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

Phase 2

Terminated

Conditions: Metastatic Malignant Neoplasm in the Brain
Primary Brain Neoplasm

Interventions: 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

Registration Number: NCT00659126

Lead Sponsor: OHSU Knight Cancer Institute

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 40

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging	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.
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	Ferumoxytol	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.
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	3 Tesla Magnetic Resonance Imaging	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.
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	Dynamic Contrast-Enhanced Magnetic Resonance Imaging	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.
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	Susceptibility Weighted Imaging	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.
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	High Field Strength Magnetic Resonance Imaging	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.
Diagnostic (Gd, ferumoxytol, 3T or 7T MRI)	Gadolinium	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.

Primary Outcome Measures

Name	Time	Method
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)	Baseline to day 1	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.
CNR, in Terms of Normalized Signal Intensity Changes, for Dynamic Susceptibility Contrast (DSC) MRI Data Sets at 3T and 7T (Gadolinium and Ferumoxytol)	Day 1 to day 2	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).

Secondary Outcome Measures

Name	Time	Method
Presence of Iron Staining	At time of surgery	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.
Change in Cerebral Blood Volume (CBV) Measurements, Quantified Using DSC Techniques	Day 1 to day 2	Blood volumes will be compared using repeated measures ANOVA to compare the imaging agents.
Change in Tumor Microvascularity on Susceptibility-weighted Images (SWI) Before and After Ferumoxytol	Day 1 to day 2	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.
Relevant Dynamic MRI (Dynamic Contrast Enhancement [DCE] and DSC) Signal Intensity Changes for Permeability and Perfusion	Day 1 to day 2	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).