Study of Avastin (Bevacizumab) to Reverse Acquired Estrogen Independence in Previously Hormone Responsive Metastatic Breast Ca.

This is a single institution, open-label study designed to evaluate safety and efficacy of
Avastin (Bevacizumab) combined with an endocrine agent in patients with estrogen and/or
progesterone receptor positive metastatic breast carcinoma who have acquired resistance to at
least one hormonal agent. Patients will be treated with the same hormonal agent that was used
previously assuming that the patient had a partial or complete response (for at least 6
months) followed by a clear disease progression using the Response Evaluation Criteria in
solid Tumors (RECIST Criteria). Patients with stable disease for a prolonged time (for at
least 6 months) will be also eligible to enter in the trial. Patients who have not had
interval studies to evaluate disease response will be considered eligible if they have
remained clinically stable (i.e. stable PS, no increasing pain) and on the same hormone for
at least 6 months, and now they have signs and symptoms of clinical progression (i.e.
elevated tumor markers, increasing bone pain, worsening performance status). Patients must
have histologically confirmed measurable and/or evaluable metastatic breast cancer with
positive estrogen and/or progesterone receptors. Patients can have up to an 8-12 week break
in therapy (discontinuation of hormonal therapy) and still remain eligible for the study as
long as the documentation of disease progression is determined before the 8-12 week break in
hormonal therapy.

The type and dose of the hormonal agent that will be used in this trial will be the same one
that the patient used before progression. Hormonal therapy may include any estrogen
deprivation reagent such as Tamoxifen, Anastrazole, Exemestane, Letrozole, or Fulvestrant.
All patients will receive Avastin (Bevacizumab) 15 mg/kg IV every three weeks. Based on
statistical evaluations, 30 patients will be enrolled. The first evaluation of efficacy will
be done at week 6; patients with objective response or stable disease will continue therapy
with re-staging every 6 weeks until evidence of disease progression. Patients with
progression of disease will be taken off study (see appendix A). PET scan will be done at
baseline and only in the first evaluation (6 weeks) to obtain early "metabolic response data"
that will be correlated with objective response and time to disease progression (PET data on
week 6 will not be used to evaluate response and to make therapeutic decisions). PET
"metabolic response" will be defined as a >20% reduction in SUV. Safety will be assessed by
the recording of adverse events, serious adverse events, laboratory test results, and changes
in vital signs. A positive response to Avastin (Bevacizumab) (reversal of hormonal
resistance) will be defined as an objective response or stable disease of ≥ 3 months
duration. All concomitant medication must be documented. Additionally, any diagnostic,
therapeutic or surgical procedure performed during the study period, should be recorded
including the date, indication, description of the procedure(s) and any clinical findings.

Inclusion Criteria:

- Patients must have cytologically or histologically proven breast cancer which is
estrogen receptor or progesterone receptor positive and is locally advanced and /or
metastatic.

- Give written informed consent prior to study specific screening procedures, with the
understanding that the patient has the right to withdraw from the study at any time,
without prejudice (Appendix E).

- Be female and greater than or equal to 19 years of age (age limit required by the
State of Alabama). Women of childbearing potential must have a negative pregnancy test
and must be willing to consent to using effective contraception while on treatment and
for a reasonable period thereafter. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- Be ambulatory (outpatient) and have an ECOG PS <2 (Appendix B).

- Previous treatment: Patients must have responded to first or second line hormonal
therapy (Partial and complete response greater than 6 months using RECIST criteria.
Patients with stable disease for more than 6 months will be eligible) and became
resistant to the hormonal agent. They must remain on the current hormone therapy to
which they initially responded but now are resistant.

- Clear documentation of acquired hormonal resistance.

- Evaluable disease will be considered eligible, but measurable disease according to
RECIST criteria will be preferable (Appendix C). The target lesion(s) must not have
been previously irradiated (newly arising lesions in previously irradiated areas are
acceptable).

- Patients must have adequate organ and marrow function as defined as follows: absolute
neutrophil count > 1,500/mm3, hemoglobin > 8.0 g/dl, platelets > 75,000/mm3, total
bilirubin < 2 mg/dl, serum creatinine < 2 mg/dl, transaminases (AST, ALT) may be up to
2.5 x institutional upper limit of normal for patients with no liver metastases and up
to 5 x institutional upper normal limit for patients with documented liver metastases.
In addition < 1 gr of protein in 24 hr urine collection and urine protein/creatinine
ratio < 1.0

- Prior chemotherapy does not exclude patients from study as long as the current therapy
was hormonal therapy alone.

- Patients with de novo hormone therapy resistance will not be eligible.

- No life threatening parenchymal disease or rapidly progressing disease warranting
cytotoxic chemotherapy.

- No history of brain metastases.

- No history of thrombosis during the previous year, including transient ischemic
attack.

- Hypertension must be controlled (< 150/100 mmHg).

- Ejection Fraction > 50%.

Exclusion Criteria:

- Patients who are "de novo" resistant to hormone therapy.

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than this Genentech-sponsored
bevacizumab cancer study.

- Blood pressure of >150/100 mmHg

- Unstable angina

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

- History of myocardial infarction within 6 months

- History of stroke within 6 months

- Clinically significant peripheral vascular disease

- History of a bleeding disorder

- Presence of central nervous system or brain metastases

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 0, anticipation of need for major surgical procedure during the course of
the study

- Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
prior to Day 0

- Pregnant (positive pregnancy test) or lactating

- Urine protein: creatinine ratio greater than or equal to 1.0 at screening. Patients
demonstrating > 1 gr of protein in 24 hr urine collection within 4 weeks prior to
study entry will not participate in the trial.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to Day 0

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

- Unwilling or unable to comply with the protocol for the duration of the study.

- Psychiatric illness/social situations that would limit compliance with study
requirements.

- Previously radiated area(s) must not be the only site of disease.

- History of another malignancy within the last five years except cured basal cell
carcinoma of skin and carcinoma in-situ of uterine cervix.