Ixabepilone and Vorinostat in Treating Patients With Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of vorinostat with
ixabepilone.

II. To determine the best schedule for delivery of this drug combination. III. To recommend a
phase II dose of vorinostat in combination with ixabepilone.

SECONDARY OBJECTIVES:

I. To determine the objective response rate and/or clinical benefit rate. II. To assess the
toxicity profile.

TERTIARY OBJECTIVES:

I. Collecting circulating tumor cells pre and post-treatment to study its deoxyribonucleic
acid (DNA) somatic mutation and methylation assay after the introduction of histone
deacetylases (HDAC) inhibitors and ixabepilone.

II. To determine whether administration of vorinostat with ixabepilone will alter the
pharmacokinetics of vorinostat.

OUTLINE: This is a phase I, dose-escalation study of vorinostat. Patients are randomized to 1
of 2 treatment arms.

Arm I (Cohort A): Patients receive oral vorinostat once daily on days 1-14 and ixabepilone
intravenously (IV) over 3 hours on day 2. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

Arm II (Cohort B): Patients receive oral vorinostat once daily on days 1-7 and 15-21.
Patients also receive ixabepilone IV over 3 hours on days 2, 9, and 16. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed stage IV adenocarcinoma
of the breast; stable brain metastasis is allowed (not on anti-seizure or steroids for
at least three months); if histological or cytological confirmation is not
available/not done, patients who demonstrate metastatic disease as documented by
computed tomography (CT) scan or magnetic resonance imaging (MRI), or Bone Scan may
continue on study, if in the investigators clinical opinion this represents metastatic
disease; also, skin disease that has not been biopsied may be used if in the
investigators clinical opinion this represents metastatic disease

- 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 CT scan

- Multiple prior chemotherapy regimens (including trastuzumab containing regimens in
human epidermal growth factor receptor 2 [Her-2] positive patients) for metastatic
disease are allowed; prior radiation therapy and/or prior hormonal therapy (will need
2 weeks wash out period prior to enrollment) are allowed

- Life expectancy of greater than 6 months

- Performance status: Eastern Cooperative Oncology Group (ECOG) performance status (PS)
0-2

- Hemoglobin >= 9.0 g/dl

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.0 times upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the
ULN

- Creatinine =< 1.5 times ULN

- The effects of vorinostat and ixabepilone on the developing human fetus at the
recommended therapeutic dose are unknown; women of childbearing potential must have a
negative serum pregnancy test performed within 7 days of registration; should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately and the patient will be withdrawn
from the study

- Female patient of childbearing potential is willing to use 2 adequate barrier methods
of contraception to prevent pregnancy or agrees to abstain from heterosexual activity
throughout the study, starting with visit 1 through 30 days after the last dose of
study drug; adequate contraceptive methods include for example, intra-uterine device,
diaphragm with spermicide, cervical cap with spermicide, or female condom with
spermicide; spermicides alone are not an acceptable method of contraception

- Male patient agrees to use an adequate method of contraception starting with the first
dose of study drug through 30 days after the last dose of study drugs

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

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy (must not include >= 30% of major
bone marrow containing area) or any systemic anti-cancer drugs within 4 weeks (2 weeks
for Hormonal therapy) (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

- Patients may not be receiving any other investigational agents

- Patients with unstable brain metastases (requirement of steroids or active seizures)
are excluded from this clinical trial; patients with neurological symptoms must
undergo a CT scan/MRI of the brain to asses brain metastasis

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2),
symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction
within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic
therapy, or psychiatric illness/social situations that would limit compliance with
study requirements

- Prior ixabepilone and/or vorinostat are not allowed

- Prior valproic acid treatment for epilepsy will need 30 days wash out period prior to
enrollment

- Pregnant women are excluded from this study because of unknown potential teratogenesis

- Human immunodeficiency virus (HIV)-positive patients are ineligible because of the
potential for pharmacokinetic interactions with study drugs through the protease
inhibition of the cytochrome P450 3A4 (CYP3A4); in addition, these patients are at
increased risk of lethal infections when treated with marrow-suppressive therapy

- Patients with chronic hepatitis B or C are also excluded from this study

- Any condition that impairs patient's ability to swallow whole pills

- Any malabsorption problem

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

- Any > grade I neuropathy is contraindicated