Study of Everolimus and Low-dose Cyclophosphamide in Patients With Metastatic Renal Cell Cancer

Inclusion Criteria:

• 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) ± sorafenib).
• Prior therapy with cytokines (i.e. IL-2, interferon) and/or VEGF-ligand inhibitors (i.e. bevacizumab) is permitted.
• Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery.
• Aged 18 years or older.
• No other current malignant disease, except for basal cell carcinoma of the skin.
• WHO performance status 0-2.
• Life expectancy of at least 12 weeks.
• Adequate hematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, Hb ≥ 6.0 mmol/L.
• 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).
• Adequate renal function: calculated creatinine clearance ≥ 50 ml/min.
• Measurable or evaluable disease as defined by RECIST 1.1.
• Patients with reproductive potential must use effective contraception. Female patients must have a negative pregnancy test.
• Signed informed consent.
• Able to receive oral medication.

Exclusion Criteria:

• 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.
• Known human immunodeficiency virus (HIV) or other major immunodeficiency.
• 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.
• Patients with an active bleeding diathesis or on oral anti-vitamin K medication.
• 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.
• Active infection or serious intercurrent illness, except asymptomatic bacteriuria.
• Presence of unstable angina, recent myocardial infarction (within the previous 6 months), or use of ongoing maintenance therapy for life-threatening ventricular arrhythmia.
• Macroscopic hematuria
• Prior therapy with mTOR inhibitors. 10. Known hypersensitivity to everolimus or other rapamycins (sirolimus/temsirolimus) or to its excipients.
• 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).
• Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient's compliance.
• Uncontrolled diabetes as defined by fasting serum glucose > 2 ULN, severely impaired lung function.
• Cirrhosis/chronic active hepatitis/chronic persistent hepatitis, history of HCV infection (for hepatitis screening indications see section 3.3).
• Drug or alcohol abuse.
• Any other major illness that, in the investigator's judgment, substantially increased the risk associated with the subject's participation in the study.