Sequential Treatment of Cabozantinib for Advanced Renal Cell Carcinoma (RCC)

Inclusion Criteria: 1. Patients with advanced RCC (defined as locally advanced unresectable or metastatic) of any histology who progressed on/after cabozantinib monotherapy in any line of treatment. Patient must have cabozantinib sensitive disease (prior treatment with cabozantinib ≥ 6 months) 2. Ability to tolerate prior cabozantinib at 60mg PO daily with manageable toxicity profile at the respective doses, at investigator discretion 3. Prior PD-1 inhibitor/PD-L1 inhibitor allowed 4. Evidence of measurable disease per RECIST 1.1 5. For up to 5 patients opting into on-treatment biopsy, one of the following must be met: 1. Archival tissue confirmed to be available and obtained within 30 days of informed consent as well as willingness to undergo an on-treatment biopsy at 12 weeks (+/- 7 days). OR 2. Willingness to undergo a baseline biopsy prior to Cycle 1 Day1, as well as an on-treatment biopsy at 12 weeks (+/- 7 days). 6. Age ≥ 18 at time of consent 7. ECOG performance status ≤ 2 8. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document 9. No washout period is needed for cabozantinib, minimum of 4 weeks or 4 half-lives washout, whichever is shorter, for other standard or experimental anti-cancer therapies. 10. Recovery to baseline or ≤ Grade 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy 11. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment: 1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor (G-CSF) support 2. White blood cell (WBC) count ≥ 2500/µL 3. Platelets ≥ 100,000/µL without transfusion 4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) (transfusion acceptable per investigator discretion) 5. Alanine transaminase (ALT), AST and alkaline phosphatase (ALP) ≤ 3 x ULN. ALP ≤ 5x ULN with documented bone metastases 6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3x ULN) 7. Serum albumin ≥ 2.8 g/dl 8. Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test \< 1.3x the laboratory ULN 9. Serum creatinine ≤ 1.5x ULN or calculated creatinine clearance ≥ 40mL/min (≥ 0.675mL/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 10. Urine protein/creatinine ratio (UPCR) ≤1 mg/mg (≤113.2 mg/mmol), or 24h urine protein ≤1 g 12. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., 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 cabozantinib Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 1. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: * documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), or * documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. 2. In addition, females \< 55 years-of-age must have a serum follicle stimulating hormone (FSH) level \> 40 mIU/mL to confirm menopause. Exclusion Criteria: 1. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible 2. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for 1) at least 2 weeks after radiotherapy or 2) at least 4 weeks after major surgery (e.g., removal or biopsy of brain metastasis) prior to first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment for the brain metastasis at the time of first dose of study treatment 3. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: 1) prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). 2) Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor 4. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: 1. Cardiovascular disorders: 1) congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias; 2) uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 1 week of treatment; 3) stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis \[DVT\], pulmonary embolism \[PE\]) within 6 months before first dose of study treatment. Note: subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #3.2.4) for at least 1 week before first dose of study treatment 2. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation, including 1) the subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., 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; 2) abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment 5. Clinically significant hematuria, hematemesis, hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 6 weeks before first dose of study treatment. (Clinically significant hematuria defined by needing transfusion; clinically significant hematemesis or hemoptysis defined by needing hospital admission) 6. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. Cavitary pulmonary lesions are allowed if not symptomatic. 7. Lesions invading or encasing any major blood vessels 8. Other clinically significant disorders that would preclude safe study participation 1. Serious non-healing wound/ulcer/bone fracture 2. Moderate to severe hepatic impairment (Child-Pugh B or C). 3. Acute COVID-19 infection - clinical recovery from COVID-19 infection at least 14 days prior to enrollment allowed. 9. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 days before first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible 10. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment. Furthermore, subjects with a history of additional risk factors for torsades de pointes (e.g., long QT syndrome) are also excluded. 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. 11. Pregnant or lactating females 12. Inability to swallow tablets 13. Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded 14. Another malignancy within 2 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, Gleason 6 prostate cancer, or carcinoma in situ of cervix or breast