Neoadjuvant Cabozantinib in Treating Patients With Locally Advanced Kidney Cancer

Inclusion Criteria: * Patients with renal mass consistent with a clinical stage ≥ T3Nx or TanyN+ or deemed unresectable by surgeon. * Renal cell carcinoma with clear cell component on pre-treatment biopsy of the primary tumor. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. * Patients must have adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment: * Absolute neutrophil count (ANC) ≥ 1500/mm³ (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support. * White blood cell count ≥ 2500/mm³ (≥ 2.5 GI/L). * Platelets ≥ 100,000/mm³ (≥ 100 GI/L) without transfusion. * Hemoglobin ≥ 9 g/dL. * Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with documented bone metastases. * Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN). * Serum albumin ≥ 2.8 g/dl. * Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft-Gault equation: * Males: (140 - age) x weight (kg)/(serum creatinine \[mg/dL\] × 72) * Females: \[(140 - age) x weight (kg)/(serum creatinine \[mg/dL\] × 72)\] × 0.85 * Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol). * No hormonal therapy, chemotherapy, immunotherapy, or any other systemic therapy for a malignancy, in the 5 years prior to current study enrollment. * Sexually active fertile subjects 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 treatment. * Female subjects of childbearing potential must not be pregnant 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, low body weight, ovarian suppression or other reasons. * Capable of understanding and complying with the protocol requirements and must have signed the informed consent document. Exclusion Criteria: * Evidence of metastatic disease on pre-treatment imaging. * The subject has received of any type of cytotoxic, biologic or other systemic anticancer therapy for kidney cancer. * The subject has received any other type of investigational agent within 28 days before the first dose of study treatment. * Known brain metastases or cranial epidural disease. * Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Allowed anticoagulants are the following: * Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted. * Low-dose low molecular weight heparins (LMWH) are permitted. * Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. * The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test ≥ 1.3 × the laboratory ULN within 14 days before the first dose of study treatment. * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: * Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. * Uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment. * Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before first dose. * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: * The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, active inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. * Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose. * Clinically significant hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose. * Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. * Other clinically significant disorders that would preclude safe study participation. * Serious non-healing wound/ulcer/bone fracture. * Uncompensated/symptomatic hypothyroidism. * Moderate to severe hepatic impairment (Child-Pugh B or C). * Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. * Prolongation of the QT corrected for HR using Fridericia's method (QTcF) interval defined as \> 500 msec per electrocardiogram (ECG) within 28 days before first dose of study treatment. Note: If a single ECG shows a QTcF with an absolute value \> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility. * Pregnant or lactating females. * Inability to swallow tablets. * Previously identified allergy or hypersensitivity to components of the study treatment formulations. * Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Patients with Gleason 6 (3+3) prostate cancer with previous treatment or on active surveillance may also be allowed on protocol.