Clinical trial NCT00659126
Conditions: Metastatic Malignant Neoplasm in the Brain Primary Brain Neoplasm
Sponsor: OHSU Knight Cancer Institute
Start date: 2006-11-16; Completion date: 2020-12-31
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: 3 Tesla Magnetic Resonance Imaging intervention 2: Dynamic Contrast-Enhanced Magnetic Resonance Imaging intervention 3: Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging intervention 4: Ferumoxytol intervention 5: Gadolinium intervention 6: High Field Strength Magnetic Resonance Imaging intervention 7: Susceptibility Weighted Imaging
Intervention descriptions: intervention 1: Undergo 3T MRI intervention 2: Undergo DCE MRI intervention 3: Undergo DSC MRI intervention 4: Given IV intervention 5: Given IV intervention 6: Undergo 7T MRI intervention 7: Undergo SWI

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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Oregon Health & Science University 
OHSU Knight Cancer Institute #SOL-06077-L 
OHSU eIRB Protocol #2864  
 
 
 
 
 
NCT#:  NCT00659126 
Supported by the National Cancer Institute (NCI) 
 
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.   
 
Principal Investigator:  
Edward A. Neuwelt, M.D. 
Department of Neurology 
Oregon Health & Science University 
Portland, Oregon  97239 
Telephone:   (503) 494-5626 
Fax:    
(503) 494-5627 
E-mail address:  neuwelte@ohsu.edu  
 
Statistician:   
 
 Rongwei (Rochelle) Fu, Ph.D. 
Department of Public Health and 
Preventive Medicine Oregon Health & Science University  
Portland, Oregon  97239 
Telephone:   (503) 494-2258 
Fax:    
(503) 494-8797 
E-mail address:  fur@ohsu.edu  
 
Study Coordinator /  
Data Manager:  
 
Lisa Muir, MPA, CCRP 
Department of Neurology 
Oregon Health & Science University 
Portland, Oregon  97239 
Telephone:   (503) 494-5626 
Fax:    
(503) 494-5627 
E-mail address:  bennetli@ohsu.edu  
 
Amy Huddleston, MPA 
Department of Neurology 
Oregon Health & Science University 
Portland, Oregon  97239 
Telephone:   (503) 494-5626 
Fax:    
(503) 494-5627 
E-mail address:  Huddlesa@ohsu.edu  
 


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Protocol Version Dates 
Protocol Approval Dates 
Initial:   09-13-2006 
 
Revised:  
Initial Approval:  
11-16-2006 
Revised:  
Approved:  
03-08-2007 
Revised:  
Approved:  
09-20-2007 
Revised 
Approved:  
10-16-2008 
Revised: 
Approved: 
09-17-2009 
Revised: 
Approved: 
01-21-2010 
Revised: 
Approved: 
08-19-2010 
Revised: 
Approved: 
09-29-2010 
Revised: 
Approved: 
07-21-2011 
Revised: 
Approved: 
12-18-2011 
Revised: 
Approved: 
05-09-2012 
Revised: 
Approved: 
07-02-2012 
Revised: 
Approved: 
05-23-2013 
Revised:  
Approved:  
5.22.2014 
Revised:  
Approved:  
8.29.2014 
Revisions:  None for CRQ  
03.09.2015 
Approved: 
4.23.2015 
Revision: 08.27.15: Black Box 
Warning 
Approved:                  11.24.2015 
Revision: 12.3.15; 25 subjects on 7T 
Approved: 3.3.2016 
Revision: 1.27.2017 QA Updates 
Approved: 3.28.2017 
Revision: 6.30.2017 
 
 
 


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Contents 
1 
OBJECTIVES 
6 
1.1 
Primary 
6 
1.2 
Secondary 
6 
2 
BACKGROUND 
6 
2.1 
The blood-brain barrier in CNS tumors 
6 
2.2 
Ferumoxytol 
7 
2.3 
Dynamic Contrast Enhanced (DCE) MR Imaging 
8 
2.4 
Ferumoxytol Pilot Data 
10 
2.5 
Study Rationale 
11 
2.6 
Safety and Preliminary Studies with Ferumoxytol 
12 
3 
SUBJECT SELECTION 
15 
3.1 
Eligibility Criteria 
15 
3.2 
Exclusion Criteria 
16 
4 
CONTRAST AGENT FORMULATION AND PROCUREMENT 
16 
4.1 
Gadolinium 
16 
4.2 
Ferumoxytol 
17 
4.3 
Expected adverse events 
17 
4.4 
Safety 
17 
5 
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
19 
5.1 
Enrollment 
19 
5.2 
Subject Registration 
19 
5.3 
Study Visits 
19 
5.4 
Adverse Events 
20 
5.5 
5.5 Follow-up: 
21 
5.6 
Subject Evaluability 
21 
5.7 
Criteria for early termination from the protocol 
21 
6 
IMAGING SCHEMA AND ACQUISITION 
21 
6.1 
Schema 
21 
1. 
Standard  precontrast anatomical MRI sequences at 3T and/or 7T:  sagittal T1, coronal FLAIR, MPRAGE, 
axial T1, T2, T2*, PD weighted images and DWI. 
22 
2. 
TOF angiography 
22 


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3. 
Quantitative T1 images 
22 
4. 
DSC MRI (T2* weighted) for perfusion with Gd bolus  administration dose: 0.1mmol/kg) 
22 
5. 
Quantitative T1 images for permeability measurement will be performed 4 times 
22 
6. 
TOF angiography (postgadolinium) 
22 
7. 
Standard postgadolinium imaging at 3T and 7T:MPRAGE, axial T1, T2, T2* weighted images. 
22 
6.2 
Schema Options 
23 
6.3 
MR Acquisition Parameters 
24 
7 
CRITERIA FOR EVALUATION USING MRI 
25 
7.1 
Lesion assessment methodology and volumetrics 
25 
7.2 
Perfusion MR 
25 
7.3 
Vascular Permeability measurement 
26 
7.4 
Ferumoxytol delayed MRI enhancement 
26 
7.5 
Diffusion weighted imaging 
26 
7.6 
Time of flight angiography (TOF) 
26 
7.7 
Susceptibility weighted imaging: 
26 
8 
ETHICAL AND REGULATORY REQUIREMENTS 
26 
8.1 
Protocol Review 
26 
8.2 
Informed Consent 
27 
8.3 
Changes to Protocol 
27 
8.4 
Maintenance of Records 
27 
8.5 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
27 
8.6 
MedWatch Reporting 
27 
8.7 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
28 
8.8 
Inclusion of Women, Minorities and Children 
28 
9 
STATISTICAL CONSIDERATIONS 
31 
9.1 
Study Objectives 
31 
9.2 
Baseline Summaries 
31 
9.3 
Descriptive Statistical Analyses 
31 
9.4 
Sample Size 
32 
9.5 
Schema to maintain balance between 3T and & 7T groups 
32 
10 
REFERENCES 
33 
 
 


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1 
OBJECTIVES 
1.1 
Primary  
The goal of this descriptive (not definitive) study is to study an adequate number of 
subjects to evaluate the impact of MRI magnet field strength (3T versus 7T), contrast 
agent (ferumoxytol and gadolinium), tumor size, and tumor permeability on a series of 
imaging measures to monitor and evaluate tumor characteristics.   
 
Following are the specific objectives for this study: 
1.1.1 Primary Aim 1: To compare quantitative blood brain barrier permeability measurements 
(Ktrans) of a standard gadolinium (Gd) MRI contrast agent at 3 T and 7 T using dynamic 
contrast enhancement (DCE) MRI. 
We hypothesize that contrast agent detection sensitivity is improved at 7 T compared to 
3 T, allowing the construction of Ktrans parametric maps with higher precision. The primary 
outcome measure for these analyses will be T1-weighted image contrast to noise ratio 
(CNR), calculated as the signal increase caused by the Gd agent divided by background 
noise. 
1.1.2 Primary Aim 2: To compare dynamic susceptibility contrast (DSC) based perfusion 
measures at 3 T and 7 T. 
We hypothesize that due to increased T2* susceptibility effects the 7 T images will 
provide a higher CNR compared to 3 T images. The primary outcome measure for these 
analyses will be the CNR, calculated as the signal intensity decrease caused by the 
Ferumoxytol bolus, divided by the background noise.  
1.2 
Secondary 
1.2.1 To describe the blood brain barrier permeability to Ferumoxytol and to a standard  
gadolinium-based MRI contrast agent using signal intensity changes as described above. 
1.2.2 To describe cerebral blood volume (CBV) measurements obtained using a standard 
gadolinium MRI contrast agent and ferumoxytol. CBV will be quantified using dynamic 
susceptibility contrast (DSC) techniques with Gd or Ferumoxytol contrast agents. The 
use of DSC techniques with standard Gd MRI contrast agents in tumors with leaky blood 
vessels can lead to inaccurate CBV estimates because of Gd extravasation. We expect 
to obtain lower blood volume estimates with ferumoxytol than with gadolinium in leaky 
tumors. We do not expect significant differences in less leaky tumors. 
1.2.3  To evaluate tumor microvascularity on susceptibility-weighted images (SWI). The 
susceptibility weighted images will be acquired before and after ferumoxytol 
administration to investigate blood vessel visibility within the tumor bed. Morphological 
and caliber differences of intratumoral vessels in comparison to normal cortical 
penetrating vessels will be analyzed. 
1.2.4 To describe the microscopic distribution of ferumoxytol particles in tissue   
 
 
 
2 
BACKGROUND 
2.1 
The blood-brain barrier in CNS tumors 
The BBB is an anatomical feature of CNS capillaries that consists of a continuous layer 
of endothelial cells bound together with tight junctions that allow very little transcellular or 
pericellular leakage of blood-borne molecules (5, 36).  In normal brain, the BBB limits 
permeability based on electric charge and lipid solubility, and normally excludes 
molecules of greater than Mr 180. The neurovascular unit is a new, integrated approach 


