A Phase III Randomized, Double-blind, Placebo Controlled Trial Comparing the Efficacy of Gemcitabine, Cisplatin and Sorafenib to Gemcitabine, Cisplatin and Placebo in First-Line Treatment of Patients with Stage IIIb with effusion and stage IV Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death in North America and worldwide
and non-small cell lung cancer (NSCLC) is responsible for 75%-80% of all lung
malignancies. More than 60% of patients present with metastatic (Stage IV)
disease (1, 2). In addition, most patients presenting with earlier-stage
disease eventually develop metastases.
The only potentially curative treatment for patients with NSCLC is surgical
resection, but surgery is an option for only a small fraction of patients with
localized disease. Fewer than 30% of patients are suitable candidates for
pulmonary resection because of regional or distant spread at the time of
diagnosis, poor pulmonary function or both. For patients presenting with
unresectable advanced disease, the primary goal of therapy is palliative.
Untreated metastatic NSCLC has a poor prognosis with a one year survival of
approximately 10% (3).
The efficacy of angiogenesis inhibitors in the treatment of NSCLC has been
demonstrated in a pivotal Phase III study, whereby bevacizumab (a recombinant,
humanized anti-VEGF (vascular endothelial growth factor) monoclonal antibody)
in combination with carboplatin and paclitaxel provides a statistically
significant survival advantage with tolerable toxicity (7). The evaluation of
bevacizumab and other platinum-based regimens, e.g. (exempli gratia, for
example) carboplatin/gemcitabine and oxaliplatin/gemcitabin is ongoing (8, 9)

The objective of this phase III study is to compare the efficacy of sorafenib
in combination with gemcitabine and cisplatin versus placebo with gemcitabine
and cisplatin for first-line treatment of patients with stage IIIB (with
effusion) or Stage IV NSCLC of non squamous cell carcinoma subtype.

This is a randomized, double blind, placebo controlled, multicenter, Phase III
study designed to compare the efficacy of sorafenib in combination with
gemcitabine and cisplatin versus placebo in combination with gemcitabine and
cisplatin for patients with NSCLC (Stage IV or Stage IIIB with effusion).
Approximately 990 patients will receive up to 6 cycles of gemcitabine and
cisplatin in combination with either sorafenib or placebo in a blinded
fashion.
It is estimated that enrollment will take approximately 17 months with an
enrollment rate of approximately 50 patients per month. The overall study
duration will be approximately 28 months.

RANDOMIZATION
Patients will be randomized in a double-blind fashion using a 1:1 allocation of
patients to either sorafenib in combination with gemcitabine and cisplatin
(sorafenib group), or placebo in combination with gemcitabine and cisplatin
(placebo group).
Stratification factors for the randomization are:
• Performance status (PS): ECOG (Eastern Cooperative Oncology Group) PS 0 vs.
(versus) 1
• Stage: IIIB with effusion vs. Stage IV

Patients will be randomized to one of the following 2 treatment groups:
Sorafenib Group- Gemcitabine 1250 mg/m2 iv (intravenous) on days 1 and 8 and
cisplatin 75 mg/m2 iv on day 1, q (every) 3 weeks for up to 6 cycles, plus
sorafenib 400 mg po (per os, taken orally) bid days 1-21
Placebo Group- Gemcitabine 1250 mg/m2 iv on days 1 and 8 and cisplatin 75 mg/m2
iv on day 1, q 3 weeks for up to 6 cycles, plus placebo po bid days 1-21
The dose of all three drugs may be adjusted or delayed for an individual
patient based on toxicities that are related to protocol therapy. Cisplatin
and gemcitabine will be administered for up to 6 cycles (Chemotherapy Phase).
Thereafter, patients continue sorafenib or placebo as a single agent
(Maintenance Phase) until tumor progression or other criteria for withdrawal
are met. Although sorafenib and placebo are dosed continuously (twice daily) in
the Maintenance Phase, cycle lengths continue defined as 21 days, and sorafenib
or placebo are administered on days 1-21 of each 21-day cycle.

Patients will be randomized to one of the following 2 treatment groups:

1. Sorafenib Group
- Gemcitabine 1250 mg/m2 iv (intravenous) on days 1 and 8 (up to 6 cycles)
- Cisplatin 75 mg/m2 iv on day 1 (up to 6 cycles)
- Sorafenib 400 mg taken orally bid days 1-21

2. Placebo Group
- Gemcitabine 1250 mg/m2 iv (intravenous) on days 1 and 8 (up to 6 cycles)
- Cisplatin 75 mg/m2 iv on day 1 (up to 6 cycles)
- Placebo taken orally bid days 1-21

Besides the study medication, there may be other risks or discomforts in the
study.

CT scans: exposure to radiation. These CT scans would normally be done to
determine if the disease is spreading, hence the patient will no be exposed to
additional radiation just because of participating in the study. However,
depending on the tumor*s response to the drugs, additional CT scans may be
performed.

Bloodsamples:drawing blood or inserting the needle in the arm for the treatment
may cause pain, bruising, lightheadedness, local skin reactions and on rare
occasions, infection. Seepage of fluids into the surrounding tissue during
intravenous infusions may cause discomfort.

It is not known if the patient will have any benefit from sorafenib. The
patient may not receive sorafenib at all if the patient has been assigned to
receive placebo. It is hoped that, through this study, it can be proven that
patients with Non-Small Cell Lung Cancer will live longer without disease
progression by using sorafenib as an additional treatment to chemotherapy.