Aflibercept in Treating Patients With Recurrent and/or Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy

Study Overview
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Brief Summary
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This phase II trial is studying how well aflibercept works in treating patients with recurrent and/or metastatic thyroid cancer that has not responded to radioactive iodine therapy. Aflibercept may stop the growth of tumor cells by blocking blood flow to the tumor and by carrying tumor-killing substances directly to thyroid cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the radiographic response rate (by RECIST criteria) of IV VEGF Trap after four cycles (approximately 8 weeks) of therapy, as well as the 6-month progression-free-survival (PFS) rate (as part of a composite primary outcome measure), in patients with recurrent and/or metastatic differentiated thyroid carcinoma of follicular cell origin (D-TC-FCO; comprising papillary, follicular, Hurthle cell, and respective variants) not amenable to RAI or curative surgery. SECONDARY OBJECTIVES: I. To determine the safety and toxicity profile of IV VEGF Trap in patients with recurrent and/or metastatic TC-FCO. Please see the adverse event table for the specifics for this protocol. II. To determine the biologic effect of IV VEGF Trap on FDG avidity after four cycles (approximately 8 weeks) of therapy through pre- and post-treatment FDG-PET scans in patients with recurrent and/or metastatic D-TC-FCO. III. To determine if changes in thyroglobulin concentration after four cycles (approximately 8 weeks) of IV VEGF-Trap therapy correlate with radiographic response after four cycles (approximately 8 weeks) and progression-free-survival at 6 months after start of therapy in patients with recurrent and/or metastatic D-TC-FCO. IV. To determine if pre-treatment serum VEGF concentration correlates with clinical outcomes after IV VEGF Trap therapy in patients with recurrent and/or metastatic D-TC-FCO. TERTIARY OBJECTIVES: I. To determine population pharmacokinetics of IV VEGF Trap for patients with thyroid cancer. II. To determine whether antibodies to VEGF Trap develop in patients with thyroid cancer. OUTLINE: Patients receive aflibercept intravenously (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), serum pharmacokinetics of aflibercept by ELISA, and anti-aflibercept antibodies. After completion of study therapy, patients are followed up for 2-4 months.

Official Title
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A Phase II Study of Single Agent Intravenous (IV) VEGF Trap in Patients With Poor Prognostic Recurrent and/or Metastatic Thyroid Cancer After RAI Therapy

Conditions
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Recurrent Thyroid Gland Carcinoma, Stage III Thyroid Gland Follicular Carcinoma, Stage III Thyroid Gland Papillary Carcinoma, Stage IV Thyroid Gland Follicular Carcinoma, Stage IV Thyroid Gland Papillary Carcinoma

Intervention / Treatment
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* Radiation: Fludeoxyglucose F-18
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Procedure: Positron Emission Tomography
* Biological: Ziv-Aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 No known history of brain metastasis 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 (≤ 5 times ULN for liver metastases) Creatinine ≤ 1.5 times ULNOR 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 Documentation of systolic blood pressure ≤150 mm Hg and diastolic blood pressure ≤100 mm Hg 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 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 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 within the past 12 months No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness or social situation that would limit study compliance No known HIV positivity 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 2 weeks since prior cyclooxygenase-2 (COX-2) inhibitors, cis-retinoic acid, or complementary medications 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

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 (ziv-aflibercept and fludeoxyglucose F 18)<br>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 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), serum pharmacokinetics of aflibercept by ELISA, and anti-aflibercept antibodies. | Radiation: Fludeoxyglucose F-18<br>* Correlative studies<br>* Other names: Fluorodeoxyglucose F18;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Procedure: Positron Emission Tomography<br>* Correlative studies<br>* Other names: proton magnetic resonance spectroscopic imaging;Biological: Ziv-Aflibercept<br>* Given IV<br>* Other names: Zaltrap;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival to Determine the 6-month Progression-free-survival (PFS) Rate | Progression-free survival to determine the 6-month progression-free-survival (PFS) rate | 6 months | 
| Radiographic Response Rate of Aflibercept in Patients With Recurrent and/or Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions & assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + P RMeasurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques (CT, MRI, x-ray) or as ≥ 10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). All other lesions (or sites of disease), including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), & cystic | After 8 weeks of study therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Safety and Toxicity Profile of IV VEGF Trap in Patients With Recurrent and/or Metastatic TC-FCO | The number of participants, with recurrent and/or metastatic TC-FCO, who experienced adverse events. Please see the adverse event table for the specifics for this protocol. | From the beginning of treatment through 30 days until participant comes off study | 
| To Determine the Biologic Effect of IV VEGF Trap on FDG Avidity After Four Cycles (Approximately 8 Weeks) of Therapy Through Pre- and Post-treatment FDG-PET Scans in Patients With Recurrent and/or Metastatic D-TC-FCO. | To determine the biologic effect of IV VEGF Trap on FDG avidity after four cycles (approximately 8 weeks) of therapy through pre- and post-treatment FDG-PET scans in patients with recurrent and/or metastatic D-TC-FCO. | 8 weeks | 
| Effect of Thyroglobulin Concentration on Progression-free Survival | The change is serum thyroglobulin was measured by the percent change between the baseline value and the lowest value obtained while on treatment. | 6 months |