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to thinking about and working with the BBB. It is comprised not only the BBB endothelial 
cells but also the basement membrane, pericytes, microglia and astrocytic foot 
processes in the capillary microenvironment. Local environmental and cellular factors 
and the varying integrity of the neurovascular unit impact barrier permeability in tumors of 
the CNS, both before and after treatment. Brain tumors often have a leaky blood-tumor 
barrier (BTB) because the neovasculature in the tumor lacks some BBB characteristics 
(5). The barrier in the brain around malignant tumors can have variable permeability due 
to neovascularization, inflammation, and gliosis. The well-vascularized, actively 
proliferating edge of the tumor is particularly variable and complex in terms of barrier 
integrity (18, 29, 36).   
Cancer treatments such as steroids, chemotherapy, radiotherapy, or anti-angiogenesis 
therapy induce changes in tumor vasculature, tumor permeability, and tumor cell viability. 
 Many of these effects will occur hours to days after treatment, but changes in gross 
tumor volume can only be measured at later times (several days to weeks).  Methods to 
measure early anti-tumor effects would be useful in predicting outcomes and modifying 
therapies to maximize response. 
Cancer therapies can also induce BBB damage and inflammation at the neurovascular 
unit. Systemic chemotherapy can cause subtle cognitive dysfunction in up to 25% of 
cancer patients (1, 49), while radiotherapy of the brain can cause significant 
neuropsychological sequelae (3, 11). Potential mechanisms for radio/chemo toxicity 
include direct neurotoxic effects in the parenchyma, free radical-induced injury of the 
BBB or microvasculature, or secondary immunologic responses causing inflammatory 
reactions.  Combination therapies have the potential for even more toxicity. For example, 
the two most commonly employed regimens for primary CNS lymphoma, whole brain 
radiation therapy (WBRT) and high dose methotrexate (MTX), have a synergistic toxic 
effect when WBRT precedes MTX (10, 38).  One goal of this proposal is to evaluate new 
methods of imaging these phenomena in intracerebral tumor and in normal brain.  
2.2 
Ferumoxytol  
MR imaging of the CNS is usually done with Gadolinium-based contrast agents with a 
short half-life (~30 min in blood), that give rapid and transient imaging of brain vascular 
permeability. The iron oxide nanoparticle MR contrast agents have also shown excellent 
potential for imaging in the CNS (14, 24). These agents consist of an iron oxide core with 
a variable coating that determines cellular uptake and biological half life.  Ferumoxides 
(Feridex IV ®), a clinically approved SPIO, is 60-185 nm in size, partially coated with 
dextran, and is rapidly opsonized and endocytosed (22, 47).  The USPIOs, with particle 
diameters of 20-50 nm, are completely coated either with native dextran (ferumoxtran-10 
(Combidex ®)) (2, 6, 37), or with a semi-synthetic carbohydrate, as in the new agent 
ferumoxytol (16, 43).  The coating bestows long plasma half lives of 14-30 hours (25, 50). 
On MR scans the iron oxide agents demonstrate hypointense signal drop out at all 
concentrations on T2-weighted images, but may show hyperintense (bright) signal on T1-
weighted images in areas of low concentration.  After MR of CNS delivery, the iron oxide 
particles may be localized within tissues with light microscopy and EM (19, 32, 33, 34, 
35).   
The USPIO MR agent, ferumoxytol may be useful for imaging brain tumors and the 
inflammatory processes associated with therapy of CNS lesions, as well as improved 
measurement of MR measurement of BBB permeability. In both animal brain tumor 
models and in brain tumor patients, IV ferumoxides alone does not show tumor 
enhancement, while ferumoxtran-10 clearly enhances most malignant tumor types tested 
(33, 34).  Our clinical trial of ferumoxtran-10 has accrued 108 subjects to date (34, 52).  


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Although some studies have shown that iron oxide particles can be detected in malignant 
glial tumors after IV administration (15, 31), we find that relatively little iron staining is 
found within tumor cells.  Instead, iron is concentrated in necrotic areas within the tumor 
and in cells around the tumor margin. Progressive accumulation of ferumoxtran-10 in 
reactive astrocytes and macrophages results in prolonged enhancement of brain tumors 
(up to 7 days) both in animal models (33) and in patients (34, 52).  The cellular 
localization of iron oxide nanoparticles may improve imaging of inflammatory responses 
within the neurovascular unit (54).   
In this proposal we will investigate the new USPIO MR contrast agent, ferumoxytol, in 
subjects with CNS tumors, in whom improved imaging of CNS lesions may be critical in 
improving patient management and therapy.  Ferumoxytol can be given as a bolus for 
MRA analysis of the vasculature and perfusion imaging of the brain as has been done in 
the heart (43), without early vascular leak unlike Gd.  Ferumoxytol has shown few 
significant adverse reactions even using extremely high doses in vitro and in preclinical 
trials (Investigator’s Drug Brochure, 2005). A total of 516 subjects have received one or 
more doses of ferumoxytol, with 396 including safety data, with very low toxicity 
(Investigator’s Drug Brochure 2005, 25, 50).  Our pilot data indicate ferumoxytol is safe 
for brain tumor imaging. 
2.3 
Dynamic Contrast Enhanced (DCE) MR Imaging 
MRI with dynamic contrast enhancement allows non-invasive in vivo quantification of 
CBV, MTT, and the permeability of the BBB. The original description of the technique by 
Tofts and Kermode (21, 51) extracted approximations of the influx rate constant (Ki) for 
Gd from time course plots of T2*-weighted signal changes after contrast infusion. The 
underlying tracer-kinetic model is referred to as the Kety-Schmidt model. Unlike indicator 
diffusion techniques that rely on direct detection of tracer, MR only indirectly detects the 
presence of contrast due to its shortening of the T2* and/or T1 spin relaxation rate 
constants of 1H in water.  Potential limitations of the dynamic imaging techniques include 
susceptibility artifacts, relative rather than absolute quantification of cerebral blood 
volume, and inaccurate estimation of CBV in patients with permeable BBB (7).  Many 
adjustments have been made to the standard model to attempt to bring results from 
dynamic MRI studies into closer agreement with more traditional methods of measuring 
permeability (45). Dynamic MRI permeability measurements have been validated against 
measurements made with 14C-sucrose autoradiography and scintillation counting (17). 
Table 1 summarizes the measurement parameters that can be extracted from the 
dynamic imaging studies, with both Gd, and USPIO (28). The observed signal intensity 
variations in tissue and the blood pool are converted through a log-transformation to R2* 
changes (= 1/T2*). The curves of R2* changes versus time for selected tissue regions of 
interest (ROI) can be fit with a gamma-variate function, to approximate the shape of the 
first pass peak. The arterial input is used to determine the cut-off point for the fit, i.e. 
before appearance of the recirculation component. With this fitting procedure, one can 
determine the mean transit time (MTT). The outcome variable for assessing effects of 
therapy on tumors will be the cerebral blood volume (CBV) parameter, estimated from 
T2*-weighted DSC MRI with USPIO contrast. We expect USPIO leakage to be minimal 
during the first pass. CBV is calculated from the area under the curve (AUC) for serial 
DCE-MRI R2* curves, normalized by the R2* AUC for an arterial ROI. Cerebral blood 
flow (CBF) is estimated by model-independent numerical deconvolution of the tissue 
curves with the arterial input (39, 40). We can also extract the BBB permeability surface 
area product (PS) from the influx rate constant Ki, obtained with the Kety-Schmidt model 
(27, 28). The influx rate constant is related to both CBF and PS, and estimation of PS, 
therefore requires an independent quantification of CBF (Table 1). In addition, one can 


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use pre- and post-contrast T1 measurements with high spatial resolution (Look-Locker 
imaging) to determine R1 (= 1/T1) from before to approx. 10 min. after contrast injection, 
when the contrast agent has reached a semi-equilibrium. The R1 changes (R1) in 
tissue, normalized by R1 in the blood pool, give the blood-brain partition coefficient, 
which will be measured for Gd contrast, which traverses the BBB relatively rapidly in 
many tumor types. The partition coefficient for Gd provides a measure of the relative 
distribution volume for Gd in different tumor types, and can be compared to the CBV 
(measured with USPIO) to assess the degree of Gd contrast leakage. 
 
 
 
The dynamic MR techniques have been shown to be sensitive to changes in the BBB in 
animal models (7, 44). Of particular interest, Cha et al. assessed dynamic contrast 
imaging in a mouse glioma model using a 7T MR scanner (7). MR measurements of 
relative CBV agreed with histological measurement of microvascular density from the 
same tumors.  This animal study correlated with the observation in our pilot ferumoxytol 
study that low molecular weight contrast agents such as gadolinium leak rapidly out of 
the vasculature. Leakage of contrast agent interferes with an accurate determination of 
CBV and MTT. Our preliminary dynamic MR measurements with ferumoxytol in patients 
(see section 2.4) show markedly reduced early leakage of the nanoparticles compared to 
Gd. 
 
In human studies, dynamic MRI has been used to examine hemodynamics in solid 
tumors, providing in vivo data on the vascular pathophysiology and response to treatment 
Table 1.  Summary of measurement parameters from dynamic contrast enhancement MRI 
Parameter 
[Measurement] 
Gamma-variate fit [42, 46] 
Kety-Schmidt model 
[21] 
Note 
MTT 
[T2*-w DSC] 
Calculated from gamma-variate fit 
to first pass tissue curve; subtract 
MTT of arterial input for 
normalization. 
n.a. 
For intravascular agent, 
MTT = CBV/flow (central 
volume principle [30]) 
CBV 
[T2*-w DSC] 
Tissue first pass AUC, normalized 
by arterial input curve area [4, 42, 
46] 
n.a. 
In tumors, leakage of Gd 
may allow CBV 
quantification only with 
USPIO 
CBF 
[T2*-w DSC] 
Only indirect estimate from CBF = 
CBV/MTT 
Can only determine 
product of CBF and 
PS = Ki [21] 
Calculated by numerical 
deconvolution of tissue 
curves [21, 39, 40] 
PS 
[T2*-w DSC] 
PS cannot be estimated with semi-
empirical gamma-variate approach 
Can only determine 
product of CBF and 
PS = Ki [21] 
With independent CBF 
quantification, one can 
estimate PS from Ki and 
CBF. 
Blood-brain partition 
coefficient -  
[Look-Locker T1 
quant.] 
Calculated by R1 change in tissue (post-contrast R1 – pre-
contrast R1, normalized by R1 change in blood). 
Quantification of Vd is not based on any specific model.  
can also be obtained from Kety-Schmidt model. 
Leakage of Gd contrast is 
assessed by comparison 
of  for Gd with CBV 
Abbreviations: MTT, mean transit time; DSC, dynamic susceptibility contrast; CBV, cerebral blood volume; AUC, 
area under curve; USPIO, ultrasmall superparamagnetic iron oxide particles; CBF, cerebral blood flow; PS, 
permeability-surface area product; Ki, influx rate constant; R1, R1=1/T1 


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for breast, lung and prostate cancer and is increasingly used in clinical practice (20, 23, 
26, 27, 41). Relative CBV (rCBV) maps derived from perfusion MR imaging data provide 
quantifiable estimates of regional blood volume that can be used to grade gliomas, 
differentiate different brain tumor types, and distinguish tumors from non-neoplastic 
lesions, and to assess brain tumor physiology (21). CBV maps and the rCBV values can 
be calculated in different areas using the ratio between the CBV in the pathological area 
and in the contralateral white matter. Large, solitary, necrotic metastases can be 
indistinguishable from high-grade astrocytomas using conventional MRI, but can be 
distinguished by dynamic contrast MRI (23). Inclusion of dynamic contrast MR imaging 
as part of a routine evaluation of brain tumors can lead to improved diagnostic accuracy, 
understanding of tumor pathophysiology, and detection and quantification of tumor 
angiogenesis. With further work, dynamic MR imaging could be used to assess existing 
and novel cancer therapies that target blood vessels. 
 
To date, few studies have used USPIO MR contrast agents in dynamic imaging.  In one 
animal study, de Lussanet evaluated a different USPIO (Clariscan NC200150) for 
dynamic MRI in a mouse subcutaneous colon carcinoma model using a 1.5T scanner 
(12, 13).  They found that USPIO was equivalent to Gd for evaluating the endothelial 
transfer coefficient surface area product, while USPIO was significantly better than Gd for 
determining the fractional plasma volume (12, 13).  However, it is difficult to draw 
conclusions from the low resolution images in this 1.5T study. The higher performance 
gradient systems with increased MR field strength will allow us to improve spatial 
resolution, while maintaining temporal resolution, and improve image quality because of 
the higher signal-to-noise ratio with increased field strength.(8, 9) Dynamic MR with 
USPIO has been reported in human breast cancer (48) and liver metastases (53).   
2.4 
Ferumoxytol Pilot Data  
 
To date, 12 subjects have been assessed for ferumoxytol MR imaging in brain tumors. 
Neoplastic lesions were well seen on both 1.5T and 3T images. The signal-to-noise is 
higher on 3T scan compared to 1.5T, which translates into shorter scans in many 
instances. The T1 relaxation times are longer at 3T compared to 1.5T, and T1 contrast 
enhancement with Gd and ferumoxytol is improved. The ferumoxytol studies were 
comparable to Gd scans, although the enhancement was delayed and was 
predominantly in the peripheral aspects of the tumor. The signal intensity of 
enhancement was maximum at around the 24 hours time point post ferumoxytol injection 
then decreased over time, while the volume of enhancement slowly increased. 
Informative images were also obtained on intraoperative low field magnets (0.1 T) 48 
hours after ferumoxytol injection. Ferumoxytol proved to be safe for bolus administration 
in subjects with primary high-grade brain tumors and/or cerebral metastases, and no 
adverse events occurred. The tumors usually showed  increased CBV compared to 
healthy white matter. Because of initially intravascular localization of ferumoxytol the 
overestimation of CBV could be avoided in leaky tumors which is usually a problem when 
using Gd (Figure 1).  Figure 1 shows the T1-weighted scans after Gd in comparison 
ferumoxytol, and the ROI analysis for evaluation of blood volume.  
 


