Phase II Study of Afinitor vs. Sutent in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma

This will be an international (USA, Canada, and UK) open-label, outpatient, multicenter,
randomized study of treatment with RAD001 (everolimus (Afinitor®) or sunitinib (Sutent®) in
subjects with mRCC and non-clear cell histology. Special emphasis is placed on papillary and
chromophobe histologies while sarcomatoid clear cell variants, medullary, and collecting duct
carcinomas will be excluded (see eligibility). Subjects may continue receiving study drugs
until disease progression, unacceptable toxicities, or withdrawal of consent, for a maximum
of 24 months. Continuation of study assigned treatment will be allowed beyond 24 months at
the discretion of the sponsor. Stratification variables will include histology (papillary vs.
chromophobe) and Motzer risk criteria (0, 1-2, and 3). Tumor progression will be assessed
locally and by independent review, in strict accordance with Response Evaluation Criteria in
Solid Tumors (RECIST 1.1) criteria measured every 12 weeks. At the time of progression,
subjects will be taken off study other than simple administrative mortality follow-up.
Primary pathologic samples and plasma/urine angiokine levels at baseline and over time will
be collected and stored centrally for biomarker analysis.

Inclusion Criteria:

1. Histologically confirmed advanced Renal Cell Carcinoma (RCC), with non-clear cell
pathology.

2. RCC tumor tissue available for correlative sciences, from either primary or metastatic
site or both.

3. At the time of screening, at least 4 weeks since prior palliative radiation therapy
and/or major surgery, and resolution of all toxic effects of prior therapy to National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version
4.0) Grade 1.

4. Subject must have radiographic evidence of metastatic disease with at least 1
measurable per RECIST 1.1 criteria (Attachment 1)].

5. Age > 18 years.

6. Adequate laboratory values

7. Karnofsky Performance Status ≥ 60 (Attachment 2).

8. Life expectancy of at least 3 months.

9. Written, signed, dated, and witnessed Institutional Review Board (IRB) or
Institutional Ethics Committee (IEC) approved informed consent form (ICF) before any
screening procedures are performed.

Exclusion Criteria:

1. Subjects with a history of or active central nervous system (CNS) metastases.

2. Prior systemic therapy for RCC, including mTOR and anti-angiogenic therapy,
chemotherapy, biologic or experimental therapy.

3. Subjects with collecting duct, medullary, small cell, oncocytoma, or lymphoma-type
pathology.

4. Subjects receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers.

5. Major surgery, open biopsy, traumatic injury, or radiotherapy within 4 weeks of the
screening visit.

6. Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or
radiation therapy.

7. Presence of a non-healing wound or ulcer.

8. Grade 3 hemorrhage within the past month.

9. Hypertension with systolic blood pressure of >180 mm Hg and/or diastolic pressure >100
mm Hg.

10. Subjects with American Heart Association (AHA) Class 2-4 heart disease or any history
of congestive heart failure with an ejection fraction <50%, or history of unstable
angina, myocardial infarction, coronary artery bypass graft, cerebrovascular accident,
transient ischemic attack, or pulmonary embolism within 6 months of entry.

11. Diabetes mellitus with glycosylated hemoglobin A1c (HbgA1c) > 10% despite therapy.

12. A history of interstitial pneumonitis.

13. Subjects with active autoimmune disorder(s) being treated with immunosuppressive
agents within 4 weeks prior to the screening visit.

14. Subjects receiving immunosuppressive agents and those with chronic
viral/bacterial/fungal illnesses such as human immunodeficiency virus (HIV).

15. Patients who have receive immunization with attenuated live vaccines within one week
of study entry or during study period.

16. Patients with active infection(s), active antimicrobial therapy or serious
intercurrent illness.

17. History of other prior malignancy in past 5 years.

18. Pregnant or nursing women.

19. Major medical/psychiatric illness that, in the investigator's judgment, will
substantially increase the risk associated with the subject's participation in this
study, including inability to absorb oral medications and history of noncompliance to
medical regimens.

20. Known hypersensitivity to any of the components in everolimus or sunitinib product

21. Subjects taking agents that significantly prolong the QTc interval are not eligible.

22. Proteinuria with a spot urine protein/creatinine ratio >2 or 24 hour urine protein >2
grams per 24 hours.

23. Severely impaired lung function as defined as spirometry and Carbon Monoxide Diffusing
Capacity (DLCO) that is 50% of the normal predicted value and/or O2 saturation that is
88% or less at rest on room air.

24. Advanced liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh
class C).