Trial of Eribulin Followed by Doxorubicin & Cyclophosphamide for Her2-negative, Locally Advanced Breast Cancer

This is a phase 2, single-arm, open label study. Patients with Her2-negative, locally
advanced breast cancer will be enrolled on the study prior to receiving neoadjuvant
chemotherapy. Patients will receive 4 cycles of neoadjuvant eribulin followed by 4 cycles of
dose-dense doxorubicin and cyclophosphamide (AC).

All patients will have a baseline biopsy prior to study entry to determine eligibility.
Patients will undergo repeat breast imaging and optional biopsy after completing 4 cycles of
eribulin. Patients will then receive 4 cycles of dose-dense AC. Patients will undergo repeat
breast imaging followed by surgical resection within 30 days of completing last cycle of
chemotherapy. Patients who are not surgical candidates after completion of chemotherapy will
be asked to undergo optional repeat biopsy prior to receiving additional treatment at the
discretion of the investigator. Patients will continue to be followed per standard practice
guideline after surgery

Clinical response will be determined by clinical breast examination prior to each cycle of
chemotherapy and by breast imaging performed at baseline, after completion of eribulin, and
prior to surgery. Pathologic complete response (pCR) will be determined at the time of
surgical resection. Correlative biomarker studies will be performed on tumor samples at the
completion of the clinical trial.

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
immunohistochemistry (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 ≥ 1 cm measurable with caliper and/or a positive mammogram or ultrasound
with at least one dimension ≥ 1 cm. 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.

- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 within 14 days of
study entry.

- Normal (greater than 50%) left ventricular ejection fraction (LVEF) by multigated
acquisition (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 creatinine clearance rate (CrCL) ≥ 50
mL/min using the Cockroft Gault equation.

- Serum glutamate oxaloacetate transaminase (SGOT)/(AST) or serum glutamate
pyruvate transaminase (SGPT)/(ALT) and alkaline phosphatase (alk phos) must be
within the range allowing for eligibility.

- Patients must be over 18 years old.

- International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial
thromboplastin time (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.

- Patient must have signed informed consent prior to registration on this study.

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 ductal carcinoma in situ (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 New York Heart Association
(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.