• Radiographic response rate as assessed by RECIST criteria after completion of 8 weeks of study therapy [ Designated as safety issue: No ]
  
• 6-month progression-free survival rate [ Designated as safety issue: No ]
  

• Safety and toxicity profile, in terms of adverse events, laboratory data, and vital sign data [ Designated as safety issue: Yes ]
  
• Biologic effect of aflibercept on fludeoxyglucose F 18 avidity at 8 weeks [ Designated as safety issue: No ]
  
• Correlation of thyroglobulin concentration with radiographic response at 8 weeks [ Designated as safety issue: No ]
  
• Correlation of thyroglobulin concentration with progression-free survival at 6 months [ Designated as safety issue: No ]
  
• Correlation of pre-treatment serum aflibercept concentration with clinical outcomes after therapy [ Designated as safety issue: No ]
  
• Pharmacokinetics [ Designated as safety issue: No ]
  
• Development of aflibercept antibodies [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine the radiographic response rate, per RECIST criteria, in patients with recurrent and/or metastatic, radioactive iodine-refractory, differentiated thyroid carcinoma of follicular cell origin after completion of 8 weeks of intravenous aflibercept therapy.
• To determine the 6-month progression-free survival rate in patients treated with this drug.

Secondary

• To determine the safety and toxicity profile of this drug in these patients.
• To determine the biologic effect of this drug on fludeoxyglucose F 18 (FDG) avidity after 8 weeks of therapy in these patients using pre- and post-treatment FDG-PET scans.
• To correlate thyroglobulin concentration with radiographic response at 8 weeks and progression-free survival at 6 months in patients treated with this drug.
• To correlate pre-treatment serum VEGF concentration with clinical outcomes after therapy in these patients.

Tertiary

• To determine the population pharmacokinetics of this drug in these patients.
• To determine whether antibodies to this drug develop in these patients.

OUTLINE: Patients receive aflibercept IV over 1 hour on day 1. Treatment repeats every 14 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients experiencing clear clinical benefit with aflibercept may continue treatment beyond 12 months, at the discretion of the study sponsor.

Patients undergo fludeoxyglucose F 18 (FDG)-PET scans at baseline and after 8 weeks of study therapy to evaluate changes in FDG avidity on FDG-PET scan. Blood samples are obtained at baseline and periodically during study for laboratory correlative studies. Samples are examined for pretreatment serum VEGF concentration, thyroglobulin levels (when elevated) after 8 weeks of therapy, serum pharmacokinetics of aflibercept by ELISA, and anti-aflibercept antibodies.

After completion of study therapy, patients are followed for up to 3 months.

DISEASE CHARACTERISTICS:

• Histopathologically confirmed differentiated thyroid carcinoma of follicular cell origin, including any of the following histologies and their respective variants:

  • Papillary
  • Follicular
  • Hürthle cell
• Must have surgically inoperable and/or recurrent or metastatic disease
• At least one fludeoxyglucose F 18 (FDG)-PET-avid lesion, defined as any focus of increased FDG uptake > normal mediastinal activity with standard uptake variable (SUV) maximum levels ≥ 3, as documented by baseline PET scan
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan

• Progressive disease, defined by ≥ 1 of the following occurring during or after prior treatment (e.g., radioactive isotope [RAI] treatment):

  • Presence of new or progressive lesions on CT scan or MRI
  • New lesions on bone scan or PET scan
  • Rising thyroglobulin level documented by a minimum of 3 consecutive rises, with an interval of > 1 week between each determination

• Refractory to RAI, as defined by one of the following:

  • Absent or insufficient RAI uptake in either all lesions and/or the index lesion (e.g., dominant mass) as documented by whole body RAI scan < 6 months prior to initiation of therapy on this protocol

    • Insufficient uptake will be defined as "faint" or "minimal" based on independent assessment by 2 observers from either endocrinology or nuclear medicine

      • In the setting of insufficient uptake, ≥ 1 evaluable lesion with absent RAI uptake must be present

  • Progression of disease after RAI treatment, as defined above

    • RAI treatment must occur within 6 months of repeat imaging and/or thyroglobulin testing
  • FDG-avid lesions via PET scan
• No known history of brain metastasis

