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 IVA Thyroid Gland Medullary Carcinoma AJCC v7, Stage IVB Thyroid Gland Medullary Carcinoma AJCC v7, Stage IVC Thyroid Gland Medullary Carcinoma AJCC v7, Stage IV Thyroid Gland Medullary Carcinoma AJCC v7
Conditions
Brief summary
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
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.
Interventions
DRUGSorafenib Tosylate
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 4 weeks after last dose of sorafenib tosylate | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient With Decreased Carcinoembryonic Antigen (CEA) Levels | Up to 4 weeks after last dose of sorafenib tosylate | Identify the number of patients with decreased Carcinoembryonic Antigen (CEA) levels |
| Percent of Baseline Dynamic-Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Exchange Rate Constant (Kep) | Up to 4 weeks after last dose of sorafenib tosylate | Median decrease in exchange rate Kep in index lesions |
| Degree of Ras-MAPK Signaling Inhibition in the Tumor | Up to 4 weeks after last dose of sorafenib tosylate | Identify the number of patients with degree of Ras-MAPK signaling inhibition |
| Degree of Vascular Endothelial Growth Factor (VEGF) Expression in the Tumor | Up to 4 weeks after last dose of sorafenib tosylate | Correlated with clinical response. |
| Number of Patients With Decreased Calcitonin Levels | Up to 4 weeks after last dose of sorafenib tosylate | Identifying the number of patients with decreased calcitonin levels |
| Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Up to 4 weeks after last dose of sorafenib tosylate | Toxicities were graded for patients using the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 |
| Number of Participants With Ret Proto-Oncogene (RET) Gene Defects in the Tumor | Baseline | Percent of patients with RET mutations |
| Selected Polymorphisms of Genes Influencing Sorafenib Tosylate Metabolism and/or Resistance Genes That May Predict Response or Toxicity | Baseline | Changes will be correlated with toxicity and clinical response to therapy. |
| Standardized Uptake Value (SUV Max) as Measured by Fludeoxyglucose F-18 Positron Emission Tomography (PET) | Up to 4 weeks after last dose of sorafenib tosylate | Identify the median SUV at baseline and 8 week follow up as measured by Fludeoxyglucose F-18 Positron Emission Tomography (PET). |
Countries
United States
Participant flow
Recruitment details
November 2006 and January 2008
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Hereditary MTC) Sorafenib (BAY 43-9006) was administered at the dose of 400 mg orally twice a day on a continuous basis. | 5 |
| Arm B (Sporadic MTC) Sorafenib (BAY 43-9006) was administered at the dose of 400 mg orally twice a day on a continuous basis. | 16 |
| Total | 21 |
Baseline characteristics
| Characteristic | Arm A (Hereditary MTC) | Arm B (Sporadic MTC) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 10 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Nonwhite | 0 patients | 3 patients | 3 patients |
| Race/Ethnicity, Customized White | 5 patients | 13 patients | 18 patients |
| Region of Enrollment United States | 5 participants | 16 participants | 21 participants |
| Sex: Female, Male Female | 0 Participants | 11 Participants | 11 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 21 |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 5 / 21 |
Outcome results
Primary
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.
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
Population: 1 patient was not evaluable for RECIST evaluation in Arm B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Hereditary MTC) | 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 | 1 Participants |
| Arm B (Sporadic MTC) | 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 | 1 Participants |
Secondary
Degree of Ras-MAPK Signaling Inhibition in the Tumor
Identify the number of patients with degree of Ras-MAPK signaling inhibition
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
Population: Due to low tumor cellularity in the samples obtained, such evaluation was not possible
Secondary
Degree of Vascular Endothelial Growth Factor (VEGF) Expression in the Tumor
Correlated with clinical response.
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
Population: No data available
Secondary
Number of Participants With Ret Proto-Oncogene (RET) Gene Defects in the Tumor
Percent of patients with RET mutations
Time frame: Baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Hereditary MTC) | Number of Participants With Ret Proto-Oncogene (RET) Gene Defects in the Tumor | 5 Participants |
| Arm B (Sporadic MTC) | Number of Participants With Ret Proto-Oncogene (RET) Gene Defects in the Tumor | 10 Participants |
Secondary
Number of Patients With Decreased Calcitonin Levels
Identifying the number of patients with decreased calcitonin levels
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
Population: 1 patient was not evaluable in Arm B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Hereditary MTC) | Number of Patients With Decreased Calcitonin Levels | 5 Participants |
| Arm B (Sporadic MTC) | Number of Patients With Decreased Calcitonin Levels | 11 Participants |
Secondary
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
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Hereditary MTC) | Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Diarrhea | 10 Participants |
| Arm A (Hereditary MTC) | Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Oral cavity pain | 13 Participants |
| Arm A (Hereditary MTC) | Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Alopecia | 16 Participants |
| Arm A (Hereditary MTC) | Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Hypertension | 10 Participants |
| Arm A (Hereditary MTC) | Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | HFSR | 14 Participants |
| Arm A (Hereditary MTC) | Number of Patients With Toxicity, Graded Using the Revised National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Pulmonary Embolism | 5 Participants |
Secondary
Patient With Decreased Carcinoembryonic Antigen (CEA) Levels
Identify the number of patients with decreased Carcinoembryonic Antigen (CEA) levels
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
Population: 1 patient was not evaluable in Arm B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Hereditary MTC) | Patient With Decreased Carcinoembryonic Antigen (CEA) Levels | 4 Participants |
| Arm B (Sporadic MTC) | Patient With Decreased Carcinoembryonic Antigen (CEA) Levels | 8 Participants |
Secondary
Percent of Baseline Dynamic-Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Exchange Rate Constant (Kep)
Median decrease in exchange rate Kep in index lesions
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
Population: kep \[exchange rate constant\]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Hereditary MTC) | Percent of Baseline Dynamic-Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Exchange Rate Constant (Kep) | 79 percentage change |
Secondary
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.
Time frame: Baseline
Population: Due to low tumor cellularity in the samples obtained, such evaluation was not possible
Secondary
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).
Time frame: Up to 4 weeks after last dose of sorafenib tosylate
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A (Hereditary MTC) | Standardized Uptake Value (SUV Max) as Measured by Fludeoxyglucose F-18 Positron Emission Tomography (PET) | Baseline | 3.73 maximum SUV |
| Arm A (Hereditary MTC) | Standardized Uptake Value (SUV Max) as Measured by Fludeoxyglucose F-18 Positron Emission Tomography (PET) | 8 week follow up | 2.94 maximum SUV |