The goal of this study is to determine the activity of sorafenib in patients with advanced (metastatic or recurrent) thyroid cancer.

Inclusion Criteria:

• Patients must have histologically confirmed thyroid cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
• Patients may have received multiple treatments of radioactive iodine, one prior biologic treatment, and at least half of the patients will have had no prior chemotherapy for metastatic disease. At least 3 weeks must have elapsed since prior treatment.
• Measurable disease defined as at least one malignant lesion that can be accurately and serially measured in at least one dimension (longest diameter to be recorded), using a caliper (diameter > 10 mm) for superficial cutaneous disease, or using contrast-enhanced CT or spiral CT (diameter > 20 mm) for visceral or nodal/soft tissue disease.
• ECOG performance status < 2 (Appendix 1).
• Life expectancy greater than 3 months.
• Adequate organ function that has been determined within 7 days prior to enrollment, defined as:Leucocyte count > 3,000/uL; Absolute neutrophil count (ANC) > 1,500/mm3, platelets > 100,000/mm3, and hemoglobin > 9 g/dl; Serum creatinine < 1.5 times ULN, or 24-hour creatinine clearance > 75 cc/min. (Note: creatinine clearance need not be determined if the baseline serum creatinine is within normal limits); Serum bilirubin < 1.5 times ULN; serum glutamyloxaloacetic transaminase (SGOT) < 2.5 ULN; alkaline phosphatase < 2.5 times ULN; PT-INR/PTT < 1.5 x upper limit of normal.
• Intellectual, emotional, and physical ability to comply with oral medication.
• Ability to understand and the willingness to sign a written informed consent
• Patients with disease accessible for biopsy will be preferentially selected for participation in the study. Accessible disease includes lymph node metastases.
• Female patients of child-bearing potential must have a negative pregnancy test within 14 days before initiation of study drug dosing. Post-menopausal women must be amenorrheic for at least 12 months to be considered non-child-bearing potential. Male and female patients of reproductive potential must agree to use adequate contraception (i.e. hormonal or barrier method of birth control). throughout the study and for 3 months after the study.

Exclusion Criteria:

• Significant medical disease including: uncontrolled congestive heart failure; active symptoms of coronary artery disease, uncontrolled seizure disorder; active infection; uncontrolled diabetes mellitus; requirement for chronic corticosteroid treatment; requirement for concurrent immunosuppressive drug(s); active autoimmune disease.
• Organ allografts.
• Known HIV-infection (HIV testing is not required for participation).
• Pregnancy or lactation. Women of childbearing potential and sexually active males must be advised to take precautions to prevent pregnancy during treatment
• History of second cancer (except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five or more years).
• Use of any experimental therapy within 3 weeks prior to baseline evaluations done prior to enrollment.
• Patients with carcinomatous meningitis are excluded from the study.
• Excluded therapies and medications, previous and concomitant:Anticancer chemotherapy or immunotherapy during the study or within 4 weeks prior to the first dose of the study drug; Radiotherapy for the treatment of a symptomatic (e.g. bone metastasis) as clinically indicated is allowed as long as it is not evidence of progressive disease (see 4.5.2); -Biological response modifiers, such as G-CSF, within 3 week prior to study entry. (G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however they may not be substituted for a required dose reduction); Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study; Investigational drug therapy outside of this trial during or within 4 weeks prior the screening assessment; Use of ketoconazole, itraconazole, and ritonavir; Use of carbamazepine, phenytoin, phenobarbital; Previous exposure to a Ras pathway inhibitor (including herceptin, EGFr inhibitors, farnesyl transferase inhibitors or MEK inhibitors); Use of grapefruit juice products; Use of cyclosporin;
• Pregnant or breast feeding.