Phase II Study of Neoadjuvant Ixabepilone/Carboplatin/Trastuzumab in HER2-Positive Locally Advanced Breast Cancer

Inclusion Criteria:

1. Female and male patients ≥18 years of age.

2. Histologically confirmed 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 (clinical T2-T3, N0-N1, M0). For patients with
clinically suspicious axillary adenopathy, the primary breast tumor can be any size
(clinical T1-T3, N1-N2, M0). (T1N0M0 lesions are excluded.)

4. Patients who have no clearly defined palpable breast mass or axillary lymph nodes but
are radiographically measurable are eligible. Accepted procedures for measuring
breast disease are mammography, MRI, and breast ultrasound. In these patients,
radiographic tumor measurements need to be repeated after 3 cycles and prior to
surgery.

5. Positive HER2 status (overexpression and/or amplification of HER2 in the primary
tumor) as defined by: IHC 3+ or fluorescence in situ hybridization (FISH) positive
(ratio >2.2) testing. Documentation of the HER2 results must be available at the
time of study enrollment.

6. An ECOG (Eastern Cooperative Oncology Group) performance score of ≤2

7. Normal bone marrow function as defined by:

- absolute neutrophil count (ANC) >1,500/µL;

- platelets >100,000/µL;

- hemoglobin >10 g/dL.

8. Normal hepatic function as defined by:

- total bilirubin within normal institutional limits;

- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 × the
institutional upper limit of normal (ULN).

9. Normal renal function as defined by creatinine ≤1.5 × ULN or estimated creatinine
clearance (CrCl) ≥50 mL/min calculated by the Cockcroft-Gault method.

10. Left ventricular ejection fraction (LVEF) within the institutional limits of normal,
whichever is lower, as measured by multi-gated acquisition (MUGA) scan or
echocardiogram (ECHO).

11. Life expectancy > 12 weeks.

12. Estrogen and progesterone (or estrogen alone) receptor status in the primary tumor
known or pending at the time of study enrollment.

13. For women of childbearing potential, negative serum pregnancy test within 7 days
prior to starting treatment.

14. For women of childbearing potential, agreement to use a method of contraception that
is acceptable to their physician from time of first signing the informed consent
until at least 3 months after the last dose of study drug. If a woman becomes
pregnant or suspects she is pregnant while participating in this study, she must
agree to inform her treating physician immediately. Patient agreement to discontinue
breast-feeding, if applicable, during study treatment. Men enrolled in the study
must also agree to use a method of contraception that is acceptable to their
physician during their study participation.

15. For patients with previous invasive cancers (including breast cancer) treated with
curative intent, completion of chemotherapy or radiation therapy more than 5 years
prior to enrollment for this study and no evidence of recurrent disease. Patients
may be receiving anti-estrogen hormonal therapy prescribed for previous invasive
breast cancer as long as the diagnosis of invasive cancer was made more than 5 years
prior to study enrollment. Patients may be using anti-estrogen hormonal therapy at
the time of current diagnosis but must discontinue this therapy before beginning
study treatment.

16. 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.

17. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Previous treatment for this breast cancer.

2. Evidence of metastatic disease.

3. Prior radiation that included ≥30% of major bone marrow-containing areas.

4. Women who are pregnant or breastfeeding.

5. Neuropathy (motor or sensory) ≥grade 1 at study entry.

6. History of significant cardiac disease or cardiac risk factors or the following:

- uncontrolled arrhythmias

- poorly controlled hypertension (e.g., systolic blood pressure [BP]> 150 mmHg or
diastolic BP >100 mmHg) in spite of optimal medical management

- angina pectoris requiring antianginal medication or unstable angina within the
previous 6 months

- history of documented congestive heart failure (CHF)

- any documented myocardial infarction within the previous 6 months

- clinically significant valvular heart disease

- current use of medications (e.g., digitalis, beta-blockers, calcium
channel-blockers) that alter cardiac conduction, if these medications are
administered for the management of cardiac arrhythmia, angina, or CHF. If these
medications are administered for other reasons (e.g., hypertension), the patient
may be eligible.

- patients with cardiomegaly on chest x-ray or ventricular hypertrophy on ECG
unless ECHO or MUGA scan within the last 3 months demonstrates that the LVEF is
≥ institutional lower limit of normal.

7. Symptomatic intrinsic lung disease.

8. Active malignancy, other than superficial basal cell carcinoma, superficial squamous
(skin) cell carcinoma, carcinoma in situ, or non-invasive breast cancer, within the
past 5 years.

9. Uncontrolled intercurrent illness including (but not limited to) ongoing or active
infection >grade 2.

10. Mental condition or psychiatric disorder rendering the subject unable to understand
the nature, scope, and possible consequences of the study or that would limit
compliance with study requirements.

11. Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving a reasonable suspicion of a disease or condition that
contraindicates the use of a study agent or that may affect the interpretation of the
results or renders the subjects at high risk from treatment complications.

12. Chronic use of CYP3A4 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 must be discontinued at least 72 hours prior to
initiation of study treatment.

13. Received chemotherapy for any indication within the 5 years preceding study
enrollment.

14. Prior treatment with trastuzumab or any other anti-HER2 agent for any indication.

15. Concurrent treatment with any other anti-cancer therapy.

16. Concurrent radiation therapy during neoadjuvant study treatment.

17. Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must
be stopped prior to study enrollment.

18. Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other
selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention
of breast cancer. These agents must be discontinued prior to study enrollment.

19. Participation within the previous 30 days in a study with an experimental drug.

20. Known or suspected allergy to Cremophor EL (polyoxyethylated castor oil), a drug
formulated in Cremophor EL such as paclitaxel, or any other agent given in the course
of this trial.

21. Inability or unwillingness to comply with study procedures including those for
follow-up.