Phase I-II Study of Vorinostat, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer

PRiMARY OBJECTIVES:

I. To determine the recommended phase II dose of oral suberoylanilide hydroxamic acid
(vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest
wall recurrent or metastatic breast cancer. (Phase I) II. To determine the efficacy
(response rate, response duration, time to disease progression, time to treatment failure,
and overall survival) and toxicity of oral suberoylanilide hydroxamic acid (vorinostat) in
combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or
metastatic breast cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins
including histone H3 and H4, b) ubiquitylation of proteins, and c) the levels of p21 and p27
levels in the peripheral blood mononuclear cells (pre treatment vs. cycle 1 day 2 after 3
VORINOSTAT doses but prior to paclitaxel.

II. To determine whether in vivo treatment with vorinostat induces a) acetylation of
proteins including histone H3 and H4, ubiquitylation of proteins, and c) the levels of Bim,
Bak, tBID, p21 and p27 levels, as well as down regulate Bcl-2, Bcl-xL and survivin in chest
wall recurrent or metastatic breast cancer cells (pre treatment vs. cycle 1 day 2 after 3
vorinostat doses but prior to paclitaxel).

III. To determine whether in the primary breast cancer (and metastatic cancer if available)
pretreatment levels of Her-2, Estrogen Receptor (ER)-alpha, Progesterone Receptor (PR), p21,
p27, p-AKT, p-ERK1/2, HDAC1, 2, 3, 4, 6, 10 and SIRT2 levels predict for the response to
treatment with VORINOSTAT plus paclitaxel.

OUTLINE: This is a phase I, multicenter, dose-escalation study of vorinostat (SAHA) followed
by a phase II, open-label study.

Phase I: Patients receive oral SAHA twice daily on days 1-3, 8-10, and 15-17, paclitaxel IV
over 1 hour on days 2, 9, and 16, and bevacizumab IV over 30-90 minutes on days 2 and 16.
Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6
patients experience dose-limiting toxicity. The recommended phase II dose is defined as one
dose level below the MTD.

Phase II: Patients receive SAHA at the recommended phase II dose and paclitaxel and
bevacizumab as in phase I.

Inclusion Criteria:

- 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

- 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

- 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;

- 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)

- Not pregnant/lactating

Exclusion criteria:

- chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C)
prior to entering the study

- 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, quinolones)

- 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.