Sorafenib in Treating Patients Undergoing Surgery for Stage II, Stage III, or Stage IV Kidney Cancer

OBJECTIVES:

Primary

- Determine the safety and feasibility of systemic sorafenib tosylate therapy when given
prior to definitive nephrectomy in patients with stage II-IV renal cell carcinoma
(RCC).

Secondary

- Determine all levels of response in primary renal tumors of patients treated with this
drug.

- Assess effects of this drug on gene expression, protein expression, and metabolic
profile using tumor tissue samples from these patients.

- Identify biomarkers or biomarker patterns associated with RCC or this drug in these
patients.

OUTLINE: This is a pilot, open-label, nonrandomized study.

Patients receive oral sorafenib tosylate twice daily for 4-8 weeks in the absence of disease
progression or unacceptable toxicity. After completion of neoadjuvant therapy, patients
undergo surgical resection of their kidney tumor.

Patients undergo blood and urine sample collection at baseline and after completion of
treatment (i.e., at 4 and 8* weeks) for VEGF analysis. Samples are examined by enzyme-linked
immunosorbent assay for measurement of serum and urinary VEGF levels.

NOTE: *Blood sampling at 8 weeks is only for those patients undergoing 8 weeks of study
therapy.

Patients also undergo tissue sample collection at the time of nephrectomy. Tissue samples
are examined by microarray analysis and IHC staining for expression of CD31/PECAM, HIF1α,
and HIF2α. Immunohistochemical staining to identify biomarkers of microvessel density is
also performed. Tissue samples are also examined for gene expression and metabolic profile
by small molecule mass spectroscopy, as well as VHL gene mutation by VHL mutation analysis.

Patients are followed at 4-8 weeks after nephrectomy.

DISEASE CHARACTERISTICS:

- Diagnosis of renal cell carcinoma (RCC) as confirmed by either of the following:

- Radiographic documentation by MRI or CT scan

- Histological evidence of primary RCC

- Stage II-IV disease, as defined by any of the following:

- T > 7 cm

- Renal vein involvement

- Local invasion

- Evidence of lymph node involvement

- Distant metastatic disease

- Deemed suitable for nephrectomy by a urologist

- No requirement for surgery earlier than 4 weeks from study entry

- No known brain metastasis

- Patients with neurological symptoms must undergo a CT scan or brain MRI to
exclude brain metastasis

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Hemoglobin ≥ 9.0 g/dL

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement)

- Creatinine ≤ 2.5 times ULN or glomerular filtration rate ≥ 50 mL/min

- INR ≤ 1.5 AND PTT normal

- Stable INR required at baseline for patients on warfarin

- Not pregnant or nursing

- Negative pregnancy test

- Fertile women must use effective contraception

- Fertile men must use effective contraception during and for ≥ 2 months after the last
dose of sorafenib tosylate

- No other active primary malignancy except skin cancer

- No active coronary artery disease

- No active bleeding diathesis

- Closely monitored therapeutic anticoagulation allowed

- No cardiac disease, including any of the following:

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

- Unstable angina (i.e., anginal symptoms at rest) or new onset angina (i.e.,
beginning within the past 3 months)

- Myocardial infarction within the past 6 months

- No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or
diastolic BP > 90 mm Hg, despite optimal medical management

- No known HIV infection or chronic hepatitis B or C

- No active, clinically serious infection > grade 2

- No thrombolic or embolic events, such as a cerebrovascular accident or transient
ischemic attacks, within the past 6 months

- No pulmonary hemorrhage or bleeding event ≥ grade 2 within the past 4 weeks (≥ grade
3 for any nonpulmonary hemorrhage or bleeding event)

- No serious nonhealing wound, ulcer, or bone fracture

- No significant traumatic injury within the past 4 weeks

- No known or suspected allergy to sorafenib tosylate or any agent given in the course
of this study

- No condition that impairs the patient's ability to swallow whole pills

- No malabsorption problem

PRIOR CONCURRENT THERAPY:

- No major surgery or open biopsy within the past 4 weeks

- Concurrent anticoagulation therapy (e.g., warfarin or heparin) allowed

- No other concurrent investigational or commercial agents or therapies for RCC

- No concurrent Hypericum perforatum (St. John's wort) or rifampin