Biomarkers Before and After Nephrectomy of Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus (NEORAD)

Inclusion Criteria:

• Advanced RCC or a resectable renal tumor and at least one measurable inoperable metastasis (at least 1 cm), in whom anti-angiogenic therapy is indicated
• Patients without target lesions, with bone metastasis
• Histologically confirmed clear cells RCC and possibility of adequate tumor sampling prior to treatment
• No prior systemic treatment for RCC
• Male or female, at least 18 years
• PS ECOG 0-1
• Life expectancy at least 3 months

• Adequate organ function with the following criteria:

  • Total serum bilirubin equal or less than 2 x ULN (Gilbert's disease exempted)
  • Serum transaminases and alkaline phosphatases equal or less than 2.5 x ULN, or in case of liver or bone metastasis equal or less than 5x ULN
  • Serum creatinine equal or less than 2 x ULN, creatinine clearance at least 50 ml/min
  • Absolute neutrophil count (ANC) at least 1500/mm3
  • Platelets at least 100,000/mm3
  • Hemoglobin at least 10.0 g/dL
  • INR equal or less than 1.7 or prothrombin time (PT) equal or less than 6 sec
  • Blood glucose less than 1.5x ULN
  • Fasting cholesterol equal or less than 5 mmol/L, triglycerides equal or less than 200 mg/dl,
• Negative pregnancy test within 7 days prior to enrollment
• Signed and dated IRB/ICE-approved informed consent form
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
• Patient covered by the national health system

Exclusion Criteria:

• Previous nephrectomy
• Histology: any histologic type different than ccRCC
• Treatment in a clinical trial in the last 30 days
• Previous treatment with everolimus or other mTOR-inhibitors and anti-angiogenic drugs
• Any of the following within 12 months prior to treatment initiation: severe/unstable angina, myocardial infarction, coronary artery bypass graft, symptomatic congestive heart failure, ischemic or hemorrhagic stroke including transient ischemic attack, abnormal lung function.
• Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg, despite optimal medical treatment
• Abnormal ECG (Clinically significant)
• Treatment with vitamin K antagonists. Ongoing treatment with therapeutic doses of coumarin derivative anticoagulants (e.g. warfarin) or treatment within the 2 weeks before the first day of everolimus administration. Prophylaxis with low dose warfarin for deep vein thrombosis is permitted (up to 2 mg/day). Low molecular weight heparin is allowed.

• Brain metastasis. (Brain scan or MRI is mandatory). Note: Previous treated brain metastasis (surgery ± radiotherapy, radiotherapy, radiosurgery or gammaknife) and satisfying the following three criteria are allowed:

  • Asymptomatic;
  • No evidence of any active brain metastasis 3 months prior inclusion;
  • No necessity of corticoid or antiepileptic treatment.
• Pregnancy or breastfeeding.
• Any second malignancy within the last 3 years with the exception of basal cell carcinoma, in situ cervical cancer and pT1/a bladder cancer with no evidence of recurrent disease for 12 months.

• Clinically significant gastrointestinal abnormalities including but not limited to:

  • Malabsorption syndrome
  • Major resection of the stomach or small bowel that could affect the absorption of the study drug
  • Active peptic ulcer disease
  • Inflammatory bowel disease
  • Ulcerative colitis or other gastrointestinal conditions with increased risk of perforation
  • History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment
  • Hepatitis B/C
• Hypersensitivity to everolimus or any excipient of everolimus.
• Any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study.