Endocrine Therapy With or Without Anti-VEGF Therapy: A Randomized, Phase III Trial of Endocrine Therapy Alone or Endocrine Therapy Plus Bevacizumab (NSC 704865; IND 7921) for Women With Hormone Receptor-Positive Advanced Breast Cancer

Inclusion Criteria:

- Histologic confirmation of invasive cancer of the female breast in either the primary
or metastatic setting

- Stage IIIB disease not amenable to local therapy or stage IV disease

- Must have measurable or nonmeasurable disease by RECIST criteria, with radiologic
scans (CT scan of the chest/abdomen)

- Measurable disease is defined as lesions that can be accurately measured in at
least one dimension (longest diameter to be recorded) as ≥ 2.0 cm with
conventional techniques or as ≥ 1.0 cm with spiral CT scan

- Nonmeasurable disease is defined as all other lesions, including small lesions
(longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral
CT scan) and truly nonmeasurable lesions, including any of the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesions

- Baseline bone scans required for all patients for determination of metastatic bone
disease

- CT scan with bone windows required only for patients with bone metastases as the
only site of disease

- No known CNS metastases or leptomeningeal disease(screening with brain imaging is not
required for asymptomatic patients)

- Hormone receptor status: tumors (from either primary or metastatic sites) must
express estrogen receptor (ER)and/or progesterone receptor (PgR) in ≥ 1% of cells

- Menopausal status: pre- or postmenopausal, meeting 1 of the following criteria:

- Age ≥ 55 years and one year or more of amenorrhea

- Age < 55 years and one year or more of amenorrhea, with an estradiol assay <
20pg/ml

- Age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay <
20 pg/ml

- Surgical menopause with bilateral oophorectomy

- Ovarian suppression on a luteinizing hormone-releasing hormone agonist
(goserelin acetate or leuprolide acetate)

- Premenopausal women must undergo ovarian suppression prior to beginning
protocol therapy

- Ovarian radiation is not permitted for induction of ovarian
suppression

- ECOG (Zubrod) performance status 0-1

- Life expectancy ≥ 12 weeks

- Granulocytes ≥ 1,000/μl

- Platelet count ≥ 100,000/μl

- Creatinine ≤ 2.0 mg/dL

- Bilirubin ≤ 1.5 times upper limit of normal (ULN) unless due to Gilbert's syndrome

- Transaminases (ALT, AST) ≤ 2.5 times ULN

- INR ≤ 1.6 unless on full dose warfarin

- Urinalysis ≤ 1+ protein

- Proteinuria ≥ 2 + at baseline must demonstrate < 1 g of protein/24 hr or
protein:creatinine ratio < 1 on 24-hoururine collection

- No "currently active" second malignancy other than nonmelanoma skin cancers

- Patients are not considered to have a "currently active" malignancy if they have
completed therapy and are considered by their physician to be at less than 30%
risk of relapse

- Taxane-related neurotoxicity must have resolved to sensory grade < 2

- No motor neuropathy of any grade

- No significant traumatic injury within 28 days prior to study registration

- No history of abdominal fistula, or intra-abdominal abscess within the past 6 months

- No history of GI perforation within the past 12 months

- No history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI
bleeding) within the past 6 months

- No clinically significant cardiovascular disease, including any of the following:

- Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg
and/or diastolic BP > 90 mm Hg on antihypertensive medications

- Prior history of hypertensive crisis or hypertensive encephalopathy

- Myocardial infarction or unstable angina within past 6 months

- New York Heart Association class II-IV congestive heart failure

- Symptomatic peripheral vascular disease

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

- Significant arterial thrombotic events

- No history of stroke or transient ischemic attack within the past 6 months

- History of seizures must be well controlled with standard medication

- No known allergies to imidazole drugs, (e.g., clotrimazole, ketoconazole, miconazole,
econazole, sulconazole, ticonazole, or terconazole) or compounds structurally similar
to bevacizumab (for patients treated with aromatase inhibitors)

- No known allergies to selective estrogen receptor modulators (e.g., tamoxifen,
raloxifene, or toremifene) or compounds structurally similar to bevacizumab (for
patients treated with tamoxifen) NOTE: As of 5/15/2011, patients only receive
letrozole.

- No serious, non-healing wound, ulcer, or bone fracture

- Not pregnant or nursing

- Negative pregnancy test

- No prior endocrine therapy in the metastatic setting unless tamoxifen or an aromatase
inhibitor was initiated within 4 weeks prior to registration

- If prior endocrine therapy was initiated within the past 4 weeks, the patients
should remain on that chosen hormonal therapy (tamoxifen or aromatase inhibitor)
as the study therapy. NOTE: As of 5/15/2011, patients only receive letrozole.

- Patients who began therapy with tamoxifen (after 5/15/2011), anastrozole or
exemestane must switch to letrozole

- Prior endocrine therapy in the adjuvant setting allowed

- Prior treatment with ovarian suppression is allowed in either the adjuvant or
metastatic setting

- If medical ovarian suppression is being administered it can be initiated any
time prior to or at the start of protocol therapy, and continued throughout the
duration of the trial

- At least 28 days since surgical castration with bilateral oophorectomy

- At least 2 weeks since prior radiotherapy and all toxicities resolved

- At least 12 months since the completion of prior adjuvant or neoadjuvant chemotherapy
and all toxicities must have resolved

- No prior anti-VEGF or VEGFR tyrosine kinase inhibitor therapy

- May have received 1 prior chemotherapy regimen for metastatic disease

- More than 28 days since prior major surgical procedure or open biopsy and fully
recovered from any such procedure

- No core biopsy or other minor surgical procedure (except placement of a vascular
access device) within 7 days prior to study registration

- Prior palliative irradiation of a symptomatic lesion, or one that may produce
disability (e.g., unstable femur) prior to study initiation, provided other
measurable or non-measurable disease is present, is allowed

- Palliative radiotherapy may not be administered during protocol therapy

- Must not have anticipation of need for major surgical procedure during the course of
the study

- Concurrent full-dose anticoagulation therapy is allowed for the treatment of prior
conditions such as venous thromboses or atrial fibrillation, but not for the
treatment of prior arterial thrombotic events

- Patients on full-dose anticoagulants must be on a stable dose of warfarin and
have an in-range INR (usually between 2 and 3) or be on a stable dose flow
molecular weight heparin

- Concurrent antiplatelet agents, daily prophylactic aspirin, or anticoagulation for
atrial fibrillation allowed

- Concurrent treatment with bisphosphonates is allowed and recommended

- No concurrent hormones or other chemotherapeutic agents except for steroids given for
adrenal failure or chronic non-cancer related diseases, hormones administered for
non-disease-related conditions (e.g., insulin for diabetes), and intermittent use of
dexamethasone as an antiemetic in solid tumor protocols