Nab-Paclitaxel and Bevacizumab Followed By Bevacizumab and Erlotinib in Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. Progression free survival.

SECONDARY OBJECTIVES:

I. Response rate.

II. Overall survival.

III. Safety and toxicity.

IV. Exploratory biomarkers will be assessed as potential predictors of response to treatment
including: expression of epidermal growth factor receptor (EGFR) and secreted protein acidic
and rich in cysteine (SPARC) in the primary tumor and changes in levels of circulating tumor
cells (CTCs) and circulating endothelial cells (CECs).

OUTLINE:

INDUCTION THERAPY: Patients receive paclitaxel albumin-stabilized nanoparticle formulation
intravenously (IV) on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and
15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE THERAPY: Patients achieving complete response, partial response, or stable
disease after completion of induction therapy will receive bevacizumab IV over 30-90 minutes
once every 14 or 21 days and erlotinib hydrochloride orally (PO) once daily (QD) in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up per physician discretion.

Inclusion Criteria:

- Have histologically confirmed invasive breast cancer that is estrogen receptor (ER)
negative (=< 10%), progesterone receptor (PR) negative (=< 10%) and human epidermal
growth factor receptor 2 (HER2) normal (=< 10% of cells) by immunohistochemistry (IHC)
or fluorescence in situ hybridization (FISH)

- Be receiving first-line therapy for metastatic disease

- Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria;
X-rays, scans or physical examinations used for tumor measurement must have been
completed within 28 days prior to registration; X-rays, scans or other tests for
assessment of non-measurable disease must have been performed within 42 days prior to
registration

- OR non-measurable disease only, with rising serum cancer antigen (CA)15-3 or CA 27.29
or carcinoembryonic antigen (CEA) documented by two consecutive measurements taken at
least 14 days apart with the most recent measurement being within 42 days prior to
registration; the second CA 15-3 or CA 27.29 or CEA value must have at least a 20%
increase over the first and for CA 15-3 or CA 27.29 be greater than or equal to 40
units/mL or for CEA be greater than or equal to 4 ng/mL

- Subjects with brain metastases as their first site of disease recurrence may be
eligible if treated by definitive radiation (stereotactic radiosurgery or whole brain)
with clinically controlled neurologic symptoms for a period of 21 days prior to study
treatment

- Bilirubin =< 1.5 mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X upper
limit of normal, unless bone metastasis is present in the absence of liver metastasis

- Alkaline phosphatase =< 2.5 X upper limit of normal, unless bone metastasis is present
in the absence of liver metastasis

- Platelets > 100,000 cells/mm^3

- Hemoglobin > 9.0 g/dL

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

- Creatinine =< 1.5 mg/dL is recommended; however, institutional norms are acceptable

- If of childbearing potential must have a negative pregnancy test and use an effective
method to avoid pregnancy for the duration of the trial and for at least 6 months
after completion of study therapy

- Pre-existing peripheral neuropathy, if present, must be < grade 2 (per Common
Terminology Criteria for Adverse Events [CTCAE] version 3.0)

- Patients must be informed of the investigational nature of this study and must sign
and give informed consent in accordance with institutional standards and federal
guidelines

Exclusion Criteria:

- Recurrent disease within 12 months after completion of adjuvant chemotherapy
containing a weekly taxane

- Central nervous system (CNS) metastases that are symptomatic and/or requiring steroids

- Pre-existing nephritic syndrome

- Serious intercurrent medical or psychiatric illness including serious active infection

- Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications)

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to study
enrollment

- History of stroke or transient ischemic attack within 6 months prior to study
enrollment

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to study enrollment

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

- Proteinuria at screening as demonstrated by either:

- Urine protein:creatinine (UPC) ratio >= 1.0 at screening OR

- Urine dipstick for proteinuria > 2+ (patients discovered to have > 2+ proteinuria
on dipstick urinalysis at baseline must have a UPC ratio done that is < 1.0 to be
eligible; if the UPC ratio is >= 1.0 then the patient should undergo a 24-hour
urine collection which must demonstrate =< 1 g of protein in 24 hours for the
patient to be eligible)

- Known hypersensitivity to any component of bevacizumab or to nab-paclitaxel
(paclitaxel albumin-stabilized nanoparticle formulation)