S0931, Everolimus in Treating Patients With Kidney Cancer Who Have Undergone Surgery

OBJECTIVES:

Primary

- to compare recurrence-free survival in renal carcinoma patients randomly assigned to 54
weeks of everolimus versus 54 weeks of placebo after nephrectomy or partial nephrectomy.

Secondary

- To compare the overall survival of patients treated with everolimus vs placebo.

- To compare qualitative and quantitative toxicity between the two study arms.

- To bank tissue and biologic specimens for future study of molecular biomarkers relevant
to the AKT/mTOR and other pathways implicated in the pathogenesis of renal carcinoma and
to investigate their potential predictive and prognostic value.

- To bank blood specimens for the future study of the relationship between steady-state
trough levels of everolimus and relevant side effects (lymphopenia, infection,
hyperglycemia, hypercholesterolemia, hypertriglyceridemia) in patients treated on this
study with everolimus.

OUTLINE: This is a multicenter study.

Patients are stratified according to pathologic stage (intermediate high-risk vs very
high-risk), histologic subtype (clear cell vs non-clear cell), and performance status (0 vs
1). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral everolimus once daily on days 1-42. Treatment repeats every
6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

- Arm II: Patients receive oral placebo once daily on days 1-42. Treatment repeats every 6
weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

Archived tumor tissue, plasma, and whole blood samples may be collected periodically for
biomarker analysis and other translational studies.

After completion of study treatment, patients are followed up every 6 months for 2 years and
then annually for 8 years.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed renal cell carcinoma

- Clear cell or non-clear cell allowed

- No disease of the collecting duct or medullary carcinoma

- Considered pathologically either intermediate high-risk or very high-risk disease

- No history of distant metastases

- Patients with microvascular invasion of the renal vein of any grade or stage (as
long as M0) are eligible

- Have undergone a full surgical resection (radical nephrectomy or partial nephrectomy)
including removal of all clinically positive nodes

- Surgical margins must be negative

- Patients with positive renal vein margins are eligible unless there is
invasion of the renal vein wall at the margin (provided no other margins are
positive)

- Patients must be registered within 84 days after the date of the first surgical
resection of the first tumor

- No evidence of residual or metastatic renal cell cancer on CT scan of the chest,
abdomen, and pelvis (all with oral and IV contrast) performed after nephrectomy and
within 28 days before registration

- MRI scans of the abdomen and pelvis with gadolinium and a non-contrast CT scan of
the chest may be substituted if the patient is not able to have CT scans with IV
contrast

PATIENT CHARACTERISTICS:

- Zubrod performance status 0-1

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Serum creatinine ≤ 2.0 times upper limit of normal (ULN) OR calculated creatinine
clearance ≥ 30 mL/min

- Bilirubin ≤ 1.5 times ULN

- SGOT and SGPT ≤ 2.5 times ULN

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for up to 8 weeks after
completion of study treatment

- Able to take oral medications

- Patients must not have any of the following:

- NYHA class III-IV cardiac disease (i.e., patients with cardiac disease resulting
in marked limitation of physical activity or resulting in inability to carry on
any physical activity without discomfort)

- Unstable angina pectoris

- Myocardial infarction within the past 6 months

- Serious uncontrolled cardiac arrhythmia

- Patients must NOT have liver disease such as cirrhosis or severe hepatic impairment
(Child-Pugh Class C)

- HBV and HCV testing are required at screening for all patients with a positive medical
history based on risk factors and/or confirmation of prior HBV/HCV infection

- Must be able to take oral medications

- No impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)

- No known history of HIV seropositivity

- No known uncontrolled, underlying pulmonary disease (spirometry and DLCO ≤ 50% of
predicted OR oxygen saturation ≤ 88% at rest on room air)

- No uncontrolled hyperlipidemia (fasting serum cholesterol > 300 mg/dL AND fasting
triglycerides > 2.5 times ULN) obtained within 28 days prior to registration

- Optimal lipid control must be achieved before registration and monitored during
protocol treatment

- No uncontrolled diabetes mellitus (defined by fasting serum glucose > 1.5 times ULN)
obtained within 28 days prior to registration.

- Optimal glucose control must be achieved before registration and monitored during
protocol treatment

- No prior malignancies except for any of the following:

- Adequately treated basal cell or squamous cell skin cancer

- In situ cervical cancer

- Adequately treated stage I or stage II cancer from which the patient is currently
in complete remission

- Any other cancer from which the patient has been disease-free for 5 years

- No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus)
or to their excipients

- No contraindications to receiving either IV iodine-based contrast or gadolinium

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Patients must have recovered from any surgery-related complications

- No prior anticancer therapy for renal cell carcinoma including systemic therapy in the
adjuvant or neoadjuvant setting, immunotherapy, investigational therapy, surgical
metastasectomy, or radiotherapy

- More than 14 days since prior and no concurrent strong CYP3A4 inhibitors (i.e.,
ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone,
nelfinavir, or ritonavir) or strong CYP3A4 inducers (i.e., phenytoin, rifampin, or
rifabutin)

- More than 7 days since prior and no concurrent live vaccines

- No other concurrent anticancer agents including investigational agents

- No concurrent chronic treatment with systemic steroids or another immunosuppressive
agent

- Topical or inhaled corticosteroids are allowed