Intra-patient Dose Escalation Study of Sorafenib in Advanced Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the
U.S. Time to progression in advanced disease remains poor and further study of newer agents
with novel mechanisms of action is needed to improve duration and quality of life for NSCLC
patients.

Sorafenib is an oral-multi-kinase inhibitor with effects on tumor proliferation and tumor
angiogenesis. Sorafenib has demonstrated activity in preclinical models of NSCLC both in
combination with chemotherapy and as monotherapy. A recent intra-patient dose escalation
trial of sorafenib in renal cell carcinoma showed positive response rates and tolerability up
to 1200mg in 91% of patients.

This study attempts a similar dose-escalation of sorafenib in NSCLC patients.

Inclusion Criteria:

- Histologically or cytologically confirmed, advanced (stage IIIB with pleural effusion,
stage IV, or recurrent), kras mutation positive, non-small cell lung cancer (NSCLC)

- Measurable disease per RECIST criteria

- Patients must have received one + prior chemotherapy regimens for NSCLC

- Patients may have treated and clinically stable brain metastases

- Adequate bone marrow, liver and renal function

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

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation, and for 3 months after last administration of sorafenib

- Patients must have the ability to understand and willingness to sign a written
informed consent

- International normalized ratio(INR) < 1.5 or prothrombin time/ partial thromboplastin
time (PT/PTT) within normal limits

Exclusion Criteria:

- Prior exposure to a Ras pathway inhibitor

- Any other anti-tumor therapy within 3 weeks of enrollment

- Prior bevacizumab within the past 6 weeks

- An active secondary malignancy except non-melanoma skin cancer

- Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have
unstable angina or new onset angina or myocardial infarction within the past 6 months

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Uncontrolled hypertension, defined as systolic blood pressure > 150mm Hg or diastolic
pressure > 90mm Hg, despite optical medical management

- Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C

- Active clinically serious infection > Common Terminology Criteria for Adverse Events
(CTCAE) Grade 2

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

- Pulmonary hemorrhage/bleeding event >/= CTCAE Grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event >/= CTCAE Grade 3 within 4 weeks of 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 first
study drug

- Use of St. John's Wort or rifampin

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

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

- Any malabsorption problem