Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER-2 Negative Breast Cancer

In this study, patients with early stage, HER2-negative breast cancer will receive neoadjuvant treatment with ixabepilone and cyclophosphamide given every three weeks for a total of six cycles. Following surgery patients with hormone receptor-positive tumors will receive anti-estrogen treatment. Patients may receive local regional radiation therapy after surgery per institutional guidelines at the investigator's discretion. Baseline tumor tissue and tumor tissue removed at the time of surgery will be tested by Oncotype Detailed Description (DX) assay to determine whether it is predictive of response to this neoadjuvant treatment regimen. This study will be one of the first investigations of the combination of ixabepilone and cyclophosphamide as neoadjuvant treatment for HER2-negative breast cancer. It will examine this treatment regimen for potential advantages gained from substitution of ixabepilone for a taxane and use of non-anthracycline agents.

Inclusion criteria

• Female patients, age ≥18 years.
• Histologically confirmed invasive adenocarcinoma of the breast.
• Primary palpable disease confined to a breast and axilla on

physical examination. For patients without clinically suspicious

axillary adenopathy, the primary tumor must be larger than 2 cm

in diameter by physical exam or imaging studies (clinical T2-T3,

N0-N1, M0). For patients with clinically suspicious axillary

adenopathy, the primary breast tumor can be any size (clinical

T1-3, N1-2, M0). (T1N0M0 lesions are excluded.)

• Patients without clearly defined palpable breast mass or axillary

lymph nodes but radiographically measurable tumor masses are

acceptable. Accepted procedures for measuring breast disease

are mammography, MRI, and breast ultrasound. This will need to

be re-evaluated after 3 cycles and prior to surgery.

• Eastern Cooperative Oncology Group performance status (ECOG

PS) 0-2.

• No metastatic disease, as documented by complete staging workup

• 6 weeks prior to initiation of study treatment.
• No previous treatment for breast cancer.
• HER2-negative tumor status. HER2-negative is defined as:

• Immunohistochemical (IHC) 0, IHC 1+ OR
• IHC 2+ or IHC 3+ must be confirmed as FISH (fluorescence in situ

hybridization) negative (defined by ratio <2.2).

• Adequate hematologic function with:

• Absolute neutrophil count (ANC) >1500/μL.
• Platelets ≥100,000/μL.
• Hemoglobin ≥10 g/dL.
• Adequate hepatic function with:

• Serum bilirubin ≤ the institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST) ≤2.5 x institutional ULN.
• Alanine aminotransferase (ALT) ≤2.5 x institutional ULN.
• Adequate renal function with serum creatinine ≤1.5 x ULN.
• Estrogen and progesterone receptor status in the primary tumor

known or pending at the time of study registration.

• Knowledge of the investigational nature of the study and ability to

provide consent for study participation.

• For patients who had, or will have sentinel lymph node and/or

axillary dissection prior to initiation of study treatment, completion

at least 4 weeks prior to starting study treatment and well-healed

wound

• Bilateral, synchronous breast cancer is allowed if one primary

tumor meets the inclusion criteria.

• Sufficient archived breast tumor specimen available at baseline

for the Oncotype DX assay.

-

Exclusion criteria

• Inflammatory breast cancer.
• Peripheral neuropathy (motor or sensory) ≥ grade 1 by the

Common Terminology Criteria for Adverse Events version 3.0

(CTCAE v 3.0).

• Prior radiation that included ≥30% of major bone marrow containing

areas (pelvis, lumbar, spine).

• Chronic use of cytochrome P450 (CYP) 3A4 inhibitors and use of

the following strong CYP3A4 inhibitors: ketoconazole,

itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir,

telithromycin, ritonavir, amprenavir, indinavir, nelfinavir,

delavirdine, and voriconazole. Use of these agents should be

discontinued at least 72 hours prior to initiation of study treatment.

• Chemotherapy within 5 years of starting study treatment except

for low doses of agents used for anti-inflammatory indications

such as rheumatoid arthritis, psoriasis, and connective tissue

disorders. Although such doses and schedules cannot result in

myelosuppression, patients must discontinue this therapy while

they are receiving study treatment.

• Known or suspected hypersensitivity to Cremophor®EL

(polyoxyethylated castor oil) or a drug formulated in

Cremophor®EL such as paclitaxel, or any other agent given in the

course of this study.

• Pregnancy or breast-feeding. A negative serum pregnancy test

within 7 days prior to first study treatment (Day 1, Cycle 1) for all

women of childbearing potential is required. Patients of

childbearing potential must agree to use a birth control method

that is approved by their study physician while receiving study

treatment and for 3 weeks after their last dose of study treatment.

Patients must agree to not breast-feed while receiving study

treatment.

• Concurrent treatment with an ovarian hormonal replacement

therapy or with hormonal agents such as raloxifene, tamoxifen or

other selective estrogen receptor modulator (SERM). Patients

must have discontinued use of such agents prior to beginning

study treatment.

• History of malignancy treated with curative intent within the

previous 5 years with the exception of skin cancer, cervical

carcinoma in situ, or follicular thyroid cancer. Patients with

previous invasive cancers (including breast cancer) are eligible if

the treatment was completed more than 5 years prior to initiating

current study treatment, and there is no evidence of recurrent

disease.

• Uncontrolled intercurrent illness including (but not limited to)

ongoing or active infection.

• Chronic treatment with corticosteroid unless treatment was begun

>6 months prior to study treatment and is at a low dose (≤20 mg

methylprednisolone or equivalent).

• Use of any investigational agent within 30 days of administration

of the first dose of study drug.

• Requirement for radiation therapy concurrent with neoadjuvant

study chemotherapy.

• Concurrent treatment with any anti-cancer therapy other than

those agents used in this study.

• Inability or unwillingness to comply with study procedures

including follow-up visits.

• Mental condition or psychiatric disorder that would prevent patient

comprehension of the nature, scope, and possible consequences

of the study or that would limit compliance with study

requirements.

• Any other disease(s), metabolic dysfunction, or findings from a

physical examination or clinical laboratory test result that would

cause reasonable suspicion of a disease or condition that

contraindicates the use of study drugs, that may affect the

interpretation of the results, or that renders the patient at high risk

from treatment complications

-