Investigational Drug in Combination With Two Chemotherapy Drugs in Women With Locally Recurrent or Metastatic Breast Cancer

Endocrine therapy and chemotherapy (using either sequential single agents or combination
regimens) remain the principal treatments for women with metastatic breast cancer. A wide
variety of classes of chemotherapeutic agents have demonstrated anti-tumor activity as
single agents or in combination regimens. Cytotoxic chemotherapeutic agents have been the
mainstay of cancer therapies for many years and have improved survival in many disease
settings. Median survivals remain approximately two years for women with metastatic breast
cancer, and less than 3% of patients experience long-term survival after initiation of
treatment. The development of new treatment strategies is therefore essential to improve
outcome for patients with metastatic breast cancer.

One of the most promising pathways for the development of new anti-neoplastic agents is
targeting tumor vascular endothelium. There is significant preclinical and clinical evidence
indicating that tumor neoangiogenesis is critical in pathogenesis and progression of solid
tumors, including breast cancer. Of the numerous known growth factors that have been
implicated in tumor angiogenesis, vascular endothelial growth factor (VEGF) is one of the
important molecules regulating new blood vessel formations and subsequent invasion and
metastases. As a result, agents that inhibit VEGF are of substantial interest for the
treatment of advanced diseases. More thorough elucidation of mechanisms behind intrinsic and
acquired resistance therefore is imperative disease and to identify patients most likely to
benefit from treatment options.

Motesanib has been shown in preclinical pharmacology and PK studies to be a potent, orally
bioavailable multi-kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by
selectively targeting all known VEGF, PDGF and Kit receptors. It has an acceptable safety
profile in both non-clinical and clinical studies, and a PK profile that appears suitable
for daily oral dosing in humans.

The investigational product motesanib (Amgen) is a small molecule tyrosine kinase inhibitor
with high efficacy against VEGFR and c-Kit kinases. C-kit has been detected in 12% of breast
cancers, correlating with basal or triple-negative breast cancer. In addition, efficacy of
the drug has been noted to PDGFRα, which is expressed in approximately 40% of breast cancers
and is associated with aggressive disease, metastatic invasion and poor prognosis.
Importantly, in more than half (56%) of these cases, the carcinoma cells bearing the
receptors expressed the PDGF-A ligand, suggesting an autocrine loop and a cancer
cell-autonomous process. Cancer cell-autonomous pathways are especially attractive as drug
targets against metastatic breast cancer because they are expected to continue to be
functional at metastatic sites, since they do not depend on stromal factors.

The primary molecular target of motesanib, VEGFR, is intriguing because neovascularization
is expected to be required also at metastatic sites. A preliminary analysis revealed that
VEGF expression correlated with the triple-negative, basal breast cancer subtype and poor
outcome. Importantly, PDGF receptors are also present on vascular pericytes, cells required
for adequate vascularization. Thus, motesanib is a unique multikinase inhibitor that targets
both growth factor receptors on the carcinoma cells and growth factor receptors related to
neovascularization.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the breast regardless of
ER, PR and Her2 status with locally recurrent or metastatic disease. Locally
recurrent disease must not be amenable to resection with curative intent.

- Disease progression after at least 1, but no more than 2, prior chemotherapy regimens
for metastatic disease.

- Patients with hormone-sensitive tumors must have received prior hormonal therapy and
not be amenable to further hormonal therapy.

- Patients with HER2/neu-overexpressing tumors (3+ by immunohistochemistry or amplified
by fluorescent in situ hybridization) should have received trastuzumab (Herceptin®)
and/or lapatinib (Tykerb®) in the adjuvant or metastatic setting (unless
contraindicated) and have progressed while on treatment of metastatic disease or
within 12 months of completion of adjuvant therapy.

- Patients will eligible if they have tumors that express one of the motesanib-directed
tyrosine kinase markers, the target markers:(PDGFR, VEGFR, c-Kit) as determined by
study pathologist. Immunohistochemical assays for these markers are provided by grant
consortium partner and CLIA-certified diagnostics laboratory MDRG.

- Measurable disease per RECIST (Response Evaluation Criteria in Solid Tumor)
guidelines.

- Complete radiology and tumor measurement within 4 weeks (28 days) prior to
enrollment.

- Chest: CT scan with intravenous contrast if the contrast is not medically
contraindicated.

- Abdomen: CT scan with intravenous and oral contrast if the contrast is not
medically contraindicated.

- Pelvis: CT scan with intravenous and oral contrast if the contrast is not
medically contraindicated.

- Brain: CT scan or MRI

- Bone: Whole body Bone Scintigraphy or PET scan

- Female 18 years of age or older at the time the written informed consent is obtained.

- ECOG Performance Status of 0 or 1.

