The goal of this clinical research study is to compare pazopanib to temsirolimus in the treatment of advanced clear-cell renal cell carcinoma. The safety of each drug will also be studied.

Pazopanib is designed to block the growth of blood vessels that supply nutrients needed for tumor growth. This may prevent or slow the growth of cancer cells.

Temsirolimus is designed to block the growth of cancer cells, which may cause cancer cells to die.

This is an investigational study. Pazopanib and temsirolimus are both FDA approved and commercially available for the treatment of kidney cancer. It is investigational to compare the 2 drugs.

Up to 90 patients will be enrolled in this study. All will be enrolled at MD Anderson.

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 flip of a coin) to 1 of 2 study groups. You will have an equal chance of being assigned to either group.

• If you are assigned to Group 1, you will take pazopanib by mouth 1 time every day at about the same time each day on an empty stomach (at least 1 hour before or 2 hours after a meal).
• If you are assigned to Group 2, you will receive temsirolimus by vein 1 time every week over 30-60 minutes. About 30 minutes before you receive each dose of temsirolimus, you will receive Benadryl (diphenhydramine) by vein over 1-2 minutes to help lower the risk of side effects.

If you are assigned to Group 1, do not crush tablets and do not repeat missed doses if it is less than 12 hours until your next scheduled dose. You will be given a pill diary to record when you take each dose. You will return the diary to the study doctor at each study visit.

If you have any side effects, you should tell the study doctor right away. If the study doctor thinks it is in your best interest, your dose may be lowered.

If the disease gets worse while you are on study, you will have the option to change to the study group you were not originally assigned to and take the other study drug. The study drug dosing and study visit schedule will be the same, and the study doctor will discuss any important details with you at the time you change study groups.

Study Visits:

Every 4 weeks on this study is called a study cycle.

Every week during Cycle 1 (Group 1 only), your blood pressure will be checked (either at home, at the clinic, or by your local doctor). If you are checking your own blood pressure at home, you will need to write down your blood pressure in a blood pressure diary each time you check it and bring the diary with you to each clinic visit.

Every 2 weeks for the first 2 cycles (Group 1 only) , blood (about 3 tablespoons) will be drawn for routine tests.

Every week (Group 2 only), blood (about 1 tablespoon) will be drawn for routine tests.

Every cycle (Group 2 only) OR Every other cycle (Group 1 only):

• You will have a physical exam, including measurement of your weight and vital signs.
• You will be asked about any drugs or treatments you may be receiving.
• You will be asked about any side effects you may have had.
• Blood (about 3 tablespoons) will be collected for routine tests.

On Day 1 of Cycle 2, Day 1 of Cycle 4, and every 4 cycles after that (Group 1 only), you will have an ECG to check your heart function.

If you are in Group 2 only, on Day 1 of Cycles 2, 3, and every other cycle after that (Cycles 5, 7, 9, and so on), blood (about 3 tablespoons) will be drawn for routine tests. You will be asked to fast (eat nothing and drink only water) for at least 8 hours before those blood draws.

Every 2 cycles:

• You will have the same imaging scans that you had at screening. After 1 year on treatment, these imaging scans may only be done every 3 cycles (Cycles 5, 8, 11, and so on).
• You will fill out the quality-of-life questionnaires.
• Blood (about 2 teaspoons) will be drawn for tests to check your thyroid function (Group 1 only).
• Urine will be collected for routine tests.

Every 4 cycles, you will have an ECG (Group 2 only).

Every 6 cycles, you will have an ECHO or MUGA scan to check your heart function.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take a study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

End-of-Treatment Follow- up:

About 30 days after you stop treatment, during a clinic visit or by phone, you will be asked about any drugs or treatments you may be receiving and any side effects you may have had.

Long-Term Follow-up:

After you stop taking the study drug, the study staff will check up on you to ask how you are doing about every 3 months from then on. The study staff will collect the information they need either from your medical records or by calling you. If you are contacted by phone, the call should only last about 5 minutes.

Inclusion Criteria:

1. Pathologic confirmation of metastatic or locally advanced RCC with a major clear cell component.
2. Measurable disease by RECIST criteria.
3. Age >/= 18 years
4. ECOG performance status 0-2 or Karnofsky Performance Status >/= 60%
5. Meets criteria for poor-risk defined as 3 or more of the following: ECOG performance status 2, anemia (hemoglobin lower than reference range), elevated serum LDH > 1.5x upper limit of normal (ULN), hypercalcemia (corrected serum calcium level > upper limit of normal), time from initial RCC diagnosis to registration on this trial < 1 year, and > 1 metastatic organ sites.
6. Adequate organ and marrow function within 14 days of registration as defined below: a) Absolute neutrophil count >/=1,500/µL b) Platelets >/=100,000/µL c) Hgb >/= 9.0 g/dL (transfusion allowed) d) Renal: serum creatinine </= 1.5 x ULN or calculated CrCl >/= 40 cc/min and random urine protein:creatinine ratio (UPC) < 1 or 24-hr urine protein < 1g e) Liver: total bilirubin </= 1.5 mg/dl; AST (SGOT) and ALT (SGPT) </= 2.5 x ULN for subjects without evidence of liver metastases, </= 5 x ULN for subjects with documented liver metastases f) INR </= 1.2 x ULN; PTT </= 1.5 x ULN. Therapeutic anticoagulation with warfarin is allowed if target INR </= 3 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks (14 days) at time of randomization.
7. 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 of study registration. Pregnancy test must be repeated if performed > 14 days before starting study drug.

Exclusion Criteria:

1. Prior malignancy, except for non-melanoma skin cancer, in situ carcinoma of any site, or other cancers for which the patient has been adequately treated and disease free for 2 years
2. Prior targeted therapy (anti-VEGF agents or mTOR inhibitors) including adjuvant therapy, and prior chemotherapy for mRCC. However, prior immunotherapy (cytokines or vaccines) is allowed.
3. Any experimental drug while on this study; however, concomitant bone targeted therapy (bisphosphonates or the anti-RANK ligand denosumab) is allowed.
4. Uncontrolled brain metastases and infections. Patients with brain metastases treated with Gamma Knife (GK) or whole brain radiation within 24 hours of registration.
5. History of stroke within 6 months of registration
6. Clinically significant cardiovascular disease, defined as myocardial infarction (or unstable angina) within 6 months of registration, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management. However, treated and controlled or stable/not clinically significant cardiovascular disease is allowed per evaluation by cardiologist.
7. Uncontrolled hypertension (home blood pressure readings are permitted) or prior history of hypertensive crisis or hypertensive encephalopathy; however, treatment of hypertension with medications is permitted.
8. History of uncontrolled hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
9. Significant vascular disease including aortic aneurysm, aortic dissection.
10. Symptomatic peripheral vascular disease
11. Pregnancy
12. HIV-positive patients receiving combination anti-retroviral therapy
13. Coagulopathy or bleeding diathesis
14. Concomitant treatment with rifampin, St. John's wort, or the cytochrome p450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital)
15. Major surgery within 28 days prior to registration
16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device within 7 days prior to starting drug
17. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study registration
18. Serious non-healing wound
19. Baseline QTcB >/= 470 msec.

Baseline to study completion or date of death from any cause, whichever came first, assessed up to 5 years.

The total at Risk are participants who received the intervention as their first drug or second drug. All participants did not received both drugs.