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

Study Overview
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Brief Summary
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This phase II trial studies how well sorafenib tosylate works in treating patients with medullary thyroid cancer that has spread to other parts of the body (metastatic), spread to the tissue surrounding the thyroid (locally advanced), or has returned after a period of improvement (recurrent). Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess objective response rate of sorafenib tosylate (sorafenib [BAY 43-9006]) 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. III. Correlate nuclear medicine functional imaging (fludeoxyglucose F 18 [F-18 fluorodeoxyglucose] positron emission tomography [PET] scan) data obtained at pre-, during, and post-treatment with tumor response. IV. 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. V. Perform pharmacogenomic studies on procured peripheral blood mononuclear cells (PBMCs) if clinical responses are observed. VI. To correlate between the degree of retrovirus-associated sequence (Ras)-mitogen-activated protein kinase (MAPK) signaling inhibition and vascular endothelial growth factor (VEGF) expression in the tumor and clinical response. VII. 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) in the absence of disease progression or unacceptable toxicity.

Official Title
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Phase II Study of Sorafenib (BAY 43-9006) in Patients With Metastatic Medullary Thyroid Carcinoma

Conditions
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Hereditary Thyroid Gland Medullary Carcinoma, Locally Advanced Thyroid Gland Medullary Carcinoma, Multiple Endocrine Neoplasia Type 2A, Multiple Endocrine Neoplasia Type 2B, Recurrent Thyroid Gland Medullary Carcinoma, Sporadic Thyroid Gland Medullary Carcinoma, Stage III Thyroid Gland Medullary Carcinoma AJCC v7, Stage IV Thyroid Gland Medullary Carcinoma AJCC v7, Stage IVA Thyroid Gland Medullary Carcinoma AJCC v7, Stage IVB Thyroid Gland Medullary Carcinoma AJCC v7, Stage IVC Thyroid Gland Medullary Carcinoma AJCC v7

Intervention / Treatment
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* Drug: Sorafenib Tosylate


Participation Criteria
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Eligibility Criteria
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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 since these agents may have anti-farnesyl transferase activity and may have some therapeutic effect in combination with sorafenib Life expectancy must be >= six months Patients must have an Eastern Cooperative Oncology Group performance status 0-2 Leukocytes >= 2,000/uL (10 days prior to patient enrollment) Absolute neutrophil count >= 1,000/uL (10 days prior to patient enrollment) Platelets >= 100,000/uL (10 days prior to patient enrollment) Total bilirubin =< within 2 x upper limit of normal (10 days prior to patient enrollment) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< within 3 x upper limit of normal (10 days prior to patient enrollment) Serum creatinine within normal institutional limits OR creatinine clearance > 30 mL/min (by Cockcroft-Gault formula) (10 days prior to patient enrollment) The effects of sorafenib (BAY 43-9006) on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because kinase inhibitors are known to be teratogenic, 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 because sorafenib (BAY 43-9006) is an investigational agent and teratogenicity has not been evaluated yet; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with sorafenib (BAY 43-9006), 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 because of possible pharmacokinetic interactions with sorafenib (BAY 43-9006); patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy Patients taking the cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital), rifampin or St. John's wort due to potential drug interactions with sorafenib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (sorafenib tosylate)<br>Patients receive sorafenib tosylate PO BID in the absence of disease progression or unacceptable toxicity. | Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate of Sorafenib Tosylate in Metastatic Medullary Thyroid Carcinoma in Setting of Inherited Tumor Syndromes as Well as in Setting of Sporadic Medullary Thyroid Cancer | Measured using MRI scans. Determined using Response Evaluation Criteria in Solid Tumors/World Health Organization response criteria. 95% confidence interval will be calculated to estimate the frequency of response. | Up to 4 weeks after last dose of sorafenib tosylate | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Decreased Calcitonin Levels | Identifying the number of patients with decreased calcitonin levels | Up to 4 weeks after last dose of sorafenib tosylate | 
| Patient With Decreased Carcinoembryonic Antigen (CEA) Levels | Identify the number of patients with decreased Carcinoembryonic Antigen (CEA) levels | Up to 4 weeks after last dose of sorafenib tosylate | 
| Percent of Baseline Dynamic-Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Exchange Rate Constant (Kep) | Median decrease in exchange rate Kep in index lesions | Up to 4 weeks after last dose of sorafenib tosylate | 
| Degree of Ras-MAPK Signaling Inhibition in the Tumor | Identify the number of patients with degree of Ras-MAPK signaling inhibition | Up to 4 weeks after last dose of sorafenib tosylate | 
| Degree of Vascular Endothelial Growth Factor (VEGF) Expression in the Tumor | Correlated with clinical response. | Up to 4 weeks after last dose of sorafenib tosylate | 
| Standardized Uptake Value (SUV Max) as Measured by Fludeoxyglucose F-18 Positron Emission Tomography (PET) | Identify the median SUV at baseline and 8 week follow up as measured by Fludeoxyglucose F-18 Positron Emission Tomography (PET). | Up to 4 weeks after last dose of sorafenib tosylate | 
| Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Toxicities were graded for patients using the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 | Up to 4 weeks after last dose of sorafenib tosylate | 
| Number of Participants With Ret Proto-Oncogene (RET) Gene Defects in the Tumor | Percent of patients with RET mutations | Baseline | 
| Selected Polymorphisms of Genes Influencing Sorafenib Tosylate Metabolism and/or Resistance Genes That May Predict Response or Toxicity | Changes will be correlated with toxicity and clinical response to therapy. | Baseline |