AN OPEN-LABEL, SINGLE SEQUENCE, CROSSOVER DRUG-DRUG
INTERACTION STUDY ASSESSING THE EFFECT OF PEXIDARTINIB ON THE PHARMACOKINETICS OF CYP3A4 AND CYP2C9 SUBSTRATES IN PATIENTS

Pexidartinib is a novel orally active small-molecule tyrosine kinase inhibitor
that targets
Colony-stimulating factor 1 (CSF1) receptor (CSF1R), KIT (the receptor for stem
cell
factor), and oncogenic fms-like tyrosine kinase 3 (FLT3), the receptor for FLT3
ligand.
When screened in vitro against a broad panel of 226 kinases, pexidartinib
showed potent and selective inhibition against its intended targets: CSF1R,
KIT, and activated FLT3. Pexidartinib also blocked osteoclast differentiation
and cell growth of CSF1-dependent cell lines. Pexidartinib blocks CSF1R
activity in a variety of in vivo models. Pexidartinib shows dose-dependent
inhibition of splenomegaly in an engineered CSF1R-dependent mouse model. In the
collagen-induced arthritis model, pexidartinib shows substantial efficacy by
blocking the activity of macrophages and osteoclasts that infiltrate the
diseased joints, reduces synovial inflammation and cartilage destruction, and
reduces clinical scores for joint and digit swelling and redness even with
treatment of advanced disease.

The effects of pexidartinib on multiple aspects of tumorigenesis have been
characterized
in cellular and in vivo assays. The proliferation of cell lines that depend on
CSF1, stem
cell factor (SCF), or endogenous FLT3- internal tandem duplications (ITD) is
inhibited at
half maximal inhibitory concentration (IC50) values below 1 *mol/L. Furthermore,
CSF1-induced autophosphorylation of CSF1R and SCF-induced autophosphorylation of
KIT are potently inhibited by pexidartinib. Finally, the receptor activator of
NF-kappa B
ligand (RANK-L)- and CSF-1-dependent differentiation of osteoclast precursors
is also
potently inhibited by pexidartinib. These in vitro results translate to
pexidartinib effects
in a variety of in vivo models for CSF1R-dependent proliferation,
CSF1R-dependent
osteoclast differentiation, FLT3-ITD-dependent tumor growth, and KIT-dependent
mast
cell proliferation.

Primary Objectives
To assess the effects of pexidartinib on the PK parameters of single-dose
midazolam and tolbutamide in patients.

Secondary Objectives
To evaluate:
- To determine the overall response rate (ORR) in patients with TGCT,
kit-mutant melanoma, kit-mutant GIST, or other tumors
- To assess the safety and tolerability of pexidartinib alone and in combination
with single-dose midazolam and tolbutamide
- To determine the safety of pexidartinib given as monotherapy over longer
periods
- To evaluate the PK of pexidartinib and ZAAD-1006a

Exploratory Objectives
To evaluate:
- Other measures of efficacy including:
- Duration of response
- Time to progression (for TGCT)
- Progression-free survival (for malignant tumors)
- Pharmacogenomic (PGx) analysis
- Optional (at the discretion of the Investigator/patient): Pharmacodynamics
(PDy) of pexidartinib in treated patients
- Optional (at the discretion of the Investigator/patient): Tumor biomarker
analysis

This open-label, single sequence, crossover study will comprise 2 parts:

Part 1: An initial single sequence crossover part to evaluate the effect of
pexidartinib on the PK of midazolam and tolbutamide, the DDI Phase.

Part 2: An evaluation of efficacy and safety of pexidartinib treatment in
various tumors.

Screening will take place between Day -21 and Day -1. The total duration of
participation (excluding Screening) for each patient in Part 1 will be
approximately 15 d. Pexidartinib treatment (800 mg/d, 400mg BID) will commence
on Day 3. Thereafter, pexidartinib treatment will continue BID into Part 2 of
the study at the doses defined below to evaluate efficacy and safety until
there is no longer clinical benefit or until other reasons for discontinuation
are met.

Part 1:
- On Day 1 patients will receive the single oral dose of midazolam (2 mg) and
tolbutamide (500 mg), and PK samples will be collected over approximately 48 h.
- On Day 3 pexidartinib (800 mg/d) in twice daily (400mg BID) dosing will be
initiated and continue throughout the remainder of Part 1 and into Part 2. On
the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2
mg) and tolbutamide (500 mg) will be co-administered with the morning
pexidartinib dose (400 mg), and PK samples will be collected over 10 h
(pexidartinib), 48 h (midazolam and tolbutamide).
- On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be
co-administered with the morning dose of pexidartinib (400 mg), and PK samples
will be collected over 10 h (pexidartinib) or 48 h (midazolam and tolbutamide).

In Part 2, patients will continue to receive pexidartinib BID at a dose of 800
mg/d. Patients will be assessed for safety and efficacy. An optional tumor
biopsy or archival tumor specimen under specific informed consent and/or blood
samples for circulating tumor DNA may be collected at Screening and during
pexidartinib treatment for exploratory analysis of tumor biomarkers at the
discretion of the Investigator/patient.

- tolbutamide reference treatment: single oral dose of tolbutamide (500 mg) on
Day 1.
- Midazolam reference treatment: single oral dose of midazolam (2 mg) on Day 1.
- tolbutamide test treatment: single oral dose of tolbutamide (500 mg) on Day 3
concomitantly with pexidartinib and on Day 13 following approximately 10 d of
pexidartinib BID dosing.
- Midazolam test treatment: single oral dose of midazolam (2 mg) on Day 3
concomitantly with pexidartinib and on Day 13 following approximately 10 d of
pexidartinib BID dosing.
- Pexidartinib treatment: Pexidartinib will be administered orally as a total
daily dose of 800 mg administered as split dose of 400 mg (am) and 400 mg (pm)
continuously in 28-d cycles starting from Day 3.

Pexidartinib demonstrated pharmacologic and anti-tumor activity in a variety of
in vitro
and tumor models. It is currently being investigated in a variety of Phase 1-3
studies for
the treatment of tumors and TGCT. Evidence of clinical activity has been
observed in
TGCT.

Safety data for pexidartinib are from nonclinical and clinical studies. Liver
toxicity and
myelosuppression are important identified risks and embryofetal toxicity is
considered as
an important potential risk with pexidartinib. Liver toxicity observed in
clinical studies
includes cases of liver cholestasis with single agent treatment in the Phase 3
PLX108-10
study. Risk minimization measures, such as frequent monitoring during the first
8 wk of
pexidartinib treatment, are included in this protocol. Protocol-defined dose
reductions
and discontinuations of pexidartinib, increased frequency of laboratory
monitoring, and
reporting of findings should be followed. In addition, rechallenge with
pexidartinib
should not be attempted without prior discussion with the Sponsor*s Medical
Monitor.
Risk benefit of pexidartinib should be assessed for each potential patient.