Ferumoxytol in Improving MR Imaging in Patients With High-Grade Brain Tumors or Cerebral Metastases

Study Overview
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Brief Summary
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This clinical trial studies magnetic resonance imaging (MRI) using a contrast imaging agent ferumoxytol (ferumoxytol non-stoichiometric magnetite) in improving viewing tumors in patients with high-grade brain tumors or cancer that has spread to the brain. Diagnostic procedures, such as MRI, may help find and diagnose brain tumors and find out how far the disease has spread. The contrast imaging agent ferumoxytol non-stoichiometric magnetite consists of small iron particles taken by the blood stream to the brain and to the area of the tumor. It may help visualize the blood flow going through the tumor better than the standard substance gadolinium-based contrast agent.

Detailed Description
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PRIMARY OBJECTIVES: I. Investigate the utility of ferumoxytol and gadolinium-based contrast agent (GBCA) for improved imaging biomarkers of malignant brain tumors in a single imaging session by comparing dynamic susceptibility contrast (DSC) determined relative cerebral blood volume (rCBV) and dynamic contrast enhancement (DCE) determined vascular permeability (derived transfer coefficient [Ktrans]). SECONDARY OBJECTIVES: I. Compare and evaluate magnetic resonance angiography (MRA) with ferumoxytol between different time points. II. Assess number and size of tumors imaged. III. Assess tumor vascularity. IV. Assess histology and electron microscopy (EM) on tissue samples. V. Assess differences in subjects with prior therapy versus (vs.) no prior therapy (radiation and/or chemotherapy). VI. Assess the long term imaging characteristics of different tumors using DSC and DCE. OUTLINE: Patients receive ferumoxytol non-stoichiometric magnetite intravenously (IV) beginning approximately 15 seconds after start of 3T DSC-MRI and GBCA IV approximately 1 minute and 50 seconds after start of 3T DCE-MRI on day 1. Patients also undergo MRI without contrast at baseline and on day 2. Imaging with ferumoxytol, GBCA, and without contrast repeats every 3 weeks for a total of 6 more imaging sessions over up to 5 years. After completion of study, patients are followed up at approximately 4-6 weeks.

Official Title
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NCI-Sponsored Multi-Disciplinary Study for MR Imaging of Intravenous Superparamagnetic Crystalline Particle Ferumoxytol in Primary High-Grade Brain Tumors and/or Cerebral Metastases

Conditions
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Central Nervous System Lymphoma, Malignant Glioma, Metastatic Malignant Neoplasm in the Brain

Intervention / Treatment
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* Procedure: 3 Tesla Magnetic Resonance Imaging
* Procedure: Dynamic Contrast-Enhanced Magnetic Resonance Imaging
* Procedure: Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging
* Drug: Ferumoxytol
* Drug: Gadolinium
* Procedure: MRI-Based Angiogram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have either radiological or established histological diagnosis of the following general categories: High-grade glioma/central nervous system (CNS) lymphoma or Brain metastases Previously untreated subjects must have a lesion on an imaging study Post treatment subjects will have radiographic abnormalities that may or may not be recurrent tumor Subjects agree to be contacted 4-6 weeks after each study visit Subjects, or their legal guardian, must sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization in accordance with institutional guidelines Sexually active women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study treatment and for the duration of study treatment; should a female become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Pre-imaging radiological scans/studies must be performed approximately 16 weeks prior to study entry; but not less than 24 hours prior Exclusion Criteria: Subjects with clinically significant signs of uncal herniation, such as acute pupillary enlargement, rapidly developing motor changes (over hours), or rapidly decreasing level of consciousness, are not eligible Subjects with known allergic or hypersensitivity reactions to parenteral iron, parenteral dextran, parenteral iron-dextran, or parenteral iron-polysaccharide preparations (Ferumoxytol Investigator's Drug Brochure, 2012); subjects with significant drug or other allergies or autoimmune diseases may be enrolled at the investigator's discretion Subjects who are pregnant or lactating or who suspect they might be pregnant Subjects who require monitored anesthesia for MRI scanning Subjects with renal insufficiency; glomerular filtration rate (GFR) < 50 Subjects who have a contraindication for MRI: metal in their bodies (a cardiac pacemaker or other incompatible device), are severely agitated, or have an allergy to gadolinium (Gd) contrast material Subjects with known hepatic insufficiency or cirrhosis Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible Subjects with known or suspected iron overload (genetic hemochromatosis or history of multiple transfusions) Subjects with three or more drug allergies from separate drug classes

