The purpose of this study is to determine the effect of a sunitinib administration schedule 2/1 (2 weeks of treatment followed by 1 week without) compared to a schedule 4/2 (4 weeks of treatment followed by 2 weeks without) on cardiopulmonary function in subjects with renal cell carcinoma. Subjects will be randomized 1:1 to one of two arms: 4/2 schedule of sunitinib administration or 2/1 schedule of sunitinib administration. Cardiopulmonary function will be assessed at baseline, week 4 (4/2 schedule only), week 5 (2/1 schedule only) and week 12. The investigators hypothesize that schedule 2/1 of sunitinib is not only better tolerated but will be associated with less fatigue and functional cardiovascular/muscular toxicity than the 4/2 schedule.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Histologically confirmed renal cell carcinoma (RCC)

3. One of the two following populations:

   1. High risk for recurrence of RCC after nephrectomy, in the opinion of the investigator, OR
   2. Locally advanced, unresectable or metastatic disease, in the opinion of the investigator, and good or intermediate risk by IDMC Heng Criteria (see Appendix I).

4. Karnofsky Performance Status (KPS) ≥ 80 (see Appendix A)

5. Good or intermediate risk by IDMC Heng Criteria (see Appendix I).4

6. Appropriate for treatment with sunitinib in the opinion of the treating physician.

7. Able to swallow sunitinib and comply with study requirements.

8. Able to walk and jog on a treadmill, in the opinion of the treating physician.

9. Must be able to complete an acceptable cardiopulmonary exercise test (CPET) at baseline (see Section 8.2), defined as at least one of the following:

   • Achieving a plateau in oxygen consumption concurrent with an increase in power output;
   • Respiratory exchange ratio ≥ 1.1 (RER);
   • Volitional exhaustion with a rating of perceived exertion ≥17 (RPE).

10. Subjects must have normal organ and marrow function as defined below:

    • Absolute neutrophil count ≥1,200/µL
    • Hemoglobin ≥9 g/dL
    • Platelets ≥75,000/µL
    • Total bilirubin ≤1.5 x institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT) <2.5 x institutional upper limit of normal
    • Urine protein creatinine (UPC) ratio of <1 (see Appendix G schedule of events footnote)
    • Creatinine ≤2.0 OR creatinine clearance >30 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal (see Appendix H).
    • Left ventricular ejection fraction (LVEF) ≥lower limit of institutional normal as assessed by echocardiography.

11. For the sixteen patients who elect to participate in the optional technology portion involving electronic step counts and blood pressure monitoring, the patient must have a Bluetooth-enabled smart phone, which is compatible with the wireless health monitors.

12. For women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to the start of the study. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of the study. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use. If you do become pregnant during this study or if you have unprotected sex, you must inform your study physician immediately.

13. For men who are sexually active, must agree to use a two medically acceptable forms of birth control (one of which must include a condom as a barrier method of contraception) in order to be in this study. Medically acceptable contraceptives include: (1) surgical sterilization (such as a vasectomy), or (2) a condom used with a spermicide. Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use. Men must also agree to inform their partner of the potential for harm to an unborn child. She should know that if pregnancy occurs, the subject will need to report it to the study doctor, and she should promptly notify her doctor. The study doctor will ask if the subject's partner is willing to provide updates on the progress of the pregnancy and its outcome. If the subject's partner agrees, this information will be provided to Pfizer, Inc. for safety monitoring follow-up.

Exclusion Criteria:

1. Any prior anti-VEGF therapies (i.e., sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, bevacizumab, etc.), including in the adjuvant or neoadjuvant setting.

2. Prior systemic therapy for advanced RCC; however, treatment with immunotherapy (i.e., high-dose bolus IL-2, ipilimumab + nivolumab, etc.) is allowed.

3. Subjects who are receiving any other investigational agents.

4. Subjects who are receiving strong CYP3A4 inhibitors or CYP3A4 inducers (see Section 5.3.2.2).

5. Radiotherapy within 2 weeks prior to taking the first dose of study drug, or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.

6. Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic, and b) have no requirement for steroids or enzyme-inducing anticonvulsants in the prior 28 days.

7. 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 within 28 days prior to beginning study treatment

8. History of any one or more of the following cardiovascular conditions within the past 6 months:

   • Cardiac angioplasty or stenting
   • Myocardial infarction
   • Unstable angina
   • Coronary artery bypass graft surgery
   • Symptomatic peripheral vascular disease
   • Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (see Appendix J)

9. Absolute contraindications to cardiopulmonary exercise testing and/or aerobic training, as determined by the attending oncologist:

   Absolute Contraindications

   • Uncontrolled arrhythmia causing symptoms or hemodynamic compromise
   • Recurrent syncope
   • Active endocarditis
   • Acute myocarditis or pericarditis
   • Symptomatic severe aortic stenosis
   • Uncontrolled heart failure
   • Suspected dissecting aneurysm
   • Uncontrolled asthma
   • Pulmonary edema
   • Room air desaturation at rest <85%
   • Respiratory failure
   • Acute non-cardiopulmonary disorders that may affect exercise performance or be aggravated by exercise (i.e., infection, renal failure, thyrotoxicosis)
   • Mental impairment leading to inability to cooperate.

10. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >150 mmHg or diastolic blood pressure (DBP) of >90 mmHg].

11. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism, or untreated deep venous thrombosis (DVT) within the past 6 months.

12. Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major surgery).

13. Osseous metastatic disease with unacceptable risk of impending fracture due to study assessments, in the opinion of the investigator

14. Evidence of active bleeding or bleeding diathesis.

15. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.

12 weeks