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Figure 1. 
Illustration of MTT 
measurement using Gd (A), 
and ferumoxytol (B). 
 
In dynamic MRA using “Keyhole” imaging sequences the temporal resolution can be 
increased, which allows us to visualize  the arterial, arterial/venous and venous phase of 
the vessels surrounding and within the tumor. Our initial experience suggests that a 
lower concentration of ferumoxytol (1:8 dilution) may decrease susceptibility artifacts.  To 
visualize the small vessels, contrast enhanced time of flight (TOF) angiography provides 
high resolution equilibrium phase images, approaching that of catheter angiography. 
Because of the long plasma half-life and initially intravascular localization of ferumoxytol, 
the enhanced high-resolution TOF MRA resulted in good visualization of the vasculature 
without having artifacts due to contrast agent leakage out of blood vessels (Figure 2).  
 
 
 
 
Figure 2. 
TOF MRA 
without 
contrast 
(A), with 
Gd (B), 
and with 
ferumoxytol 
(C). 
 
2.5 
Study Rationale  
Based on our preliminary study using ferumoxytol for dynamic MR imaging of brain 
tumors, we plan to extend this work to the highest available MR field strength for 
improved measurement of dynamic MR parameters.  This study will show the feasibility 
of ferumoxytol administration and MR imaging using 3T and 7T MRI.  Dynamic MR 
imaging to determine tumor permeability will be performed in two groups of subjects, 
those who have or have not had prior therapy for their brain tumor, in order to compare 
changes in BBB permeability before and after therapy. The utilization of ferumoxytol will 
allow more accurate measurements. In addition, tumor microvascularity changes will be 
studied pre- and post-treatment using susceptibility weighted imaging (SWI).  
Subjects may be imaged at up to 4 time points to evaluate permeability and 
microvascularity changes of the tumor. 
A
B


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2.6 
Safety and Preliminary Studies with Ferumoxytol 
Ferumoxytol has provided improved imaging with minimal safety concerns in pre-clinical 
studies and IND sponsored studies. Ferumoxytol has few systemic reactions and can be 
given as a bolus for MRA analysis of vasculature. This agent did not show significant 
preclinical toxicity even using extremely high doses in preclinical trials with animals and 
in vitro using human blood cells.  
2.6.1 Preclinical studies 
Three animal studies evaluated the potential cardiovascular effects of ferumoxytol. 
Ferumoxytol and the vehicle control material, mannitol, were administered in escalating 
doses of 4, 40, and 200 mg Fe/kg intravenously to male and female beagle dogs.  Each 
animal received all three doses. No effect on cardiovascular and respiratory parameters 
and no cardiac electrocardiographic abnormalities were detected. (Ferumoxytol 
Investigator’s Drug Brochure, 2005).  Additionally, there was no effect on arterial blood 
pressure, heart rate, femoral artery blood flow, left ventricular function, or respiratory 
function.  No treatment related electrocardiographic abnormalities were found.  There 
was an increase in urinary flow rate with both the vehicle control and ferumoxytol, this 
increase in diuresis was considered attributable to the mannitol.  (Ferumoxytol 
Investigator’s Drug Brochure, 2005).  In a hemodynamic study in anesthetized rats, 
ferumoxytol caused no change in blood pressure parameters (mean arterial, systolic, 
diastolic, and pulse pressures) in three animals following intravenous administration of 
120 mg Fe/kg.   In a third hemodynamic study, guinea pigs received i.v. ferumoxytol at a 
dose level of 120 mg Fe/kg or a saline control (n = 9).  One animal had a reduction in 
mean arterial blood pressure graded as mild.  One animal appeared to be unstable post 
injection with fluctuating blood pressure over a period of 60 minutes.  There were no 
hemodynamic changes in the other seven animals administered ferumoxytol or in two 
animals administered saline. A full panel of toxicity studies has been performed, which 
include: evaluation of acute and repeat dose administration, mutagenicity, reproduction, 
and immunotoxicity.  Additional information can be found in the investigator’s brochure.  
(Ferumoxytol Investigator’s Drug Brochure, 2005).   
 
 
Non-clinical toxicology-pathology studies are described in the investigator’s brochure and 
include the following:  
• 
Single dose studies in small and large animals 
• 
Repeat dose studies in small and large animals 
• 
Special studies: acute intravenous irritation study in rabbits, compatibility with 
human erythrocytes, compatibility with human plasma or serum, effect on in vitro 
clotting times, effect on coagulation in rat plasma, effect on rat paw edema, 
evaluation of the formation of immune complexes with Dextran Reactive 
Antibodies 
• 
Genotoxicity studies: mutagenic activity, ability to induce chromosomal 
aberrations, in vivo clastogenic activity and/or disruption of the miotic apparatus 
• 
Maternal and developmental toxicity in small animals 
 
2.6.2 Clinical studies of Ferumoxytol 
 
On June 20, 2009, the FDA approved ferumoxytol (FerahemeTM) to treat Iron Deficiency 
Anemia and Adult Chronic Kidney Disease Patients.  The recommended dose is an initial 


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510 mg IV injection followed by a second 510 mg IV injection three to eight days later.  
Ferumoxytol is now commercially available in the U.S.A. 
2.6.2.1 From the Investigational brochure 2009: 
 
The ferumoxytol clinical development program has been comprised of eleven studies. 
These included three Phase 1 studies (two dose-escalation studies and a study of the 
electrocardiographic/QTC effects of ferumoxytol), two Phase 2 studies that evaluated the 
safety and efficacy of ferumoxytol for iron replacement in patients with Chronic Kidney 
Disease (CKD), and two Phase 2 imaging studies that assessed the feasibility of 
ferumoxytol as an MRI contrast agent. There were three open-label Phase 3 studies that 
examined the efficacy and safety of ferumoxytol relative to oral iron in patients with CKD 
Stages 1-5 either on or not on dialysis. A fourth Phase 3 study in patients with any stage 
of CKD evaluated the safety of ferumoxytol relative to placebo in a cross-over, double-
blind manner. Ferumoxytol has been evaluated at exposures up to 2 x 510 mg, including 
two courses of 2 x 510 mg in three of the four Phase 3 studies. Specifically, the following 
regimens of ferumoxytol were given during the clinical program:  
• 
≤4 mg Fe/kg  
• 
1 x 125 mg  
• 
1 x 250 mg  
• 
1 x 510 mg  
• 
8 x 128 mg  
• 
4 x 255 mg  
• 
2 x 510 mg 
 
 
Approximately 1,740 patients have been exposed to ferumoxytol in the entire clinical 
program, and approximately 1,509 patients have been exposed to ferumoxytol in the 
Phase 3 studies. To date, only one patient (0.06% of all patients exposed to ferumoxytol) 
has experienced an anaphylacoid reaction following treatment with ferumoxytol; this 
patient had a history of multiple drug allergies and experienced an anaphylactoid reaction 
(hot flashes and itching, with no respiratory compromise) and severe hypotension a few 
minutes after receiving ferumoxytol. There have been no deaths that were considered to 
be related to ferumoxytol treatment. There were 28 deaths in the clinical program, all of 
which have occurred in Phase 3 studies, with 16 deaths among the 1,740 patients 
exposed to ferumoxytol (0.9%) and 8 deaths among the 296 patients exposed to oral iron 
(2.7%). Four deaths occurred in patients who had signed an informed consent for 
enrollment but did not receive any test article. All deaths in the clinical program have 
been in patients with CKD, who have a high risk of death due to cardiovascular disease 
and other causes. In completed studies that used oral iron as a comparator, there was a 
lower rate of SAEs among patients exposed to ferumoxytol than among patients exposed 
to oral iron: 4.4% of ferumoxytol treated patients (64 of 1,451 patients) vs. 10.7% of oral 
iron-treated patients (17 of 159 patients). Patients exposed to placebo had the lowest 
rate of SAEs (1.7%; 13 of 780 patients). One patient each following ferumoxytol (0.1%), 
oral iron (0.6%), and placebo (0.1%) experienced an SAE that was considered by the 
investigator to be related to treatment. In Phase 3 Study 62,745-5, which enrolled CKD 
patients undergoing hemodialysis, 31 of 199 (15.6%) patients experienced an SAE 
following ferumoxytol administration and 8 of 70 (11.4%) patients experienced an SAE 
following oral iron administration. These data were taken from an unlocked database and 


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therefore are preliminary and patient to final verification. In the Phase 3 studies in 
patients with CKD (62,745-5, 62,745-6, 62,745-7, and 62,745-8, in which approximately 
1,509 patients were exposed to ferumoxytol), the most common adverse events following 
ferumoxytol administration included nausea, diarrhea, dizziness, headache, and 
peripheral edema. These adverse events were usually more common in the oral iron 
group than the ferumoxytol group (in Studies 62,745-5, 62,745-6, and 62,745-7, which 
utilized oral iron as a comparator). Hypotension was one of the more common adverse 
events in Study 62,745-7 and occurred more frequently in the ferumoxytol group (5.0%) 
than the oral iron group (1.4%). By contrast, preliminary data show that there have been 
lower rates of hypotension in Study 62,745-5 (1.8%, 1.7%, and 0% in the ferumoxytol 
2x510 mg, ferumoxytol 4x255 mg, and oral iron groups, respectively); hypotension rates 
were similar between the ferumoxytol and placebo groups (1.3% vs. 0.8%) in the large 
safety study, Study 62,745-8; and there were no hypotension adverse events in Study 
62,745-6.  An independent Data Monitoring Committee met to review the clinical safety 
data for all Phase 3 studies in October 2005, February 2006, June 2006, October 2006, 
and March 2007, and they identified no safety concerns. 
 
 
The dose of 510mg ferumoxytol has not been used in imaging studies before.  The 
highest dose used was 4mg/kg (280mg for a 70kg patient). However 2 x 510mg dose 
was studied for iron replacement therapy in large number of patients without significant 
adverse effects. (Besarab et al 2007). If there is no history of iron over load, there is no 
need to screen for iron over load since 0.5 g will not hurt patients, even if they have 
asymptomatic iron over load. Phase 3 data by Besarab using two doses of 510 mg in a 
phase 3 trial showed no significant toxicity. A higher dose of ferumoxytol will result in a 
better contrast enhancement 24 hours after injection due to a higher plasma level. 
2.6.2.2 From the Investigational brochure April 30, 2012: 
 
 
Since approval, AMAG has conducted one clinical trial (Protocol Number FER-CKD-201). 
This was a randomized, open-label trial that compared the safety and efficacy of 
ferumoxytol to iron sucrose for the treatment of IDA in CKD subjects either on or not on 
dialysis. In this trial, 162 patients were randomized in a 1:1 ratio to either ferumoxytol or 
iron sucrose. Ferumoxytol was administered as a 1.02 g course given as a regimen of 2 x 
510 mg within 2 to 8 (5±3) days. Related AEs experienced by ferumoxytol-treated 
subjects included one of each of the following (1.3%): anaphylactic reaction, dysgeusia, 
feeling hot, flushing, headache, injection site hematoma, injection site pain, and nausea.  
 
