Trial of Paclitaxel/Bevacizumab +/- Everolimus for Patients With HER2-Negative Metastatic Breast Cancer

Inclusion Criteria

• Female or male patients >=18 years of age.
• Histologically confirmed invasive breast cancer, locally unresectable or metastatic.
• No prior chemotherapy for MBC. Patients may have received adjuvant or

neoadjuvant chemotherapy (including taxanes and/or bevacizumab) as long as

treated was completed >12 months prior to relapse. Prior hormonal therapy in the

adjuvant or metastatic setting will be permitted.

• Prior hormonal therapy in the adjuvant or metastatic setting is permitted. Estrogen receptor positive patients should be considered candidates for chemotherapy.
• HER2-negative breast cancer, defined as follows:
• FISH-negative (FISH ratio 1500/mm3
• Platelet count >=100,000/mm3
• Hemoglobin >9 g/dL
• Adequate liver function, defined by:

· AST and ALT =40 ml/min

• International normalized ratio (INR) 1.0 at screening

or

• Urine dipstick for proteinuria >=2+ (patients discovered to have

>=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour

urine collection and must demonstrate =12 weeks.

• Ability to swallow oral medications.
• Adequate cardiac function, defined by baseline left ventricular ejection fraction (LVEF) value >= normal per institutional guidelines by MUGA scan or

echocardiogram (ECHO).

• Adequate recovery from recent surgery.
• Major surgical procedure >28 days from study entry
• Minor surgical procedure >7 days from study entry (Portacath placement

excepted - patients can start treatment 4 weeks prior to study entry are eligible, if they meet all of the following criteria: 1) residual symptoms =12 months prior to recurrence.

• Previous radiotherapy for metastatic disease completed 150 mmHg or

diastolic pressure >100 mmHg, despite optimal medical management.

• Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of study treatment until the end of treatment with everolimus.
• Cardiac disease, including: congestive heart failure (CHF) > Class II per New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• History of stroke or transient ischemic attack within 6 months prior to first

bevacizumab dose.

• Patients with any non-healing wound, ulcer, or long-bone fracture.
• Patients with clinical history of hemoptysis or hematemesis.
• Patients with any history of a bleeding diathesis or coagulopathy.
• Patients with a PEG or G tube cannot be enrolled into this trial.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning bevacizumab.
• Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Patients who have any severe and/or uncontrolled medical conditions or other

conditions that could affect their participation such as:

• severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
• uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.
• History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the subject at high risk for treatment complications.
• History of hypersensitivity to Cremophor EL (polyoxyethylated castor oil) or a drug formulated in Cremophor EL, such as paclitaxel.
• Patients may not receive any other investigation