Everolimus Versus Sunitinib in Non-Clear Cell Renal Cell Carcinoma

The Study Drugs:

Everolimus is designed to stop cells from multiplying. It may also stop the growth of new
blood vessels that help tumor growth, which may cause the tumor cells to die.

Sunitinib is designed to block pathways that control important events (such as the growth of
blood vessels) that are essential for the growth of cancer.

Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the toss of a coin) to 1 of 2 groups.

- If you are assigned to Group 1, you will take 2 everolimus tablets by mouth once every
day.

- If you are assigned to Group 2, you will take sunitinib capsules by mouth every day for
4 weeks, followed by 2 weeks off.

If you have any side effects from any of the drugs, tell the study doctor right away. The
study doctor may then lower the dose or keep the dose level the same.

Every 6 weeks on this study is called a study "cycle."

If the disease gets worse or you have intolerable side effects while you are on study, you
will have the chance to receive the study drug that you did not receive at first. The dosing
and follow-up will be the same as for all participants in that group.

Study Visits:

On Day 1 of every cycle:

- You will have a physical exam, including measurement of your vital signs.

- You will be asked about any drugs or treatments you may be receiving.

- Your performance status will be recorded.

- Blood (about 3 teaspoons) and urine will be collected for routine tests and a fasting
blood sugar test. Blood or urine will also be used for a pregnancy test for women who
are able to have children. If you are in Group 1, you will have an additional 1 teaspoon
of blood drawn to test your cholesterol.

On Day 15 and 29 of Cycle 1:

- Your vital signs and weight will be measured.

- Blood (about 2 teaspoons) will be drawn for routine tests. If you are in Group 1, an
additional 1 teaspoon of blood will be drawn to measure your cholesterol.

The Day 15 and Day 29 tests may be done at your local doctor's office.

On Day 1 of Cycles 2 and 3, and every other cycle after that (Day 1 of Cycle 5, 7, 9 and so
on):

°You will have a CT scan of the chest and a CT scan or MRI of the abdomen to check the status
of the disease.

Every 4 cycles (24 weeks):

°If you are in Group 2, you will have an echocardiogram or MUGA scan to check your heart's
health.

Length of Study:

You may continue taking the study drugs for as long as you are benefiting. You will be taken
off study if the disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

If you have stopped taking the study drug because of intolerable side effects, the treating
physician will make every effort to check the status of the disease before you are taken off
of study.

Long-Term Follow-up:

Once you are no longer on this study, the research staff will check up on you about every 6
months. This update will consist of a phone call or a review of your medical and/or other
records. You will not have any extra tests, procedures, or study visits. If contacted by
phone, the call would only last about 5 minutes.

This is an investigational study. Sunitinib and everolimus are both FDA approved and
commercially available for the treatment of advanced kidney cancer.

Up to 108 patients will be enrolled in this multicenter trial. Up to 108 patients will be
enrolled at MD Anderson.

Inclusion Criteria:

1. Patients must have advanced non-clear cell RCC, which may include but is not limited
to the following subtypes: papillary I or II, chromophobe, collecting duct carcinoma
(CDC), translocation or unclassified. Patients with conventional-type renal cell
carcinoma who have >/= 20% sarcomatoid component in their primary tumor are eligible.
Patients who have sarcomatoid features in FNA or core biopsy of any metastatic site
are eligible, if they have an underlying renal cell carcinoma primary tumor.

2. Patients must have at least one measurable site of disease that has not been
previously irradiated. If the patient has had previous radiation to the marker
lesion(s), there must be evidence of progression since the radiation

3. ECOG performance status 0-1

4. Age >/= 18 years

5. Patients must have adequate organ and marrow function within 14 days prior to study
entry as defined below: a) Hemoglobin >/= 9 g/dl (tx allowed); b) absolute neutrophil
count >/=1,500/microL; c) platelets >/= 100,000/microL; d) total bilirubin mg/dl; e) AST(SGOT) or ALT (SGPT) metastasis, wherein may be patient does not require dialysis)

6. INR and PTT anticoagulation with warfarin is allowed if target INR warfarin or on a stable dose of LMW heparin for > 2 weeks (14 days) at time of
randomization.

7. Fasting serum cholesterol
8. Female patients of childbearing potential (not postmenopausal for at least 12 months
and not surgically sterile) must have a negative serum or urine pregnancy test within
14 days before study entry. Pregnancy test must be repeated if performed > 14 days
before starting study drug.

9. Patients must give written informed consent prior to study entry, in keeping with the
policies of each institution.

10. Patients with a history of major psychiatric illness must be judged (by the treating
physician) able to fully understand the investigational nature of the study and the
risks associated with the therapy.

11. Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected or treated with radiosurgery or Gamma
knife, without recurrence or edema for 3 months (90days).

Exclusion Criteria:

1. No other malignancies within the past 2 years except for adequately treated carcinoma
of the cervix or basal (without recurrence post-surgery or post-radiotherapy) or
squamous cell carcinomas of the skin.

2. No prior systemic therapy for RCC including prior adjuvant therapy or investigational
drug is allowed.

3. Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks (28 days) from enrollment into this study (including
chemotherapy and targeted therapy) are excluded. However, patients are permitted to
receive bisphosphonates. Also, patients who completed palliative radiation therapy
prior to enrollment in this trial are eligible.

4. Patients, who have had a major surgery or significant traumatic injury (injury
requiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of study
drug, patients who have not recovered from the side effects of any major surgery
(defined as requiring general anesthesia) or patients that may require major surgery
during the course of the study.

5. Concomitant treatment with rifampin, St. John's wort, or the cytochrome p450
enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital) or
CYP3A4 inhibitors is not recommended on this study.

6. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as: a) Symptomatic
congestive heart failure of New York heart Association Class III or IV; b) unstable
angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6
months of start of study drug, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease; c) severely impaired lung function as defined
as 02 saturation that is 88% or less at rest on room air

7. (#6 cont'd) d) uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN;
e) active (acute or chronic) or uncontrolled severe infections requiring antibiotic
intervention; f) liver disease such as cirrhosis, chronic active hepatitis or chronic
persistent hepatitis

8. Patients must not have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of sunitinib or everolimus or that
might affect the interpretation of the results of the study or render the subject at
high risk from treatment complications.

9. Concomitant treatment with drugs with dysrhythmic potential (terfenadine, quinidine,
procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and
indapamide) is not recommended.

10. Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

11. Patients should not receive immunization with attenuated live vaccines within one week
(7 days) of study entry or during study period.

12. Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.

13. A known history of HIV sero-positivity.

14. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus and/or sunitinib (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
bowel resection).

15. Patients with an active, bleeding diathesis.

16. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. If barrier contraceptives
are being used, these must be continued throughout the trial by both sexes. Hormonal
contraceptives are not acceptable as a sole method of contraception. (Women of
childbearing potential must have a negative urine or serum pregnancy test within 7
days prior to study entry. Pregnancy test must be repeated if performed > 7 days
before administration of everolimus and sunitinib)