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diagnostic (ferumoxytol, gadolinium, DCE-MRI, DSC-MRI)<br>Study patients: adult patients with high grade primary malignant brain tumors or with known or suspected brain metastases from histologically confirmed primary cancer Study procedures: patients will receive IV ferumoxytol (maximum dose 4 mg/kg, over at least 15 minutes) beginning approximately 15 seconds after start of 3T DSC-MRI and GBCA IV approximately 1 minute and 50 seconds after start of 3T DCE-MRI on day 1. Patients will also undergo MRI without contrast at baseline (before and on day 2. Imaging with ferumoxytol, GBCA and without contrast repeats every 3 weeks for a total of 6 more imaging sessions over up to 5 years. 3 Tesla Magnetic Resonance Imaging: Undergo 3T MRI Dynamic Contrast-Enhanced Magnetic Resonance Imaging: Undergo 3T DCE-MRI Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging: Undergo 3T DSC-MRI Ferumoxytol: Given IV Gadolinium: Given IV MRI-Based Angiogram: Undergo MRA | Procedure: 3 Tesla Magnetic Resonance Imaging<br>* Undergo 3T MRI<br>* Other names: 3T MRI;Procedure: Dynamic Contrast-Enhanced Magnetic Resonance Imaging<br>* Undergo 3T DCE-MRI<br>* Other names: DYNAMIC CONTRAST ENHANCED MRI;Procedure: Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging<br>* Undergo 3T DSC-MRI<br>* Other names: Dynamic Susceptibility Contrast-Enhanced MRI;Drug: Ferumoxytol<br>* Given IV<br>* Other names: FERUMOXYTOL NON-STOICHIOMETRIC MAGNETITE;Drug: Gadolinium<br>* Given IV<br>* Other names: Gd;Procedure: MRI-Based Angiogram<br>* Undergo MRA<br>* Other names: MRA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Utility of Femumoxytol and Gadolinium Based Contrast Agents for Improved Imaging Biomarkers of Malignant Brain Tumors in a Single Session by Comparing Dynamic Contrast Enhanced Determined Vascular Permeability (Ktrans) | Appropriate descriptive statistics (mean, standard deviation, minimum, median, and maximum) will be estimated for the imaging parameters Ktrans. Frequency distributions of each parameter will also be described to assess normality. Pearson's correlation coefficients will be estimated to describe potential relationships among these various measures. | Assessed after each visit for up to 6 imaging sessions (up to 5 years) | 
| Utility of Ferumoxytol and Gadolinium Based Contrast Agents for Improved Imaging Biomarkers of Malignant Brain Tumors in a Single Imaging Session by Comparing Dynamic Susceptibility Contrast (DSC) Determined Relative Cerebral Blood Volume (rCBV) Maps. | Compare rCBV measurements in regions of interest obtained from ferumoxytol DSC-MRI with gadolinium based contrast agent (GBCA) MR images to evaluate vascular properties of brain tumors. CBV maps were generated by applying tracer kinetic model to the first pass of the contrast bolus. Voxelwise CBV maps were coregistered to T1 weighted images and then normalized by dividing by the mean of normal appearing white matter CBV in the same region in the contralateral hemisphere. RCBV values (as the area under the signal intensity curve, normalized by the area under the curve for the control region) were obtained. Values range from 0 (low intensity) to 180 (highest intensity). | Summarized after completion of up to 6 imaging sessions (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Cube Root Volume) | We analyzed 193 sets of post-gadoteriol and 24 hours post-ferumoxytol T1 weighted scans from 58 patient with high grade glioma. Enhancement volumes normalized to normal appearing white matter were calculated with histogram analysis. Enhancement cube root volumes were compared between the two contrast agents. Ferumoxytol and gadolinium enhanced MR images were obtained from each participant. | Summarized after completion of up to 6 imaging sessions (up to 5 years) | 
| Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Signal Intensity) | We analyzed 193 sets of post-gadoteriol and 24 hours post-ferumoxytol T1 weighted scans from 58 patient with high grade glioma. Signal intensities normalized to normal appearing white matter were calculated with histogram analysis. Signal intensities were compared between the two contrast agents. Ferumoxytol and gadolinium enhanced MR images were obtained from each participant. Signal intensities were normalized to the signal intensity value of non-enhancing voxels inside the manual ROI (the relative complement of the final mask in Q, i.e. Q \ [A ∩ B ∩ C]). Higher values in signal intensity indicated increased image enhancement. | Summarized after completion of up to 6 imaging sessions (up to 5 years) | 
| Overall Survival in Participants With Pseudoprogression With or Real Tumor Progression Using Ferumoxytol Enchanced Perfusion MRI | We evaluated overall survival in patients with pseudopregression or real tumor progression by using relative cerebral blood volume values on ferumoxytol enhanced perfusion MRIs. | Assessed after each visit for up to 6 imaging sessions (up to 5 years) |