Erlotinib Hydrochloride and Bevacizumab in Treating Patients With Stage IV Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the efficacy of bevacizumab in combination with OSI-774 (erlotinib
hydrochloride) in patients with previously treated metastatic breast cancer, as measured by
objective response rate.

SECONDARY OBJECTIVES:

I. To determine the toxicity of bevacizumab in combination with OSI-774 in patients with
previously treated metastatic breast cancer.

II. To evaluate the efficacy of bevacizumab in combination with OSI-774 in patients with
previously treated metastatic breast cancer, as measured by time to disease progression,
duration of response and the proportion of patients with stabilization of disease >= 6
months.

III. To determine the molecular profile of the patient's primary breast tumor, and to
explore the relationship between these molecular characteristics and the response to
treatment.

IV. To explore changes in biological markers in pre- and post-treatment tumor tissue in a
subset of patients with accessible sites of disease.

V. To explore a pre- and post-treatment analysis of circulating endothelial cells and the
relationship of this analysis to serum markers of angiogenesis as well as response to
treatment.

VI. To obtain serial measurements of circulating epithelial cells and explore the
relationship of these cells with circulating endothelial cells, markers of angiogenesis, and
epidermal growth factor receptor (EGFR) expression.

OUTLINE:

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21 and
bevacizumab intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed carcinoma of the breast
with metastatic (stage IV) disease that is currently stable or progressing after
therapy

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography
(CT) scan

- Patients must have either stable disease or disease progression on or after therapy
with one or two conventional chemotherapy regimens for the treatment of metastatic
(stage IV) breast cancer

- Prior treatment with high-dose chemotherapy and autologous stem cell/bone marrow
transplantation is allowed, and is considered one prior regimen when
administered for metastatic disease

- There is no restriction for the number of prior hormonal therapies or
immunotherapies

- If human epidermal growth factor receptor 2 (Her2)/neu-positive (defined as 3+
by immunohistochemistry [IHC] or positive by fluorescence in situ hybridization
[FISH]), prior therapy with trastuzumab required

- Any number of prior regimens of chemotherapy and/or hormonal therapy are allowed
in the adjuvant setting, and do not count towards prior therapy when determining
eligibility for this trial

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/ul

- Absolute neutrophil count >= 1,000/ul

- Platelets >= 75,000/ul

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT[)
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min
for patients with creatinine levels outside institutional normal using the
Cockcroft-Gault formula

- Women of childbearing potential must agree to use adequate contraception (barrier
method of birth control) prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Patients must have breast cancer tissue available as either paraffin blocks or
unstained slides for planned correlative science sub study

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy immunotherapy or investigational
therapy within 3 weeks prior to starting treatment (6 weeks for nitrosoureas or
mitomycin C), or hormonal therapy within 2 weeks prior to starting treatment

- Patients may not be receiving any other investigational agents

- History or evidence upon physical examination of central nervous system (CNS) disease
(e.g., primary brain tumor, seizures not controlled with standard medical therapy,
any brain metastases, or history of stroke); all subjects must have a baseline CT or
magnetic resonance imaging (MRI) of the head

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to OSI-774 or bevacizumab

- Prior treatment with kinase insert domain receptor (KDR) inhibitors (e.g. vascular
endothelial growth factor [VEGF] Trap, Su5416, Su6668, ZD6474, PTK757, IMC-1CII)

- Prior treatment with EGFR targeting therapies (e.g. ZD1839 or C225)

- Major surgery, open biopsy or significant traumatic injury occurring within 28 days
prior to treatment; this does not apply to indwelling catheters, which require an
interval of at least 24 hours between placement of the catheter and treatment with
bevacizumab

- Current or recent (within 10 days prior to treatment) use of full-dose oral or
parenteral anticoagulants or thrombolytic agents (except as required to maintain
patency of preexisting, permanent indwelling IV catheters; for subjects receiving
warfarin, international normalized ratio [INR] should be < 1.5)

- Chronic daily treatment with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory
medications known to inhibit the platelet function (e.g. cyclooxygenase [COX]-1
inhibitors)

- Presence of bleeding diathesis or coagulopathy

- Cumulative anthracycline and anthracenedione exposure as follows: doxorubicin > 450
mg/m^2; epirubicin > 700 mg/m^2; liposomal doxorubicin > 550 mg/m^2; mitoxantrone >
140 mg/m^2

- Proteinuria at baseline; subjects unexpectedly discovered to have >= 1+ proteinuria
should undergo a 24-hour urine collection, which must be an adequate collection and
must demonstrate =< 500 mg protein/ 24 hours to allow participation in the study

- Cardiac ejection fraction (multigated acquisition scan [MUGA] or echocardiogram) less
than the local institution lower limit of normal

- Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjögren's
syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp
examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal
corneal sensitivity test (Schirmer test or similar tear production test)

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

- Clinically significant cardiovascular disease (e.g., uncontrolled hypertension,
myocardial infarction, unstable angina), New York Heart Association (NYHA) grade II
or greater congestive heart failure, serious cardiac arrhythmia requiring medication,
or grade II or greater peripheral vascular disease within 1 year prior to day 0

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, or prior surgical procedures affecting absorption

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with OSI-774

- Human immunodeficiency virus (HIV)-positive patients receiving combination
anti-retroviral therapy are excluded from the study

- Patients with recent (within 6 months) arterial thrombotic events, including
transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina,
myocardial infarction (MI), or clinically significant peripheral artery disease