ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma

Inclusion Criteria:

- Histologically or cytologically confirmed renal cell carcinoma, including any of the
following subtypes:

- Clear cell carcinoma

- Nonclear cell carcinoma

- No collecting duct or medullary carcinomas

- Meets 1 of the following risk categories:

- Intermediate high-risk disease

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

- pT2, G1-2 N0 (or pNX where clinically N0) M0

- pT2, G3-4 N0 (or pNX where clinically N0) M0

- pT3a, G1-2 (as long as pT3a is not due to adrenal involvement) N0 (or pNX
where clinically N0) M0

- Patients with microvascular invasion of the renal vein of pT1a-pT3a (as
long as pT3a is not due to adrenal involvement and grade 1-2) N0 (or pNX
where clinically N0) M0

- Very high-risk disease

- pT3a, G3-4 (or any grade pT3a if due to adrenal involvement) N0 (or pNX
where clinically N0) M0

- pT3b-c G any N0 (or pNX where clinically N0) M0

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

- pT any G any N+

- Patients with microvascular invasion of the renal vein with above other
characteristics

- Planning to start study treatment between 4-12 weeks after radical or partial
nephrectomy

- Underwent full surgical resection (i.e., radical or partial nephrectomy) by
either open or laparoscopic technique within the past 3-10 weeks

- Clinical evidence of lymph node positivity requires complete regional
lymphadenectomy

- All surgical specimens must have negative margins

- Planning to undergo the above surgical resection AND meets all of the following
criteria:

- Primary intact renal cell carcinoma, eligible for nephrectomy with curative
intent

- pT1b-4, N0 or any fully resectable N (i.e., N1-2), M0 disease by radiologic
criteria, meeting any of the following criteria:

- Tumors ≥ 4 cm

- Macroscopic fully resectable nodes

- Surgically resectable renal vein thrombus

- Surgically resectable inferior vena caval thrombus by radiologic
criteria

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

- No evidence of residual or metastatic renal cell cancer by chest, abdomen, and pelvic
CT scan with oral and IV contrast (or MRI scan of the abdomen and pelvis with
gadolinium and a CT scan of the chest with or without IV contrast) within 4 weeks of
randomization (after radical or partial nephrectomy)

- Patients unable to tolerate either gadolinium or IV contrast should not
participate in this study

- No history of distant metastases

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Absolute granulocyte count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Creatinine ≤ 2.0 times upper limit of normal (ULN) OR creatinine clearance ≥ 30
mL/min

- Bilirubin ≤ 1.5 times ULN

- SGOT and SGPT ≤ 2.5 times ULN

- Absolute baseline LVEF ≥ 50% by MUGA within 4 weeks of randomization

- No other malignancy within the past 5 years except basal cell or squamous cell skin
cancer, in situ cervical cancer, or ductal or lobular carcinoma in situ of the breast

- No serious intercurrent illness, including, but not limited to, any of the following:

- Clinically significant cardiovascular disease(e.g., uncontrolled hypertension,
myocardial infraction, or unstable angina)

- New York Heart Association class II-IV congestive heart failure

- Peripheral vascular disease ≥ grade 2

- Psychiatric illness or social situation that would preclude study compliance

- At least 6 months since any of the following:

- Myocardial infarction

- Severe or unstable angina

- Coronary or peripheral artery bypass graft

- Symptomatic congestive heart failure

- Cerebrovascular accident

- Transient ischemic attack

- Pulmonary embolism

- No ongoing ventricular cardiac dysrhythmias ≥ grade 2

- No ongoing atrial fibrillation

- No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation ≥ 3 beats in a row)

- QTc interval < 500 msec by baseline EKG

- No uncontrolled hypertension (i.e., diastolic blood pressure ≥ 100 mm Hg despite
optimal medical therapy)

- No pre-existing thyroid abnormality with thyroid stimulating hormone that cannot be
maintained in the normal range with medication

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No known HIV infection

- Able to swallow pills

- Recovered from prior surgery

- No prior anticancer therapy for renal cell carcinoma in either the adjuvant or
neoadjuvant setting, including any of the following:

- Metastectomy

- Radiotherapy to the renal bed

- At least 2 weeks since prior and no concurrent treatment with any of the following*:

- Cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine,
or phenobarbital)

- Hypericum perforatum (St. John's wort)

- Ketoconazole

- Dexamethasone

- Dysrhythmic drugs (i.e., terfenadine, quinidine, procainamide, sotalol,
probucol, bepridil, indapamide, or flecainide)

- Haloperidol

- Risperidone

- Rifampin

- Grapefruit juice or grapefruit

- Concurrent participation in protocol ECOG-E1Y03 allowed

- No other concurrent investigational anticancer agents