Sorafenib Tosylate in Treating Patients With Metastatic, Locally Advanced, or Recurrent Medullary Thyroid Cancer

PRIMARY OBJECTIVES:

I. To assess objective response rate of sorafenib (BAY 43-9006) (sorafenib tosylate) in
metastatic medullary thyroid carcinoma in setting of inherited tumor syndromes, such as
multiple endocrine neoplasia (MEN) 2A, MEN 2B, or familial medullary thyroid carcinoma
(FMTC).

II. To assess objective response rate of sorafenib (BAY 43-9006) in sporadic metastatic
medullary thyroid carcinoma.

SECONDARY OBJECTIVES:

I. To assess toxicity of sorafenib (BAY 43-9006) in patients with metastatic medullary
thyroid carcinoma.

II. Measure serum tumor markers calcitonin and carcinoembryonic antigen (CEA) pre-, during,
and post-treatment to correlate with disease response.

II. Correlate nuclear medicine functional imaging (fludeoxyglucose F 18 positron emission
tomography [PET] scan) data obtained at pre-, during, and post-treatment with tumor response
in these patients.

III. Correlate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data obtained
at pre-, during, and post-treatment with changes in tumor permeability and vascularity with
tumor response.

IV. Perform pharmacogenomic studies on procured peripheral blood mononuclear cells (PBMCs) if
clinical responses are observed in these patients.

V. To correlate between the degree of retrovirus-associated deoxyribonucleic acid (DNA)
sequences (Ras)-mitogen-activated protein kinase (MAPK) signaling inhibition with vascular
endothelial growth factor (VEGF) expression in the tumor and clinical response.

VI. To correlate between the presence and type of ret proto-oncogene (RET) gene defects in
tumor and clinical response.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-56. Treatment
repeats every 8 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 4 weeks.

Inclusion Criteria:

- ELIGIBILITY CRITERIA SPECIFIC FOR ARM A

- Histologically confirmed medullary thyroid carcinoma under the clinical setting of
inherited tumor syndromes, such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, or
familial medullary thyroid carcinoma (FMTC)

- ELIGIBILITY CRITERIA SPECIFIC FOR ARM B

- Histologically confirmed medullary thyroid carcinoma under the clinical setting of
sporadic medullary thyroid carcinoma (MTC)

- ELIGIBILITY CRITERIA COMMON FOR ARMS A AND B

- Patients must have measurable disease

- Metastatic and/or locally advanced or locally recurrent disease

- Oral or intravenous (IV) bisphosphonates therapy will be allowed for patients with
bony metastasis at the investigator's discretion; bisphosphonate usage should be
recorded if used

- Life expectancy must be >= six months

- Patients must have an Eastern Cooperative Oncology Group performance status 0-2

- Leukocytes >= 2,000/uL

- Absolute neutrophil count >= 1,000/uL

- Platelets >= 100,000/uL

- Total bilirubin =< within 2 x upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< within 3 x upper limit of normal

- Serum creatinine within normal institutional limits OR creatinine clearance > 30
mL/min (by Cockcroft-Gault formula)

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for at least 30 days after completion of
therapy; should a woman become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- EXCLUSION CRITERIA FOR ARM A AND B

- Patients who have had systemic anti-tumor therapy (such as chemotherapy, biologic
modifiers or antiangiogenic therapy) within 4 weeks (6 weeks if nitrosourea or
mitomycin chemotherapy) prior to study entry

- Patients who have had external beam radiation therapy within 1 week or if the adverse
events associated with radiation are not resolved to grade 1 or less prior to study
entry

- Prior therapy with sorafenib (BAY 43-9006), ZD 6474 or AMG-706

- Patients currently receiving any other tumor-specific therapy for thyroid cancer or
investigational therapy; patients receiving adjuvant hormonal therapy for a second
primary (such as breast cancer or prostate cancer) are allowed to participate as far
as there are no known drug interactions

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sorafenib (BAY 43-9006)

- Patients unable to swallow sorafenib tablets (e.g. any condition that impairs
patient's ability to swallow pills)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled hypertension, or psychiatric illness/social situations that
would limit compliance with study requirements

- Patients with any evidence of a bleeding diathesis

- Patients actively receiving anticoagulation with therapeutic intent; prophylactic
anticoagulation (i.e. low dose warfarin) or venous or arterial access devices is
allowed provided that the prothrombin time (PT), international normalized ratio (INR)
or partial thromboplastin time (PTT) are normal

- Pregnant women or women who are breast-feeding are excluded from this study;
breastfeeding should be discontinued if the mother is treated with sorafenib (BAY
43-9006)

- Human immunodeficiency virus (HIV)-positive patients receiving combination
anti-retroviral therapy

- Patients taking the cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin,
carbamazepine, or phenobarbital), rifampin or St. John's wort