This study will evaluate everolimus as second-line therapy in patients with metastatic renal cell carcinoma. Each patient will be enrolled and stratified in one of three cohorts based upon their first-line therapy: 1) prior cytokines, 2) prior sunitinib, or 3) prior anti-VEGF therapy other than sunitinib.

Inclusion Criteria:

1. Age ≥ 18 years old.

2. Patients with advanced renal cell carcinoma of a histological or cytological confirmation of clear cell (or with a component of clear cell) renal carcinoma that have previously progressed on or were intolerant to first-line therapy with sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, or cytokine therapy.

3. Patients must have had prior nephrectomy (partial or total).

4. Patients with at least one measurable lesion at baseline as per the RECIST 1.0 criteria. If skin lesions are reported as target lesions, they should be documented (at baseline and at every physical exam) using color photography and a measuring device (such as a caliper) in clear focus to allow the size of the lesion(s) to be determined from the photograph.

5. Patients with a Karnofsky Performance Status ≥ 70%.

6. Adequate bone marrow function as shown by:

   1. ANC ≥ 1.5 x 109/L,
   2. Platelets ≥ 100 x 109/L,
   3. Hemoglobin >9 g/dL

7. Adequate liver function as shown by:

   1. Serum bilirubin ≤ 1.5 x ULN,
   2. ALT and AST ≤ 2.5 x ULN. Patients with known liver metastases may enroll if their AST and ALT ≤ 5 x ULN,
   3. INR < 1.3 (INR < 3 in patients treated with anticoagulants)

8. Adequate renal function: serum creatinine ≤ 2.0 x ULN.

9. Fasting serum cholesterol ≤300 mg/dl OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN.

10. Written informed consent obtained before any trial related activity and according to local guidelines.

Exclusion Criteria:

1. Patients with brain metastases.

2. Patients within 4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal or intrapelvic), open biopsy, or significant traumatic injury to avoid wound healing complications.

   Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry.

3. Patients in anticipation of the need for major surgical procedure during the course of the study.

4. Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed up to 2 weeks prior to study treatment start).

5. Patients with a serious non-healing wound, ulcer, or bone fracture.

6. Patients with a history of seizure(s) not controlled with standard medical therapy.

7. Patients who have received more than one prior treatment regimen for metastatic renalcell carcinoma

8. Patients who have received adjuvant therapy for RCC

9. Patients who have previously received systemic mTOR inhibitors (eg, sirolimus, temsirolimus, everolimus)

10. Patients with a known hypersensitivity to everolimus or other rapamycins (eg, sirolimus, temsirolimus) or to its excipients.

11. History or clinical evidence of central nervous system (CNS) metastases.

12. Clinically significant gastrointestinal abnormalities including, but not limited to:

    1. Malabsorption syndrome:
    2. Major resection of the stomach or small bowel that could affect the absorption of study drug
    3. Active peptic ulcer disease
    4. Inflammatory bowel disease:

    i. Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation ii. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.

13. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required.

14. Active bleeding diathesis

15. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 2.0 x ULN.

16. Patients who have any severe and/or uncontrolled medical conditions such as:

    1. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction

       ≤ 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia,

    2. active or uncontrolled severe infection,

    3. history of invasive fungal infections,

    4. severe hepatic impairment (Child-Pugh class C),

    5. severely impaired lung function

17. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA) ≤ 6 months before start of study treatment.

18. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

19. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix or breast, and localized cancer of the bladder (T1) and prostate (T1 - T2).

20. Female patients who are pregnant or nursing (lactating).

21. Adults of reproductive potential who are not using effective birth control methods.

    Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in female patients. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug.

22. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start. This should not include sunitinib, sorafenib, axitinib, pazopanib and cytokines.

23. Patients unwilling or unable to comply with the protocol.