Phase II Study of Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER2-Negative Breast Cancer

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. -

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 -