Trial of Cabozantinib (XL184) in Non-Small Cell Lung Cancer With Brain Metastases

Inclusion Criteria: 1. Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. (Patients must have received at least one regimen for systemic disease which may be cytotoxic or oral tyrosine kinase inhibitor therapy.) * Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating physician * Patients who have undergone treatment for their brain metastases with whole brain radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically stable and recovered from all procedures at the time of study enrollment. 2. Patients must have tumor tissue available for submission that is sufficient to complete c-MET Fluorescence in Situ Hybridization (FISH) studies as well as routine molecular profiling at the UPMC. Patients must agree to submission of these specimens as defined in Section 9. * c-MET amplification will be determined by FISH ratio (c-MET/CEP7) \> 2.0, based on testing of the primary tumor and/or site of metastatic disease * Patients' tumors must undergo testing for Epidermal Growth Factor Receptor (EGFR) exon 19 deletion, EGFR exon 21 L858R substitution, and anaplastic lymphoma kinase (ALK) rearrangements. If positive, patients must have been treated with an appropriate tyrosine kinase inhibitors (TKI) prior to enrolling to the study. 3. The subject has had an assessment of all extracranial disease sites (e.g., by computerized tomography (CT) scan, positron emission tomography-CT, and bone scan as appropriate) within 28 days before the first dose of cabozantinib. 4. The subject must have a baseline brain MRI scan or CT scan of the head (in patients unable to obtain an MRI) within 14 days prior to first dose of cabozantinib. * Patients receiving glucocorticoids must be on a stable dose of glucocorticoids during the 5 days prior to the baseline brain imaging. 5. Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 6. Subjects having undergone recent resection or biopsy of an intracranial tumor will be eligible as long as all of the following conditions apply: * First dose of cabozantinib occurs at least 28 days after surgery, and the subject has recovered from the effects of surgery 7. Age ≥18 years 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%) 9. Patients must have normal organ and marrow function as defined below: (within 4 days of beginning treatment unless noted otherwise) * Hemoglobin ≥9 g/dL * Absolute Neutrophil Count (ANC) ≥1,500/mm3 (no CSF support) * Platelets ≥100,000/mm3 * Bilirubin ≤ 1.5 x upper limit of normal (ULN) * Bilirubin (Gilbert's Disease) \< 3.0 mg/dL * Aspartate Aminotransferase (AST) (SGOT) ≤3.0 × ULN * Alanine Aminotransferase (ALT) (SGPT) ≤3.0 × ULN * Serum creatinine ≤ 1.5 x ULN * Creatinine clearance (CrCl) ≥40 mL/min * For creatinine clearance estimation, the Cockcroft and Gault equation should be used: * Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) * Female: Multiply above result by 0.85 ≤ 1.5 x ULN * Lipase (no radiologic or clinical evidence of pancreatitis) \< 2.0 x ULN * Urine protein/creatinine ratio (UPCR) ≤1 * Serum phosphorus, calcium, magnesium and potassium ≥ LLN 10. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document. 11. Women of childbearing potential must have a negative serum pregnancy test at screening. 12. The effects of cabozantinib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 4 months after the last dose of study drug, even if oral contraceptives are used. Exclusion Criteria: 1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies; including investigational biologic agents) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment. 2. The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. 3. Prior treatment with cabozantinib or other c-MET directed therapy. 4. The subject has received radiation therapy as follows: * To the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study treatment or has with ongoing complications or is without complete recovery and healing from prior radiation therapy * 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 5. The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment. 6. The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs. 7. 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 study treatment. 8. The subject is receiving concomitant treatment with warfarin, warfarin-related agents, or low molecular weight heparin (LMWH) at the time of study entry at therapeutic doses. Low-dose warfarin (≤ 1 mg/day) or LMWH at prophylactic doses are permitted. 9. The subject has received enzyme-inducing anti-epileptic agents within 2 weeks before the first dose of cabozantinib (e.g., carbamazepine, phenytoin, phenobarbital, primidone). Other enzyme inducing agents prohibited within 2 weeks before the first dose of cabozantinib include rifampin, rifabutin, rifapentin, and St. John's Wort. 10. The subject has experienced any of the following: * Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment b.Hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment 11. The subject has radiographic evidence of cavitating pulmonary lesion(s) 12. The subject has tumor abutting, invading or encasing any major blood vessels. 13. The subject has evidence of tumor invading the Gastro Intestinal (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. 14. 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 BP \> 140 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment * Any history of congenital long QT syndrome * Any of the following within 6 months before the first dose of study treatment: 1.unstable angina pectoris 2.clinically-significant cardiac arrhythmias 3.stroke (including Transient Ischemic Attack (TIA), or other ischemic event) 4.myocardial infarction (MI) 5.thromboembolic event requiring therapeutic anticoagulation (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 within 28 days before the first dose of study treatment 1. Intra-abdominal tumor/metastases invading GI mucosa 2. Active peptic ulcer disease, 3. Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis 4. Malabsorption syndrome * Any of the following within 6 months before the first dose of study treatment: 1. Abdominal fistula 2. Gastrointestinal perforation 3. Bowel obstruction or gastric outlet obstruction 4. 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 study treatment. * 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: * Serious active infection requiring systemic treatment within 28 days before the first dose of study treatment. * Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment. * History of organ transplant * Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment. * History of surgery as follows: 1. Subjects having undergone recent resection or biopsy of an intracranial tumor will be eligible as long as all of the following conditions apply: First dose of cabozantinib occurs at least 28 days after surgery, and the subject has recovered from the effects of surgery. 2. Other minor surgery within 28 days of the first dose of cabozantinib if there were no wound healing complications. If there is evidence of wound dehiscence, subjects will be eligible for trial after a minimum of 3 months after surgery to the first dose of cabozantinib, provided complete wound healing is confirmed at least 28 days before the first dose of cabozantinib. 3. Other major surgery within 2 months of the first dose of cabozantinib if there were no wound healing complications. If there is evidence of wound dehiscence, subjects will be eligible for trial after a minimum of 6 months after surgery to the first dose of cabozantinib, provided complete wound healing in confirmed at least 28 days before the first dose of cabozantinib. 4. The subject is unable to swallow tablets. 5. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) \>500 ms within 28 days before randomization. Note: if initial QTcF is found to be \> 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 6. The subject is pregnant or breastfeeding. 7. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation. 8. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee. 9. The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment. Note: Subjects with a history of early stage or locally advanced non-metastatic prostate cancer within 2 years of the start of study treatment may be included in the study.