Sunitinib in Sarcomas of the Central Nervous System

Background:

- Gliosarcoma and primary CNS sarcomas are malignant brain tumors uniformly associated
with poor outcome.

- There are no known effective medical therapies for these cancers.

- Sunitinib is an orally administered small molecule that inhibits signaling of multiple
receptor tyrosine kinases including those known to be activated in CNS sarcomas.

Objectives:

To determine the anti-tumor effect of sunitinib in recurrent gliosarcomas and primary CNS
sarcomas as assessed by objective response rate (ORR).

Eligibility:

- Patients with histologically proven gliosarcoma and primary CNS sarcoma at disease
relapse after failing standard therapy (surgery and irradiation).

- Tumor tissue blocks or 15 unstained slides should be available

- Subjects must be greater than or equal to 18 years old.

- Karnofsky performance status of greater than or equal to 60

- Patients must have adequate organ function.

- Patients must not have received tyrosine kinase inhibitor(s) in the past.

Design:

- This is a prospective, single institution, single arm, multi-cohort phase II study of
sunitinib in subjects with recurrent gliosarcoma and primary CNS sarcoma that have
failed prior surgery and irradiation (unless radiation therapy was contraindicated).

- Subjects will be classified into three cohorts: 1) Primary gliosarcoma; 2) Secondary
gliosarcoma; 3) Primary CNS sarcoma. Cohort expansion will be carried out at indication
of promising response.

- Sunitinib will be administered orally using a continuous schedule at 50 mg per day (with
dose adjustments allowed for toxicity) for 2 weeks with 1 week off to constitute a
3-week cycle until disease progression or development of intolerable side-effects.

- Toxicity will be assessed every cycle by CTCAE version 5.0.

- INCLUSION CRITERIA:

- Patients must have histologically confirmed gliosarcoma (primary or secondary) or
primary central nervous system sarcoma confirmed by the Laboratory of Pathology, NCI.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured bidimensionally by MRI (or CT scan if MRI is contraindicated).

- Patients must have failed standard therapy consisting of surgery, irradiation, and
chemotherapy if indicated.

- Age greater than or equal to 18 years.

- Karnofsky greater than or equal to 60%.

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine within normal institutional limits OR creatinine clearance greater
than or equal to 60 mL/min/1.73 m(2) for patients with

creatinine levels above institutional normal.

- Patients must have the ability to understand and the willingness to sign a written
informed consent document indicating that they are aware of the investigational nature
of this study.

- The effects of sunitinib on the developing human fetus are unknown. For this reason
and because anti-angiogenic agents are known to be teratogenic, 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.

- Tumor tissue blocks or at least 10-15 unstained slides from the diagnosis should be
available.

- At the time of registration, all subjects must be removed greater than or equal to 28
days from any investigational agents.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

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

- Prior use of tyrosine kinase inhibitors or VEGF inhibition.

- Patients who are receiving strong CYP450 inducers or inhibitors are ineligible.

- Pregnant women are excluded from this study because sunitinib has 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
sunitinib, breastfeeding should be discontinued if the mother is treated with
sunitinib.

- Patients with known HIV history on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with sunitinib. In addition,
these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy.

- Uncontrolled hypertension (> 150/100 mmHg) while on antihypertensive medications.

- New York Heart Association class II or greater congestive heart failure.

- Serious cardiac arrhythmia requiring medication.

- Baseline echocardiogram with ejection fraction < 50% or greater than or equal to 20%
decrease from a prior study.

- QTc interval > 500 msec on baseline EKG

- Patients who require use of therapeutic doses of coumarin-derivative anticoagulants
such as warfarin are excluded, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis. Note: Low molecular weight heparin is permitted provided
the patient s INR is less than or equal to 1.5.

- Previous exposure to anthracyclines.