Trial Information

A Multi-Institutional Double-Blind Phase II Study Evaluating Response and Surrogate Biomarkers to Carboplatin and Nab-Paclitaxel (CP) With or Without Vorinostat as Preoperative Chemotherapy in HER2-negative Primary Operable Breast Cancer

OBJECTIVES:

Primary

- To determine pathological complete response (pCR) rates in patients with HER2-negative
primary operable breast cancer treated with neoadjuvant therapy comprising carboplatin
and paclitaxel albumin-stabilized nanoparticle formulation (CP) with vs without
vorinostat.

Secondary

- To evaluate the safety of these regimens in these patients.

- To estimate clinical complete response (cCR) rates in patients treated with these
regimens.

- To correlate baseline and change (day 15) in surrogate uptake values (SUV) on FDG-PET
with pathological and clinical response in patients treated with these regimens, and to
determine what percent of women with ≥ 25% or ≥ 50% reduction in SUV on day 15 achieve
a pCR and a cCR to CP with vs without vorinostat.

- To correlate baseline and change in markers of proliferation with pathological and
clinical response in patients treated with these regimens.

- To evaluate long term outcomes (e.g., recurrence of the breast cancer, development of a
new cancer, or death) for patients treated with these regimens.

Tertiary

- To evaluate baseline and change in candidate gene methylation and expression profiles.

- To evaluate baseline and change in tissue and peripheral blood mononuclear cell histone
acetylation.

- To compare cCR and pCR in women with basal-like features versus other subtypes.

OUTLINE: This is a multicenter, randomized, double-blind, phase II study (primary study
portion) with a 6-12 patient run-in portion.

- Run-in portion: Patients receive carboplatin IV and paclitaxel albumin-stabilized
nanoparticle formulation IV on day 1 and oral vorinostat on days 1-3. Treatment repeats
weekly for 12 weeks in the absence of disease progression or unacceptable toxicity.
Once safety of the combination of chemotherapy and vorinostat is confirmed,
subsequently enrolled patients are entered to the primary study portion.

- Primary study portion: Patients are stratified by hormone receptor status (estrogen
receptor [ER]-negative and progesterone receptor [PR]-negative vs ER-positive and/or
PR-positive). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive carboplatin IV and paclitaxel albumin-stabilized
nanoparticle formulation IV on day 1 and an oral placebo on days 1-3. Treatment
repeats weekly for 12 weeks in the absence of disease progression or unacceptable
toxicity.

- Arm II: Patients receive carboplatin and paclitaxel albumin-stabilized
nanoparticle formulation as in arm I and oral vorinostat on days 1-3. Treatment
repeats weekly for 12 weeks in the absence of disease progression or unacceptable
toxicity.

Within 2-4 weeks after completion of neoadjuvant chemotherapy, patients undergo breast
conserving surgery or mastectomy at the discretion of the treating physician.

Patients undergo tumor tissue biopsy at baseline, day 15, and at the time of definitive
surgery. Samples are analyzed by immunohistochemistry (IHC), RNA extraction, and gene
expression analysis using RT-PCR to identify candidate markers for response and molecular
profiles that may be relevant to an understanding of drug mechanisms. Methylation of
relevant genes (e.g., ERalpha, APC-1, RARbeta, cyclin D2, Twist, RASSF1A, and HIN-1) are
evaluated by quantitative multiplex methylation-specific PCR. Changes in gene expression as
a result of treatment are determined by IHC or quantitative RT-PCR. Blood samples are
collected at baseline, day 15, at the time of definitive surgery, and 4 weeks after surgery
for DNA methylation studies, pharmacogenomic studies, and histone acetylation assays.
Patients also undergo fludeoxyglucose F 18-positron emission tomography (FDG-PET) or PET/CT
at baseline and day 15 to assess treatment response as measured by standardized uptake
values.

After completion of study treatment, patients are followed every 6 months.