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

We propose to evaluate ixabepilone in combination with cyclophosphamide for the neoadjuvant treatment of locally advanced breast cancer. In this regimen, ixabepilone is substituted for docetaxel, since preclinical and clinical

studies suggest that ixabepilone is more active than either docetaxel or paclitaxel. The combination of ixabepilone and cyclophosphamide could further improve the efficacy of non-anthracycline neoadjuvant therapy.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Female patients, age ≥18 years.
2. Histologically confirmed invasive adenocarcinoma of the breast.
3. 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.)
4. 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.
5. Eastern Cooperative Oncology Group performance status (ECOG

   PS) 0-2.
6. No metastatic disease, as documented by complete staging workup

   * 6 weeks prior to initiation of study treatment.
7. No previous treatment for breast cancer.
8. 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).
9. Adequate hematologic function with:

   * Absolute neutrophil count (ANC) \>1500/μL.
   * Platelets ≥100,000/μL.
   * Hemoglobin ≥10 g/dL.
10. 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.
11. Adequate renal function with serum creatinine ≤1.5 x ULN.
12. Estrogen and progesterone receptor status in the primary tumor

    known or pending at the time of study registration.
13. Knowledge of the investigational nature of the study and ability to

    provide consent for study participation.
14. 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
15. Bilateral, synchronous breast cancer is allowed if one primary

    tumor meets the inclusion criteria.
16. Sufficient archived breast tumor specimen available at baseline

for the Oncotype DX assay.

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Exclusion Criteria:

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

   Common Terminology Criteria for Adverse Events version 3.0

   (CTCAE v 3.0).
3. Prior radiation that included ≥30% of major bone marrow containing

   areas (pelvis, lumbar, spine).
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Uncontrolled intercurrent illness including (but not limited to)

    ongoing or active infection.
11. 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).
12. Use of any investigational agent within 30 days of administration

    of the first dose of study drug.
13. Requirement for radiation therapy concurrent with neoadjuvant

    study chemotherapy.
14. Concurrent treatment with any anti-cancer therapy other than

    those agents used in this study.
15. Inability or unwillingness to comply with study procedures

    including follow-up visits.
16. 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.
17. 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

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