Sorafenib Tosylate and Whole Brain Radiation Therapy in Treating Patients with Brain Metastases from Breast Cancer

Inclusion Criteria

• Histologically-confirmed metastatic adenocarcinoma of the breast (confirmation will be done at Memorial Sloan Kettering Cancer Center [MSKCC])
• Radiologic evidence of new and/or progressive brain metastasis (>= 10 mm in longest dimension) by magnetic resonance (MR) imaging of the brain
• Life expectancy of > 12 weeks
• Karnofsky performance status (KPS) of >= 70%
• If a patient is on corticosteroids, he/she must be on a non-escalating corticosteroid dose (not exceeding more than 16 mg daily of dexamethasone oral) for >= 5 days
• No limit to prior therapies with last anti-cancer treatment >= 2 weeks from initiation of protocol-based therapy provided all toxicities (other than alopecia) have resolved to =< grade 1 or baseline
• Planned WBRT based on number (>= 3 lesions) and/or size (>= 1 cm) of brain metastases (BMs); patients who require additional clinically indicated stereotactic radiosurgery (SRS) in addition to WBRT will also be eligible
• Patients with prior SRS will also be eligible, provided that there are new, non-irradiated measurable brain lesions
• No limit to prior therapies with last anti-cancer treatment >= 2 weeks from initiation of WBRT; please note: there is no washout period required for trastuzumab and pertuzumab
• Prior hormonal therapy for locally advanced or metastatic disease is allowed but this must have been discontinued prior to enrollment; no washout period will be required
• Continuation of trastuzumab and pertuzumab are allowed for those patients already on trastuzumab and pertuzumab therapy
• Granulocyte count >= 1,000/uL (must be assessed at least 14 days after a prior transfusion, if any)
• Platelet count >= 100,000/uL (must be assessed at least 14 days after a prior transfusion, if any)
• Hemoglobin >= 10 g/dL (must be assessed at least 14 days after a prior transfusion, if any)
• Hematologic parameters must be assessed at least 14 days after a prior transfusion, if any
• Serum bilirubin =< 1.5 mg/dL; except for patients with Gilbert's disease: serum bilirubin < 5 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN); except for patients with hepatic metastases: ALT and AST =< 5 x ULN
• Alkaline phosphatase =< 2.5 x ULN; except for patients with hepatic and/or bone metastases: alkaline phosphatase =< 5 x ULN
• Serum creatinine =< 1.5 mg/dL or creatinine clearance >= 60 mL/min based on 24-hour urine collection
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to enrollment and must agree to use adequate contraception prior to enrollment and for the duration of study participation; subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 30 days after the last dose of study drug
• Patients must be able to swallow and retain oral medication

Exclusion Criteria

• Leptomeningeal metastases, hemorrhagic metastases, presence of midline shift; please note: leptomeningeal metastases may be allowed if it is limited to cranial metastasis (magnetic resonance imaging [MRI] spine should be completed, within 4 weeks of enrollment, to show that no other leptomeningeal metastases is present) and is not the only metastasis present in the brain
• Contraindications to sorafenib
• Prior treatment with any agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR) (licensed or investigational including sorafenib), except bevacizumab
• Craniotomy or any other major surgery, open biopsy, or significant traumatic injury within 4 weeks of enrollment
• Serious, non-healing wound, ulcer, or bone fracture
• Uncontrolled seizures
• Use of cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin, carbamazepine, or phenobarbital) is not allowed
• Cardiac disease: * Congestive heart failure > class II New York Heart Association (NYHA), or * Unstable angina (anginal symptoms at rest), or new-onset angina (begun within the last 3 months), or myocardial infarction within the 6 months prior to enrollment, or * Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy * Congenital long QT syndrome or taking drugs known to prolong the QT interval * Subjects taking any drugs with a known risk of causing torsades de pointes
• Grade 3 hypertension (systolic blood pressure [SBP] >= 160 mmHg and/or diastolic blood pressure [DBP] >= 100 mmHg despite maximal medical therapy)
• >= grade 2 lipase increased (> 1.5 x ULN)
• Thrombolytic, embolic, venous, or arterial events such as cerebrovascular accident including transient ischemic attacks within the past 6 months
• Evidence or history of bleeding diathesis or coagulopathy at the time of enrollment
• Pulmonary hemorrhage/bleeding event > National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0) grade 2 within 4 weeks of enrollment
• Any other hemorrhage/bleeding event >= NCI-CTCAE grade 3 within 4 weeks of enrollment
• Therapeutic anticoagulation with vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids; however, prophylactic anticoagulation as described below is allowed: * Low dose warfarin (1 mg orally, once daily) with prothrombin time (PT)-international normalized ratio (INR) =< 1.5 x ULN is permitted; infrequent bleeding or elevations in PT-INR have been reported in some subjects taking warfarin while on sorafenib or capecitabine therapy; therefore, subjects taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes * Low dose aspirin (=< 100 mg daily)
• Active clinically serious infection > NCI-CTCAE grade 2
• Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
• Previous or concurrent cancer that is distinct in primary site or histology from breast cancer within 5 years prior to enrollment EXCEPT cervical cancer in situ, treated basal cell carcinoma, squamous cell carcinoma (SCC), as long as it is other than SCC involving skin of the head and/or neck, and superficial bladder tumors (Ta and Tis)
• Subjects who have used strong cytochrome CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, St. John's wort [Hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily for more than one day, or rifampin [rifampicin], and/or rifabutin) within 28 days before randomization
• Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy [other than that specified by the protocol], surgery, immunotherapy, biologic therapy including lapatinib, bevacizumab, tyrosine kinase inhibitors other than sorafenib or tumor embolization); trastuzumab will be allowed to continue for human epidermal growth factor receptor 2 positive (HER2+) patients
• Women who are pregnant or breast-feeding
• Use of any investigational drug within 28 days or 5 half-lives, whichever is longer, preceding enrollment; for the purposes of this study, bevacizumab will not be considered investigational therapy
• Inability to comply with protocol and/or not willing or not available for follow-up assessments
• Any condition which in the investigator's opinion makes the patient unsuitable for the study participation