Cabozantinib S-malate with or without Trastuzumab in Treating Patients with Stage IV Breast Cancer with Brain Metastases

Inclusion Criteria

• Patients must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease; patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation * Measurable disease: patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with the longest diameter >= 10 mm by local radiology review (measurable non-CNS disease is not required for study participation) * Patients will be defined as HER2 positive (+) if either the primary tumor and/or the metastasis are HER2-positive, defined as 3+ by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) >= 2.0
• New or progressive CNS lesions, as assessed by the patient’s treating physician * It is anticipated that some patients may have multiple progressive CNS lesions, one or several of which are treated with stereotactic radiosurgery (SRS) or surgery with residual untreated lesions remaining; such patients are eligible for enrollment on this study providing that at least one lesion is measurable (>= 10 mm) per RECIST 1.1; the location of the measurable lesion should be documented in the patient chart and case report form * Patients who have had prior cranial surgery are eligible provided that there is evidence of measurable residual or progressive lesions, and at least 3 months have passed since surgery; if a patient has surgical resection followed by whole brain radiation therapy (WBRT), then there must be evidence of progressive CNS disease after the completion of WBRT * Patients who had had prior WBRT and/or SRS and then whose lesions have progressed thereafter are also eligible; in this case, lesions that have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression * Patient who have not previously been treated with cranial radiation (e.g. WBRT or SRS) are eligible to enter the study, but such patients must be asymptomatic or minimally symptomatic from their CNS metastases and not requiring corticosteroids
• For patients who have received prior cranial radiation, no increase in corticosteroid dose in the week prior to the baseline brain magnetic resonance imaging (MRI)
• Prior therapy: Patients must have discontinued all chemotherapy, investigational therapy or biologic therapy at least 14 days prior to initiating study treatment (with the exception of trastuzumab for patients with HER2+ breast cancer)
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0) from toxicities related to any prior treatments, unless adverse event(s) (AE[s]) are clinically nonsignificant and/or stable on supportive therapy: * Cohort 1: HER2-positive, defined by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2013 guidelines: ** IHC 3+ based on circumferential membrane staining that is complete, intense OR ** FISH positive based on one of the three following criteria: *** Single-probe average HER2 copy number >= 6.0 signals/cell; OR *** Dual-probe HER2/chromosome 17 centromere (CEP17) ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell; OR *** Dual-probe HER2/CEP17 ratio >= 2.0 * Cohort 2: Hormone receptor positive (estrogen receptor [ER]-positive and/or progesterone receptor [PR]-positive, defined as >= 1% staining by immunohistochemistry) and HER2-negative * Cohort 3: Triple negative (ER-negative, PR-negative, HER2-negative)
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count >= 1000/mm^3 without colony stimulating factor support (within 14 days before the first dose of cabozantinib)
• Platelets >= 100,000/mm^3 (within 14 days before the first dose of cabozantinib)
• Hemoglobin >= 9 g/dL (within 14 days before the first dose of cabozantinib)
• Total bilirubin =< 1.5 mg/dL x the upper limit of normal (ULN) (within 14 days before the first dose of cabozantinib)
• Serum albumin >= 2.8 g/dl (within 14 days before the first dose of cabozantinib)
• 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 (within 14 days before the first dose of cabozantinib)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x the ULN; for patients with documented liver metastases, AST/ALT =< 5.0 times the upper limit of normal (within 14 days before the first dose of cabozantinib)
• Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis (within 14 days before the first dose of cabozantinib)
• Urine protein: creatinine ratio =< 1 (within 14 days before the first dose of cabozantinib)
• Serum phosphorus, calcium, magnesium and potassium >= lower limit of normal (LLN) (within 14 days before the first dose of cabozantinib)
• The subject is capable of understanding and complying with the protocol and has signed the informed consent document
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)
• Female subjects of childbearing potential must not be pregnant at screening; females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., 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, low body weight, ovarian suppression or other reasons
• Patients on bisphosphonates may continue receiving bisphosphonate therapy during study; patients wanting to initiate bisphosphonate therapy may do so
• The subject has had an assessment of all known non-CNS disease sites e.g., by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib
• Research MRI sequences performed at Massachusetts General Hospital Charlestown Navy Yard must be completed =< 7 days of cycle 1 day 1
• Clinical MRIs performed at baseline must be completed within 28 days before the first dose of cabozantinib

Exclusion Criteria

• The subject has received cabozantinib or another c-Met inhibitor (please note ARQ 197 is not considered a MET inhibitor for purposes of this study)
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders including: ** Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening ** Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of cabozantinib ** Any history of congenital long QT syndrome ** Any of the following within 6 months before the first dose of cabozantinib: unstable angina pectoris; clinically-significant cardiac arrhythmias; stroke (including transient ischemic attack [TIA], or other ischemic event); myocardial infarction; thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter [e.g., vena cava filter] are not eligible for this study) * Gastrointestinal (GI) disorders particularly those associated with a high risk of perforation or fistula formation including: ** Any of the following within 28 days before the first dose of cabozantinib: intra-abdominal tumor/metastases invading GI mucosa; patients must be completely recovered from any evidence of active peptic ulcer disease; patients must be completely recovered from these conditions - any evidence or inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis; malabsorption syndrome ** Any of the following within 6 months before the first dose of cabozantinib: 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 before the first dose of cabozantinib * 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 * Other clinically significant disorders such as: ** Active infection requiring systemic treatment within 28 days before the first dose of cabozantinib ** Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of cabozantinib ** History of organ transplant ** Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of cabozantinib
• Leptomeningeal disease as the only site of CNS involvement
• Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker, shrapnel, or ocular foreign body
• More than 2 seizures over the last 4 weeks prior to study entry
• Grade 1 or higher CNS hemorrhage on baseline brain MRI, or history of grade 2 or higher CNS hemorrhage within 12 months
• The subject has experienced any of the following: * Clinically-significant GI bleeding within 6 months before the first dose of cabozantinib * Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of cabozantinib * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of cabozantinib
• The subject has tumor in contact with, invading or encasing any major blood vessels
• The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
• The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of cabozantinib
• Inability to swallow intact tablets
• Pregnant or lactating females
• Diagnosis of another malignancy within 2 years before the first dose of cabozantinib, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy
• Radiation therapy within 7 days before the first dose of cabozantinib; subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
• The subject is known to be positive for the human immunodeficiency virus (HIV)
• Major surgery within 12 weeks before the first dose of cabozantinib; complete wound healing from major surgery must have occurred 1 month before the first dose of cabozantinib; minor surgery (including uncomplicated tooth extractions) is allowed if it occurred 28 days before the first dose of cabozantinib with complete wound healing at least 10 days before the first dose of cabozantinib; subjects with clinically relevant ongoing complications from prior surgery are not eligible
• QT interval corrected using Fridericia formula (QTcF) > 500 msec on average of screening electrocardiograms (EKGs) performed within 28 days of first dose of cabozantinib; three EKGs must be performed at screening; if the average of these three consecutive results for QTcF is > 500 msec, the subject is ineligible
• Active infection requiring IV antibiotics at day 1 of cycle 1
• No prior lapatinib within 7 days prior to initiation of protocol treatment
• Patients may not receive any concurrent investigational agents while on study
• Patients may not receive any cancer-directed concurrent therapy, such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study
• Previously identified allergy or hypersensitivity to components of the cabozantinib formulations
• The subject requires chronic concomitant treatment with strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s wort)