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• ANC ≥ 1,500/mcL
• Platelet count ≥ 75,000/mcL
• WBC ≥ 3,000/mcL
• Total bilirubin ≤ 1.5 times upper limit of normal(ULN)
• AST and ALT ≤ 2.5 times ULN
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• INR ≤ 1.2 (≤ 1.5 times ULN if on prophylactic-dose anticoagulation)
• Urine protein:creatinine ratio < 1 OR 24-hour urine protein < 500 mg
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• Must have documentation of stable blood pressure on 3 separate days prior to the start of treatment, including the reading at the screening visit and two historical readings within the past 3 months
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to other agents used in the study
• No serious or non-healing wound, ulcer, or bone fracture
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess in the past 28 days
• No significant traumatic injury within the past 28 days

• No clinically significant cardiovascular disease, defined as any of the following:

  • Cerebrovascular accident within the past 6 months
  • Uncontrolled hypertension, defined as systolic blood pressure > 180 mm Hg OR diastolic blood pressure > 105 mm Hg on ≥ 2 repeated determinations on separate days within the past 3 months
  • Myocardial infarction within the past 6 months
  • Coronary artery bypass grafting or unstable angina within the past 6 months
  • NYHA grade III-IV congestive heart failure
  • Serious cardiac arrhythmia requiring anti-arrhythmic medication
  • Canadian Cardiovascular Class grade III or greater angina within the past 6 months
  • Clinically significant peripheral vascular disease within the past 6 months
  • Pulmonary embolism, deep-vein thrombosis, or other thromboembolic event within the past 6 months
  • Uncontrolled coronary artery disease, angina, congestive heart failure, or ventricular arrhythmia requiring acute medical management
  • Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months
• No evidence of bleeding diathesis or coagulopathy
• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness or social situation that would limit study compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior therapy
• No prior VEGF-targeted antibody therapy (e.g., bevacizumab or aflibercept)
• More than 4 weeks since prior systemic therapy or radiotherapy
• More than 7 days since prior core biopsy
• Up to 1 prior targeted biologic agent (e.g., small-molecule tyrosine kinase inhibitor or histone deacetylase inhibitor) allowed provided treatment was stopped ≥ 4 weeks prior to initiation of therapy on this study
• Up to 1 prior cytotoxic chemotherapy (e.g., doxorubicin hydrochloride) allowed provided treatment was stopped ≥ 4 weeks prior to initiation of therapy on this study
• Prior systemic chemotherapy administered as part of initial definitive treatment (e.g., as a radiation sensitizer or as initial adjuvant therapy) allowed provided treatment was stopped ≥ 3 months prior to initiation of therapy on this study and does not count in the determination of prior targeted or cytotoxic therapy

• At least 4 weeks since prior cyclooxygenase-2 (COX-2) inhibitors, cis-retinoic acid, or complementary medications, even if given with anti-cancer intent

  • Medications given for a specific clinical indication (e.g., daily aspirin status post myocardial infarction or COX-2 inhibitors at standard anti-inflammatory/pain doses) may be continued based on the clinical judgment of the involved investigator

• Prior RAI therapy allowed provided it was stopped > 3 months prior to initiation of therapy on this protocol and evidence of progression (as defined above) has been documented in the interim

  • A diagnostic study using < 10 mCi of RAI is not considered RAI therapy

• Prior external-beam radiotherapy to index lesions allowed provided there has been documented progression by RECIST criteria and at least 4 weeks have elapsed

  • At least 4 weeks since prior external-beam radiation therapy to non-index lesions
• At least 4 weeks since prior surgery

• Concurrent therapeutic-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed provided that both of the following criteria are met:

  • In-range INR appropriate to the treatment indication (e.g., between 2 and 3 for atrial fibrillation) AND on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
  • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
• Patients receiving concurrent antihypertensive agents must have documentation of the date of the last change in dosage
• No other concurrent investigational agents
• No major surgical procedure or open biopsy within the past 28 days
• No anticipation of need for major surgical procedures during the course of the study