Pazopanib Versus Temsirolimus in Poor-Risk Clear-Cell Renal Cell Carcinoma (RCC)

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
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
7. Uncontrolled hypertension defined a history of at least two blood pressures > 140/90 over the last two months (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 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.