 
There was 1 SAE considered related to ferumoxytol treatment. The subject experienced 
an anaphylactic reaction, described as a systemic allergic reaction, after receiving the 
first dose, and was treated with epinephrine, Benadryl, Solu-Cortef and IV normal saline 
on the day of the event. The event was subsequently resolved the same day. 
2.6.3 Post-Marketing Program 
 
 
In March of 2015 the FDA placed a black box warning on ferumoxytol stating: 
 
 
WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS 
 
 
Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in 
patients receiving Feraheme. Initial symptoms may include hypotension, syncope, 
unresponsiveness, cardiac/cardiorespiratory arrest.  
• 
Only administer Feraheme when personnel and therapies are immediately available 
for the treatment of anaphylaxis and other hypersensitivity reactions. 


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• 
Observe for signs or symptoms of hypersensitivity reactions during and for at least 30 
minutes following Feraheme infusion including monitoring of blood pressure and 
pulse during and after Feraheme administration. 
• 
Hypersensitivity reactions have occurred in patients in whom a previous Feraheme 
dose was tolerated. 
 
 
In the black box warning the FDA updated their recommendations of how ferumoxytol 
should be given.  The option to give ferumoxytol (510mg) as a fast undiluted injection in 
approximately 1 minute has been removed.  It was recommended that ferumoxytol 
(510mg) be given over at least 15 minutes. To accommodate for this, the dose of 
ferumoxytol will be given in three separate, fractionated doses. The rate of administration 
of the second and third doses will be slowed down to no faster than  1 mL/s.  
 
 
Based on communication with AMAG Pharmaceuticals, manufacturer of ferumoxytol, all 
recommendations apply to iron replacement therapy where infusion rate and dilution do 
not impact efficacy. However, for an imaging indication certain infusion parameters are 
required to gain information, such as dynamic imaging. Increased infusion rate will only 
affect the first injection of 1 mg/kg, which is a small fraction of the full therapeutic dose, 
and therefore may minimally increase the risk of adverse reactions. The next two 
injections are given at a slower rate. The recommended 15 minutes has no scientific 
basis, it has been chosen arbitrarily. For MR imaging stopping the scanner for 15 
minutes would be disadvantageous. Applying multiple injections, which is not the case 
with iron replacement therapy, may increase safety, compared to continuous injection. 
This may contribute to the fact that in our patient population only minor adverse reactions 
have been reported. 
2.6.4 OHSU Toxicity Data 
As of April 1, 2015, a total of 621 infusions of ferumoxytol had been completed on 287 
study subjects as part of OHSU’s Blood Brain Barrier sponsored IRB approved protocols. 
The dose has ranged from 75 to 510 mg of ferumoxytol (0.5 to 11 mg/kg). Toxicities for 
this group as of April 1, 2015 show no grade 4 or 5 toxicities (CTCAE version 3) that 
were attributed to ferumoxytol. Two incidents of grade 3 toxicities were possibly 
attributable to ferumoxytol (one incident of constipation and one of neck pain). The most 
common adverse events associated with ferumoxytol were 20 (3% of total infusions) 
incidents of mild, transient hypertension and 5 (0.8% of total infusions) incidents of 
diarrhea. There have been no incidents of hypotension, syncope, unresponsiveness or 
cardiorespiratory arrest with these 621 administrations of ferumoxytol. 
3 
SUBJECT SELECTION 
3.1 
Eligibility Criteria 
1) Subjects with radiographically suspected, histologically or cytologically confirmed 
primary brain tumors or brain metastasis are eligible.    
2) Subjects may be enrolled at any point in diagnosis or treatment. 
3) Subjects must have had radiographically evaluable or measurable disease with 
standard MR imaging.      
4) .  
5) Age >18 years.  Both men and women and members of all races and ethnic groups 
will be included.  
6) ECOG performance status < 3 (KPS ≥ 30). 


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7) Ability to understand and the willingness to sign a written informed consent 
document, or have a representative able to consent for the subject. 
8) 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. 
9) Subject agrees to complete follow up visit. 
3.2 
Exclusion Criteria 
1) 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. 
2) 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. 
3) Subjects with known hepatic insufficiency or cirrhosis 
4) History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ferumoxytol  
5) Subjects with known or suspected iron overload (genetic hemochromatosis or history 
of multiple transfusions) 
6) 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. 
7) 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. 
8) Pregnant or lactating women are excluded from this study because of possible risk to 
the fetus or infant. 
9) Inability or unwillingness to undergo the complete series of imaging sessions. Inability 
or unwillingness to complete the one month follow-up.  
10) HIV-positive subjects on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with ferumoxytol. 
11) Subjects with GFR < 50. 
12) Subjects with three or more drug allergies from separate drug classes. 
 
4 
CONTRAST AGENT FORMULATION AND PROCUREMENT 
4.1 
Gadolinium 
Gadolinium is a standard contrast agent used in clinical practice and will be administered 
on day 1 as an I.V. bolus of 0.1 mmol/kg at a flow rate of up to 3 mL/s, followed by a 
saline flush. for dynamic MR imaging followed by routine MR imaging.  The appropriate 


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volumes of contrast agents are based on the patient’s weight (0.2 ml/kg gadoteridol + 
20ml saline flush). 
4.2 
Ferumoxytol 
4.2.1 Agent Accountability:  The Investigator, or a responsible party designated by the 
Investigator, must maintain a careful record of the inventory and disposition of the study 
agent. 
4.2.2 Availability:   Ferumoxytol is purchased by the investigators from the manufacturer, 
AMAG Pharmaceuticals, Inc. (Cambridge, MA) 
4.2.3 Product description: Ferumoxytol is a semi synthetic carbohydrate coated ultrasmall 
superparamagnetic iron oxide particle.  The drug is formulated with mannitol; each vial 
contains 30 mg/mL of iron and 44 mg/mL of mannitol.  A dose of 510 mg of iron is 17 mL. 
 Ferumoxytol is isotonic: the osmolality is 270-330 mOsm.  The amount of free (BDI) iron 
for ferumoxytol is approximately six - fold lower than for currently approved parenteral 
iron products at a similar dose.  The product contains no preservatives. The pH is 6 to 9. 
    
4.2.4 Preparation: The appropriate volume of drug is based on the subject’s weight.  The drug 
will be stored at room temperature (68-77 degree Fahrenheit) away from direct sunlight. 
The solution will be prepared and dispensed by the investigational drug pharmacist.  The 
Ferumoxytol will be injected in the MR suite by either a nurse or technician.  
The ferumoxytol will be diluted 1:1 to make a 15mg/ml solution.  The total dose of 
ferumoxytol will be 4 mg/kg (to a maximum of 510 mg), and will be administered 
intravenously on day 2.  
The dilution and injection parameters may be adjusted to obtain optimal signal changes.  
The total dose will not exceed 4 mg/kg or 510 mg. 
See Section 5.3.4 for admistration. 
4.3 
Expected adverse events 
As described in the Investigtor’s Drug Brochure for ferumoxytol, a total of 1740 subjects 
(patients and healthy volunteers) were given one or more doses of ferumoxytol.  Safety 
was determined in subjects through an analysis of changes in pre and post-dose blood 
chemistry, urinalysis, vital signs, results of physical examinations, electrocardiograms 
(ECG), and by the incidence of adverse events.  There were no clinically significant 
changes noted by the investigators in ECG, vital signs, or clinical chemistries. There 
have been three serious adverse events considered related or possibly related to 
ferumoxytol. Two cases of peritonitis in patients undergoing continuous ambulatory 
peritoneal dialysis, occurring 13 and 30 days after administration of ferumoxytol were 
considered ‘possibly related’.  Both patients had prior histories of peritonitis. One patient 
with a history of allergies had an anaphylactic reaction that was considered ‘related’ to 
ferumoxytol. 
On June 20, 2009, the FDA approved ferumoxytol (FerahemeTM) to treat iron deficiency 
anemia and adult chronic kidney disease patients.  The recommended dose is an initial 
510 mg IV injection followed by a second 510 mg IV injection three to eight days later. 
Ferumoxytol is now commercially available in the U.S.A. 
4.4 
Safety 
The ferumoxytol clinical development program has been comprised of eleven studies. 
These included three Phase 1 studies (two dose-escalation studies and a study of the 


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electrocardiographic/QTC effects of ferumoxytol), two Phase 2 studies that evaluated the 
safety and efficacy of ferumoxytol for iron replacement in patients with CKD, and two 
Phase 2 imaging studies that assessed the feasibility of ferumoxytol as an MRI contrast 
agent. There were three open-label Phase 3 studies that examined the efficacy and 
safety of ferumoxytol relative to oral iron in patients with Chronic Kidney Disease (CKD) 
Stages 1-5 either on or not on dialysis. A fourth Phase 3 study in patients with any stage 
of CKD evaluated the safety of ferumoxytol relative to placebo in a cross-over, double-
blind manner. Ferumoxytol has been evaluated at exposures up to 2 x 510 mg, including 
two courses of 2 x 510 mg in three of the four Phase 3 studies. Specifically, the following 
regimens of ferumoxytol were given during the clinical program:  
• ≤4 mg Fe/kg  
• 1 x 125 mg  
• 1 x 250 mg  
• 1 x 510 mg  
• 8 x 128 mg  
• x 255 mg  
• x 510 mg 
 
Approximately 1,740 patients have been exposed to ferumoxytol in the entire clinical 
program, and approximately 1,509 patients have been exposed to ferumoxytol in the 
Phase 3 studies. To date, only one patient (0.06% of all patients exposed to ferumoxytol) 
has experienced an anaphylacoid reaction following treatment with ferumoxytol; this 
patient had a history of multiple drug allergies and experienced an anaphylactoid reaction 
(hot flashes and itching, with no respiratory compromise) and severe hypotension a few 
minutes after receiving ferumoxytol. There have been no deaths that were considered to 
be related to ferumoxytol treatment. There were 28 deaths in the clinical program, all of 
which have occurred in Phase 3 studies, with 16 deaths among the 1,740 patients 
exposed to ferumoxytol (0.9%) and 8 deaths among the 296 patients exposed to oral iron 
(2.7%). Four deaths occurred in patients who had signed an informed consent for 
enrollment but did not receive any test article. All deaths in the clinical program have 
been in patients with CKD, who have a high risk of death due to cardiovascular disease 
and other causes. In completed studies that used oral iron as a comparator, there was a 
lower rate of SAEs among patients exposed to ferumoxytol than among patients exposed 
to oral iron: 4.4% of ferumoxytoltreated patients (64 of 1,451 patients) vs. 10.7% of oral 
iron-treated patients (17 of 159 patients). Patients exposed to placebo had the lowest 
rate of SAEs (1.7%; 13 of 780 patients). One patient each following ferumoxytol (0.1%), 
oral iron (0.6%), and placebo (0.1%) experienced an SAE that was considered by the 
investigator to be related to treatment. In Phase 3 Study 62,745-5, which enrolled CKD 
patients undergoing hemodialysis, 31 of 199 (15.6%) patients experienced an SAE 
following ferumoxytol administration and 8 of 70 (11.4%) patients experienced an SAE 
following oral iron administration. These data were taken from an unlocked database and 
therefore are preliminary and patient to final verification. In the Phase 3 studies in 
patients with CKD (62,745-5, 62,745-6, 62,745-7, and 62,745-8, in which approximately 
1,509 patients were exposed to ferumoxytol), the most common adverse events following 
ferumoxytol administration included nausea, diarrhea, dizziness, headache, and 
peripheral edema. These adverse events were usually more common in the oral iron 
group than the ferumoxytol group (in Studies 62,745-5, 62,745-6, and 62,745-7, which 
utilized oral iron as a comparator). Hypotension was one of the more common adverse 
events in Study 62,745-7 and occurred more frequently in the ferumoxytol group (5.0%) 
than the oral iron group (1.4%). By contrast, preliminary data show that there have been 


