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

Phase 2

Completed

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Cabozantinib	Cabozantinib	Oral cabozantinib therapy daily
Cabozantinib plus fulvestrant	Cabozantinib	Combination therapy with oral cabozantinib daily plus fulvestrant monthly Intramuscularly (IM)
Cabozantinib plus fulvestrant	Fulvestrant	Combination therapy with oral cabozantinib daily plus fulvestrant monthly Intramuscularly (IM)

Primary Outcome Measures

Name	Time	Method
Bone Scan Response Rate	2 years	Bone scan response rate will be defined as the percentage of patients experiencing a complete resolution of bone lesions or partial response in the isotope bone scan per Bone Scan Time Point Response Criteria, as defined in the protocol. Complete resolution is defined as the disappearance of all areas of radiotracer uptake attributable to metastatic disease, and a partial response is defined as significant improvement in radiotracer uptake in areas attributable to metastatic disease, but not meeting the criteria for CR.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate by RECIST v 1.1	2 years	The overall response rate (ORR) is defined as the percentage of patients experiencing a complete response or partial response on PET imaging per mRECIST (modified response evaluation criteria in solid tumors), as defined in the protocol. A complete response is defined as resolution of all areas of FDG uptake attributable to metastatic disease. A partial response is defined as significantly decreased FDG uptake in areas attributable to metastatic disease, but not meeting the criteria for a complete response.
Overall Survival	5 years	Overall Survival (OS) is defined as the difference between the date of a patient's enrollment onto this study until the date of death. Patients who are alive at last contact will be censored for OS at this date.
Progression Free Survival	5 years	Progression Free Survival (PFS) is defined as the difference between the date of a patient's enrollment onto this study until the earlier of the date of progression or the date of death. Patients who are alive and progression-free at last contact will be censored for PFS at this date.

Locations (4): Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
Dana Farber Cancer Institute
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Boston, Massachusetts, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States