Central Nervous System Lymphoma, Malignant Glioma, Metastatic Malignant Neoplasm in the Brain
Conditions
Brief summary
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
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.
Interventions
PROCEDURE3 Tesla Magnetic Resonance Imaging
Undergo 3T MRI
PROCEDUREDynamic Contrast-Enhanced Magnetic Resonance Imaging
Undergo 3T DCE-MRI
Undergo 3T DSC-MRI
DRUGFerumoxytol
Given IV
DRUGGadolinium
Given IV
PROCEDUREMRI-Based Angiogram
Undergo MRA
Sponsors
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Assessed after each visit for up to 6 imaging sessions (up to 5 years) | 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. |
| 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. | Summarized after completion of up to 6 imaging sessions (up to 5 years) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Cube Root Volume) | Summarized after completion of up to 6 imaging sessions (up to 5 years) | 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. |
| Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Signal Intensity) | Summarized after completion of up to 6 imaging sessions (up to 5 years) | 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. |
| Overall Survival in Participants With Pseudoprogression With or Real Tumor Progression Using Ferumoxytol Enchanced Perfusion MRI | Assessed after each visit for up to 6 imaging sessions (up to 5 years) | We evaluated overall survival in patients with pseudopregression or real tumor progression by using relative cerebral blood volume values on ferumoxytol enhanced perfusion MRIs. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) 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 | 155 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Screen failure | 3 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) |
|---|---|
| Age, Continuous | 51.71 years STANDARD_DEVIATION 13.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 150 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 147 Participants |
| Sex: Female, Male Female | 70 Participants |
| Sex: Female, Male Male | 85 Participants |
| Type of brain malignancy Anaplastic Astrocytoma | 19 Participants |
| Type of brain malignancy Anaplastic Oligodendroglioma | 19 Participants |
| Type of brain malignancy Brain metastasis | 18 Participants |
| Type of brain malignancy Glioblastoma | 67 Participants |
| Type of brain malignancy Other | 17 Participants |
| Type of brain malignancy Primary CNS Lymphoma | 4 Participants |
| Type of brain malignancy Unknown | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 119 / 155 |
| other Total, other adverse events | 12 / 152 |
| serious Total, serious adverse events | 0 / 152 |
Outcome results
Primary
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.
Time frame: Assessed after each visit for up to 6 imaging sessions (up to 5 years)
Population: Software to derive K trans values from acquired images is not available and enhancement comparison between gadolinium and ferumoxytol K trans values is not possible to date.
Primary
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).
Time frame: Summarized after completion of up to 6 imaging sessions (up to 5 years)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | 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. | Peritumor area gadolinium rCBV | 146 Values on a scale |
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | 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. | Peritumor area ferumoxytol rCBV | 136 Values on a scale |
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | 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. | Tumor area gadolinium rCBV | 39 Values on a scale |
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | 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. | Tumor area ferumoxytol rCBV | 54 Values on a scale |
Secondary
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.
Time frame: Summarized after completion of up to 6 imaging sessions (up to 5 years)
Population: 58 participants had both appropriate ferumoxytol and gadolinium scans available for analysis for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Cube Root Volume) | 21.71 mm | Standard Deviation 6.396 |
| Malignant Brain Tumor Patients Undergoing Brain- Ferumoxytol-enhanced MRI | Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Cube Root Volume) | 18.71 mm | Standard Deviation 6.884 |
Secondary
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.
Time frame: Summarized after completion of up to 6 imaging sessions (up to 5 years)
Population: 58 participants had both appropriate ferumoxytol and gadolinium scans available for analysis for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Signal Intensity) | 1.36 ratio | Standard Deviation 0.107 |
| Malignant Brain Tumor Patients Undergoing Brain- Ferumoxytol-enhanced MRI | Compare Number and Size of Tumors Imaged With Ferumoxytol and Gadolinium Based Contrast Agents (Signal Intensity) | 1.26 ratio | Standard Deviation 0.108 |
Secondary
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.
Time frame: Assessed after each visit for up to 6 imaging sessions (up to 5 years)
Population: 68 participants had appropriate ferumoxytol scans available for analysis for this outcome.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | Overall Survival in Participants With Pseudoprogression With or Real Tumor Progression Using Ferumoxytol Enchanced Perfusion MRI | Median survival in patients with pseudoprogression seen on Fe-MRI | 34.7 months |
| Malignant Brain Tumor Patients Undergoing Brain MRI (With Both Ferumoxytol and Gadolinium) | Overall Survival in Participants With Pseudoprogression With or Real Tumor Progression Using Ferumoxytol Enchanced Perfusion MRI | Median survival in patients with real progression seen on Fe-MRI | 13.4 months |