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 oftreatment. Patient must have cabozantinib sensitive disease (prior treatment withcabozantinib ≥ 6 months)

2. Ability to tolerate prior cabozantinib at 60mg PO daily with manageable toxicityprofile 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 bemet:

6. Archival tissue confirmed to be available and obtained within 30 days ofinformed consent as well as willingness to undergo an on-treatment biopsy at 12weeks (+/- 7 days).OR

7. Willingness to undergo a baseline biopsy prior to Cycle 1 Day1, as well as anon-treatment biopsy at 12 weeks (+/- 7 days).

8. Age ≥ 18 at time of consent

9. ECOG performance status ≤ 2

10. Capable of understanding and complying with the protocol requirements and must havesigned the informed consent document

11. No washout period is needed for cabozantinib, minimum of 4 weeks or 4 half-liveswashout, whichever is shorter, for other standard or experimental anti-cancertherapies.

12. Recovery to baseline or ≤ Grade 1 National Cancer Institute (NCI) Common TerminologyCriteria for Adverse Events (CTCAE) Version 5 from toxicities related to any priortreatments, unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy

13. Adequate organ and marrow function, based upon meeting all of the followinglaboratory criteria within 14 days before first dose of study treatment:

14. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocytecolony-stimulating factor (G-CSF) support

15. White blood cell (WBC) count ≥ 2500/µL

16. Platelets ≥ 100,000/µL without transfusion

17. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) (transfusion acceptable per investigatordiscretion)

18. Alanine transaminase (ALT), AST and alkaline phosphatase (ALP) ≤ 3 x ULN. ALP ≤ 5x ULN with documented bone metastases

19. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3x ULN)

20. Serum albumin ≥ 2.8 g/dl

21. Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastintime (PTT) test < 1.3x the laboratory ULN

22. 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 urineprotein ≤1 g

11. Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 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 thefollowing criteria is met:

• documented permanent sterilization (hysterectomy, bilateral salpingectomy, orbilateral 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 stimulatinghormone (FSH) level > 40 mIU/mL to confirm menopause.

Exclusion Criteria:

1. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible

2. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for 1) at least 2weeks after radiotherapy or 2) at least 4 weeks after major surgery (e.g., removalor biopsy of brain metastasis) prior to first dose of study treatment. Subjects musthave complete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Eligible subjects must be neurologically asymptomatic and withoutcorticosteroid treatment for the brain metastasis at the time of first dose of studytreatment

3. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or plateletinhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: 1)prophylactic use of low-dose aspirin for cardio-protection (per local applicableguidelines) and low-dose low molecular weight heparins (LMWH). 2) Therapeutic dosesof LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban,or apixaban in subjects without known brain metastases who are on a stable dose ofthe anticoagulant for at least 1 week before first dose of study treatment withoutclinically significant hemorrhagic complications from the anticoagulation regimen orthe tumor

4. The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

5. Cardiovascular disorders: 1) congestive heart failure New York HeartAssociation Class 3 or 4, unstable angina pectoris, serious cardiacarrhythmias; 2) uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimalantihypertensive treatment within 1 week of treatment; 3) stroke (includingtransient ischemic attack [TIA]), myocardial infarction (MI), or other ischemicevent, or thromboembolic event (e.g., deep venous thrombosis [DVT], pulmonaryembolism [PE]) within 6 months before first dose of study treatment. Note:subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 monthsare allowed if stable, asymptomatic, and treated with a stable dose ofpermitted anticoagulation (see exclusion criterion #3.2.4) for at least 1 weekbefore first dose of study treatment

6. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation, including 1) the subject has evidence oftumor invading the GI tract, active peptic ulcer disease, inflammatory boweldisease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomaticcholangitis or appendicitis, acute pancreatitis, acute obstruction of thepancreatic duct or common bile duct, or gastric outlet obstruction; 2)abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose of study treatment. Note: Completehealing of an intra-abdominal abscess must be confirmed before first dose ofstudy treatment

7. Clinically significant hematuria, hematemesis, hemoptysis, or other history ofsignificant bleeding (e.g., pulmonary hemorrhage) within 6 weeks before first doseof study treatment. (Clinically significant hematuria defined by needingtransfusion; clinically significant hematemesis or hemoptysis defined by needinghospital admission)

8. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation. Cavitary pulmonary lesions are allowed if not symptomatic.

9. Lesions invading or encasing any major blood vessels

10. Other clinically significant disorders that would preclude safe study participation

11. Serious non-healing wound/ulcer/bone fracture

12. Moderate to severe hepatic impairment (Child-Pugh B or C).

13. Acute COVID-19 infection - clinical recovery from COVID-19 infection at least 14 days prior to enrollment allowed.

14. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 2 weeks before first dose of study treatment. Minorsurgeries within 10 days before first dose of study treatment. Subjects must havecomplete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible

15. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment.Furthermore, subjects with a history of additional risk factors for torsades depointes (e.g., long QT syndrome) are also excluded. Note: If a single ECG shows aQTcF with an absolute value > 500 ms, two additional ECGs at intervals ofapproximately 3 min must be performed within 30 min after the initial ECG, and theaverage of these three consecutive results for QTcF will be used to determineeligibility.

16. Pregnant or lactating females

17. Inability to swallow tablets

18. Previously identified allergy or hypersensitivity to components of the studytreatment formulations or history of severe infusion-related reactions to monoclonalantibodies. Subjects with rare hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption are also excluded

19. Another malignancy within 2 years prior to first dose of study treatment thatrequires active treatment, except for locally curable cancers that have beenapparently cured, such as basal or squamous cell skin cancer, superficial bladdercancer, Gleason 6 prostate cancer, or carcinoma in situ of cervix or breast