Phase I/II Study of a Combination of Suberoylanilide Hydroxyamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed adenocarcinoma of the
breast; effective with version 2.2 (1/26/09), only patients with disease that is
accessible to biopsy and consent to serial biopsy are eligible

- Patient must have stage IV disease, locally recurrent inoperable chest wall disease;
at least one bidimensional and/or unidimensional, measurable indicator lesion must be
present (patients with only non-measurable disease are eligible for the phase I trial
only); all sites of disease should be noted and followed

- PRIOR CHEMOTHERAPY: Patients are eligible if they have received no prior chemotherapy
for metastatic disease; patients previously treated with a taxane (docetaxel or
paclitaxel) are eligible if they received taxanes as a component of adjuvant and/or
neoadjuvant therapy, and have relapsed at least 12 months after completion of the
taxane; (NOTE: effective with version 2.5 dated 9/15/09 patients are eligible if they
have received 0-2 prior chemotherapy regimens for metastatic disease; patients
previously treated with a taxane (docetaxel or paclitaxel) are eligible if they
received taxanes as a component of adjuvant and/or neoadjuvant therapy, or for
metastatic disease, and have not experienced progressive disease during or within 3
months of completing taxane therapy)

- PRIOR HORMONAL THERAPY, TRASTUZUMAB (HERCEPTIN), OR BEVACIZUMAB (AVASTIN): Patients
may have received any prior number of hormonal therapies; hormonal therapy should be
discontinued at least 1 week before the patient is enrolled on this study; patients
previously treated with Herceptin are eligible if Herceptin is discontinued, and
there is at least a 4 week interval between the last Herceptin dose and registration,
and the left ventricular ejection fraction is performed within 4 weeks prior to
registration and demonstrates an LVEF that is at or above the lower institutional
limit of normal range; patient who have received prior bevacizumab are ineligible

- ECOG performance status =< 1 (Karnofsky >= 70%)

- Absolute neutrophil count >= 1,500/ul

- Platelets >= 100,000/ul

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal

- PTT and either INR or PT < 1.5 x normal

- Creatinine within normal institutional limits OR

- Creatinine clearance >= mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level
should be < 1000 mg for patient enrollment; Note: UPC ratio of spot urine is an
estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent
to a 24-hour urine protein of 1 gm; UPC ratio is calculated using on of the following
formula: [urine protein]/[urine creatinine] - if both protein and creatinine are
reported in mg/dL [(urine protein) x 0.088]/[urine creatinine] - if urine creatinine
is reported in mmol/L

- Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible
provided that both of the following criteria are met: (a) The patient has an in-range
INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable
dose of low molecular weight heparin; (b) the patient has no active bleeding or
pathological condition that carries a high risk of bleeding (e.g., tumor involving
major vessels or known varices)

- LVEF must be at or above the lower institutional limit of the normal range (on MUGA
or Echo obtained within 12 weeks of registration, or within 4 weeks of prior
Herceptin)

- The effects of vorinostat on the developing human fetus at the recommended
therapeutic dose are unknown; women of childbearing potential must agree to use
adequate contraceptive measures during study therapy and for at least 6 months after
the completion of bevacizumab therapy; should a woman become pregnant or suspect she
is pregnant while participating in this study, she should inform her treating
physician immediately; a negative serum or urine pregnancy test is required within 2
weeks of registration for women of childbearing potential

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier;
other exclusions for prior therapy include prior hormonal therapy within one week of
registration, prior trastuzumab within 4 weeks of registration, or prior bevacizumab
at any time

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or other agents used in the study (e.g., paclitaxel,
bevacizumab)

- 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 the effects of vorinostat on the
developing human fetus at the recommended therapeutic dose are unknown; breastfeeding
should be discontinued if the mother is treated with vorinostat; these potential
risks may also apply to other agents used in this study; women must agree to use
adequate contraceptive measures during study therapy and for at least 6 months after
the completion of bevacizumab therapy

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions with vorinostat or other
agents administered during the study

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

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days

- Invasive procedures defined as follows: (a) major surgical procedure, open biopsy or
significant traumatic injury within 28 days prior to Day 1 therapy, (b) anticipation
of need for major surgical procedures during the course of the study, (c) core biopsy
within 7 days prior to D1 therapy

- NOTE: Patients who undergo the pretreatment core biopsy for optional correlative
studies may be enrolled within 7 days prior to the planned day 1 if delaying
therapy to meet this criterion is not feasible, and if there are no bleeding
complications as a consequence of the biopsy; in addition, patients may also
undergo the second post-treatment core biopsy (ie, this would not be regarded as
an eligibility or protocol violation)

- Evidence of CNS metastases; all patients are required to undergo a CT scan or MRI of
the brain with contrast within 4 weeks of registration

- Patients with clinically significant cardiovascular disease: (a) History of CVA
within 6 months, (b) uncontrolled hypertension, (c) myocardial infarction or unstable
angina within 6 months, (d) New York heart association grade II or greater congestive
heart failure, serious cardiac arrhythmia requiring medication, unstable angina
pectoris, (e) clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy; PT INR > 1.5, unless the patient is
on full dose warfarin

- Patients with known hypersensitivity of Chinese hamster ovary cell products or other
recombinant human antibodies

- Patients may not be receiving any other investigational agents nor had prior
treatment with histone deacetylase (HDAC) inhibitors (i.e. Valproic acid, PXD-001,
Depsipeptide, MS-275 and LAQ-824); patients who have received such agents for other
indications, (i.e. epilepsy) may enroll in the trial after a 30 day washout period)

- Inability to take oral medications on a continuous basis, or history of GI surgery or
other procedures that might, in the opinion of the investigator, interfere with the
absorption or swallowing of the study drugs