A Study of Cabozantinib and Nivolumab With Radiation Therapy for People With Renal Cell Carcinoma That Has Spread to the Brain

Inclusion Criteria:

1. Unresectable advanced or metastatic clear cell or non-clear cell RCC; allhistologies acceptable except for chromophobe RCC

2. Brain metastases present, meeting the following criteria:

3. At least 1 brain metastasis measuring ≥0.5cm in any dimension (intracranialRANO-BM measurable disease required)

4. SRS is indicated per treating radiation oncologist

5. Surgical intervention for brain metastases is not planned

6. Able to undergo MRI Brain assessments for radiation planning.

7. Availability of archival tissue that enables the definitive diagnosis of RCC,accompanied by an associated pathology report. If archival tissue cannot beobtained, PI to provide documented confirmation patient can still enroll onto thestudy. Specimens can be collected by surgical resection or biopsy of the primarytumor or biopsy or resection of a metastatic lesion.

8. Age ≥18 years

9. KPS ≥ 80

10. Adequate hematologic and end organ function, defined by the following laboratoryresults obtained within 28 days prior to the first study treatment:

11. ANC ≥ 1500 cells/μL (without granulocyte colony stimulating factor supportwithin 4 weeks prior to Cycle 1, Day 1)

12. WBC counts ≥ 2500/μL

13. Absolute lymphocyte count ≥ 500/μL

14. Platelet count ≥100,000/μL (without transfusion within 4 weeks prior to Cycle 1, Day 1)

15. Hemoglobin ≥9.0 g/dL o Patients may be transfused or receive erythropoietictreatment to meet this criterion.

16. AST, ALT, and alkaline phosphatase ≤ 2.5 x ULN, with the following exceptions:

17. Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN

18. Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 xULN

19. Serum bilirubin ≤ 1.5 x ULN

20. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be-enrolled.

21. INR and aPTT ≤ 1.5 x ULN a. This applies only to patients who are not receiving therapeutic anticoagulation;patients receiving therapeutic anticoagulation should be on a stable dose.

22. Creatinine ≤ 1.5 x ULN or Calculated Creatinine clearance ≥ 30mL/min byinstitutional standard measurement

23. For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use two adequate methods ofcontraception, including at least one method with a failure rate of ≥ 1% per year

24. If any Grade ≥1 toxicities occurred in relation to prior treatment, patients musthave recovered to baseline or ≤ Grade 1 unless adverse events are clinicallyinsignificant or stable on supportive medication if needed.

Exclusion Criteria:

1. Prior treatment with cabozantinib for RCC

2. Receipt of any small molecule kinase inhibitor (including investigational) orVEGFtargeted therapy within 2 weeks before the first dose of study treatment o 2-week washout period was selected in order to facilitate rapid enrollment andtreatment of patients given the target population with active brain metastases.

3. Patients requiring whole brain radiotherapy (WBRT).

4. Any prior brain radiotherapy within 28 days prior to enrollment

5. Incomplete healing from prior radiotherapy as determined by the treating radiationoncologist or treating investigator

6. Diagnosis of autoimmune condition that may worsen during immune checkpoint blockade,with the following exceptions: o Diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiringimmunosuppressive treatment are eligible.

7. Any active or suspected autoimmune disease requiring systemic steroids > 10 mg dailyprednisone (or equivalent) or other immunosuppression, except for:

• those not expected to reoccur

• Chronic physiologic replacement of ≤10mg prednisone (or equivalent) fortreatment of adrenal insufficiency

• Steroids required for pre-medication reactions

• Local steroid use is permitted (e.g. intranasal, topical, inhaled, or localsteroid injection, i.e. intra-articular)

8. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures

9. Uncontrolled hypercalcemia (≥ 1.5 mmol/L ionized calcium or Ca ≥ 12 mg/dL orcorrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued useof bisphosphonate therapy or denosumab

10. Participation in an experimental drug study within 28 days of study enrollment

11. Pregnant and lactating women

12. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

13. Significant cardiovascular disease, such as New York Heart Association cardiacdisease (Class II or greater), myocardial infarction within the previous 3 months,unstable arrhythmias, unstable angina, or EF < 50% o Patients with known coronary artery disease, congestive heart failure not meetingthe above criteria must be on a stable medical regimen that is optimized in theopinion of the treating physician, in consultation with a cardiologist ifappropriate.

14. Uncontrolled hypertension (>140 mm Hg systolic or >90 mm Hg diastolic) despiteoptimal antihypertensive treatment

15. QTcF > 500 msec within 28 days before the first dose of study treatment

16. Major surgical procedure within 14 days prior to Cycle 1, Day 1 or anticipation ofneed for a major surgical procedure during the course of the study o Patients must have completed wound healing from major or minor surgery beforefirst dose of study treatment

17. History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1

18. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair orrecent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1

19. Evidence of bleeding diathesis or significant coagulopathy (in the absence oftherapeutic anticoagulation) o Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml)of red blood or other history of significant bleeding within 12 weeks before firstdose of study treatment.

20. Clinical signs or symptoms of gastrointestinal obstruction or requirement forroutine parenteral hydration, parenteral nutrition, or tube feeding

21. Evidence of abdominal free air not explained by paracentesis or recent surgicalprocedure

22. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

23. Concomitant anticoagulation with coumarin agents, direct thrombin inhibitors, factorXa inhibitor betrixaban, or platelet inhibitors. Other anticoagulants are allowed.

24. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscesswithin 6 months before first dose of study treatment. o Complete healing of intra-abdominal abscess must be confirmed before the firstdose of study treatment

25. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation

26. Lesions invading or encasing major blood vessels

27. Uncompensated or symptomatic hypothyroidism

28. History of solid organ or allogeneic stem cell transplant

29. Clinically significant active infection including HIV, Hepatitis B, Hepatitis C,acute COVID-19 infection, or other

• For patients with HIV infection, clinically significant/exclusionary featuresinclude: detectable viral load, CD4+ T cell count <300 cells/microL, or historyof opportunistic infection

• For patients with HBV infection, clinically significant/exclusionary featuresinclude: HBV surface antigen positivity, detectable HBV DNA by polymerase chainreaction (PCR). Patients with prior HBV infection (HBV core Ab positive, HBVDNA undetectable by PCR, HBV surface antigen negative) are eligible for thestudy if they are already stable on entecavir or tenofovir

30. Inability to swallow tablets

31. Previously identified allergy or hypersensitivity to components of the treatment

32. Malignancy that requires anti-cancer directed therapy within the last 3 years.Exceptions include those cancers that are considered cured by local therapy (e.g.Basal cell carcinoma, squamous cell carcinoma, ductal carcinoma in situ of breast,bladder, or cervix) or other cancers that have low malignant potential and do notrequire systemic therapy (e.g. Gleason grade <6 prostate adenocarcinoma)

33. Patients in whom nivolumab treatment is not otherwise feasible (for example, forfinancial reasons)