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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Recurrent Thyroid Cancer, Stage III Follicular Thyroid Cancer, Stage III Papillary Thyroid Cancer, Stage IV Follicular Thyroid Cancer, Stage IV Papillary Thyroid Cancer

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Radiographic response rate of aflibercept in patients with recurrent and/or metastatic thyroid cancer that did not respond to radioactive iodine therapy

Outcome Description:

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.

Outcome Time Frame:

After 8 weeks of study therapy

Safety Issue:

No

Principal Investigator

David Pfister

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00178

NCT ID:

NCT00729157

Start Date:

August 2008

Completion Date:

Related Keywords:

  • Recurrent Thyroid Cancer
  • Stage III Follicular Thyroid Cancer
  • Stage III Papillary Thyroid Cancer
  • Stage IV Follicular Thyroid Cancer
  • Stage IV Papillary Thyroid Cancer
  • Thyroid Neoplasms
  • Thyroid Diseases
  • Adenocarcinoma, Follicular

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021