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lower rates of hypotension in Study 62,745-5 (1.8%, 1.7%, and 0% in the ferumoxytol 
2x510 mg, ferumoxytol 4x255 mg, and oral iron groups, respectively); hypotension rates 
were similar between the ferumoxytol and placebo groups (1.3% vs. 0.8%) in the large 
safety study, Study 62,745-8; and there were no hypotension adverse events in Study 
62,745-6.  
An independent Data Monitoring Committee met to review the clinical safety data for all 
Phase 3 studies in October 2005, February 2006, June 2006, October 2006, and March 
2007, and they identified no safety concerns. 
5 
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
5.1 
Enrollment 
Targeted enrollment is 150 subjects for this study. Study length is 2 years.  Subjects will 
be assigned to 3T or 7T magnet to maintain a balance within the subgroups (primary with 
or without prior treatment and metastatic with or without prior treatment).  
A subset of 25 of the 150 subjects will only undergo MRIs on the 7T magnet. We have 
recently performed upgrades to the magnet and need to test these new upgrades in 
order to get the best images to compare with the 3T magnet in the remaining subjects.     
5.2 
Subject Registration  
5.2.1 Informed consent will be obtained, refer to section 8.2. 
5.2.2 New subject registrations will be submitted to the study coordinator, who will record study 
data on all patients entered into the study and complete subsequent forms. 
5.2.3 A subject’s tumor type (primary versus metastatic) and prior treatment status (yes or no) 
determine to which of four strata the subject will be assigned.  Subjects will be assigned 
to either 3T or 7T groups in an effort to keep the subgroups balanced and/or possibly 
depending on MRI availability. We expect up to 20% of subjects will not be able to 
complete the imaging at the assigned magnet strength and, further, that the proportion 
may be somewhat higher in those assigned to the 7T magnet (as this magnet is more 
likely to not be available due to technical and, more rarely, subjects may not be able to 
tolerate the more confined space).  This approach is designed to, as well as possible, 
maintain balance between the 3T and 7T subgroups . 
5.3 
Study Visits 
5.3.1 Each study visit consists of 3 days.  There may be up to 7 days between Day 1 and Day 
2 visits. A study visit may be repeated up to four times, but not any more frequently than 
every 3 weeks.   
5.3.2 The subject may be given Benadryl before MRI scanning to help with relaxation during 
the MRI scan  and/or to prevent an allergic reaction to the Ferumoxytol. Subject’s need 
for anti-anxiolytics for each MRI study visit will be evaluated and administered as needed. 
Common anti-anxiolytics include lorazepam and diazepam; diphenhydramine may also 
be used.  The administration of a relaxing/anti-anxiolytic agent will be given at the 
treating physician or the PI’s discretion and is considered routine prior to MRI and as 
such is not being evaluated on this study. 
5.3.3 Day 1  
Laboratory testing:  
• creatinine to calculate GFR prior to gadolinium administration (may be done up to 3 
weeks prior) 


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• Urine pregnancy test in women of child bearing potential. 
Imaging: 
• Anatomical imaging on 3T & 7T and dynamic MRI (with gadolinium, see section 4.1) 
on either 3T or 7T (dependent on which group subject is assigned and as described in 
section 5.1.3) 
• Day 1 and Day 2 imaging sessions may be separated by up to 7 days. 
• A subset of 25 of the 150 subjects will only undergo MRIs on the 7T magnet.  
5.3.4 Day 2 
Imaging 
• Anatomical imaging on 3T & 7T and dynamic MRI (with ferumoxytol, see section 4.2). A 
subset of 25 of the 150 subjects will only undergo MRIs on the 7T magnet.  
• Dynamic imaging will be performed on the same scanner as on which the dynamic the 
dynamic imaging was acquired on Day 1(as described below on Section:  6.0). 
Ferumoxytol Administration: 
• The ferumoxytol will be diluted 1:2  to make a 10mg/ml solution.  The dose of 
ferumoxytol will be 4 mg/kg (to a maximum of 510 mg), and will be administered 
intravenously on day 2. 
• Dose 1:  Give 1/4th of the total dose (1mg/kg); inject at up to 3 ml/sec followed by a 
saline flush. This rate is required for adequate signal change during the dynamic 
imaging.   
• Dose 2:  Give 3/4th of the total dose (3mg/kg); inject no faster than 1 ml/sec and 
followed by a saline flush 
•  
 
 
• The dilution and injection parameters of the ferumoxytol may be adjusted to obtain 
optimal signal changes on MRI/MRA and to decrease the possibility of an allergic 
reaction.  Injection rate can be varied based on the participant’s IV site, but the total 
dose will never exceed 510mg. 
Monitoring 
• A clinical examination will be performed before and after the MRI session on Day 2.. 
Blood pressure and pulse will be monitored before the first dose of ferumoxytol and 
after each dose  of ferumoxytol, and at 30 minutes after the initial dose of ferumoxytol. 
5.3.5 Day 3  
Imaging:  
• Post-ferumoxytol MR imaging at both 3T and 7T (as described below in section: 6.0). 
No contrast agent will be administered on this day. A subset of 25 of the 150 
subjects will only undergo MRIs on the 7T magnet.  
 
5.4 
Adverse Events 
Toxicities and adverse experiences will be assessed using the NCI Common 
Terminology Criteria for Adverse Events v3.0. .  Adverse events related to or potentially 
related to the administration of ferumoxytol will be recorded; adverse events related to 


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the MRI’s experience itself, such as claustrophobia/anxiety, nausea with GBCA injection, 
or  discomfort due to positioning, is not being studied and will not be reported.  Adverse 
events that will be monitored during the infusion include localized discomfort at the IV 
injection site, pain, respiratory difficulties, flushing, dizziness, pruritis/rash, and any other 
symptoms that could be secondary to an anaphylactoid type reaction.   
5.5 
5.5 
Follow-up: 
The subject will be seen in an outpatient clinic or have a telephone follow up interview 
approximately 4-6 weeks after the study visit to assess for adverse events. 
5.6 
Subject Evaluability 
Subjects who are assigned to either the 3T or the 7T magnet strength MRI instruments 
may not be able to complete the imaging on the assigned strength on a given day.   This 
will most likely be due to an MRI technical issue on the day the subject has been 
assigned.  The 7T MRI is more likely to experience technical difficulties as this is a 
research instrument and is not a standard clinical product.  In addition, a few subjects 
may not be able to tolerate an MRI examination on a particular day.  If one MRI 
instrument is unavailable and the other one is available, the subject will be “crossed-
over” for that day.  For Primary Aims 1 and 2, crossing a subject on either day 1 or day 2 
(but not both) will mean that the subject will be evaluable for one aim (corresponding to 
the non-crossover day) but not for the other.  The sample size is adequate to allow up to 
20% of subjects to be crossed over on at least one day.  If one MRI instrument is not 
available on Study Day 3, data will be collected from that subject on only one instrument 
and these data will be used only to describe the range of values for that magnet strength. 
5.7 
Criteria for early termination from the protocol 
• 
Voluntary subject withdrawal 
• 
Investigator’s decision that is in the subject’s best interest to withdraw  
• 
Subject becomes pregnant 
• 
Noncompliance 
• 
Significant protocol violation 
• 
For any reason, at the Sponsor or Investigators discretion 
6 
IMAGING SCHEMA AND ACQUISITION 
6.1 
Schema 
Day 1 


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1. Standard  precontrast anatomical MRI sequences at 3T and/or 7T:  
sagittal T1, coronal FLAIR, MPRAGE, axial T1, T2, T2*, PD weighted images and 
DWI. 
2. TOF angiography 
3. Quantitative T1 images 
4. DSC MRI (T2* weighted) for perfusion with Gd bolus  administration dose: 
0.1mmol/kg) 
5. Quantitative T1 images for permeability measurement will be performed 4 times   
6. TOF angiography (postgadolinium) 
7. Standard postgadolinium imaging at 3T and 7T:MPRAGE, axial T1, T2, T2* weighted 
images.  
A subset of 25 of the 150 subjects will only undergo MRIs on the 7T magnet. 
 
[Section 6.1 and 6.2 numbers 4 and 5 will be assigned to either 3 or 7 Tesla. 1, 2, 3, 6 
and 7 will be performed on both magnet fields, the order of the scanners will be 
balanced, see Study Procedures section 5.2.3.] In subjects who cannot tolerate long MRI 
study either 3T or 7T (MRI with no dynamic imaging) pre-contrast sequences 1, 2 and 3 
maybe acquired on Day 2 (dash line in the figure below).  
Day 2 
1. Standard MRI sequences: axial T1, (MPRAGE, T2, T2*, PD, DWI images will be 
acquired only when quality of images are not good or if they were not acquired for 
some reason in first session)  
2. TOF angiography (only when quality of image is not good or was not acquired for 
some reason on first session) 
3. Quantitative T1 images 
4. DSC MR (T2* weighted) for perfusion with  ferumoxytol bolus (maximum dose: 1mg 
Fe/kg) the remaining 3mg/kg to be administered after this series) 
5. Quantitative T1 images for permeability measurement will be performed 4 times  
6. TOF angiography (post ferumoxytol) 
7. Standard MRI sequences (post contrast): MPRAGE, axial T1, T2, T2* weighted 
images. 
Day 3 
1. (24±6h post-ferumoxytol administration in both magnets.) 
2. Standard MRI sequences (post contrast): sagittal T1, coronal FLAIR, axial MPRAGE, 
 T1, T2, T2* weighted images, TOF angiography and Quantitative T1 images. 
 


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6.2 
Schema Options 
There are two schema options 
 
    
      
 Duration (min) 
6.2.1 Option A 
 
Three times in MRI on Day 1 (3T-7T-3T or 7T-3T-7T)   
  150 
 
One time on MRI scanner Day 2 (3T or 7T)  
 
 
 90 
 
Two times on MRI scanner Day 3 (3T and 7T) 
 
 
100 
 
6.2.2 Option B 
 
Two times on MRI scanner Day1 (3T and 7T) 
 
 
 100 
 
Two times on MRI scanner Day 2 (3T and 7T) 
 
 
 130 
 
Two times on MRI scanner Day 3 (3T and 7T)      
 
 
 100 
 
 
 


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6.3 
MR Acquisition Parameters 
 
Images will be acquired at 3T (Siemens TIM) using a 12-channel receive only phased 
array RF head coil and at 7T (Siemens MAGNETOM) using an 8 channel phased array 
transmit/receive RF head coil. 
3T acquisition parameters: 
Scan type 
 
 
 
 
 
 
 
Scan time (min) 
0. Setup/localizer/B0 shimming/B1 mapping  
 
 
 
 
3 
1. T1-w sagittal (TE 2.5/TR 300/FA 60) 
    220mm x 220mm FOV 256 x 256 matrix 4 mm contiguous    
 
 
2 
2. FLAIR coronal (TE 9000/TR 95/TI 2500) 
    230mm x 172mm FOV 256 x 205 matrix 3 mm contiguous 
 
 
4 
3.. T1-w axial TSE (TE14/TR700 TSE factor 4 4NEX; PAT=2)  
    180mm x 240mm FOV 192 x 256 matrix 3 mm contiguous, interleaved  
4 
4. MPRAGE axial (TE 2300/TR 3.4/FA 12) 
    256 mm x 192 mm FOV 256 x 256 matrix 1 mm contiguous 
 
 
7 
5. T2-w axial TSE (TE72/TR9000 TSE factor 9 PAT=2) 
 
