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