Ferumoxytol- and Gadolinium-Labeled MRI in Measuring Tumors Before or After Treatment in Patients With Primary or Metastatic Brain Tumors

Study Overview
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Brief Summary
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This phase II trial studies how well magnetic resonance imaging (MRI) using contrast imaging agent ferumoxytol works in comparison to standard imaging agent gadolinium in measuring tumors in patients undergoing treatment for brain tumors or other tumors that have spread to the brain. Diagnostic procedures, such as MRI, may help find and diagnose disease and find out how far the disease has spread. MRI scans use radio waves and a powerful magnet linked to a computer to create detailed pictures of areas inside the body. The contrast imaging agent ferumoxytol consists of small iron particles taken by the blood stream to the brain and to the area of the tumor. It is highly visible on the MRI, and may help visualize the blood flow going through the tumor better than gadolinium can. Using a more sensitive and faster 7 Tesla (7T) magnet MRI in conjunction with a contrast imaging agent may provide a better way to measure tumors than the 3 Tesla (3T) magnet MRI in patients with brain tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare quantitative blood brain barrier permeability measurements (derived transfer coefficient [Ktrans]) of a standard gadolinium (Gd) MRI contrast agent at 3T and 7T using dynamic contrast enhancement (DCE) MRI. II. To compare dynamic susceptibility contrast (DSC) based perfusion measures at 3T and 7T. SECONDARY OBJECTIVES: I. To describe the blood brain barrier permeability to ferumoxytol (ferumoxytol non-stoichiometric magnetite) and to a standard gadolinium-based MRI contrast agent using signal intensity changes as described above. II. To describe cerebral blood volume (CBV) measurements obtained using a standard gadolinium MRI contrast agent and ferumoxytol. III. To evaluate tumor microvascularity on susceptibility-weighted images (SWI). IV. To describe the microscopic distribution of ferumoxytol particles in tissue removed from subjects undergoing surgery. OUTLINE: Patients are assigned to 3T or 7T magnet within the subgroups. Patients receive gadolinium intravenously (IV) on day 1 and ferumoxytol non-stoichiometric magnetite IV on day 2. Patients undergo anatomical MRI sequences with 3T or 7T at baseline and on days 1-3. Patients also undergo DSC MRI and DCE MRI on days 1-2. Day 1 and day 2 imaging sessions may be separated by up to 7 days. After completion of study, patients are followed up at approximately 4-6 weeks.

Official Title
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A Phase II Study of Ferumoxytol and Gadolinium Magnetic Resonance Imaging at 3T and 7T in Subjects With Primary or Metastatic Brain Tumors Either Before or After Therapy

Conditions
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Metastatic Malignant Neoplasm in the Brain, Primary Brain Neoplasm

