Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery

PRIMARY OBJECTIVES:

I. To demonstrate an improvement in disease-free survival in locally advanced renal cell
carcinoma patients randomly assigned to adjuvant sunitinib (sunitinib malate) (Arm A) or
sorafenib (sorafenib tosylate) (Arm B) versus placebo (Arm C) after radical or partial
nephrectomy.

SECONDARY OBJECTIVES:

I. To compare overall survival of patients randomized to each of the two regimens with
placebo.

II. To further define the toxicity of prolonged administration of sunitinib or sorafenib in
this patient population.

III. To evaluate cardiac function in each arm

OTHER PRE-SPECIFIED OBJECTIVES:

I. To prospectively collect tumor and biological specimens to assess their characteristics
and associations: novel approaches to assess angiogenesis markers in tissue, blood and urine
as predictors of disease-free survival and of therapeutic benefit.

II. To prospectively collect tumor and biological specimens to assess their characteristics
and associations: the frequency of oncogene and tumor suppressor gene mutations as predictors
of disease-free survival and therapeutic benefit.

III. To prospectively collect tumor and biological specimens to assess their characteristics
and associations: tumor and genetic polymorphisms as predictors of disease-free survival and
therapeutic benefit.

IV. To prospectively collect tumor and biological specimens to assess their characteristics
and associations: deoxyribonucleic acid (DNA) methylation profiles as predictors of outcome
and of therapeutic benefit.

V. To prospectively collect tumor and biological specimens to assess their characteristics
and associations: The relationship of polymorphisms in drug metabolizing enzymes with steady
state concentrations of sorafenib and sunitinib in selected patients.

VI. To study the effect of vascular endothelial growth factor (VEGF) targeted therapy on
circulating endothelial cells and circulating endothelial progenitors.

VII. To prospectively assess patient-reported fatigue in order to compare the magnitude and
trajectory of fatigue among renal cell carcinoma (RCC) patients randomized to adjuvant
sunitinib (Arm A) or sorafenib (Arm B) to placebo (Arm C). (Quality of life objectives) VIII.
To evaluate the Patient Reported Outcomes Measurement Information System (PROMIS)
Fatigue-Short Form (SF)1, a newly developed state-of-the-science PROMIS measure for fatigue
and to calibrate the PROMIS Fatigue-SF1 with the established, validated Functional Assessment
of Chronic Illness Therapy (FACIT) -Fatigue scale. (Quality of life objectives)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Beginning 4-12 weeks following radical or partial nephrectomy, patients receive
sunitinib malate orally (PO) once daily (QD) for 4 weeks and placebo sorafenib tosylate PO QD
or twice daily (BID) for 6 weeks.

ARM B: Beginning 4-12 weeks following radical or partial nephrectomy, patients receive
sorafenib tosylate PO QD or BID for 6 weeks and placebo sunitinib malate PO QD for 4 weeks
followed.

ARM C: Beginning 4-12 weeks following radical or partial nephrectomy, patients receive
placebo sorafenib tosylate as in Arm A and placebo sunitinib malate as in Arm B.

In all arms, treatment repeats every 6 weeks for 9 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then every 12 months for 5 years.

Pre-Registration Inclusion Criteria:

- Pre-surgical criteria:

- Patients must have primary-intact renal cell carcinoma, eligible for nephrectomy
with curative intent

- Tumors >= 4 cm AND/OR macroscopic fully resectable nodes AND/OR surgically
resectable renal vein thrombus AND/OR surgically resectable inferior vena caval
thrombus by radiologic criteria to be clinically >= pT1bNany (resectable) M0
disease

- Multifocal ipsilateral renal cell carcinoma is allowed provided fully resectable
and does not exceed inclusion criteria

- Patients must have corrected QT (QTc) interval < 500 msec on baseline
electrocardiogram (EKG)

- Women of child-bearing potential and men must agree to use an accepted and effective
method of contraception prior to study entry and for the duration of study
participation; should a woman become pregnant while participating in this study, she
should inform her treating physician immediately; if a man impregnates a woman while
participating in this study, he should inform his treating physician immediately as
well

- The date of randomization must be less than 12 weeks after the date of surgery;
patients must have recovered from any surgical related complications

Inclusion Criteria at Randomization:

- Within 4 weeks prior to randomization, patients must meet preoperative eligibility
requirements

- Patients must complete surgery less than 12 weeks prior to randomization

- Patients must have histologically or cytologically confirmed renal cell carcinoma.
Using 2002 (American Joint Committee on Cancer [AJCC] 6th edition) TNM Staging,
patients must be one of the following:

