- 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.
- 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.
- 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.
- Histologically confirmed infiltrating ductal breast cancer by core needle biopsy
- Mixed ductal and lobular disease allowed
- Infiltrating lobular cancer allowed in the run-in portion only
- Unresected, clinically measurable disease, meeting 1 of the following clinical staging criteria:
- T2, T3, or T4 lesion, any N, M0
- T1c, N1-3,M0
- Patients with skin metastases to the ipsilateral breast for whom chemotherapy is planned prior to definitive surgery are eligible for the primary study portion
- HER2-negative disease
- Hormone receptor status* meeting 1 of the following criteria:
- Estrogen receptor (ER)-negative and progesterone receptor (PR)-negative
- ER-positive (grade II or III) and PR-positive or PR-negative NOTE: *Any ER or PR status for the run-in portion
- ECOG performance status 0-1
- Menopausal status not specified
- ANC ≥ 1,500/mm³
- Platelet count ≥ 150,000/mm³
- Hemoglobin ≥ 9 g/dL
- Creatinine ≤ 1.5 times the upper limit of normal (ULN)
- Creatinine clearance ≥ 50 mL/min
- Total bilirubin normal
- AST(SGOT) and ALT(SGPT) ≤ 2.5 times (ULN)
- alkaline phosphatase ≤ 2.5 times ULN
- PT such that INR ≤ 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and PTT ≤ ULN
- Adequate cardiac function defined as no evidence of PR prolongation or AV block on baseline electrocardiogram (ECG)
- Willing to use effective, non-hormonal contraception while on treatment and for at least 3 months thereafter
- Not pregnant or nursing
- No pre-existing peripheral neuropathy ≥ grade 2
- No history of severe hypersensitivity reaction to any drug formulated with polysorbate 80 or to E. coli-derived products
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat
- No medical condition which, in the opinion of the investigator, puts the patient at risk of potentially serious complications while on this therapy
PRIOR CONCURRENT THERAPY:
- At least 4 weeks since prior valproic acid or other histone deacetylase inhibitor
- No prior chemotherapy, radiotherapy, or endocrine therapy for this cancer
- Prior tamoxifen or raloxifene or another agent for prevention of breast cancer allowed as long as the patient has discontinued the treatment ≥ 1 month prior to baseline study biopsy
- No systemic treatment for prior cancer within the past 5 years (primary study portion)
- No prior or ongoing systemic treatment for this cancer (primary study portion)
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No other concurrent histone deacetylase inhibitor
- No other concurrent chemotherapy, antiestrogen therapy, radiotherapy, or other investigational systemic therapy
- No other concurrent biologic therapy
- No other concurrent investigational drugs
Last updated: 03/18/2013