Sunitinib Malate in Treating Patients With Thyroid Cancer That Did Not Respond to Iodine I 131 and Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Determine the response rate of single agent sunitinib (sunitinib malate) in patients with
iodine refractory, unresectable well-differentiated thyroid cancer (WDTC) who have evidence
of disease progression within 6 months of study enrollment.

II. Determine the response rate of single agent sunitinib in patients with medullary thyroid
cancer (MTC) who have evidence of disease progression within 6 months of study enrollment.

III. Determine the toxicity, duration of response, progression free survival, and overall
survival in patients with WDTC or MTC treated with single agent sunitinib.

IV. Determine whether the presence of ret proto-oncogene (RET) gene rearrangements in
patients with WDTC or RET mutations in patients with MTC predict response to sunitinib.

V. Determine whether therapy with sunitinib affects phosphorylation of downstream RET
effector, mitogen-activated protein kinase 1 (ERK), in WDTC and MTC tissue.

VI. Determine whether specific germ-line polymorphisms in the RET gene are associated with
favorable outcome in patients with WDTC treated with sunitinib.

OUTLINE: Patients are assigned to 1 of 2 cohorts according to type of thyroid cancer
(medullary vs well-differentiated).

Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Courses repeat
every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed papillary, follicular, or
Hurthle cell carcinoma (cohort A) or medullary thyroid carcinoma (cohort B); their
disease must have progressed despite treatment with iodine-131 therapy or they are not
candidates for iodine-131 therapy and their disease cannot be completely removed by
surgery; all patients with WDTC are expected to be on thyroxine suppression therapy

- Patients must have radiographically or biochemically measurable disease;
radiographically measurable disease is defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT)
scan; biochemically measurable disease is defined as an elevated thyroglobulin (WDTC
patients) or calcitonin (MTC patients)

- Patients must have evidence of disease progression (objective growth of existing
tumors or rising thyroglobulin or calcitonin levels) within the last 6 months

- Patients cannot have received prior receptor tyrosine kinase inhibitors; patients
cannot have received more than one prior chemotherapy regimen for metastatic disease;
patients cannot have received prior external beam radiation to the measured tumor
constituting the target lesion(s)

- Life expectancy of greater than 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Serum calcium =< 12.0 mg/dL

- Total serum bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal OR =< 5 X institutional upper limit of
normal if patient has liver metastases

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Patients must have corrected QT interval (QTc) < 500 msec

- The following groups of patients are eligible provided they have New York Heart
Association class II (NYHA) cardiac function on baseline echocardiogram
(ECHO)/multigated acquisition scan (MUGA):

- Those with a history of class II heart failure who are asymptomatic on treatment

- Those with prior anthracycline exposure

- Those who have received central thoracic radiation that included the heart in the
radiotherapy port

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; all women of childbearing potential must have a
negative pregnancy test prior to receiving sunitinib; 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:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (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 more than 4 weeks earlier; at
least 4 weeks must have elapsed since any major surgery

- Patients may not be receiving any other investigational agents

- Patients who have received prior treatment with any other antiangiogenic agent (e.g.,
bevacizumab, sorafenib, pazopanib, AZD2171, PTK787, vascular endothelial growth factor
[VEGF] Trap, etc.)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sunitinib

- Patients with QTc prolongation (defined as a QTc interval equal to or greater than 500
msec), serious ventricular arrhythmia (ventricular fibrillation or ventricular
tachycardia greater than or equal to 3 beats in a row) or other significant
electrocardiogram (ECG) abnormalities are excluded

- Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg or
higher or diastolic blood pressure of 90 mmHg or higher) are ineligible

- Patients who require use of therapeutic doses of Coumarin-derivative anticoagulants
such as warfarin are excluded, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis; Note: Low molecular weight heparin is permitted provided
the patient's prothrombin time (PT) international normalized ratio (INR) is =< 1.5

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for intravenous [IV] alimentation,
prior surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow and retain sunitinib tablets are excluded

- Patients with any of the following conditions are excluded:

- Serious or non-healing wound, ulcer, or bone fracture

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days of treatment

- Any history of cerebrovascular accident (CVA) or transient ischemic attack within
12 months prior to study entry

- History of myocardial infarction, cardiac arrhythmia, stable/unstable angina,
symptomatic congestive heart failure, or coronary/peripheral artery bypass graft
or stenting within 12 months prior to study entry

- History of pulmonary embolism within the past 12 months

- Class III or IV heart failure as defined by the NYHA functional classification
system

- The eligibility of patients taking medications that are potent inducers or inhibitors
of that enzyme will be determined following a review of their case by the principal
investigator; every effort should be made to switch patients taking such agents or
substances to other medications, particularly patients with gliomas or brain
metastases who are taking enzyme-inducing anticonvulsant agents

- Patients with known brain metastases should be excluded; N.B.: Patients with brain
metastases with stable neurologic status following local therapy (surgery or
radiation) for at least 8 weeks from definitive therapy and without neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events
are eligible for participation; patients cannot be receiving enzyme inducing
anti-convulsants including carbamazepine, phenobarbital, and phenytoin

- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infections or psychiatric illness/social situations that would limit
compliance with study requirements are ineligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with sunitinib malate

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- Patients with conditions classified as NYHA III or IV per the New York Heart
Association classifications