Sorafenib Tosylate and Stereotactic Radiosurgery in Treating Patients With Brain Metastases

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and maximum tolerated dose (MTD) of sorafenib, when
administered in combination with SRS to patients with 1-4 metastatic brain tumors.

SECONDARY OBJECTIVES:

I. To assess the six-month intra-cranial progression-free survival (PFS) of sorafenib when
administered in combination with SRS to patients with 1-4 metastatic brain tumors. PFS is
defined as the time to intra-cranial tumor progression or death.

II. To assess the six-month overall survival (OS) of sorafenib when administered in
combination with SRS to patients with 1-4 metastatic brain tumors.

III. To compare results to patients who are treated with SRS alone (concurrent controls).

OUTLINE: This is a dose-escalation study of sorafenib tosylate.

Patients receive oral (PO) sorafenib tosylate once daily and undergo SRS 5-7 days later.
Treatment with sorafenib continues for 2 weeks after SRS in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 8, 26, and 52 weeks.

Inclusion Criteria:

- Histologically confirmed cancer with 1-4 brain metastases (except lymphoma or small
cell histologies)

- ECOG PS 0 or 1

- Patients are candidates for stereotactic radiosurgery as determined by the treating
radiation oncologist. Intra-cranial tumors must measure 4cm or less in greatest
dimension. Patients may have received prior neurosurgical resection(s) of
intra-cranial metastases if their operation(s) was (were) completed at least 6 months
prior to study enrollment. Patients may have had prior whole brain radiation therapy
(WBRT) if it was completed at least 6 months prior to study enrollment.

- Age ≥ 18 years and willing and able to sign a written informed consent; a signed
informed consent must be obtained prior to any study specific procedures

- INR < 1.5 or a PT/PTT within normal limits; patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate;
for patients on warfarin, the INR should be measured prior to initiation of sorafenib
and monitored at least weekly (INR must be therapeutic in the range of 2-3)

Subjects must receive 1st dose of sorafenib 5-7 days prior to administration of
Stereotactic Radiosurgery.

Exclusion Criteria:

- Congestive heart failure > class II NYHA; patients must not have unstable angina
(anginal symptoms at rest) or new onset angina (began within the last 3 months) or
myocardial infarction within the past 6 months

- Unable to undergo brain MRI

- CNS metastases from lymphoma or small cell lung cancer

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Uncontrolled hypertension defined as systolic blood pressure > 140mm Hg or diastolic
pressure > 90 mm Hg, despite optimal medical management

- Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C

- Active clinically serious infection > CTCAE v 4.0 Grade 2

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event >= CTCAE v 3.0 Grade 2 within 4 weeks of first
dose of study drug

- Any other hemorrhage/bleeding event >= CTCAE v 3.0 Grade 3 within 4 weeks of first
dose of study drug

- Serious non-healing wound, ulcer, or bone fracture

- Any drug that results in hepatic enzyme induction such as anti-convulsants (dilantin,
depakote, tegretol, phenobarbital); keppra is allowed

- Evidence or history of bleeding diathesis or coagulopathy

- Any pulmonary hemorrhage CTCAE v 4.0 Grade 2 or higher within 4 weeks of first study
drug

- Any other bleeding or hemorrhage CTCAE v 4.0 Grade 3 or higher within 4 weeks of
first drug

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug

- Use of St. John's Wort or rifampin (rifampicin) within the last 8 weeks

- Known or suspected allergy to sorafenib

- Any condition that impairs patient's ability to swallow whole pills

- Concurrent investigational drugs

- Concurrent steroids are allowed if Dexamethasone dose is =< 16mg daily; if feasible,
steroids should be weaned off once sorafenib has been initiated

- Prior therapy with sorafenib or other tyrosine kinase inhibitors within the last 12
months; patients are allowed to have been on prior bevacizumab therapy as long as it
was stopped at least 6-8 weeks prior to enrolling on this trial

- Any malabsorption problem

- Hemoglobin =< 9.0 g/dl

- Absolute neutrophil count (ANC) =< 1,500/mm^3

- Platelet count =< 100,000/mm^3

- Total bilirubin >= 1.5 times upper limit of normal (ULN)

- ALT and AST >= 2.5 times the ULN ( =< 5 x ULN for patients with liver involvement)

- Creatinine >= 1.5 times ULN

- Women of childbearing potential with a positive serum pregnancy test performed within
7 days prior to the start of treatment; women and men of childbearing potential that
do not agree to use adequate contraception (barrier method of birth control) prior to
study entry and for the duration of study participation; men who do not agree to use
adequate birth control for at least three months after the last administration of
sorafenib

- All toxicities from prior therapies must have resolved to CTCAE v3.0 Grade I or
better by the time of study enrollment