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
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
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.
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.
Inclusion Criteria:
Histopathologically confirmed differentiated thyroid carcinoma of follicular cell origin, including any of the following histologies and their respective variants:
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):
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:
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
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
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 surgery
Concurrent therapeutic-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed provided that both of the following criteria are met:
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