- Adequate organ and hematological function as evidenced by the following laboratory
studies within 2 weeks (14 days) of study enrollment, unless stated otherwise:

- Cardiac function, as follows:

- Normal sinus rhythm (no significant ECG changes)

- Left ventricular ejection fraction ≥ Lower Limit of Normal, as determined
by echocardiogram or MUGA scan, according to institutional standards within
28 days prior to study enrollment.

- Hematological function, as follows:

- Absolute neutrophil count ≥ 1.5 x 109/L

- Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L

- Hemoglobin ≥ 9 g/dL.

- PTT and INR < 1.5 x ULN.

- Renal function, as follows:

- Serum creatinine ≤ 175 µmol/L (= 2mg/dL). If creatinine is between 140-175
µmol/L, creatinine clearance (calculated or measured) should be > 40
mL/min.

- Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤ 1 + on
dipstick unless protein is < 500 mg in a 24-hour urine sample.

- Hepatic function, as follows:

- Aspartate aminotransferase (AST) ≤ 2.5 x ULN

- Alanine aminotransferase (ALT) ≤ 2.5 x ULN

- Total bilirubin ≤ 1 x ULN

- Patients of child-bearing potential and sexually active must provide a negative
pregnancy test within 7 days prior to enrollment.

- More than 4 weeks since prior therapy for breast cancer

- No other concurrent investigational or commercial agents or therapies for metastatic
breast cancer

- No prior capecitabine or fluorouracil for metastatic breast cancer

- More than 4 weeks since prior radiotherapy **Previously irradiated area(s) must not
be the only site of disease**

- More than 4 weeks since prior major surgery

Exclusion Criteria:

Disease Related:

- Current or prior history of central nervous system metastasis.

- Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 peripheral neuropathy ≥
grade 2 at enrollment.

- Average systolic blood pressure > 150 mm Hg or average diastolic blood pressure > 90
mm Hg (average blood pressure of the 3 separate blood pressure values measured
according to the Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure.

- History of arterial or venous thrombosis within 1 year prior to enrollment.

- History of bleeding diathesis or bleeding within 14 days of enrollment.

- Major surgical procedure within 4 weeks (28 days) prior to enrollment.

- Minor surgical procedure, placement of access device, or fine needle aspiration
within 7 days of enrollment.

- Known positive test for human immunodeficiency virus (HIV), hepatitis C, or
malignancy (other than in situ cervical cancer, or basal cell cancer of the skin),
unless treated with curative intent and without evidence of disease for ≥ 3 years
before study enrollment.

- Clinically significant cardiac disease within 12 months of study enrollment,
including myocardial infarction, unstable angina, grade II or greater peripheral
vascular disease, cerebrovascular accident, transient ischemic attack, congestive
heart failure, or ongoing arrhythmias requiring medication or pacemaker.

- Non-healing wound, ulcer or fracture.

- Ongoing or active infection.

- Known chronic hepatitis.

Medications:

- Currently or previously treated with small molecule inhibitors of VEGF including, but
not limited to, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AZD 6474, AEE-788,
BAY 43-9006 (sorafenib) and motesanib.

- Treatment with rifampin, carbamazepine, rifabutin or phenobarbital within 14 days
prior to study enrollment.

- Treatment with strong CYP 3A inhibitors or inducers such as ketoconazole,
itraconazole, fluconazole, clarithromycin, erythromycin, nefazodone, or any HIV
protease inhibitors within 7 days prior to study enrollment.

- Treatment with immune modulators such as cyclosporine and tacrolimus within 7 days
prior to study enrollment.

- Treatment with herbal medications containing St. John's Wort within 7 days prior to
study enrollment.

- Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or other
selective estrogen receptor modulators (SERMS), given for breast cancer prevention or
for osteoporosis. Patients must have discontinued these agents prior to enrollment.

General:

- Known hypersensitivity to any study medications (motesanib, and Chinese Hamster Ovary
cell products or other human or humanized recombinant proteins) or Cremaphor.

- Any condition which in the investigator's opinion makes the patient unsuitable for
the study participation. This includes substance abuse, medical, psychological or
social conditions that may interfere with the patient's participation in the study or
evaluation of the study results.

- Participation in other investigational device drug trials, or administration of other
investigational treatments within 30 days prior to study enrollment.

- Pregnant (i.e., positive beta-human chorionic gonadotropin test)

- Not willing to use a highly effective method of birth control (i.e. those which
result in low failure rates, less than 1% per year), such as nonhormonal IUD,
condoms, sexual abstinence or vasectomised partner.

**Contraception must be used during the study and for 6 months after last dose of study
treatment**

- Unable to swallow oral medications.

- Inability to comply with protocol and/or not available for follow-up assessments.

- Males of any age.