Neoadjuvant AXITINIB plus AVELUMAB for patients with localized RCC and a moderate to high risk of recurrence

Prior treatment

• Treatment with any of the following anti-cancer therapies:  chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of axitinib or avelumab
• Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment
• Prior organ transplantation, including allogeneic stem cell transplantation
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
• Known alcohol or drug abuse
• Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:  Malabsorption syndrome  Major resection of the stomach or small bowel.
• Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery).

Other illness

• Evidence of active bleeding or bleeding diathesis.
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures.
• Significant acute or chronic infections including, among others: Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive)
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
• Metastatic disease, M1
• All other significant diseases (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment
• Any psychiatric condition that would prohibit the understanding or rendering of informed consent
• History of any one or more of the following cardiovascular conditions within the past 6 months:  Cardiac angioplasty or stenting  Myocardial infarction  Unstable angina  Coronary artery bypass graft surgery  Symptomatic peripheral vascular disease  Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
• Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Lab values

• Corrected QT interval (QTc) > 480 msecs

Other

• Renal tumors of low risk
• Pregnancy or lactation
• Non-clear cell histology at biopsy

• Male or female patients age ≥ 18 years
• Highly effective contraception for both male and female subjects if the risk of conception exists.
• Signed and written informed consent
• Histologically confirmed diagnosis of non-metastatic clear-cell renal cell carcinoma of intermediate to high risk with completely resectable primary tumours. For the purpose of this study intermediate to high risk will be based on clinical TNM and biopsy nuclear grade since the full pathological specimen is not available. These are: • cT1b-cT2a grade 4 cN0 cM0 • cT2b grade 3 cN0 cM0 • cT3a grade 3-4 cN0 cM0 • cT3b-cT4 any grade cN0 cM0 • cT any cN1 (fully resectable) cM0
• World Health Organization (WHO) performance status of 0-1.
• Adequate coagulation function
• Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 5,6 mmol/L (may have been transfused)
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN for all subjects
• Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
• Negative serum pregnancy test at screening for women of childbearing potential