    180mm x 240mm FOV 192 x 256 matrix 3 mm contiguous, interleaved  
2 
6. PD-w axial TSE (TE14/TR9000 TSE factor 9  PAT=2) 
 
    180mm x 240mm FOV 192 x 256 matrix 3 mm contiguous, interleaved  
2 
7. Diffusion weighted MRI axial (TE90/TR6000 SE EPI b=0, 500, 1000 s/mm2) 
    220mm x 220mm FOV 128 x 128 matrix 3 mm contiguous, interleaved  
 4 
8. MRA 3D-TOF  (TE3.2/TR18/FA20; PAT=2) 
    170mm x 200mm x 150 mm FOV 200 x 400 x 140 
 
 
 
5 
9. Quantitative T1 axial (3D GRE TE3/TR15/FA5,20) 
    180mm x 240mm x 144 FOV 192 x 256 x 48 matrix 3 mm contiguous, 3D 
5 
10. T2*-w axial; GEPI (TE25/TR2000/FA50; PAT=2) x 45 volumes 
    220mm x 220mm FOV 128 x 128 matrix 3 mm contiguous, interleaved  
6 
11. PWI Echo-Planar Gradient Echo and Spin Echo 20- 90  Flip Angle  
     TR=2000 msec/TE=28 msec 3mm Slices in Axial Plane  
 
 
 3 
 


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7T acquisiton parameters: 
 
0. Setup/localizer/B0 shimming/B1 mapping 
 
 
 
 
3 
1. MPRAGE axial (TE2.7/TR26.5/FA8)180mm x 220mm x 160mm FOV 
 
320mm x 256mm x 224mm matrix 0.7mm contiguous, 3D  
 
 
2. Quantitative T1 axial (EPI GRE TE16/TR10000) 256mm x 256mm FOV 
 
128mm x 128mm matrix 2 mm contiguous, interleaved 
 
 
 
3. T2-w axial TSE (TE91/TR10000; ETL 11) 240mm x 180mm FOV  
 
512mm x 384mm matrix 3 mm contiguous, interleaved 
 
 
 
 
4. SWI axial (TE12/TR26) 240mm x 180mm FOV  
 
512mm x 384mm matrix 1.5mm contiguous, interleaved 
 
 
 
 
5. T2*-w High Resolution axial (TE20/TR950) 220mm x 160mm FOV  
 
960mm x 704mm matrix 1.5 mm contiguous, interleaved  
 
 
 
 
6. Diffusion weighted MRI axial (TE90/TR6000 SE EPI b=0, 500, 1000 s/mm2) 
 
220mm x 220mm FOV  128 x 128 matrix 3 mm contiguous, interleaved 
 
 
7. DSC: T2*-w axial; GEPI (TE20/TR1500/FA30) x 90 volumes 
 
200mm x 200mm FOV 64mm x 64mm matrix 3 mm contiguous, interleaved 
 
The above detailed sequences are subject to change in order to acquire the best 
imaging results on the applied field strength. 
7 
CRITERIA FOR EVALUATION USING MRI  
7.1 
Lesion assessment methodology and volumetrics 
To be eligible for this study, subjects must have had a radiographically evaluable or 
measurable lesion on standard MRI. Anatomical images acquired pre- and   post 
contrast, including T1-w, T2-w, FLAIR, PD images will be assessed. Lesions should be 
measurable on at least two dimensions. Depending on the MR mophological abnormality 
of the lesion, volumetric measurement maybe performed  using T1-w, T2-w,  
FLAIR, PD images. MR signal abnormality refers to:  
 
 
 
1. T1 signal abnormality on precontrast images 
 
 
 
2. Abnormal hyperintensity on T1-w postcontrast images 
 
 
 
3. T2/FLAIR signal abnormality 
7.2 
Perfusion MR 
7.2.1 T2* weighted MR images will be collected during contrast agent administration to obtain a 
dynamic susceptibility contrast (DSC) data set.  
7.2.2 Time-intensity curves, cerebral blood volume (CBV) parametric maps and relative CBV 
(rCBV) values (as area under the signal intensity curve, normalized by area under the 
curve for control region) will be obtained. Relative mean transit time (rMTT) values will be 
obtained by gamma variate fitting the time-intensity curves,50 using Matlab environment 


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(Mathworks, Natick, MA). The relative perfusion values will be plotted as a function of 
time with both agents.  
7.3 
Vascular Permeability measurement 
T1 weighted MR data will be collected before and after contrast agent administration.  
Permeability will be evaluated by applying dynamic contrast enhanced (DCE) scans for 
quantitative T1 measurements 4 times over 45 minutes and also 24±6 hours after 
contrast administration. Using the R1 (=1/T1) values, Ktrans will can be calculated in the 
selected ROIs, (i. tumor core, ii. tumor rim, iii. ipsilateral control region iv. contralateral 
control region).  
7.4 
Ferumoxytol delayed MRI enhancement  
3 T and 7 T T1-w scans acquired 24±6 hours post-ferumoxytol administration will be 
compared.  Scans will be evaluated by two radiologists, measuring the enhancing volume 
from a volumetric T1-w image set using a manual trace technique. Total delayed 
enhancement volumes will be calculated by multiplying the enhancing pixel area by the 
pixel volume. Volume measurements will be compared between 3T and 7 T. 
7.5 
Diffusion weighted imaging  
For diffusion evaluation, the same ROIs will be defined as were done for perfusion 
evaluation. (i. tumor core, ii. tumor rim, iii. ipsilateral control region iv. contralateral control 
region). Apparent diffusion coefficient (ADC) values will be calculated using Matlab 
environment (Mathworks, Natick, MA).  
7.6 
Time of flight angiography (TOF) 
Time of Flight angiography will be evaluated semi quantitatively by two radiologists. 
Vascular density will be compared between ferumoxytol and gadolinium and also 
between time points. We expect more visible vessels than without contrast agent. In our 
previous study TOF angiography was done after the injection of 4mg Fe/kg ferumoxytol. 
We hypothesize that the reduced dose of ferumoxytol also allows good visualization of 
blood vessels without leakage artifact.  
7.7 
Susceptibility weighted imaging:  
The size of the vascular structures within the tumor bed will be semi-quantitively 
analyzed. The size of the tumor vessels will be compared to that of the normal 
penetrating vessels. Ttumor vessels are considered to be small if their diameter is 
smaller than the diameter of the penetrating vessels. If the diameter is equal to or larger, 
they are determined to be medium and large respectively. The presence of tortuous 
vessels within the tumor bed is also recorded as present or absent. The resulting images 
will be evaluated in a blinded fashion by two neuroradiologists. 
 
8 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Protocol Review 
The protocol and informed consent form for this study must be reviewed and approved in 
writing by the OHSU Knight Cancer Institute (CI) Clinical Research Review Committee 
(CRRC) and appropriate Institutional Review Board (IRB) prior to any subject being 
registered on this study.   
  


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8.2 
Informed Consent 
Written informed consent will be obtained from all subjects, or the legally authorized 
representative of the subject, participating in this trial, as stated in the Informed Consent 
section of the case of Federal Regulations, Title 21, Part 50.  If a subjects signature 
cannot be obtained, the investigator must ensure that the informed consent is signed by 
the subject’s legally authorized representative.  Documentation of the consent process 
and a copy of the signed consent shall be maintained in the subject’s medical record.  
8.3 
Changes to Protocol  
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment signed by the principal investigator and approved by the CRRC and IRB, 
before the revision or amendment may be implemented.  The only circumstance in which 
the amendment may be initiated without regulatory approval is for a change necessary to 
eliminate an apparent and immediate hazard to the subject.  In that event, the 
investigator must notify the CRRC and IRB in writing within 10 working days after the 
implementation. Investigators holding the IND must notify FDA of substantive changes to 
the protocol. 
8.4 
Maintenance of Records 
If the investigator relocates or, for any reason, withdraws from the study, the study 
records must be transferred to an agreed upon designee, such as another institution, 
another investigator, or to the OHSU Knight Cancer Institute Clinical Research 
Management. Records must be maintained according to sponsor or FDA requirements.  
8.5 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events  
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to IRB according 
to the policies, procedures and guidelines posted on the OHSU IRB web site  
http://www.ohsu.edu/research/rda/irb/policies.shtml. 
Fatal and life-threatening UP will be reported to OHSU IRB within 7 days of notification of 
the event.  All other UP reports will be submitted to OHSU IRB no later than 15 days of 
occurrence or notification of the event. Copies of the report documents will be kept in the 
study regulatory binder.  
UP and AE reports are submitted through OHSU e-IRB and will be reviewed by OHSU 
Knight Cancer Institute and IRB.  Monthly accumulative reports will be reviewed by a 
DSMC Oncologist and forwarded to the CRRC.   
8.6 
MedWatch Reporting  
For this investigator-initiated study, the investigator is considered the sponsor. The 
investigator/sponsor is required to report adverse experiences to the FDA through the 
MedWatch reporting program, even if the trial involves a commercially available agent. 
Adverse experiences to be reported include any unexpected (not listed in the package 
label), serious adverse experiences with a suspected association to the study drug. 
Adverse events that occur during clinical studies are to be reported to FDA as specified 
in the investigational new drug/biologic regulations using the FDA 3500A Mandatory 
Reporting form, which is available online at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085568.htm  
This is available as a .pdf document for printing. (At this time, MedWatch does not have 
a 3500A form that can be submitted electronically).   


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When the serious adverse event is reported to the FDA, copies of the MedWatch 3500A 
form and supporting materials will be submitted to the OHSU Knight Cancer Institute and 
the IRB.   A copy of the MedWatch 3500A form and supporting materials will be kept on 
file in the study regulatory binder. 
8.7 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
In addition to complete study and pharmacy files, complete records must be maintained 
on each subject treated on this protocol.  OHSU Knight Cancer Institute, through the 
auditing function of the Knight Clinical Trials Office, is responsible for ensuring that all 
member investigators and affiliate investigators conduct clinical research studies in 
compliance with local IRB standards, FDA regulations and NIH policies and in 
accordance with the Data and Safety Monitoring Plan policies and procedures 
http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm  
Locally initiated studies will be audited by OHSU Knight CI Auditor.  Newly approved 
studies may be audited anytime after enrollment has been initiated.  Each OHSU Knight 
approved treatment protocol will be audited on an annual basis in accordance with the 
Knight Data and Safety Monitoring Plan.   
8.8 
Inclusion of Women, Minorities and Children 
8.8.1 Inclusion of Women and Minorities 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or 
ethnic subset. No subject will be excluded from the study on the basis of gender, racial or 
ethnic origin. Male, female and minority volunteers will be recruited for this study from the 
general population and approximately 50% men and 50% women will be studied.  
The projected gender, racial, and ethnic composition of the study will represent that of 
the state of Oregon.  
 


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Table 5: Population Demographics - Oregon (%)              
Source:   U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
Ethnic Category 
Sex/Gender 
Femal
es
Males 
Total 
Hispanic or Latino 
 
 
11.7 
Not Hispanic or Latino 
 
 
88.3 
Ethnic Category: Total of all 
subjects* 
 
 
100* 
Racial Category 
 
American Indian or Alaskan 
Native 
 
 
1.4 
Asian 
 
 
3.7 
Black or African American 
 
 
1.8 
Native Hawaiian or other Pacific 
Islander 
 
 
0.3 
White 
 
 
83.6 
More than one race 
 
 
3.8 
Unknown/Other 
 
 
5.3 
Racial Category: Total of all 
subjects* 
 
 
100* 
TOTALS 
50.4 
49.6 
100* 


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Table 6: Projected Accrual for the Present Study (enter actual estimates, not 
percentages). 
Ethnic Category 
Sex/Gender 
Femal
es
Males 
Unkn
own
Total 
Hispanic or Latino 
9 
9 
 
18 
Not Hispanic or Latino 
66 
66 
 
132 
Unknown 
 
 
 
 
Ethnic Category: 
Total of all subjects* 
75 
75 
 
150* 
Racial Category 
 
American Indian or 
Alaskan Native 
1 
1 
 
2 
Asian 
3 
3 
 
6 
Black or African 
American 
2 
1 
 
3 
Native Hawaiian or 
other Pacific Islander 
 
 
 
0 
White 
62 
63 
 
125 
More than one race 
3 
3 
 
6 
Unknown 
4 
4 
 
8 
Racial Category: 
Total of all subjects* 
75 
75 
 
150* 
 
Source: Investigator projections based on Table 5*Totals must agree.    
 
