Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of anaplastic thyroid cancer (a diagnosis that is noted to be "consistent with anaplastic thyroid cancer" with the presence of a thyroid mass is acceptable)
  • Note: Tissue collection for central review is mandatory, but central review is not required for eligibility; treatment will be started prior to central review
• If there was a total or partial thyroidectomy completed within 3 months of enrollment, the surgical specimen must show the area of anaplastic thyroid cancer to be at least 1 cm in greatest dimension
• The following minimum diagnostic workup is required:
  • History/physical examination within 2 weeks prior to registration
  • Imaging of neck and brain (computed tomography [CT] scan or magnetic resonance imaging [MRI]) and chest/abdominal imaging (chest x-ray or chest CT scan, or full body positron emission tomography [PET]/CT are acceptable) within 4 weeks prior to registration
  • Note: The CT scan of the neck must be done with contrast or if an MRI is done, with gadolinium; therefore, the CT portion of a full body PET/CT has to be a high resolution CT to be acceptable for eligibility
  • Abdominal imaging must cover the liver and adrenal glands; therefore, separate imaging is not required if these areas are covered by a chest CT scan
• Electrocardiogram within 10 days prior to registration
• Zubrod performance status 0-2
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin (Hgb) ≥ 9.0 g/dL (note: the use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dL is acceptable)
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (except for patients with Gilbert's syndrome and elevations of indirect bilirubin)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x institutional ULN ; note: patients who have both bilirubin > ULN and AST/ALT > ULN are not eligible (unless they have Gilbert's syndrome and elevations of indirect bilirubin)
• Spot urine protein to creatinine ratio (UPCR) < 1 or a 24-hour urine protein collection < 1 gm) within 10 days prior to registration
• Creatinine < 1.5 mg/dL or within normal institutional limits; Note: if neither criteria is met, the creatinine clearance must be > 50 mL/min^2 per either the Cockcroft-Gault equation, Jeliffe method, or 12- or 24-hour urine collection
• Serum electrolytes including sodium, potassium, blood urea nitrogen (BUN), creatinine, glucose, magnesium, phosphate, and calcium within 10 days prior to registration
• Documentation of the patient's history of corrected QT (QTc) prolongation, family history of prolonged QTc, and relevant cardiac disease within 10 days prior to registration
• Evaluation of the patient's medications within 10 days prior to registration with attempt to change any medication that affects cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
• Blood pressure ≤ 140/90 within 10 days of registration (must be taken and recorded by a health care professional); Note: if the systolic blood pressure is > 140 and/or diastolic blood pressure is > 90 at the time of registration, the patient's blood pressure must be controlled; systolic blood pressure must be < 140 and diastolic blood pressure must be < 90 on at least 2 separate measurements prior to the start of treatment, and the treating physician must believe that this is feasible in order to enroll the patient
• Negative pregnancy test (serum or urine) within 10 days of registration in women of child-bearing potential
• Women of childbearing potential and male participants who are sexually active must agree to practice adequate contraception during treatment and for 6 months post-treatment
• The patient must provide study specific informed consent prior to study entry

Exclusion Criteria:

• Known active invasive malignancy (except for non-melanomatous skin cancer or anaplastic thyroid cancer; the presence of prostate cancer confined to the prostate with a prostate-specific antigen [PSA] ≤ 1 ng/mL for more than 6 months also is allowed)
• Prior systemic chemotherapy for anaplastic thyroid cancer
  • Patients who have had chemotherapy or radiotherapy within 4 weeks of registration (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered > 4 weeks previously
  • Patients receiving other investigational agents
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Patients with any of the following cardiovascular conditions within the past 6 months:
  • Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
  • Admission for unstable angina
  • Myocardial Infarction
  • Cardiac angioplasty or stenting
  • Coronary artery bypass graft surgery
  • Pulmonary embolism, untreated deep venous thrombosis (DVT), or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks
  • Arterial thrombosis
  • Symptomatic peripheral vascular disease
  • Class II or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; Note: a patient who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible for the study
• Certain medications that are associated with a risk for QTc prolongation and/or Torsades de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible
• Patients with an arrhythmia are excluded; patients with atrial fibrillation, supraventricular tachycardia, or bradycardia are eligible as these conditions must be well controlled with medication or a pacemaker
• Patients who require heparin (other than low-molecular weight heparin)
• Patients with any condition that may impair the ability to absorb oral medications/investigational product including:
  • Prior surgical procedures affecting absorption including, but not limited to, major resection of stomach or small bowel
  • Active peptic ulcer disease
  • Malabsorption syndrome
• Patients with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including:
  • Active peptic ulcer disease
  • Known intraluminal metastatic lesions
  • Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal conditions which increase the risk of perforation
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
• History of hemoptysis within 30 days of registration; Note: patients who have minimal bleeding from the mouth which is clearly not related to a source in the lungs i.e., surgery such as a non-lung biopsy are eligible only after good hemostasis has been documented
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Prior allergic reaction to the study drug(s) involved in this protocol
• QTc prolongation defined as a QTc interval ≥ 480 msecs or other significant electrocardiogram (EKG) abnormalities are ineligible; Note: if unsure about EKG abnormality, the treating physician should discuss this with Drs. Sherman or Bible
• Known brain metastasis
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
• Certain medications that act through the cytochrome P450 (CYP450) system are specifically prohibited in patients receiving pazopanib and others should be avoided or administered with extreme caution
  • Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinivir, retonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; although, in exceptional circumstances, they may be administered in conjunction with lowering the dose of pazopanib by 50% of what would otherwise be administered; grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib
  • Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are strictly prohibited
  • Medications that have narrow therapeutic windows and are substrates of CYP3A4, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) should be avoided and, if necessary, administered with caution