A PHASE 3, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, PARALLEL-ARM
STUDY OF AVELUMAb (MSB0010718C) IN COMBINATION WITH AXITINIB
(INLYTA®) VERSUS SUNITINIB (SUTENT®) ) MONOTHERAPY IN THE
FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED RENAL CELL
CARCINOMA

1. Diagnosis:
Histologically or cytologically confirmed advanced or metastatic renal cell
carcinoma with a clear cell component. A formalin-fixed, paraffin-embedded
(FFPE) tumor tissue block from a de novo tumor biopsy during screening will be
required. Alternatively, a recently obtained archival FFPE tumor tissue block
(not cut slides) from a primary tumor resection or biopsy can be provided. If
an FFPE tissue block cannot be provided as per documented regulations then 15
unstained slides will be acceptable. Availability of an archival FFPE tumor
tissue block from primary diagnosis specimen (or 15 unstained slides). At least
one measurable lesion defined by RECIST that has not been previously irradiated;
2. Evidence of a personally signed and dated informed consent document
indicating that
the patient (or a legally acceptable representative, as allowed by local
guideline/practice) has been informed of all pertinent aspects of the study.
3. Patients who are willing and able to comply with scheduled visits, treatment
plans,
laboratory tests, and other study procedures.
4. Age *18 years (*20 years in Japan).
5. Estimated life expectancy of at least 3 months.
6. ECOG PS 0 or 1.
7. No evidence of uncontrolled hypertension as documented by 2 baseline blood
pressure (BP) readings taken at least 1 hour apart. The baseline systolic BP
readings
must be *140 mm Hg, and the baseline diastolic BP readings must be *90 mm Hg.
Use of antihypertensive medications to control BP is allowed.
8. Adequate bone marrow function, including:
a. Absolute Neutrophil Count (ANC) *1,500/mm3 or *1.5 x 109/L;
b. Platelets *100,000/mm3 or *100 x 109/L;
c. Hemoglobin *9 g/dL (may have been transfused).
9. Adequate renal function, including:
a. Estimated creatinine clearance >=50 mL/min as calculated using the
Cockcroft-Gault (CG) equation.
b. Urinary protein <2+ by urine dipstick. If dipstick is *2+, then 24-hour
urinary
protein <2 g per 24 hours.
10. Adequate liver function, including:
a. Total serum bilirubin *1.5 x ULN;
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
*2.5 x ULN.
11. Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) as
assessed
by either multigated acquisition (MUGA) scan or echocardiogram (ECHO).
12. Serum pregnancy test (for females of childbearing potential) negative at
screening.
13. Male patients able to father children and female patients of childbearing
potential and
at risk for pregnancy must agree to use 2 highly effective methods of
contraception
(see Section 4.3.1) throughout the study and for at least 90 days after the
last dose of
assigned treatment.

1. The following prior therapies are excluded:
* Prior systemic therapy directed at advanced or metastatic RCC.
* Prior adjuvant or neoadjuvant therapy for RCC if disease progression or
relapse
has occurred during or within 12 months after the last dose of treatment,
immunotherapy, or any other antibody or drug specifically targeting T-cell
co-stimulation or immune checkpoint pathways.
* Prior therapy with axitinib and/or sunitinib as well as any prior therapies
with
other VEGF pathway inhibitors.
2. Participation in other therapeutic studies within 4 weeks prior to
randomization.
3. Patients with newley diagnosed brainmetastases or patients with known
symptomatic brain metastases requiring steroids.
4. Major surgery within 4 weeks or major radiation therapy within 2 weeks prior
to study entry
5. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1;
6. Current or prior use of immunosuppressive medication within 7 days prior to
study entry.
8. Known prior or suspected hypersensitivity to study drugs or any component in
their
formulations.
9. Diagnosis of any other malignancy within 5 years prior to randomization,
except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in
situ of the
breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on
surveillance.
10. Active autoimmune disease that might deteriorate when receiving an
immunostimulatory agents.
11. Gastrointestinal :
12. Active infection requiring systemic therapy.
13. Diagnosis of prior immunodeficiency or organ transplant requiring
immunosuppressive therapy
Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness.
14. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating
acute or
chronic infection.
15. Vaccination within 4 weeks of the first dose of avelumab and while on trial
is
prohibited except for administration of inactivated vaccines (for example,
inactivated
influenza vaccines).
16. Requirement of anticoagulant therapy with oral vitamin K antagonists.
17. Evidence of inadequate wound healing.
18. Grade 3 hemorrhage within 4 weeks of patient randomization.
19. Any of the following in the previous 12 months: myocardial infarction,
severe/unstable
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart
failure, LVEF less than LLN, clinically significant pericardial effusion,
cerebrovascular accident, transient ischemic attack
20. Any of the following in the previous 6 months prior to study entry:
deep vein thrombosis or symptomatic pulmonary embolism;
21. Evidence of tumor involvement of the myocardium or pericardium or
tumor thrombus extending to the heart;
22. Ongoing cardiac dysrhythmias of NCI CTCAE Grade >= 2 or
prolongation of the QTc interval to > 500 msec;
23. Current use or anticipated need for treatment with drugs or foods that are
known
strong CYP3A4/5 inhibitors, including their administration within 10 days prior
to
study entry
24. Current use or anticipated need for drugs that are known strong CYP3A4/5
inducers,
including their administration within 10 days prior to patient randomization.
25. Patients who are investigational site staff members directly involved in
the conduct of
the trial and their family members, site staff members otherwise supervised by
the
investigator, or patients who are Pfizer employees directly involved in the
conduct of
the study.
26. Pregnant female patients; breastfeeding female patients.
27. Other severe acute or chronic medical conditions including colitis,
inflammatory
bowel disease, uncontrolled asthma, and pneumonitis or psychiatric condition
including recent (within the past year) or active suicidal ideation or behavior
or laboratory abnormality that may
increase the risk associated with study participation or investigational product
administration or may interfere with the interpretation of study results and,
in the judgment of the investigator, would make the patient inappropriate for
entry into this study.