Clinical Trial Details
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NCT02584647 : PLX3397 Plus Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors
PhasePhase 1/Phase 2
AgesMin: 18 Years Max: N/A
Inclusion Criteria:

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

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

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

- Extent of disease: Unresectable

- Allowable prior therapy

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

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

- 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

- ANC ?1.5 X 10^9/L, Hgb >9 g/dL, and platelet count ?100 X 10^9/L

- AST/ALT ? upper limit of normal (ULN) or < 2.5X ULN in the presence of liver
metastases, bilirubin ? 1.5 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

- 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

- 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

- 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

- 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

- 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 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 PLX3997. 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 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. During the study, if the use of any concomitant treatment becomes necessary
(e.g., for treatment of an adverse event), the treatment must be recorded on the
eCRF, including the reason for treatment, generic name of the drug, dosage, route,
and start and stop dates of administration. 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
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