Phase II Neoadjuvant Trial of Eribulin Followed by Dose Dense Doxorubicin and Cyclophosphamide for Her2-negative, Locally Advanced Breast Cancer

Inclusion Criteria:

- Histologically or cytologically confirmed invasive breast carcinoma

- Locally advanced breast cancer (Stage IIIA to IIIC)

- Invasive breast cancer must be Her2-negative. If breast cancer is Her2 2+ by IHC,
then FISH must be negative for Her2 gene amplification.

- No evidence of disease outside the breast or chest wall, except ipsilateral axillary
lymph nodes on staging scans (CT chest/abdomen/pelvis and bone scan or PET scan)

- Patients must have measurable disease as defined by palpable lesion with both
diameters >1cm measurable with caliper and/or a positive mammogram or ultrasound with
at least one dimension >1cm. Bilateral mammogram and clip placement is required for
study entry. Baseline measurements of the indicator lesions must be recorded on the
Patient Registration Form. To be valid for baseline, the measurements must have been
made within the 14 days if palpable. If not palpable, a mammogram or MRI must be
done within 14 days. If palpable, a mammogram or MRI must be done within 2 months
prior to study entry. If clinically indicated, xrays and scans must be done within 28
days of study entry.

- ECOG performance status 0 to 1 within 14 days of study entry

- Normal (greater than 50%) left ventricular ejection fraction (LVEF) by MUGA scan or
echocardiography

- Signed informed consent

- Adequate organ function within 2 weeks of study entry:

- Absolute neutrophil count >1500/mm3, Hgb >9.0 g/dl and platelet count
>100,000/mm3

- Total bilirubin < upper limit of normal

- Creatinine < 1.5 mg/dL or calculated CrCL >50mL/min using the Cockroft Gault
equation

- SGOT(AST) or SGPT(ALT) and Alkaline Phosphatase must be within the range
allowing for eligibility, as in the table below:

AST or ALT:

ALK PHOS: ≤ULN >1x but >1.5x >1.5x but ≤5x >5x ULN

≤ ULN Eligible Eligible Eligible Ineligible >1x but ≤2.5x Eligible
Eligible Ineligible Ineligible >2.5x but ≤5x Eligible Ineligible
Ineligible Ineligible >5x ULN Ineligible Ineligible Ineligible
Ineligible

- Patients must be over 18 years old.

- INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of treatment

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation.

Exclusion Criteria:

- Prior chemotherapy, hormonal therapy, biologic therapy, investigational agent,
targeted therapy or radiation therapy for current breast cancer. Patients with
history of breast cancer greater than 5 years from initial diagnosis are eligible for
the study. Patients may not have received anthracycline-based chemotherapy in the
past. Patients with history of DCIS are eligible if there were treated with surgery
alone.

- Medical, psychological or surgical condition which the investigator feels might
compromise study participation.

- History of previous or current malignancy at other sites with the exception of
adequately treated carcinoma in-situ of the cervix or basal or squamous cell
carcinoma of the skin. Patients with a history of other malignancies, who remain
disease free for greater than five years are eligible.

- Evidence of sensory and/or peripheral neuropathy > grade 1.

- Serious, uncontrolled, concurrent infection(s).

- Major surgery within 4 weeks of the start of study treatment, without complete
recovery.

- Pregnant or lactating women are not eligible. Women of childbearing potential must
have a negative serum or urine pregnancy test completed within 7 days of study
treatment. Women or men of childbearing potential not using a reliable and
appropriate contraceptive method are not eligible. (Postmenopausal woman must have
been amenorrheic for at least 12 months to be considered of non-childbearing
potential).

- Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.

- Active clinically serious infection > CTCAE Grade 2.

- Thromboembolic events such as a cerebrovascular accident including transient ischemic
attacks within the past 6 months.

- Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of
study drug.

- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of
study drug.

- Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months.

- Known brain metastasis. Patients with neurological symptoms must undergo a CT
scan/MRI of the brain to exclude brain metastasis.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.