Lenvatinib With Everolimus Versus Cabozantinib for Second-Line or Third-Line Treatment of Metastatic Renal Cell Cancer

Inclusion criteria:

1. Patients with histologically or cytologically confirmed metastatic/advanced clearcell RCC, or RCC with a clear cell component, who have received 1 or 2 prior linesof systemic treatment in the advanced or metastatic setting, including a PD-1/PD-L1checkpoint inhibitor.

2. Patients must have previously progressed on or after treatment (at any point aftercompleting prior therapy) with a PD-1/PD-L1-containing regimen. Patients whoexperienced an immune-mediated adverse event related to their PD-1/PD-L1containing-regimen and cannot receive additional PD-1/PD-L1 checkpoint inhibitor arepermitted, without evidence of progression, if the treating physician intends tochange treatment per standard care.

3. Patients must have at least one measurable site of disease per RECIST version 1.1.This is defined as a lesion that can be accurately measured in at least onedimension (longest diameter to be recorded). For non-lymph node tumor lesions, theymust be a minimum size of

≥ 10 mm. For malignant lymph node lesions, they must be at least ≥ 15 mm in shortaxis with conventional techniques or ≥ 10 mm with more sensitive techniques such asMRI or spiral CT scan. If the patient has had previous radiation to the markerlesion(s), there must be evidence of progression since the radiation.

4. ECOG performance status ≤ 2

5. Age ≥ 18 years Patients must have adequate organ and marrow function prior to studyentry as defined below: Hemoglobina ≥9 g/dl (treatment allowed) Absolute neutrophilcount ≥1,000/µL Platelets ≥75,000/µL Total bilirubinb ≤1.5 mg/dL AST(SGOT) or ALT (SGPT) ≤2.5 X institutional ULN, except in known hepatic metastasis, wherein may be < 5 x ULN Serum CreatinineC ≤1.5 x ULN (as long as patient does not requiredialysis) aMay receive transfusion b For patients with Gilbert's disease, totalbilirubin should ≤ 3 mg/dL (≤ 51.3 µmol/L). b If creatinine is not <1.5×ULN, thencalculate by Cockcroft-Gault methods or local institutional standard and CrCl mustbe ≥30 mL/kg/1.73 m2

6. INR and PT ≤ 1.5 x ULN prior to study entry. Therapeutic anticoagulation is permitted if: on a stable dose of low molecular weight heparin (LMWH) for > 2 weeks (14 days) at the time of enrollment or on a direct oral anticoagulant (DOAC) for > 2 weeks at time ofenrollment.

7. Female patients of childbearing potential (not postmenopausal for at least 12 months and not surgically sterile) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before study entry. Pregnancy test must be repeated if performed > 14 days before starting study drug. 9. Women must not be breastfeeding. 10. Patients with a history of major psychiatric illness must be judged (by the treating physician) able to fully understand the investigational nature of the study and the risks associated with the therapy. 11. Patients with treated/stable brain metastases are allowed on protocol if they had brain metastases that received CNS-directed therapy, such as surgery or treatment with radiosurgery or Gamma knife, without recurrence for at least 1 month (4 weeks).

Exclusion criteria:

1. Prior receipt of lenvatinib, a c-MET inhibitor, such as cabozantinib orsitravatinib, or an mTOR inhibitor, such as everolimus or temsirolimus.

2. Patients must not have any other malignancies within the past 3 years except for insitu carcinoma of any site, adequately treated (without recurrence post-resection orpostradiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas ofthe skin, or active non-threatening second malignancy that would not, in theinvestigator's opinion, potentially interfere with the patient's ability toparticipate and/or complete this trial. Examples include but are not limited to:urothelial cancer grade Ta/T1 or adenocarcinoma of the prostate treated with activesurveillance.

3. Patients currently receiving anticancer therapies or who have received anticancertherapies within 2 weeks (14 days) from enrollment into this study (includingchemotherapy and targeted therapy) are excluded. Also, patients who have completedpalliative radiation therapy more than 14 days prior to the first dose of lenvatinibplus everolimus or cabozantinib are eligible.

4. Patients who had a major surgery or significant traumatic injury (injury requiring > 28 days to heal) within 28 days of start of study drug, patients who have notrecovered from the side effects of any major surgery (defined as requiring generalanesthesia), or patients that are expected to require major surgery during thecourse of the study.

5. Active inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

6. Immunocompromising conditions, as follows:

7. Known acute or chronic human immunodeficiency virus (HIV) infection with CD4+Tcell count < 350 cells/µL. Patients with a history of an AIDS-defininginfection can be included if their CD4+ T cell count > 350 cells/µL and havenot had an AIDS-defining infection within prior 12 months. If patients are onantiretroviral therapy (ART), it must be started at least 4 weeks prior totrial enrollment and the HIV viral load should be < 400 copies/mL. Medicationinteractions with ART should be screened prior to enrollment.

8. History of primary immunodeficiency

9. History or allogeneic transplant

10. Any underlying medical condition, which in the opinion of the Investigator, willmake the administration ofstudy drug hazardous or obscure the interpretation ofadverse events, such as a condition associated with frequent diarrhea, uncontrollednausea, vomiting, malabsorption syndrome or small bowel resection that maysignificantly alter the absorption of lenvatinib, everolimus, or cabozantinib.

11. Patients receiving any concomitant systemic therapy for renal cell cancer areexcluded.

12. Patients must not be scheduled to receive another experimental drug while onthisstudy.

13. Patients who have any severe and/or uncontrolled medical conditions or otherconditions that could affect their participation in the study such as:

14. Symptomatic congestive heart failure of New York Heart Association Class IIIorIV

15. Unstable angina pectoris, symptomatic congestive heart failure, myocardialinfarction within 6 months of start of study drug, serious uncontrolled cardiacarrhythmia, or any other clinically significant cardiac disease

16. Severely impaired lung function as defined as 02 saturation that is 88% or lessat rest on room air

17. Uncontrolled diabetes as defined by a hemoglobin A1C ≥ 9%

18. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection andwithout improvement) despite appropriate antibiotics or other treatment.

19. Established liver disease,such as cirrhosis or chronic active viral hepatitis,as defined here.For hepatitis B virus (HBV), a positive test using HBV surface antigen (HBsAg)test. For hepatitis C virus (HCV), patients with a positive HCV antibody testand HCV RNA positive are excluded. If a patient is receiving HCV curativetreatment, they must complete therapy and have HCV RNA below level ofdetection. For patients with a history of HCV infection, they are eligible ifthey have completed curative therapy and have HCV viral load below the levelofdetection.

20. Uncontrolled blood pressure (systolic blood pressure > 140 mmHg or diastolicblood pressure > 90 mmHg) in spite of optimized regimen of anti-hypertensiveregimens.

21. Subjects having > 1+ proteinuria on urine dipstick testing unless a spot urineprotein to creatinine ratio is ≤ 2 mg/mg

22. Patients must not have history of other diseases, metabolic dysfunction, physicalexamination finding, or clinical laboratory finding giving reasonable suspicion of adisease or condition that contraindicates the use of lenvatinib, everolimus, orcabozantinib or that might affect the interpretation of the results of the study orrender the subject at high risk from treatment complications.

23. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. Thedegree of tumor invasion/infiltration of blood vessels should be considered becauseof the risk of severe hemorrhage associated with tumor shrinkage/necrosis followinglenvatinib treatment.

24. Any patients who cannot be compliant with the appointments required in this protocolmust not be enrolled in this study.

25. Severe hypersensitivity (≥ grade 3) to lenvatinib and/or any of its excipients.

26. Patients with left ventricular ejection fraction < 40%