8.8.2 Inclusion of Children 
This protocol does not include children for the following reason: 
the number of children with this type of cancer is limited and limited dosing and adverse 
event data are currently available on the use of  ferumoxytol in subjects <18 years of 
age, therefore, children are excluded from this study. 
 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
Study Objectives 
Refer to section 1. 
9.2 
Baseline Summaries 
Descriptive statistics will be provided for all baseline characteristics including 
demographic variables (age, gender, race), disease characteristics (prior treatment, 
baseline KPS and steroid use), tumor characteristics (size and permeability) and pre-
imaging variables.  For continuous data, mean and standard deviation and minimum, 
median and maximum will be estimated.  For categorical variables, the number and 
percent for each category will be estimated.  
 
Data from those subjects already enrolled will be summarized both separately from the 
rest of the subjects and combined with the other subjects. These first eleven subjects will 
be considered as feasibility subjects. Summaries of imaging measures will include data 
on relative normalized signal intensity changes (CNR) for dynamic MRI data sets, 
cerebral blood volume and relative mean transit time for the perfusion data and Ktrans for 
vascular permeability. 
9.3 
Descriptive Statistical Analyses  
All analyses described are viewed as descriptive in nature to better understand the 
variation in these parameters and not to provide definitive results as would be expected 
in a Phase III trial.  The statistical analyses provide appropriate frameworks for assessing 
the relative magnitudes of effects while potentially controlling for other parameters of 
interest.  Results will be used to plan for future definitive studies of the parameters that 
have appropriate power calculations and sample sizes.   These analyses will be 
performed when target sample sizes are achieved and not on as interim analyses. 
For Primary Aim 1, the primary descriptive comparisons are paired sample t-tests 
comparing the normalized signal intensity changes (CNR) for T1-weighted MRI signal at 
3T and at 7T.  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.  These tests are descriptive in nature and 
are not powered to provide a complete answer.  Subjects who are scheduled to be 
imaged by a magnet of one field strength but are “crossed-over” to the other magnet or 
who otherwise fail to complete the scheduled imaging will not be included in these 
analyses.  For the baseline characteristics, if two-sample tests of hypotheses indicate a 
significant difference (p<0.10) between 3T and 7T signal intensity changes for a 
particular variable, that variable will be included in the ANOVA model as a covariate.  
Normality will be assessed graphically and, if needed, a transformation (e.g. the 
logarithmic transform) will be applied.  These analyses will be performed for Gd T1-
weighted MRI data only 
For Primary Aim 2, the analyses will be similar to those for Aim 1 above using normalized 
(CNR) signal intensity decreases in the DSC data sets.  .  The same factors and 
analyses will be used.  This objective assesses only Ferumoxytol.   
For the first Secondary Aim, mixed model repeated measures ANOVA’s will be fit.  The 
outcomes will be relevant dynamic MRI (DCE and DSC) signal intensity changes for 
permeability and for perfusion.  Factors will include imaging agent (Gd or ferumoxytol) 


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and field strength (3T and 7T).  Each subject will contribute one measure for each 
combination of imaging agent and field strength (4 measures total).  This will not be a 
definitive analysis as the power cannot be determined a priori.  The mixed model allows 
for estimation of the means and confidence intervals for imaging agent and field strength 
(57).  These data will be used to plan future comparative studies.  For the second 
Secondary Aim, blood volumes will be compared using repeated measures ANOVA to 
compare the imaging agents.  For the third Secondary Aim, analyses will add covariates 
of prior therapy to the analyses listed above.  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 listed 
above.  Since prior treatment is likely confounded with other variables (e.g. disease 
severity), these comparisons will also be descriptive in nature and mainly be used to plan 
future studies.   
For Secondary Aim five, 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. 
9.4 
Sample Size 
There is no statistical justification for the sample size used in this study.  This study plans 
to enroll 150 subjects with either primary or metastatic tumors. Subjects may or may not 
have had previous treatment.  
9.5 
Schema to maintain balance between 3T and & 7T groups 
Subjects will be assigned to a subgroup (with or without prior treatment) and will be 
assigned to undergo dynamic MR imaging at either 3T or 7T in an attempt to balance the 
subgroup. We expect up to 20% of subjects will not be able to complete the imaging at 
the assigned magnet strength and, further, that the proportion may be somewhat higher 
in those assigned to the 7T magnet (as this magnet is more likely to not be available due 
to technical and, more rarely, subjects may not be able to tolerate the more confined 
space.  This approach is designed to, as well as possible, maintain balance between the 
3T and 7T groups with respect to tumor type and prior treatment.  This schema is not 
intended to provide the same validity as randomization within a Phase III trial as this is an 
exploratory study and not a definitive trial. 


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29. Long DM. Capillary ultrastructure in human metastatic brain tumors.  J Neurosurg 
51:53-58,1979. 
 
30. Meier P, Zierler KL. On the theory of the indicator-dilution method for measurement of 
blood flow and volume. J Appl Physiol 1954; 6: 731-744. 
 
31. Moore A, Marecos E, Bogdanov AJ, Weissleder R. Tumoral distribution of long-
circulating dextran-coated iron oxide nanoparticles in a rodent model. Radiology 
214:568–574, 2000. 


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32. Muldoon LL, Pagel MA, Kroll RA, Roman-Goldstein S, Jones RS, Neuwelt EA.  A 
physiologic barrier distal to the anatomic blood-brain barrier in a model of transvascular 
delivery. AJNR:  Am J Neuroradiol 20:217-222, 1999. 
 
33. Muldoon LL, Manninger S, Pinkston KE, Neuwelt EA. Imaging, distribution, and 
toxicity of superparamagnetic iron oxide magnetic resonance nanoparticles in the rat 
brain and intracerebral tumor.  Neurosurgery 57:785-96, 2005. 
 
34. Neuwelt EA, Varallyay P, Bago AG, Muldoon LL, Nesbit G, Nixon R.  Imaging of iron 
oxide nanoparticles by MR and light microscopy in patients with malignant brain tumors. 
Neuropathology Applied Neurobiology 30:456-471, 2004. 
 
35. Neuwelt EA, Weissleder R, Nilaver G, Kroll RA, Roman-Goldstein S, Szumowski J, 
Pagel MA, Jones RS, Remsen LG, McCormick CI, Shannon EM, Muldoon LL.  Delivery 
of virus-sized iron oxide particles to rodent CNS neurons. Neurosurgery 34:777-784, 
1994. 
 
36. Neuwelt EA.  Mechanisms of disease: the blood-brain barrier. Neurosurg 54:131-142, 
2004.  
 
37. Nguyen BC, Stanford W, Thompson BH, Rossi NP, Kernstine KH, Kern JA, Robinson 
RA, Amorosa JK, Mammone JF, Outwater EK.  Multicenter clinical trial of ultrasmall 
superparamagnetic iron oxide in the evaluation of mediastinal lymph nodes in patients 
with primary lung carcinoma. J Magnetic Res Imaging 10:468-473, 1999. 
 
38. O’Neill BP.  Neurocognitive outcomes in primary CNS lymphoma (PCNSL).  
Neurology 62:532-533, 2004. 
 
39. Ostergaard L, Sorensen AG, Kwong KK, Weisskoff RM, Gyldensted C, Rosen BR. 
High resolution measurement of cerebral blood flow using intravascular tracer bolus 
passages. Part II: Experimental comparison and preliminary results. Magn Reson Med 
36:726-736, 1996. 
 
40. Ostergaard L, Weisskoff RM, Chesler DA, Gyldensted C, Rosen BR. High resolution 
measurement of cerebral blood flow using intravascular tracer bolus passages. Part I: 
Mathematical approach and statistical analysis. Magn. Reson. Med 36:715-725, 1996. 
 
41. Parikh AH, Smith JK, Ewend MG, Bullitt E.  Correlation of MR perfusion imaging and 
vessel tortuosity parameters in assessment of intracranial neoplasms.  Technology 
Cancer ResTreatment 3:585-90, 2004. 
 


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42. Perkio J, Aronen HJ, Kangasmaki A, Liu Y, Karonen J, Savolainen S, Ostergaard L. 
Evaluation of four postprocessing methods for determination of cerebral blood volume 
and mean transit time by dynamic susceptibility contrast imaging. Magn Reson Med  
47:973-81, 2002. 
 
43. Prince MR, Zhang HL, Chabra SG, Jacobs P, Wang Y.  A pilot investigation of new 
superparamagnetic iron oxide (ferumoxytol) as a contrast agent for cardiovascular MRI. J 
X-Ray Sci Technol 11:231-240, 2003. 
 
44. Quarles CC, Krouwer HGJ, Rand SD, Schmainda KM.  Dexamethasone normalizes 
brain tumor hemodynamics as indicated by dynamic susceptibility contrast MRI perfusion 
parameters.  Technology in Cancer Research & Treatment 4:245-249, 2005. 
 
45. Quarles CC, Ward BD, Schmainda KM. Improving the reliability of obtaining tumor 
hemodynamic parameters in the presence of contrast agent extravasation. Magn Reson 
Med. Jun 2005;53(6):1307-1316. 
 
46. Rempp KA, Brix G, Wenz F, Becker CR, Guckel F, Lorenz WJ. Quantification of 
regional cerebral blood flow and volume with dynamic susceptibility contrast-enhanced 
MR imaging. Radiology 1994; 193: 637-641. 
 
47. Ros PR, Freeny PC, Harms SE, Seltzer SE, Davis PL, Chan TW, Stillman AE, Muroff 
LR, Runge VM, Nissenbaum MA. Hepatic MR imaging with ferumoxides: a multicenter 
clinical trial of the safety and efficacy in the detection of focal hepatic lesions. Radiology 
196:481-488, 1995. 
 
48. Rydland J, BjOrnerud A, Haugen O, Torheim G, Torres C, Kvistad KA, Haraldseth O. 
 New intravascular contrast agent applied to dynamic contrast enhanced MR imaging of 
human breast cancer.  Acta Radiologica, 44(3):275-83, 2003. 
 
49. Saykin AJ, Ahles TA, McDonald BC.  Mechanisms of chemotherapy-induced 
cognitive disorders: neuropsychological, pathophysiological, and neuroimaging 
perspectives.  Semin Clin Neuropsychiatry 8:201-16, 2003. 
 
50. Spinowitz BS, Schwenk MH, Jacobs PM, Bolton WK, Kaplan MR, Charytan C, Galler 
M. The safety and efficacy of ferumoxytol therapy in anemic chronic kidney disease 
patients. Kidney International 68:1801-7, 2005. 
 
51. Tofts PS, Kermode AG. Measurement of the blood-brain barrier permeability and 
leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med. 
Feb 1991;17(2):357-367. 
 


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52. Varallyay P, Nesbit G, Muldoon LL, Nixon RR, Delashaw J, Cohen JI, Petrillo A, Rink 
D, Neuwelt EA.  Comparison of two superparamagnetic viral-sized iron oxide particles 
ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial 
tumors. AJNR Am J Neuroradiol 23:510-519, 2002. 
 
