Sorafenib in Treating Patients With Locally Advanced or Metastatic Kidney Cancer

OBJECTIVES:

Primary

- To demonstrate the feasibility and safety of sorafenib tosylate when given prior to
nephrectomy or metastasectomy.

- To evaluate the ability of diffusion-weighted magnetic resonance imaging (DW-MRI) to
detect early and ongoing microstructural changes in primary and metastatic renal cell
carcinoma lesions during neoadjuvant therapy with sorafenib tosylate.

- To correlate early and ongoing microstructural changes in primary and metastatic renal
cell carcinoma lesions with pathologic and clinical findings at the time of nephrectomy
or metastasectomy.

- To evaluate the ability of changes in DW-MRI to predict subsequent favorable response to
treatment (complete or partial response or stable disease) after 4 weeks of therapy.

OUTLINE: Patients receive oral sorafenib tosylate twice daily on days 1-28. Patients then
undergo a nephrectomy or metastasectomy in week 5. Patients with residual metastatic disease
may continue sorafenib tosylate twice daily and undergo a diffusion-weighted MRI (DW-MRI)
every 8 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo a DW-MRI of the abdomen and pelvis at baseline and prior to week 5 to
evaluate microstructure tumor changes and to allow for prediction of sorafenib tosylate
benefit. DW-MRI results are correlated with surgical and pathologic findings obtained at week
5.

Resected tumor tissue are analyzed for vascular density and to distinguish apoptotic cell
death from necrotic cell death via immunohistochemistry and to measure apoptotic cell death
via TUNEL assay.

After completion of study treatment, patients are followed every 3 months for 2 years.

DISEASE CHARACTERISTICS:

- Histologically confirmed newly diagnosed clear cell renal cell carcinoma, meeting 1 of
the following criteria:

- Localized disease, as evidenced by intact, bulky, and primary renal lesions (T1 >
3 cm, any T2, T3, or T4) appropriate for nephrectomy

- Limited metastatic disease, as evidenced by any renal primary (T1 > 3 cm, any T2,
T3, or T4) appropriate for cytoreductive nephrectomy

- Isolated abdominal/pelvic recurrence with limited metastatic burden (minimum size
> 2 cm) appropriate for metastasectomy

- No known brain metastasis

- Patients with neurological symptoms must undergo a CT scan/MRI of the brain 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

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

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

- Creatinine ≤ 1.5 times ULN

- Estimated glomerular filtration rate > 30 mL/min (for patients receiving Gd-enhanced
MRI)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to, during (men and women),
and for at least 3 months after (men) completion of study therapy

- Adequate cardiac and pulmonary status for operative therapy

- No active clinically serious infection > CTCAE grade 2

- No known HIV, hepatitis B, or hepatitis C infections

- No serious non-healing wound, ulcer, or bone fracture

- No significant traumatic injury withing the past 4 weeks

- No pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within the past 4 weeks

- No other hemorrhage/bleeding event ≥ CTCAE grade 3 within the past 4 weeks

- No history of an uncontrolled bleeding disorder including, but not limited to, any of
the following:

- Bleeding diathesis

- Coagulopathy

- No cardiac disease or condition including, but not limited to, any of the following:

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

- Unstable angina (anginal symptoms at rest)

- New onset angina beginning within the last 3 months

- Myocardial infarction within the past 6 months

- Cardiac ventricular arrhythmias requiring antiarrhythmic therapy

- No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or
diastolic BP > 100 mm Hg) despite optimal medical management

- No thrombolic or embolic events within the past 6 months (e.g., cerebrovascular
accident including transient ischemic attacks)

- No condition that impairs the ability to swallow whole pills

- No malabsorption problem

- No contraindication to MRI, including, but not limited to, any of the following:

- Ferromagnetic implants

- Dental work

- Pacemakers

- Metallic implants

- Severe claustrophobia which precludes closed MRI testing

- No known or suspected allergy to sorafenib tosylate

- No contraindication or allergy to gadolinium (e.g., end stage renal disease requiring
hemodialysis)

- No intercurrent illness or situation which, in the judgment of the investigator, would
affect assessments of clinical status and study endpoints significantly

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- More than 4 weeks since prior major surgery or open biopsy

- No prior therapy with tyrosine kinase or VEGF inhibitors (e.g., sunitinib malate,
sorafenib, or bevacizumab)

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

- No concurrent use of illicit drugs or other substances that may, in the opinion of the
investigator, have a reasonable chance of contributing to toxicity or interfering with
study results