A Phase II Study of Bevacizumab + Sorafenib in Metastatic Breast Cancer

OUTLINE: This is a multi-center study.

Sorafenib 200mg po daily Bevacizumab 5mg/kg every other week

1 Cycle = 4 weeks Imaging every third cycle

Acceptable toxicity and non-PD = Protocol therapy will continue Un-acceptable toxicity or PD
= Protocol therapy will be discontinued

ECOG Performance Status 0-1

Life Expectancy: at least 12 weeks

Hematopoietic:

- Platelets > 100 K/mm3

- Absolute neutrophil count (ANC) > 1.5 K/mm3

- Hemoglobin > 10 g/dL

Hepatic:

- Total Bilirubin < 1.5 x ULN

- Aspartate aminotransferase (AST, SGOT) < 2 x ULN (up to 5 x ULN in patients with known
liver involvement)

Renal:

- Creatinine < 1.5 x ULN

- No proteinuria as demonstrated by either Urine protein:creatinine (UPC) ratio < 1.0 or
Urine dipstick for proteinuria < 2+

Cardiovascular:

- No known myocardial infarction, unstable angina, > grade II New York Heart Association
(NYHA) classification, congestive heart failure, uncontrolled hypertension defined as
SBP >150 or DBP >100, > grade II peripheral vascular disease or significant vascular
disease (e.g. aortic aneurysm, aortic dissection) within 12 months prior to being
registered for protocol therapy.

- No uncontrolled or clinically significant arrhythmia. NOTE: Controlled atrial
fibrillation is allowed.

- LVEF ≥ LLN by MUGA or ECHO as obtained within 28 days prior to being registered for
protocol therapy.

Pulmonary:

- No pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within 28 days prior to being
registered for protocol therapy.

Inclusion Criteria:

- Histologic or cytologic diagnosis of breast cancer with evidence of metastatic
disease. NOTE: Patients with Her-2 positive (3+ by IHC or gene amplification by FISH)
are eligible only if they have had prior trastuzumab therapy.

- Must have measurable or non-measurable lesions as defined by the Response Evaluation
Criteria in Solid Tumors (RECIST).

- Two or fewer prior chemotherapy regimens in any disease setting. NOTE: All adjuvant
and neoadjuvant chemotherapy will be considered one regimen. NOTE: Prior hormonal
therapy for metastatic disease is allowed. NOTE: Prior radiation therapy is allowed as
long as the irradiated area is not the only source of evaluable disease.

- Age > 18 years at the time of consent.

- Written informed consent and HIPAA authorization for release of personal health
information.

- Females of childbearing potential and males must be willing to use an effective method
of contraception (hormonal or barrier method of birth control; abstinence) from the
time consent is signed until 8 weeks after treatment discontinuation.

- Females of childbearing potential must have a negative pregnancy test within 7 days
prior to being registered for protocol therapy.

- Ability to comply with study and/or follow-up procedures.

Exclusion Criteria:

- No prior therapy with bevacizumab, sorafenib or any other known VEGF inhibitors.

- No known hypersensitivity to any component of the study drugs.

- No other forms of cancer therapy including radiation, chemotherapy and hormonal
therapy within 21 days prior to being registered for protocol therapy.

- No history or radiologic evidence of CNS metastases including previously treated,
resected, or asymptomatic brain lesions or leptominigeal involvement. A head CT or MRI
must be obtained within 28 days prior to being registered for protocol therapy.

- No other participation in another clinical drug study within 28 days prior to being
registered for protocol therapy.

- No known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C

- No major surgical procedure within 28 days prior to being registered for protocol
therapy or anticipation of need for major surgical procedure during the course of the
study. Placement of a vascular access device and breast biopsy will not be considered
major surgery.

- No minor surgical procedure within 7 days prior to being registered for protocol
therapy.

- No known history of cerebrovascular disease including TIA, stroke or subarachnoid
hemorrhage.

- No known history of ischemic bowel.

- No known history of deep venous thrombosis or pulmonary embolism.

- No history of hypertensive crisis or hypertensive encephalopathy.

- No non-healing wound or fracture.

- No active infection requiring parenteral antibiotics.

- No other hemorrhage/bleeding event ≥ CTCAE grade 3 within 28 days prior to being
registered for protocol therapy.