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