCT-TS. The primary
objective of this study is to compare the response rate of Pexidartinib with
that of placebo per Response Evaluation Criteria in Solid Tumors, version 1.1
(RECIST 1.1) at Week 25 in subjects with symptomatic, locally advanced PVNS or
GCT-TS.

The primary objective of this study is to compare the response rate of
Pexidartinib with that of placebo per Response Evaluation Criteria in Solid
Tumors, version 1.1 (RECIST 1.1) at Week 25 in subjects with symptomatic,
locally advanced PVNS or GCT-TS.
The secondary efficacy objectives are to evaluate: (i) patient-reported
outcomes (PROs), including the Brief Pain Inventory (BPI) Worst Pain Numeric
Rating Scale (NRS) item, Patient-reported Outcomes Measurement Information
System (PROMIS) Physical Function Scale, and Worst Stiffness NRS item, at Week
25; (ii) response based on Tumor Volume Score (TVS) at Week 25; (iii) range of
motion at Week 25; and (iv) duration of response. Other objectives are to
evaluate: (i) other measures of efficacy, (ii) long-term safety, (iii)
pharmacokinetics (PK), and (iv) pharmacodynamics (PDy) of Pexidartinib in
treated subjects.

This trial is a two-part multi-center Phase 3 study in subjects with
symptomatic PVNS or GCT-TS for whom surgical resection would be associated with
potentially worsening functional limitation or severe morbidity (locally
advanced disease). In Part 1, the double-blind phase, eligible candidates will
be centrally randomized in a 1:1 ratio to receive either Pexidartinib or
placebo for 24 weeks. Randomization will be stratified by US versus non-US
sites and by upper extremity vs. lower extremity involvement.

Subjects will take five capsules a day (1000 mg/d Pexidartinib or matching
placebo) divided into a morning dose of two capsules and an evening dose of
three capsules for the first 2 weeks in Part 1. Thereafter, the dose will be
reduced to four capsules a day (800 mg/d Pexidartinib or matching placebo)
divided equally between the morning and evening doses. Doses will be taken in
the fasting state at approximately the same times of the day and approximately
12 hours apart. Each treatment cycle is 28 days and subjects will be treated
for up to 6 Cycles.
Dose reductions, interruptions, and re-escalations after previous reductions
for toxicity are permitted according to pre-specified guidelines. Those
subjects, on Pexidartinib, who complete Part 1 (ie, complete 24 weeks of
dosing and the Week 25 assessments) will be eligible to advance to Part 2, a
long-term treatment phase where all subjects will receive open-label
Pexidartinib at a maximum starting dose of four capsules a day (800 mg/d
Pexidartinib).
MRIs will be performed at Week 13 (Cycle 4, Day 1 visit of Part 1) and Week 25.
For the Week 13 assessment, if clinically indicated, the investigator may
request a central MRI reading for evaluation of disease progression. If a
central reading confirms RECIST 1.1- defined disease progression, treatment
assignment will be unblinded. Subjects receiving Pexidartinib will be
discontinued from the study unless the investigator and the Sponsor*s Medical
Monitor judge that the subject would potentially benefit from continued
treatment with Pexidartinib. All subjects in Part 2 will continue to receive
open-label Pexidartinib until all subjects have either reached at least the
Week 49 visit (ie, an additional 24 weeks of open-label Pexidartinib treatment
beyond the placebo-controlled phase) or withdrawn from the trial. Those
subjects who complete Part 2 will be eligible to enter a separate protocol to
continue receiving Pexidartinib.

PVNS and GCT-TS are progressive diseases with no ideal or standardized
treatments. No systemic treatments and no treatments specifically directed to
the recently identified pathogenetic pathways have been approved for these
diseases. Although the standard of care is surgery, guidelines and
evidence-based data for the timing and extent of surgical intervention are
lacking. Surgical outcomes, even when curative, may result in marked patient
morbidity as reflected in post-operative pain, limitation in function, and
cosmetic disfigurement. In extreme or recurrent cases, the tumor may be
aggressive and require limb amputation. The use of Pexidartinib, a selective
kinase inhibitor that targets CSF1R (which is overexpressed in PVNS and
GCT-TS), offers a promising new therapeutic option for patients with PVNS or
GCT-TS. In summary, given the acceptable safety profile of the Pexidartinib at
the selected dose and the promising Phase 1 data in subjects with PVNS/GCT-TS,
the potential for a positive benefit/risk profile is assumed for the Phase 3
study.

Patients will have additional hospital visits, additional blood draw, MRI,
ECHO/MUGA, ECGs and questionnaires/diaries to be completed. Please refer to
sections E2, E4 and E6 of this ABR form for details burden with participation
in this study.