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: High Field Strength Magnetic Resonance Imaging
* Procedure: Susceptibility Weighted Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with radiographically suspected, histologically or cytologically confirmed primary brain tumors or brain metastasis are eligible Subjects may be enrolled at any point in diagnosis or treatment Subjects must have had radiographically evaluable or measurable disease with standard magnetic resonance (MR) imaging Members of all races and ethnic groups will be included Eastern Cooperative Oncology Group (ECOG) performance status =< 3 (Karnofsky performance status [KPS] >= 30) Ability to understand and the willingness to sign a written informed consent document, or have a representative able to consent for the subject 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 Subject agrees to complete follow up visit 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 Subjects who have a contraindication for MRI: metal in their bodies (a cardiac pacemaker or other incompatible device), are severely agitated, need monitored anesthesia for scanning, or have an allergy to Gd contrast material Subjects with known hepatic insufficiency or cirrhosis History of allergic reactions attributed to compounds of similar chemical or biologic composition to ferumoxytol Subjects with known or suspected iron overload (genetic hemochromatosis or history of multiple transfusions) Subjects expecting to undergo surgery between the imaging sessions; subjects may undergo surgery at any time before the first, or after the last imaging session; this exclusion only applies to each study visit (3 day scanning session), and does not apply to the time (at least 3 weeks) between each study visit Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or lactating women are excluded from this study Inability or unwillingness to undergo the complete series of imaging sessions; inability or unwillingness to complete the one month follow-up Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible Subjects with glomerular filtration rate (GFR) < 50 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 (Gd, ferumoxytol, 3T or 7T MRI)<br>Patients receive gadolinium IV on day 1 and ferumoxytol non-stoichiometric magnetite IV on day 2. Patients undergo anatomical MRI sequences with 3T or 7T at baseline and on days 1-3. Patients also undergo DSC MRI and DCE MRI on days 1-2. Day 1 and day 2 imaging sessions may be separated by up to 7 days. | Procedure: 3 Tesla Magnetic Resonance Imaging<br>* Undergo 3T MRI<br>* Other names: 3T MRI;Procedure: Dynamic Contrast-Enhanced Magnetic Resonance Imaging<br>* Undergo DCE MRI<br>* Other names: DYNAMIC CONTRAST ENHANCED MRI;Procedure: Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging<br>* Undergo DSC MRI<br>* Other names: DYNAMIC SUSCEPTIBILITY-CONTRAST MRI;Drug: Ferumoxytol<br>* Given IV<br>* Other names: Ferumoxytol Non-Stoichiometric Magnetite;Drug: Gadolinium<br>* Given IV<br>* Other names: Gd;Procedure: High Field Strength Magnetic Resonance Imaging<br>* Undergo 7T MRI<br>* Other names: High Field Strength MRI;Procedure: Susceptibility Weighted Imaging<br>* Undergo SWI<br>* Other names: SWI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contrast to Noise Ratio (CNR), in Terms of Normalized Signal Intensity Changes, for T1-weighted MRI Signal at 3T and 7T (Gadolinium [Gd] T1-weighted Magnetic Resonance Imaging [MRI] DCE Data Only) | Paired sample t-tests will be used for primary descriptive comparisons. Secondary analyses will use a repeated measures analysis of variance (ANOVA) model to compare 3T and 7T while adjusting for other factors including tumor type, prior therapy, and, potentially, important baseline factors that differ between the subjects assigned to the two field strengths. Normality will be assessed graphically and, if needed, a transformation (e.g. the logarithmic transform) will be applied. | Baseline to day 1 | 
| CNR, in Terms of Normalized Signal Intensity Changes, for Dynamic Susceptibility Contrast (DSC) MRI Data Sets at 3T and 7T (Gadolinium and Ferumoxytol) | A two sample t-test was used for primary descriptive comparisons since CNR was measured on different subjects at 3T and 7T. There were no repeated measures in the resulting data. Given the small sample size, a linear regression was conducted to compare CNR between 3T and 7T only adjusted for Fe dose. No other adjusted analyses were conducted. CNR was compared between 3T and 7T for both Ferumoxytol and Gadolinum. Ferumoxytol was administered using three injections and CNR was measured after each injection, thus we have three measures of CNR (Fe1CNR, Fe2CNR and Fe3CNR). | Day 1 to day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relevant Dynamic MRI (Dynamic Contrast Enhancement [DCE] and DSC) Signal Intensity Changes for Permeability and Perfusion | Mixed model repeated measures ANOVAs will be fit. Factors will include imaging agent (Gd or ferumoxytol) and field strength (3T and 7T). Each subject will contribute one measure for each combination of imaging agent and field strength (4 measures total). | Day 1 to day 2 | 
| Change in Cerebral Blood Volume (CBV) Measurements, Quantified Using DSC Techniques | Blood volumes will be compared using repeated measures ANOVA to compare the imaging agents. | Day 1 to day 2 | 
| Change in Tumor Microvascularity on Susceptibility-weighted Images (SWI) Before and After Ferumoxytol | Analysis will also include covariates of prior therapy. For the comparisons between treated and untreated subjects, means and confidence intervals will be estimated for each group for the perfusion and permeability measures and for the baseline characteristics. | Day 1 to day 2 | 
| Presence of Iron Staining | The pathology will be analyzed qualitatively for the presence of iron staining. The amount and localization of the staining will be assessed, with attention paid to whether the tumor cells themselves or reactive cells in and around the tumor demonstrate iron uptake. | At time of surgery |