Cabozantinib in Treating Patients with Hormone Receptor-Positive Metastatic Breast Cancer with Bone Involvement

Inclusion Criteria

• The subject must have clear evidence of metastases to bone on isotope bone scan at screening, with or without soft tissue metastases; in subjects with bone-only disease, at least two bone lesions must be evident on baseline imaging that are not within a previously irradiated field
• The subject must have histologically or cytologically confirmed metastatic estrogen-receptor positive (ER+) and/or progesterone-receptor positive (PR+) and human epidermal growth factor receptor 2 (HER2) negative breast cancer; (stains may be performed on either primary or metastatic tumor samples, ER and PR assays will be considered positive if there are at least 1% positive tumor nuclei in the sample as per American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines, HER2 negative as per ASCO/CAP guidelines)
• The subject must have progressive disease following at least one prior line of hormonal or chemotherapy for treatment of their metastatic disease
• The subject must have discontinued any endocrine therapy for at least 2 weeks before the first dose of study treatment; in the cases of fulvestrant and leuprolide, these must be discontinued for at least 4 weeks before the first dose of study treatment
• The subject has recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicities related to prior treatment, except alopecia, lymphopenia, other non-clinically significant adverse events (AEs)
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• The subject has an estimated life expectancy of more than three months
• Absolute neutrophil count (ANC) >= 1500/mm^3, without colony stimulating factor support
• Platelets >= 100,000/mm^3
• Hemoglobin >= 9 g/dL, without ongoing chronic blood transfusion or colony stimulating factor support to maintain normal levels; principal investigator approval is required; (limited red blood cell [RBC] transfusion is allowed for an acute change in hemoglobin)
• Total bilirubin =< 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert’s disease, =< 3 mg/dl
• Alkaline (Alk) phosphatase =< 5 x upper limit of normal
• Serum albumin >= 2.8 g/dL
• Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x the ULN if no liver involvement, or =< 5 x the ULN with liver involvement
• Lipase < 1.5 times the ULN
• Urine protein/creatinine ratio (UPCR) =< 1
• Serum phosphorus >= lower limit of normal
• Calcium >= lower limit of normal
• Magnesium >= lower limit of normal
• Potassium >= lower limit of normal
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Sexually active fertile subjects (male and female), and their partners, must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study drug(s)
• Female subjects of childbearing potential must have a negative pregnancy test at screening; females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy); however, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, or ovarian suppression or other reasons
• The subject is able to lie flat for up to 45 minutes for imaging studies
• ADDITIONAL INCLUSION CRITERIA FOR PATIENTS IN COMBINATION FULVESTRANT/CABOZANTINIB COHORT
• Subject is post-menopausal defined as age over 60 or status post bilateral oophorectomy; in subjects aged 50-60 years they shall be considered eligible if follicle stimulating hormone (FSH)/luteinizing hormone (LH) and estradiol is within institutional post-menopausal range at the time of study entry
• Subject has hormone-receptor positive metastatic breast cancer with disease progression following antiestrogen therapy

Exclusion Criteria

• The subject has a corrected QT interval (QTc) > 500 ms at screening or has a history of long QT syndrome
• The subject has experienced clinically-significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The subject has cavitating pulmonary lesion(s) or a pulmonary lesion abutting or encasing a major blood vessel
• The subject has tumor in contact with, invading or encasing any major blood vessels
• The subject has received systemic chemotherapy (including investigational agents) within 4 weeks, or biological agents (antibodies, immune modulators, cytokines, or vaccines) within 6 weeks, or hormonal anticancer therapy within 2 weeks before the first dose of study treatment (within 4 weeks in the case of fulvestrant) (vaccines, such as flu shot or, pneumovax are not exclusions)
• The subject has received small-molecular kinase inhibitors or any other type of investigational agent within 4 weeks before the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is shorter
• The subject has received radiation therapy: * To the thoracic cavity or gastrointestinal tract within 3 months of the first dose of study treatment * To bone or brain metastasis within 14 days of the first dose of study treatment * To any other site(s) within 28 days of the first dose of study treatment
• The subject has started treatment with drugs used to control loss of bone mass (eg, bisphosphonates or denosumab) within 4 weeks prior to the first dose of study treatment
• The subject has untreated, symptomatic or uncontrolled brain metastasis requiring current treatment including steroids and anti-convulsants; neurosurgical resection of brain metastasis or brain biopsy is permitted if completed at least 3 months before the first dose of study treatment
• The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test results at screening >= 1.3 x the laboratory ULN
• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or coumadin-related agents, thrombin or factor Xa (FXa) inhibitors, and antiplatelet agents (eg, clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted; therapeutic anticoagulation with LMWHs may be allowed in certain circumstances as outlined
• The subject has experienced any of the following within 3 months before the first dose of study treatment: * Clinically-significant hematemesis or lower gastrointestinal bleeding * Hemoptysis of > 0.5 teaspoon of red blood * Any other signs indicative of pulmonary hemorrhage
• The subject has uncontrolled or significant intercurrent illness including, but not limited to, the following conditions: * Cardiovascular disorders such as symptomatic congestive heart failure (CHF), uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening), unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke (including transient ischemic attack [TIA], or other ischemic event) within 6 months of study treatment, myocardial infarction within 6 months of study treatment, history of thromboembolic event requiring therapeutic anticoagulation within 6 months of study treatment or main portal vein or vena cava thrombosis or occlusion; (Note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)
• Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: * Any of the following at the time of screening ** Intra-abdominal tumor/metastases invading gastrointestinal (GI) mucosa ** Active peptic ulcer disease ** Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis * Any of the following within 6 months before the first dose of study treatment; history of abdominal fistula; gastrointestinal perforation; bowel obstruction or gastric outlet obstruction; intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months ago * GI surgery (particularly when associated with delayed or incomplete healing) within 28 days; Note: complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more than 28 days ago
• Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus
• Other clinically significant disorders such as: * Active infection requiring systemic treatment * Serious non-healing wound/ulcer/bone fracture * History of organ transplant * Concurrent uncompensated hypothyroidism or thyroid dysfunction * History of major surgery within 4 weeks or minor surgical procedures within 1 week before randomization
• The subject is unable to swallow capsules or tablets
• The subject is pregnant or breastfeeding
• The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation
• The subject requires chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort)
• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
• The subject has had another diagnosis of malignancy, requiring systemic treatment, within the last two years, unless non-melanoma skin cancer, in-situ carcinoma of the cervix, or superficial bladder cancer
• ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COMBINATION FULVESTRANT/CABOZANTINIB COHORT
• Subject has had prior progression on treatment with fulvestrant (prior adjuvant treatment or brief exposure in the advanced setting is allowed)
• Subject has received more than 1 prior line of chemotherapy treatment for metastatic breast cancer
• Subject has had prior treatment with cabozantinib