Cabozantinib in Women With Metastatic Hormone-Receptor-Positive Breast Cancer

Cabozantinib will be taken orally once a day in cycles of 28 days (4 weeks). Fulvestrant will
be given intramuscularly on days 1 and 15 of cycle 1 and on day 1 of all subsequent cycles.

On Day 1 of each cycle subjects will have the following tests and procedures:

- Performance status

- Physical exam

- Vital signs

- Routine blood samples

- Blood and urine samples to look at bone markers (Cycle 1 through 6 only)

Subjects will also have the following additional tests and procedures:

- Tumor assessment by Computed Tomography (CT) scan and bone scan at Cycle 3, then every
12 weeks

- Blood or urine pregnancy test (if applicable) on Day 1 of Cycles 1, 2, 4, then every 12
weeks

- Urine sample and blood test for thyroid function (Cycle 1, 3, 5, then every 6 weeks)

- Blood test for breast cancer tumor marker (Cycle 1 and 4, then every 6 weeks)

- Pain questionnaire and painkiller medication diary at 7-day intervals during Week 3,
Week 6, and every 6 weeks thereafter.

Inclusion Criteria:

- Clear evidence of metastases to bone on isotope bone scan

- Histologically or cytologically confirmed metastatic Estrogen-receptor-positive (ER+)
and/or Progesterone-receptor-positive (PR+) and Human Epidermal Growth Factor Receptor
(HER) 2 negative breast cancer

- Received at least one prior line of hormonal or chemo-therapy for metastatic disease

- must be post menopausal

- Recovered from toxicities related to prior treatment, except alopecia, lymphopenia, or
other non-clinically significant Adverse Events (AEs)

- Life expectancy > 3 months

- Adequate organ and marrow function

- Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception

- Able to lie flat for up to 45 minutes for imaging studies

- Able to swallow capsules or tablets

Exclusion Criteria:

- Pregnant or breast-feeding

- Has experienced clinically-significant hematemesis or hemoptysis of > 0.5 teaspoons of
red blood, or other signs indicative of pulmonary hemorrhage within 3 months before
the first dose of study treatment

- Untreated, symptomatic or uncontrolled brain metastasis requiring current treatment
including steroids and anti-convulsants

- more than 1 prior line of chemotherapy for treatment of metastatic breast cancer

- prior treatment with fulvestrant

- Requires concomitant treatment, in therapeutic doses, with anticoagulants such as
warfarin or coumadin-related agents, thrombin or Factor Xa inhibitors, and
antiplatelet agents (eg, clopidogrel)

- Uncontrolled or significant intercurrent illness

- Gastrointestinal disorders, particularly those associated with a high risk of
perforation or fistula formation

- Active infection requiring systemic treatment

- Serious non-healing wound/ulcer/bone fracture

- History of organ transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction

- Previously-identified allergy or hypersensitivity to components of the study treatment
formulation

- Diagnosis of another malignancy, requiring systemic treatment, within the last 2
years, unless non-melanoma skin cancer, in-situ carcinoma of the cervix, or
superficial bladder cancer