A Study of Combination of Gemcitabine, Oxaliplatin (GEMOX)-Sorafenib in Patients With Advanced Biliary Tract Cancer

The purpose of this study is to build on the efficacy of the GEMOX regimen by adding
Sorafenib in the treatment of Biliary Tract Cancer. Since there are no data on the
combination of these three agents, the investigators plan to evaluate the safety in a run-in
phase I portion in order to define the recommended phase II dose (RPTD). The phase II trial
will enroll 40 patients at the RPTD level within 2 years in order to provide a preliminary
estimate of progression-free survival (primary endpoint of the trial) in the target
population.

Inclusion Criteria:

- Age >= 18 years

- Histologically or cytologically confirmed biliary tract or gallbladder carcinoma

- Any stage of disease is allowed but the patients must not be candidates for curative
resection

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 in Ph I

- ECOG performance status 0-2 in Ph II. Patients with ECOG PS of 2 will only be enrolled
if they will comprise at most 25% of the total accruals. This will be monitored in
real time to ensure that at any point during accrual, PS 2 patients will comprise <=
25% of the total accruals

- Patients must have normal organ and marrow function as defined below within 14 days of
study entry:

- Absolute neutrophil count >= 1,500 cells/mm3

- Platelet count >= 60,000/mm3

- Creatinine < 1.5 upper limit of normal (ULN).

- Aspartate transaminase (AST) and Alanine transaminase (ALT) <= 2.5 x ULN.

- Bilirubin <= 3.0 mg/dl

- International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial
thromboplastin time (PTT) within normal limits. Patients receiving
anti-coagulation treatment with an agent such as warfarin will not be candidates
for the trial. Patients on anticoagulation with low molecular weight or
heparinoids are protocol candidates.

- Any number of previous lines of chemotherapy is allowed for the phase I portion

- During the phase II trial, no prior chemotherapy for inoperable or metastatic disease
is allowed except 5-FU or Capecitabine as radiosensitizers. Prior adjuvant
chemotherapy is allowed.

- Women of childbearing potential must have a negative serum pregnancy test performed
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. Men should use adequate birth control for at least three months after
the last administration of sorafenib.

- 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.

- Life expectancy of greater than 12 weeks

Exclusion Criteria:

- Investigational agents within 28 days prior to Day 1 of study

- Chemotherapy within 4 weeks prior to Day 1 of study

- Nitrosoureas, mitomycin-C within 6 weeks prior to Day 1 of study.

- Prior treatment with sorafenib, gemcitabine or oxaliplatin

- Prior history of peripheral neuropathy > Grade 1 (e.g., diabetic neuropathy)

- Pregnant or breast-feeding female

- Patients with a history of allergic reactions or sensitivity attributed to compounds
of similar chemical or biologic composition to sorafenib, oxaliplatin or gemcitabine

- Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative
colitis)

- Cardiac disease: Congestive heart failure > class II New York Heart Association
(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.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.

- Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI
of the brain to exclude brain metastasis.

- Known human immunodeficiency virus (HIV) infection and Hepatitis B and Hepatitis C.

- Active clinically serious infection > CTCAE Grade 2.

- Arterial thrombotic/embolic events like myocardial infarct and cerebrovascular
accident including transient ischemic attacks 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 (rifampicin).

- Any medical condition, which in the opinion of the investigator places the patient at
an unacceptably high risk for toxicities