Randomized Phase IIb Study of Sorafenib Dose Escalation in Patients With Previously Untreated Metastatic Renal Cell Carcinoma (RCC)

Inclusion Criteria:

- Age ≥18 years old.

- Diagnosis of unresectable/metastatic renal cell carcinoma (RCC). Nonclear cell
histology is permitted (except for medullary, collecting duct, or sarcomatoid >50% of
specimen). Prior metastasectomy is permitted as long as there is measurable disease
at time of consent.

- Karnofsky Performance Status of 50% or greater at study entry.

- Adequate bone marrow, liver and renal function as assessed by the following: o
Hemoglobin ≥ 9.0 g/dL. o ANC ≥ 1500/mm3. o Platelet count ≥ 100,000/mm3. o Total
bilirubin ≤ 1.5 ULN. o ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver
involvement). o Creatinine ≤ 1.5 × ULN.

- Women of childbearing potential must have a negative serum or urine pregnancy test
performed within 7 days prior to the start of treatment.

- Women of childbearing potential and sexually active men must agree to use adequate
barrier contraception prior to study entry, for the duration of study participation,
and for at least three months after the last administration of sorafenib.

- INR < 1.5 or a PT/ PTT within normal limits. Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.
For patients on warfarin, the INR should be measured prior to initiation of sorafenib
and monitored at least weekly, or as defined by the local standard of care, until INR
is stable.

- Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

- Prior systemic anticancer treatment for metastatic disease, including investigational
therapy.

- Prior treatment with bevacizumab, sunitinib, or sorafenib even in the adjuvant
setting.

- Prior cytokine therapy with interleukin (IL)-2 or interferon (IFN) for metastatic
disease.

- Active malignancy other than RCC (except non-melanoma skin cancer) within 5 years of
enrollment.

- Hemodialysis or peritoneal dialysis.

- Treatment with radiotherapy within 2 weeks of enrollment.

- Cardiac disease: Congestive heart failure Class II or higher per NYHA. Patients must
not have unstable angina (anginal symptoms at rest) or new onset angina (began within
the last 3 months) or myocardial infarction within the past 6 months.

- Uncontrolled CNS metastases. All patients must undergo a CT) scan/MRI of the brain
to exclude brain metastasis. Patients with adequately treated CNS disease may be
considered for participation as long as the first dose of sorafenib is 4 weeks after
completion of CNS therapy.

- Uncontrolled hypertension defined as SBP > 150 mmHg or DBP > 90 mmHg, despite optimal
medical management.

- Active clinically serious infection > Grade 2 per the CTCAE v3.

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months.

- Pulmonary hemorrhage/bleeding event ≥ Grade 2 per CTCAE v3.0 within 4 weeks of
administration of the first dose of study drug.

- Any other hemorrhage/bleeding event ≥ Grade 3 per CTCAE v3.0 within 4 weeks of
administration of the first dose of study drug.

- Serious non-healing wound, ulcer, or bone fracture.

- Evidence or history of bleeding diathesis or coagulopathy.

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of
administration of the first study drug dose.

- Use of St. John's Wort, rifampin (rifampicin), phenytoin, Phenobarbital,
carbamazepine, dexamethasone.

- Known or suspected allergy to sorafenib or any agent given in the course of this
trial.

- Any condition that impairs patient's ability to swallow whole pills.

- Any malabsorption problem.

- Pregnancy or lactation.