Inclusion criteria to be eligible for the trial
1. Signed informed consent.
2. Age ≥ 18 years.
3. Histological or cytological confirmed clear-cell mRCC with progressive disease and not amenable to, or progressive on, or within 6 months of stopping treatment with a VEGF receptor tyrosine kinase inhibitor (sunitinib (or pazopanib) ± sorafenib).
4. No other current malignant disease, except for basal cell carcinoma of the skin.
5. WHO performance status 0-2.
6. Life expectancy of at least 12 weeks.
7. Adequate hematologic function: ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, Hb ≥ 6.0 mmol/L.
8. Adequate hepatic function: serum bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 2.5 × ULN (or ≤ 5 times ULN if liver metastases are present).
9. Adequate renal function: calculated creatinine clearance ≥ 50 ml/min.
10. Measurable or evaluable disease as defined by RECIST 1.1.
11. Patients with reproductive potential must use effective contraception, negative pregnancy test for female patients.
12. Able to receive oral medication.
13. Prior therapy with cytokines (i.e. IL-2, interferon) and/or VEGF-ligand inhibitors (i.e. bevacizumab) is permitted.
14. Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery.
1. Currently receiving chemotherapy, immunotherapy, or radiotherapy, or having received either one of these ≤ 4 weeks prior to visit 1. The wash-out period for sunitinib or sorafenib is at least 2 weeks.
2. Known human immunodeficiency virus (HIV) or other major immunodeficiency.
3. Treatment with immunosuppressive agents within 3 weeks of study entry, except for low dose corticosteroids.
4. Active bleeding diathesis or oral anti-vitamin K medication.
5. Patients with untreated CNS metastases with clinical symptoms or who have received treatment for CNS metastases within 2 months of study entry.
6. Active infection or serious intercurrent illness, except asymptomatic bacteriuria.
7. Presence of unstable angina, recent myocardial infarction (within the previous 6 months), or use of ongoing maintenance therapy for life-threatening ventricular arrhythmia.
8. Macroscopic hematuria.
9. Prior therapy with mTOR inhibitors.
10. Known hypersensitivity to everolimus or other rapamycins (sirolimus/temsirolimus) or to its excipients.
11. Pregnant or nursing women or women of childbearing potential not utilizing an effective contraceptive method. Men with partners of childbearing potential not using an effective method of contraception. (Use of effective contraceptives must continue for 3 months after the last dose of everolimus).
12. Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient's compliance.
13. Uncontrolled diabetes as defined by fasting serum glucose > 2 ULN, severely impaired lung function.
14. Cirrhosis/chronic active hepatitis/chronic persistent hepatitis, history of hepatitis B or C virus infection.
15. Drug or alcohol abuse.
16. Any other major illness that, in the investigator's judgment, substantially increases the risk associated with the subject's participation in the study.