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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


Phase 2
18 Years
N/A
Open (Enrolling)
Female
Breast Cancer

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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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- 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

PATIENT CHARACTERISTICS:

- 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Pathological complete response (pCR) rate

Outcome Time Frame:

Time of breast cancer surgery

Safety Issue:

No

Principal Investigator

Vered Stearns, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

JHOC-J0785, CDR0000586335

NCT ID:

NCT00616967

Start Date:

May 2008

Completion Date:

June 2017

Related Keywords:

  • Breast Cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • ductal breast carcinoma
  • lobular breast carcinoma
  • Breast Neoplasms

Name

Location

Mayo Clinic Cancer CenterRochester, Minnesota  55905
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Indiana University Purdue University of IndianapolisIndianapolis, Indiana  46202
Anne Arundel Health SystemAnnapolis, Maryland  21401