Een fase 1-2 studie van everolimus en lage dosis orale cyclofosfamide bij patiënten met uitgezaaide niercelkanker.

1. Patients with histologically or cytologically 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) ¡À sorafenib);

2. Prior therapy with cytokines (i.e. IL-2, interferon) and/or VEGF-ligand inhibitors (i.e. bevacizumab) is permitted;

3. Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery;

4. Aged 18 years or older;

5. No other current malignant disease, except for basal cell carcinoma of the skin;

6. WHO performance status 0-2;

7. Life expectancy of at least 12 weeks;

8. Adequate hematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, Hb ≥ 6.0 mmol/L;

9. Adequate hepatic function: serum bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 2.5 x ULN (or ≤ 5 times ULN if liver metastases are present);

10. Adequate renal function: calculated creatinine clearance ≥ 50 ml/min;

11. Measurable or evaluable disease as defined by RECIST 1.1;

12. Patients with reproductive potential must use effective contraception. Female patients must have a negative pregnancy test;

13. Signed informed consent;

14. Able to receive oral medication.

1. Patients currently receiving chemotherapy, immunotherapy, or radiotherapy or who have received these <= 4 weeks prior to visit 1. The wash-out period for sunitinib or sorafenib is at least 2 weeks from the first dose of the study medication;

2. Known human immunodeficiency virus (HIV) or other major immunodeficiency;

3. Immunosuppressive agents within 3 weeks of study entry, except for low dose corticosteroids when given for disorders such as rheumatoid arthritis, asthma, or adrenal insufficiency. Topical or inhaled corticosteroids are permitted;

4. Patients with an active bleeding diathesis or on 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. Patients with treated CNS metastases, who are neurologically stable and off of corticosteroids for more than 2 months prior to study entry are eligible to enter the study;

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 who were of childbearing potential and who were not utilizing an effective contraceptive method. A woman of childbearing potential is defined as a female who is biologically capable of becoming pregnant. 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 HCV infection (for hepatitis screening indications see section 3.3);

15. Drug or alcohol abuse;

16. Any other major illness that, in the investigator's judgment, substantially increased the risk associated with the subject's participation in the study.