PLX3397 Plus Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) represent up to 10% of adult soft tissue
sarcomas. Due to its rarity, few MPNST-specific prospective trials exist, and treatments are
largely based on extrapolation from results from other sarcoma subtypes. Since the molecular
pathways driving pathogenesis within sarcoma subtypes are distinct, these treatment options
are likely suboptimal at best. Targeted therapies that block key pathways known to drive
MPNST will likely result in superior tumor responses with limited toxicities.

Inclusion Criteria:

- Disease site/type with pathologic confirmation of diagnosis at participating cancer
site.

- Phase 1: Advanced, unresectable sarcoma (any subtype)

- Phase 2: Advanced, unresectable malignant peripheral nerve sheath tumors (MPNSTs)

- Extent of disease: Unresectable

- Allowable prior therapy

- Phase 1: Progressed on standard of care therapy with up to three prior treatments

- Phase 2: MPNST with 0-3 prior systemic treatments (no prior radiotherapy is
necessary).

- Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2

- Age greater or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of PLX3397 in combination with sirolimus in patients
<18 years of age, children are excluded from this study, but will be eligible for
future pediatric trials.

- Presence of measurable lesions by Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1

- Allowable laboratory values with date range

- Absolute neutrophil count (ANC) ≥1.5 x 10^9/L, hemoglobin (Hgb) >9 g/dL, and
platelet count ≥100 X 10^9/L

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ upper limit of
normal (ULN) or < 2.5 x ULN in the presence of liver metastases, bilirubin ≤ 1.5
x ULN, albumin ≥ 3.0g/dL.

- Bilirubin ≤ ULN; patients with hyperbilirubinemia clinically consistent with an
inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be
eligible at the discretion of the principal investigator.

- Albumin ≥ 3.0g/dL.

- Creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) > 60 mL/min
using the Cockcroft-Gault formula less than eight days pior to start of
treatment.

- Women of child-bearing potential must have a negative serum pregnancy test at
screening and must agree to use an effective form of contraception from the time of
the negative pregnancy test and for a minimum of 3 months after the last dose of study
drug. Effective forms of contraception include abstinence, hormonal contraceptive
(injectable or implantable) in conjunction with a barrier method, or a double barrier
method. Women of non-child-bearing potential must have been postmenopausal for ≥ 1
year or surgically sterile. The effects of PLX3397 and sirolimus on the developing
human fetus are unknown. For this reason women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 3 months after
completion of PLX3397 and sirolimus administration.

- Fertile men must agree to use an effective method of birth control during the study
and for up to 3 months after the last dose of study drug.

- Willingness and ability to provide written informed consent prior to any study-related
procedures and to comply with all study requirements.

- Agree to pre and post-treatment tumor biopsies.

- Prior treatment-related Adverse Events must be ≤ grade 1 (CTCAE v4.0), except
alopecia, at time of initiating study drug.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier or
within 14 days from cycle 1 day 1 of PLX3397 and sirolimus.

- Patients who are receiving any other investigational agents concurrently.

- Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable).

- Patients with symptomatic brain metastases. Subjects with untreated brain metastasis ≤
1 cm can be considered eligible if deemed asymptomatic by the investigator upon
consultation with the medical monitor and do not require immediate radiation or
steroids. Subjects with brain metastasis that is treated and stable for 1 month may be
considered eligible if they are asymptomatic and on stable dose of steroids or if they
do not require steroids following successful local therapy.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to PLX3397 or sirolimus.

- For Phase 2 - Prior exposure to a receptor tyrosine kinase or mammalian target of
Rapamycin inhibitor.

- Pregnant women are excluded from this study because PLX3397 and sirolimus are agents
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with PLX3397 and sirolimus, breastfeeding should be
discontinued if the mother is treated with PLX3397 and sirolimus.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, active liver disease, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Active secondary malignancy unless the malignancy is not expected to interfere with
the evaluation of safety and is approved by the Sponsor. Examples of the latter
include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix,
and isolated elevation of prostate-specific antigen. Subjects with a completely
treated prior malignancy and no evidence of disease for ≥ 2 years are eligible.

- Major surgical procedure or significant traumatic injury within 14 days of initiating
study drug or anticipation of the need for major surgery during the study.

- Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy
within 28 days prior to study entry.

- Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an
external biliary shunt, or significant bowel resection that would preclude adequate
absorption.

- Congestive heart failure (CHF) New York (NY) Heart Association class III or IV;
unstable coronary artery disease (myocardial infarction (MI) more than 6 months prior
to study entry is permitted); or serious cardiac arrhythmia.

- Baseline QTc corrected by Fridericia's formula (QTcF) ≥ 450 ms (males) or ≥ 470 ms
(females)

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with PLX3397. In addition, these
patients are at increased risk of lethal infections when treated with marrow
suppressive therapy. Similarly, patients with chronic or acute hepatitis C virus (HCV)
or hepatitis B virus (HBV) infection are also ineligible.

- Of the five major cytochrome P450 (CYP) isoforms, 3A4 (BFC) may be involved in Phase I
metabolism of PLX3397, with possibly CYP1A2 playing a minor role. Until information
regarding exposure toxicity and exposure-response relationships are available with
PLX3397, concomitant strong CYP3A4 inhibitors and inducers are not permitted in the
event they alter the systemic exposure to PLX3397 (see Attachment 1 for a list of
common CYP3A4 inhibitors and inducers). These include anticonvulsants, mycin
antimicrobials, and antiretrovirals. Some common examples include inhibitors such as
erythromycin, fluoxetine, gemfibrozil, and inducers such as rifampicin, carbamazepine,
phenytoin, efavirenz, and nevirapine. Concomitant treatment is permitted if the
medication is not expected to interfere with the evaluation of safety or efficacy of
the study drug. Sirolimus undergoes extensive hepatic and intestinal metabolism via
CYP3A4 and CYP3A5, as well as excretion by P-glycoprotein. Strong CYP3A inhibitors
such as ketoconazole or grapefruit juice are not permitted. Patients should be
monitored for supratherapeutic toxic levels of sirolimus and PLX3397. As bone marrow
suppression including anemia, neutropenia, and thrombocytopenia have been reported in
patients receiving sirolimus monotherapy, these adverse effects may be exacerbated in
combination with PLX3397 for which patients will be closely monitored.

- Any patients on warfarin therapy