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

Recurrent Thyroid Gland Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00729157
• Other study ID #: NCI-2009-00178
• Secondary ID: NCI-2009-00178MS
• Status: Completed
• Phase: Phase 2
• First received: August 6, 2008
• Last updated: June 1, 2015
• Start date: August 2008
• Est. completion date: November 2012

Study information

• Verified date: December 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: November 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• 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
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

Radiation:
• Fludeoxyglucose F-18
Correlative studies

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Procedure:
• Positron Emission Tomography
Correlative studies

Biological:
• Ziv-Aflibercept
Given IV

Locations

Country	Name	City	State
United States	Memorial Sloan-Kettering Cancer Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival rate in patients with recurrent and/or metastatic differentiated thyroid carcinoma	Defined as the duration of time from day 1 of treatment to time of disease progression, or death from any cause.	At 6 months	No
Primary	Radiographic response rate of aflibercept in patients with recurrent and/or metastatic thyroid cancer that did not respond to radioactive iodine therapy	Assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed a minimum interval of 4 weeks after the criteria for response are first met.	After 8 weeks of study therapy	No
Secondary	Biologic effect of aflibercept on fludeoxyglucose F 18 avidity	Quantified by maximum SUV and number of lesions. Results will be correlated with cross-sectional and tumor marker response assessments as previously described.	Baseline and 8 weeks after start of study treatment	No
Secondary	Effect of pre-treatment serum VEGF concentration on clinical outcomes after therapy	Analyzed using validated ELISA methods.	Baseline and 8 weeks after start of study treatment	No
Secondary	Effect of thyroglobulin concentration on progression-free survival	If a patient's thyroglobulin antibody is < 20 units/mL, then the serum thyroglobulin does not need to continue to be drawn throughout treatment.	At 6 months	No
Secondary	Effect of thyroglobulin concentration on radiographic response	If a patient's thyroglobulin antibody is < 20 units/mL, then the serum thyroglobulin does not need to continue to be drawn throughout treatment.	Baseline and 8 weeks after start of study treatment	No
Secondary	Safety and toxicity profile of aflibercept in patients with recurrent and/or metastatic thyroid cancer that did not respond to radioactive iodine therapy	Graded using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0. Assessed in terms of AEs, laboratory data and vital sign data.	Up to 4 months post-treatment	Yes