Inclusion Criteria:

• Age ≥ 18 years old.
• Histological confirmation of clear cell renal cancer.
• Documented metastatic or unresectable disease and at least one measurable lesion by RECIST criteria.
  • NOTE: Nephrectomy or ablation of the primary tumor is allowed prior to enrollment.
• No prior systemic therapy for clear cell renal cancer; or have progressed after immunotherapy such as ipilimumab plus nivolumab in the first line. Other immunotherapies (e.g., interleukin-2) or additional lines of immunotherapy may be allowed after discussion with the Principal Investigator.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤ 21 days prior to randomization:
  • ANC ≥ 1500/mm^3;
  • PLT ≥ 100,000/mm^3;
  • Hgb ≥ 9.0 g/dL NOTE: Subjects may not have had a transfusion ≤ 7 days of randomization;
  • Total Bilirubin ≤ 1.5 x ULN.
    • NOTE: For bilirubin elevation 1 to 1.5 x ULN, ALT above 1.5 x ULN (upper limit of normal) is not permitted.
    • NOTE: For bilirubin elevation 1 to 1.5 x ULN, AST above 1.5 x ULN (upper limit of normal) is not permitted.
  • Alanine amino transferase (ALT) < 2.5 X ULN, with normal bilirubin.
    • NOTE: Concomitant elevations in bilirubin and ALT above 1.5 x ULN (upper limit of normal) is not permitted.
  • Aspartate aminotransferase (AST) < 2.5 X ULN, with normal bilirubin.
    • NOTE: Concomitant elevations in bilirubin and AST above 1.5 x ULN (upper limit of normal) is not permitted.
• Creatinine ≤ 1.5 mg/dl OR creatinine > 1.5 mg/dl, estimated creatinine clearance must be ≥ 55 mL/minute by CockcroftGault formula:
  • Creatinine Clearance for Males = (140 - age)(weight in kg)               (72)(serum creatinine in mg/dL) 
  • Creatinine Clearance for Females = (140-age)(weight in kg)(0.85)     (72)(serum creatinine in mg/DL)
• INR and aPTT ≤ 1.5 × ULN.
  • NOTE: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
• Individuals of non-childbearing potential, or individual of childbearing potential with negative serum pregnancy test ≤ 7 days prior to randomization and willing to practice total abstinence or use a highly effective method of contraception, as outlined in item "c" below:
  • Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female individual who has had the following:
    • A hysterectomy;
    • A bilateral oophorectomy (ovariectomy);
    • A bilateral tubal ligation;
    • Is post-menopausal.
  • NOTE: Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥ 1 year and be greater than 45 years in age OR, in questionable cases, have a follicle stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40pg/mL (< 140 pmol/L).
  • Childbearing potential, including any individual who has had a negative serum pregnancy test, ≤ 7 days prior to randomization.
  • Agrees to use adequate contraception. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:
    • Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product;
    • Oral contraceptive, either combined or progestogen alone
    • Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year;
    • Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject.
• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).
• Provide informed written consent.
• Willing to provide archive tissue samples for correlative research purposes.

Exclusion Criteria:

• Any of the following because this study involves an agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Individuals/or persons who are nursing ;
  • Individual/or persons who are pregnant;
  • Individuals/or persons of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be HIV positive.
• Prior history of receiving pazopanib or any other tyrosine kinase inhibitor treatments for malignancy.
• Uncontrolled intercurrent illness including, but not limited to:
  • Chronic ongoing or active infection;
  • Symptomatic anemia;
  • Uncontrolled hypertension [defined as systolic blood pressure (SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 100mmHg];
  • Symptomatic congestive heart failure as defined by the New York Heart Association (NYHA) (see Appendix III; does not exclude Class III CHF);
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • evidence of active bleeding or bleeding diathesis;
  • psychiatric illness/social situations that would limit compliance with study requirements;
  • any other serious uncontrolled medical disorders in the opinion of the investigator.
• History of a major thromboembolic event ≤ 6 months prior to randomization, including cerebrovascular accident, transient ischemic attack (TIA), myocardial infarction, symptomatic pulmonary embolism (PE) or untreated deep venous thrombosis (DVT), or coronary artery bypass graft surgery. NOTE: Subjects with recent DVT or asymptomatic PE who have been treated with therapeutic anticoagulating agents for at least 6 weeks are eligible.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤5 years prior to randomization. EXCEPTIONS: Nonmelanoma skin cancer or carcinoma-in-situ of the cervix, or cancers with low metastatic potential (e.g. Gleason score 6 prostate cancer) treated with curative therapy. NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.
• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for ≤ 6 months prior to randomization.. Note: Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
  • Active peptic ulcer disease;
  • Known intraluminal metastatic lesion/s with risk of bleeding;
  • Inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease), or other gastrointestinal conditions with increased risk of perforation;
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 28 days prior to randomization;
  • Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: 
    • Malabsorption syndrome;
    • Any prior major resection of the stomach or small bowel.
• Corrected QT interval (QTc) > 480 msecs using Bazett’s formula. Receiving any medications or substances with risk of Torsades de Pointes.
  • Note: Medications or substances on the list "Drugs with Risk of Torsades de Pointes" are prohibited. Medications or substances on the list "Drugs with Possible or Conditional Risk of Torsades de Pointes" may be used while on study with extreme caution and careful monitoring.
• Treatment with any of the following anti-cancer therapies ≤ 14 days prior to randomization:
  • radiation therapy;
  • surgery or tumor embolization;
  • chemotherapy, immunotherapy;
  • biologic therapy;
  • investigational therapy;
  • hormonal therapy.
• Prior autologous or allogeneic organ or tissue transplantation.
• Elective or planned major surgery to be performed during the course of the trial.
• Receiving any medications or substances that are strong or moderate inhibitors of CYP3A4.  Use of strong or moderate inhibitors are prohibited ≤ 7 days prior to randomization.
• Receiving any medications or substances that are inducers of CYP3A4. Use of inducers are prohibited ≤ 7 days prior to randomization.
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (i.e., below normal limits).
• End-stage renal disease (estimated GFR < 55 ml/min/BSA), unless the estimated creatinine clearance by Cockcroft Gault is ≥ 55 ml/min prior to randomization.
• History of calcium oxalate stones.
• History of iron overload.
• Unable to swallow oral medications.
• History of myocardial infarction ≤6 months, current symptomatic CHF or LVEF < 40% or > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure.