Everolimus (RAD001) For Advanced Renal Cell Carcinoma (RCC) Before Kidney Removal

Everolimus has significantly improved outcomes following prior therapy. This study is a
biomarker driven Phase II trial that will assess the activity of everolimus as first-line
therapy for renal cell carcinoma. Following initial kidney tumor biopsy, everolimus is
administered for 3-5 weeks before cytoreductive nephrectomy and everolimus is then resumed
and continued until tumor progression or intolerable toxicities. Any correlation of tumor
tissue biomarker changes from initial biopsy to nephrectomy specimen with long-term
progression-free survival will be determined. This trial may enable the identification of
factors predictive of significant benefit from everolimus administered as first-line therapy
by employing the neoadjuvant therapy paradigm.

Inclusion Criteria:

- Advanced (metastatic) RCC

- Histology: clear cell, papillary or chromophobe

- 3 out 6 risk factors (by Memorial Sloan Kettering Cancer Center criteria and one
additional criterion: multiple sites of metastasis) or not candidates for or refuse
sunitinib.

- Must have at least one measurable metastatic site according to Response Evaluation
Criteria In Solid Tumors (RECIST) criteria that has not been previously irradiated.

- Must be deemed surgical candidates for cytoreductive nephrectomy by the urologist.

- Age 18 years of age or older

- Eastern Cooperative Oncology Group (EGOG) PS 0-2

- Adequate bone marrow function

- Adequate liver function as shown by:

- Adequate renal function

- Fasting serum cholesterol AND fasting triglycerides within normal limits

- Signed informed consent

Exclusion Criteria:

- Collecting duct, medullary histologies or sarcomatoid differentiation.

- Central Nervous System (CNS) or leptomeningeal metastases.

- Inappropriate candidates for cytoreductive nephrectomy or who have any severe and/or
uncontrolled medical conditions or other conditions that could affect their
participation in the study

- severely impaired lung function

- uncontrolled diabetes

- active (acute or chronic) or uncontrolled severe infections

- liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- Ineligible for cytoreductive nephrectomy

- Current or prior systemic anticancer therapies (including chemotherapy, antibody
based therapy, or investigational drugs)

- Other malignancies within the past 3 years except for localized carcinoma of the
cervix, basal or squamous cell carcinomas of the skin, or localized prostate cancer
with Gleason Score less than 7 treated with radiation or surgery and no evidence of
progression.

- Major surgery (defined as requiring general anesthesia) or significant traumatic
injury within 4 weeks of start of enrollment

- Anticipated major surgery (other than CN) during the course of the study

- A known history of HIV seropositivity

- Hepatitis C seropositivity

- Chronic, systemic treatment with corticosteroids or another immunosuppressive agent.
Topical or inhaled corticosteroids are allowed.

- Immunization with attenuated live vaccines within one week of study entry or during
study period

- Known hypersensitivity to RAD001 (everolimus) or other rapamycins or to its
excipients

- Impairment of gastrointestinal function or gastrointestinal disease

- Active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods.

- History of noncompliance to medical regimens

- Unwilling to or unable to comply with the protocol including mandated biopsies