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

• Overall Response Rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate overall response rate (ORR) (defined as the percentage of patients experiencing a complete response or partial response)
• Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate Overall Survival
• Progression Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate Progression Free Survival
• Effects on bone and tumor markers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate the effects of cabozantinib on biochemical markers of bone turnover and tumor markers
• Skeletal related event rates (includes analgesic usage, incidence of fractures, need for radiation or surgical intervention and pain at sites of bone disease) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  All intercurrent adverse events, treatments and interventions will be recorded. For the purpose of determining the effects of cabozantinib treatment on pain and analgesic medication usage, pain will be assessed by a participant-reported questionnaire, and daily analgesic medication usage will be recorded during regular intervals.
• FDG-PET (Flurodeoxyglucose Positron Emission Tomography) Response Rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate FDG-PET response rate

The study drug cabozantinib works by inhibiting several different proteins which are believed to be involved in breast cancer tumor growth, its ability to spread, and its ability to form new blood vessels. This drug has been used in other research studies and information from those other research studies suggests that this drug may help to prevent cancer growth.

The single agent portion of this study is now closed to accrual. This research study is now examining the efficacy of cabozantinib in combination with fulvestrant for treatment of hormone-receptor-positive breast cancer that has spread to bone.

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 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 HER2 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 FXa 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