A Combination Clinical Study of PLX3397 and Pembrolizumab To Treat Advanced Melanoma and Other Solid Tumors

Inclusion Criteria:

A subject must satisfy all of the following criteria to be considered for inclusion in the
study:

- Subjects with histologically or cytologically-confirmed diagnosis of cancer that is
recurrent, metastatic, or persistent, who have relapsed from or are refractory to
treatment and who also meet the following corresponding requirements for the cohort or
phase of the study into which they will enroll:

- Dose-escalation Phase: Subjects with advanced solid tumors (any tumor type)
considered to have no standard-of-care treatment for their malignancy with a
curative intent, either as initial therapy or after progressing to prior
therapies; subjects who have been treated previously with a CSF1R inhibitor or an
anti PD1/PDL1 inhibitor may enroll.

- Expansion Phase: Subjects with advanced melanoma, non-small-cell lung cancer
(non-squamous; EGFR, ALK wild type), squamous cell carcinoma of the head and
neck, ovarian cancer, or gastrointestinal stromal tumor.

- Subjects with melanoma must have a histologically confirmed diagnosis of stage III
disease not amenable to local therapy. Melanoma subjects may have received any number
of prior lines of therapy for metastatic disease and must have measurable disease per
RECISTv1.1. Subjects with melanoma who have received prior treatment with a BRAF/MEK
inhibitor are acceptable candidates.

- Expansion cohorts: Subjects must have relapsed or been refractory to standard
treatment. NSCLC, SCCHN, and Melanoma must show primary progression with
antiPD1/anti-PDL1 therapy. They must have tumor accessible for sequential biopsy (core
needle biopsy or excision required) and be willing to provide on study tumor tissue
biopsy. Subjects for whom newly obtained samples cannot be obtained (e.g. inaccessible
or patient safety concern) may submit an archived specimen only upon agreement from
the Sponsor.

- ECOG performance status 0 or 1.

- Adequate organ function as demonstrated by laboratory values.

Exclusion Criteria:

A subject who meets any of the following criteria will be disqualified from entering the
study:

- Disease that is suitable for local therapy administered with curative intent.

- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of study
treatment.

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 28 days prior to the first dose of study treatment.

- Has had monoclonal antibody within 28 days of first dose of study treatment or has not
recovered from AEs due to agents administered more than 28 days earlier.

- Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 14
days prior to first dose of study treatment or who has not recovered from AEs due to a
previously administered agent.

- Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception
to this criterion and may qualify for the study.

- Note: If a subject received major surgery, he or she must have recovered
adequately from the toxicity and/or complications from the intervention prior to
starting study treatment.

- Has received transfusion of blood products (including platelets or red blood cells
[RBC]) or administration of colony stimulating factors (including granulocyte
colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or
recombinant erythropoietin) within 28 days prior to Day 1.

- Evidence of interstitial lung disease or active, noninfectious pneumonitis.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy, in situ cervical cancer and
isolated elevation of prostate-specific antigen. Subjects with a completely treated
prior malignancy with no evidence of disease for ≥ 2 years are eligible.

- For Expansion cohort subjects who have previously received an anti-PD-1, anti-PD-L1,
or anti‑PD-L2 agent or has previously participated in pembrolizumab clinical trials
are excluded, except the following tumor types Melanoma, NSCLC and SCCHN (who must
show primary progression to anti-PD1/anti-PDL1 therapy).

- Radiation therapy within 14 days of first dose of study treatment.

- Has active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy is not considered a form of systemic treatment.

- Has an active infection requiring systemic therapy.

- Has known central nervous system metastases and/or carcinomatous meningitis.

o Note: Subjects with previously treated brain metastases may participate if they meet
the following criteria: 1) are stable for at least 28 days prior to the first dose of
study treatment and if all neurologic symptoms returned to baseline); 2) have no
evidence of new or enlarging brain metastases; and 3) have not been using steroids for
at least 7 days prior to first dose of study treatment. This exception does not
include carcinomatous meningitis, which is excluded regardless of clinical stability.

- Uncontrolled intercurrent illness.

- Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant
small bowel resection that would preclude adequate absorption.

- QT interval corrected using Fridericia's formula (QTc) ≥ 450 msec (males) or ≥ 470
msec (females) at Screening.

- Congenital long QT syndrome or patients taking concomitant medications known to
prolong the QT interval.

- Major surgery within 28 days prior to first dose of study treatment.

- Has received a live vaccine administered within 30 days prior to first dose of study
treatment.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Active and clinically significant bacterial, fungal or viral infection, including
hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus
(HIV) or acquired immunodeficiency syndrome related illness (HIV testing is not
required), including subjects who have an active infection requiring systemic therapy.

- Any of the following within 48 weeks (~1 year) prior to first dose of study treatment:
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic
attack.

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of study treatment.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Has had prior exposure to PLX3397.