- pT1b G3-4 N0 (or pNX where clinically N0) M0

- pT2 G (any) N0 (or pNX where clinically N0) M0

- pT3 G (any) N0 (or pNX where clinically N0) M0

- pT4 G (any) N0 (or pNX where clinically N0) M0 or

- T (any) G (any) N+ (fully resected) M0

- Patients with microvascular invasion of the renal vein of any grade or stage
(as long as M0) are also eligible

- Patients must have undergone a full surgical resection (radical nephrectomy
or partial nephrectomy) by either open or laparoscopic technique; clinical
evidence of lymph node positivity requires removal of all clinically
positive nodes; surgeons should designate extent of node dissection; all
surgical specimens must have negative margins; patients with positive renal
vein margins are eligible unless there is invasion of the renal vein wall at
the margin (provided no other margins are positive)

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0-1

- Patients must have an absolute baseline left ventricular ejection fraction (LVEF) of
>= 50% by multigated acquisition (MUGA) scan within 4 weeks prior to randomization

- Patients must have paraffin-embedded tumor specimen available for central core review
of tumor histology and other correlative studies; tumor samples will be shipped as
specified

- Patients must have no evidence of residual or metastatic renal cell cancer as
documented on computed tomography (CT) scans of the chest, abdomen, and pelvis, all
with oral and intravenous (IV) contrast (magnetic resonance imaging [MRI] scans of the
abdomen and pelvis with gadolinium and a non-contrast CT of the chest may be
substituted if patient is not able to have CT scans with intravenous contrast);
patients unable to tolerate either gadolinium or IV contrast should not participate in
this study (limitations to a patient's renal function should be taken into
consideration when screening for this study)

- Scans must be obtained within 4 weeks of randomization; changes on these scans
that are felt to be post surgical must be documented

- Patients without reported lymph nodes in the resected surgical specimen and a
reported pathologic stage (post-nephrectomy) of pNX MUST undergo a post-operative
contrast-enhanced CT scan (or MRI with gadolinium) within 4 weeks of
randomization to document that there is no evidence of residual disease

- Absolute granulocyte count (AGC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Serum creatinine =< 2.0 x upper limit of normal (ULN) or calculated creatinine
clearance (CrCl) >= 30 mL/min (neither drug is cleared by the kidney)

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) =< 2.5 x ULN

- Patients must be able to swallow pills

Exclusion Criteria:

- History of distant metastases

- Prior anti-cancer therapy for renal cell carcinoma in either the adjuvant or
neoadjuvant setting; this includes metastatectomy for renal cell carcinoma, or
radiation therapy to the renal bed

- Other current malignancies, other than basal cell skin cancer, squamous cell skin
cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast;
patients with other malignancies are eligible if they have been continuously
disease-free for >= 5 years prior to the time of registration

- Serious intercurrent illness including, but not limited to, the following: clinically
significant cardiovascular disease (e.g. uncontrolled hypertension, myocardial
infarction, unstable angina); New York Heart Association grade II or greater
congestive heart failure; serious cardiac arrhythmia requiring medication; grade II or
greater peripheral vascular disease; or psychiatric illness/social situations that
would limit compliance with study requirements

- Any of the following within the 6 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident or transient
ischemic attack, or pulmonary embolism

- Ongoing ventricular cardiac dysrhythmias of National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 grade >= 2; history of
serious ventricular arrhythmia (ventricular tachycardia [VT] or ventricular
fibrillation [VF] >= 3 beats in a row); ongoing atrial fibrillation

- Hypertension that cannot be controlled by medications (>= diastolic blood pressure 100
mm Hg despite optimal medical therapy)

- Pre-existing thyroid abnormality with thyroid stimulating hormone that cannot be
maintained in the normal range with medication

- Pregnant or breastfeeding; all females of childbearing potential must have a blood
test or urine study within 2 weeks prior to pre-registration to rule out pregnancy; if
pre-registration occurs prior to surgery, the blood or urine study must be repeated
within 2 weeks prior to randomization to rule out pregnancy; (note: should a woman
become pregnant while participating in this study, she should inform her treating
physician immediately)

- Patients with known human immunodeficiency virus (HIV)

- Collecting duct carcinomas or medullary carcinomas

- Patients taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin,
carbamazepine or phenobarbital), St John's Wort, ketoconazole, dexamethasone, the
dysrhythmic drugs (terfenadine, quinidine, procainamide, sotalol, probucol, bepridil,
indapamide or flecainide), haloperidol, risperidone, rifampin, grapefruit, or
grapefruit juice within two weeks of randomization and during the course of therapy;
(medications are not prohibited unless listed above); topical and inhaled steroids are
permitted

- Receiving any other investigational anti-cancer agents during the period on study

- Serious intercurrent illness, including ongoing or active infection requiring parental
antibiotics