Clinical trial NCT00729157: Aflibercept in Treating Patients With Recurrent and/or Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-08-07
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free Survival to Determine the 6-month Progression-free-survival (PFS) Rate
timeFrame: 6 months
measure: Radiographic Response Rate of Aflibercept in Patients With Recurrent and/or Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy
timeFrame: After 8 weeks of study therapy
Secondary outcomes:
measure: The Safety and Toxicity Profile of IV VEGF Trap in Patients With Recurrent and/or Metastatic TC-FCO
timeFrame: From the beginning of treatment through 30 days until participant comes off study
measure: 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.
timeFrame: 8 weeks
measure: Effect of Thyroglobulin Concentration on Progression-free Survival
timeFrame: 6 months
Other outcomes:
measure: 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.
timeFrame: Baseline-6 months post treatment
measure: 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)
timeFrame: 8 weeks
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: David Pfister
role: PRINCIPAL_INVESTIGATOR
References: