Taxane Therapy With or Without Bavituximab for the Treatment of HER2-Negative Metastatic Breast Cancer

This is an open-label randomized trial in patients with HER2-negative metastatic breast
cancer. Patients will be treated with either taxane alone (investigator choice of paclitaxel
or docetaxel) or taxane with bavituximab. Paclitaxel will be given 3 of 4 weeks, docetaxel
will be given once every 3 weeks, and bavituximab will be given weekly. All therapy will
continue until disease progression, toxicity, withdrawal or consent, investigator decision,
or study termination. Efficacy (overall response rate) is the primary endpoint while safety
is the secondary endpoint.

Inclusion Criteria

1. Written informed consent obtained prior to screening.

2. Females or males at least 18 years of age.

3. Histologically or cytologically documented metastatic HER2-negative breast cancer.

4. Measurable disease per RECIST 1.1 (Phase II); evaluable disease (Phase III)

5. ECOG performance status of 0 or 1.

6. Adequate hematologic function: absolute neutrophil count ≥1500 cells/µL; hemoglobin
≥9 g/dL; platelets ≥100,000/µL.

7. Adequate renal function: serum creatinine ≤1.8 mg/dL or calculated creatinine
clearance >50 mL/min using the Cockcroft-Gault equation.

8. Adequate hepatic function: total bilirubin ≤ upper limit of normal (ULN), serum
albumin ≥3.0 g/dL, alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) ≤1.5 × ULN. ALT and/or AST may be ≤5 × ULN if due to liver metastases. If ALT
or AST is >1.5 and ≤5 × ULN in patients with liver metastases, alkaline phosphatase
must be ≤2.5 × ULN. Patients with Gilbert's syndrome are allowed if total bilirubin
is ≤2 × ULN and direct bilirubin is ≤ULN.

9. Prothrombin time (PT) and/or international normalized ratio (INR) ≤1.5 × ULN and
activated partial thromboplastin time (aPTT) ≤1.5 × ULN if patient is not on
anticoagulant therapy (a therapeutic PT and/or INR and aPTT is acceptable if the
patient is on anticoagulants).

10. Patients must have a negative serum human chorionic gonadotropin test within 1 week
of Day 1 (pregnancy test not required for patients with bilateral oophorectomy and/or
hysterectomy or for those patients who are >1 year postmenopausal).

11. All patients of reproductive potential (ie, not surgically sterile or postmenopausal)
must agree to use a highly effective method of contraception (<1% failure rate per
year) during and 3 months after end of study treatment (female) or during and 6
months after the end of study treatment (male).

Exclusion Criteria

1. HER2-positive breast cancer.

2. Less than 6 months since last dose of prior adjuvant non-taxane regimen.

3. Less than 12 months since last dose of prior adjuvant taxane-containing regimen.

4. Any chemotherapy regimen for MBC within 3 weeks before Day 1.

5. Known history of bleeding diathesis or coagulopathy (eg, von Willebrand disease or
hemophilia).

6. Bleeding:

- Clinically significant bleeding, such as gross hematuria, gastrointestinal
bleeding, and hemoptysis within the 6 months before screening, unless the cause
has been identified and adequately treated (eg, cystitis, ulcer).

- Minor biopsy-related bleeding lasting <24 hours and resolved at least 1 week
before Day 1 is allowed.

7. Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, arterial
thrombosis) within 6 months before screening.

8. Grade 2 or higher peripheral neuropathy (eg, numbness, tingling, and/or pain in
distal extremities).

9. Radiotherapy within 1 week preceding Day 1; ongoing acute toxicity from prior
radiotherapy.

10. Either symptomatic or clinically active brain metastases (ie, requiring ongoing
treatment). Patients are eligible if brain metastases are adequately treated.
Patients must be either off corticosteroids, or on a stable or decreasing dose of ≤10
mg daily prednisone (or equivalent).

11. Major surgery within 4 weeks of Day 1.

12. Uncontrolled intercurrent disease (eg, diabetes, hypertension, thyroid disease,
active infections).

13. Autoimmune disease, being treated with immunosuppressive drugs (eg, methotrexate or
biological agents), or other conditions requiring immunosuppressive therapy (eg,
prior allotransplantation).

14. History of hypersensitivity to bavituximab, docetaxel, paclitaxel, or to any of their
excipients.

15. Symptomatic coronary artery disease, cerebrovascular accident or transient ischemic
attack, myocardial infarction, arterial embolism, or unstable angina pectoris within
6 months of screening.

16. Currently pregnant, nursing, or planning a pregnancy during the study.

17. Investigational therapy within 28 days prior to Day 1.

18. Patient has a condition or is in a situation which, in the investigator's opinion,
may put the patient at significant risk, may confound the study results, or may
interfere significantly with the patient's participation in the study.