53. Ward J, Robinson PJ, Guthrie JA, Downing S, Wilson D, Lodge JP, Prasad KR, 
Toogood GJ, Wyatt JI.  Liver metastases in candidates for hepatic resection: comparison 
of helical CT and gadolinium- and SPIO-enhanced MR imaging.  Radiology 237:170-80, 
2005. 
 
54. Xu S, Jordan Ek, Brocke S, Bulte JW, Quigley L, Tresser N, Ostuni JL, Yang Y, 
McFarland HF, Frank JA.  Study of relapsing remitting experimental allergic 
encephalomyelitis SJL mouse model using MION-46L enhanced in vivo MRI: early 
histopathological correlation. J Neurosci Res 52:549–558, 1998. 
 
55. Rooney WD, Johnson G, Li X, Cohen ER, Kim S-G, Ugurbil K, and Springer CS. The 
Magnetic Field and Tissue Dependences of Human Brain Longitudinal 1H2O Relaxation 
in Vivo. Submitted, Magn. Reson. Med. 
 
56. Aime S, Botta M, Fasano M, and Terreno E. Lanthanide(III) Chelates for NMR 
Biomedical Applications. Chem. Soc. Rev. 1998;27:19-29. 
 
57. Littell RC, Milliken GA, Stroup WW, Wolfinger RD.  SAS® System for Mixed Models.  
SAS Institute Inc.  Cary, NC.  C. 1996. 
 


IRB#: 2864  
Protocol Approval Date: 4/7/2016
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 1 of 15   
Protocol Version: dated 12/03/2015
OHSU Knight Template Form Version: 01/04/2016
Consent Version: dated 2/17/2016
OHSU Knight Cancer Institute Consent and Authorization Form
Title: A Phase II study of ferumoxytol and gadolinium magnetic resonance imaging at 3T and 
7T in patients with primary or metastatic brain tumor either before or after treatment.
Funded by: The Walter S. and Lucienne Driskill Foundation
Supported by: AMAG Pharmaceuticals, Inc. and the National Cancer 
Institute (NCI)
Conflict of Interest Statement: Dr. Rooney and Dr. Li are inventors of a 
technology that may be used in this research and that has been licensed to 
Imbio, Inc. If this study and others like it are successful, then Imbio, OHSU 
and Drs. Rooney and Li could financially benefit.  The nature of this 
financial interest and the design of the study have been reviewed by two 
committees at OHSU. They have put in place a plan to make sure this 
research study is not affected by the financial interest. If you would like 
more information, you may contact the OHSU Research Integrity Office at 
(503) 494-7887
Table of Contents
Introduction
2
Purpose
2
Procedures
3
Risks
5
Benefits
9
Privacy
10
Participation
11
Signature  
14
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 2 of 15   
OHSU Knight Template Form Version: 01/04/2016
STUDY CONTACT INFORMATION
Purpose
Role
Contact Name
Contact Phone 
Number
Email
Principal 
Investigator
Edward A. Neuwelt, 
M.D.
503-494-5626 
neuwelte@ohsu.edu 
Co-Investigator
Joao Prola Netto, MD
Csanad Varallyay, MD 
Jenny Firkins, RN
Prakash Ambady, MD
Jessica Jensen, NP
Kirsten Johansson, FNP
Tricia White, RN
 503-494-5626
503-494-5626
503-494-5626
503-494-5626
503-494-5626
503-494-5626
503-494-5626
 
For medical questions 
about the study
Research Nurse
Jenny Firkins, RN
 503-494-5626 
 firkinsj@ohsu.edu
For non-medical 
questions about the 
study
Study Coordinator
Amy Huddleston, MPA
503-494-5626
 huddlesa@ohsu.edu
INTRODUCTION
This is a clinical trial (a type of research study).  Clinical trials include only subjects who choose to take part.  
Please take your time to make your decision.  Discuss it with your friends, family and/or your primary care 
provider. 
 
You have been asked to take part in this research study because you have or are suspected to have a primary 
brain tumor or a brain metastasis – cancer that has spread to the brain from another part of your body. Your 
brain tumor(s) can be seen on a MR scan. 
WHAT ARE MY OTHER CHOICES IF I DO NOT TAKE PART IN THIS STUDY?
If you decide not to take part in this study, you have other choices. For example:

you may choose to have the standard treatment

you may choose to take part in a different study, if one is available

or you may choose not to be treated for your brain lesion, but you may want to receive comfort 
care to relieve symptoms.
PURPOSE
WHY IS THIS STUDY BEING DONE?
This is a clinical trial, a type of research study. Medical personnel who carry out research studies are called 
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


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MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
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OHSU Knight Template Form Version: 01/04/2016
“investigators.” The investigator will explain the clinical trial to you. Clinical trials include only people who 
choose to take part. Please take your time to make your decision about taking part. You can discuss your 
decision with your friends and family. You can also discuss it with your health care team or another doctor.  If 
you have any questions, ask the investigator. 
Your participation will enable us to compare the standard magnetic resonance (MR) contrast agent, 
gadolinium, with the study agent, ferumoxytol. The study agent consists of small iron particles which are taken 
by the blood stream to your brain and to the area of the tumor. Because it is highly visible on the MR scans, 
we hope it will help us to look at the blood flow going through your tumor, evaluating the size, number, and 
integrity of the blood vessels feeding your tumor in a different way than the standard contrast agent, 
gadolinium.
We are also studying the newer, more sensitive and faster MR 7 tesla (7T) magnet. Standard MR magnets are 
1.5 to 3T strength. If you choose to participate in this study, your images on the 7T magnet will allow us to 
optimize the 7T magnet so we can most effectively compare images from the 7T magnet to those from the 3T 
magnet.
The study agent is approved by the Food and Drug Administration (FDA) for iron replacement therapy but is 
considered investigational as used in this study.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
As many as 25 subjects will take part in this study at Oregon Health & Science University (OHSU). 
PROCEDURES
HOW LONG WILL I BE IN THIS STUDY?
You may be in the study for up to 2 years.  At the investigator’s discretion, you may be asked to repeat additional study 
visits; up to a total of 4 study visits.  Each “study visit” would consist of 3trips to the study site.  You would be repeating 
Day 1, 2, and 3, for each additional “study visit”. The “study visit” may be repeated at the discretion of the investigator.  
There must be at least 3 weeks between study visits.  
WHAT TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS STUDY?
Before you begin the study:
As part of your regular care, you will have a brief clinical exam and your medical history will be reviewed. The 
investigator will evaluate your eligibility for the study based on your medical history, kidney function, evidence of tumor 
on MR scan, your present physical condition, and your ability to tolerate multiple MR scans.
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 4 of 15   
OHSU Knight Template Form Version: 01/04/2016
During the study:
Your MRs will take place at the Advanced Imaging Research Center (AIRC).  
The study will last for up to 2 years or until you have completed up to 4 of the 3 day MR study visits.  The 3 day 
study visit may not occur any more often than once every 3 weeks.  Each study visit will be the same as the 
first one.
 Study Visit 
A study visit consists of 3 days of MR scanning days as follows:
Day 1:   

An IV will be placed in your arm and you will be asked to give less than a teaspoon of blood prior to 
exposure of the gadolinium.  The blood test checks how well your kidneys are working. For women, 
you may be asked to take a urine pregnancy test. This preparation time will take approximately 20 
– 30 minutes. During the MR, gadolinium contrast agent will be injected in the standard dose and 
will be given through the IV by either the study nurse or the MR technician. You will be in the MR 
for about 60 minutes.

Day 1 and Day 2 imaging sessions may be separated by up to 7 days.
Day 2:

You will have a clinical examination before and after the MR. An IV will be placed in your arm. We will 
give you the study agent through your IV. You will have your blood pressure and heart rate checked 
before and after each infusion. You will receive IV injections of the study agent; the total dose given 
is based on your weight and is given IV in several smaller doses during the MR (total dose 4 mg/kg).

You will be in the MR scanner for about 90 minutes.

You will be monitored for 30 minutes after receiving the final dose of the study agent.  When the 
investigator thinks you are stable, you will be discharged.  
Day 3:  

You will not receive any contrast agent during this MR.

You will be in the MR scanner for about 45 minutes.
After the Study:
Approximately 4-6 weeks after receiving the study agent, you will be evaluated during a routine clinic visit or 
be contacted by telephone to see if you experienced any side effects after receiving the study agent. 
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
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OHSU Knight Template Form Version: 01/04/2016
Any complaints or problems potentially related to the infusion of the study agent will be recorded.
SCHEDULE OF EVENTS:
Test / Procedure
Day 1
Day 2 
Day 3
Final 
Inclusion/Exclusion 
Criteria
Xa
Consent
Xa
Clinical 
Exam/Assessment
Xa
Xc
Laboratory 
Monitoring
X, b
MR scan with and 
without gadolinium 
as contrast agent 
X
MR scan with the 
study agent as 
contrast agent
X
MR scan without 
contrast, 24 hrs after 
the study agent 
infusion 
X
Blood pressure/heart 
rate
Xd
Monitor for side 
effects
X
a May be done prior to visit 1
b Creatinine to check GFR (may be done within the previous 3 weeks ) and urine pregnancy test if female   
  of child bearing potential
c Before and after the day 2 MR
d Before and after each study agent injection and 30 minutes after the final study agent injection
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
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OHSU Knight Template Form Version: 01/04/2016
RISKS
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
While you are in the study, you are at risk for a number of side effects. You should discuss these with the 
researchers and/or your regular doctor.  There may also be side effects that we cannot predict.  Other drugs 
will be given to make side effects less serious and less uncomfortable if they occur. 
Here are important points about side effects:

The investigators do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.

You may have some side effects we do not expect because we are still learning about ferumoxytol. 

There may be unanticipated risk to an embryo or fetus if you or your partner becomes pregnant.
Here are important points about how you and the investigator can make side effects less of a problem:

Tell the investigator if you notice or feel anything different so they can see if you are having a side 
effect.

The investigator may be able to treat some side effects.
The most common and the most serious side effects that researchers know about are explained below. There 
might be other side effects that researchers do not yet know about. If important new side effects are found, 
the investigator will discuss these with you.
PHYSICAL RISKS
Study agent ferumoxytol
In March 2015, the FDA updated the risks of the study agent, ferumoxytol. They placed a “black box” warning on 
ferumoxytol due to reports of severe allergic reactions (anaphylaxis) in patients receiving ferumoxytol for iron 
replacement therapy.  There are data to show that people with multiple drug allergies may be at higher risk for 
anaphylaxis (a severe, whole body allergic reaction) following study agent administration. Please tell the 
investigator if you have any known drug allergies. It is important to note that an allergic reaction can occur even 
if you have received the study agent previously, with no reaction. If an allergic reaction were to happen during a 
study visit, you might experience low blood pressure, breathing difficulties, and/or a rash. There is a very small 
possibility that serious hypersensitivity (allergic) reactions may be life threatening. 
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 7 of 15   
OHSU Knight Template Form Version: 01/04/2016
A nurse or physician will be present and monitor you during, and for at least 30 minutes after, you receive the 
study agent.
A total of 1700 subjects have received one or more doses of the study agent. There have been 3 serious adverse 
events possibly related to the administration of the study agent—two cases of peritonitis (the inflammation of 
the lining the abdomen) that were possibly related and one case of serious allergic reaction related to the study 
agent. 
The reactions that have been observed during the infusion include discomfort, pain and/or bruising at the IV 
injection site.  More common but less severe side effects include a metallic taste in your mouth, which usually 
resolves quickly. 
Other reported side effects (reported in 1-2 % of patients) are: gastrointestinal (GI) discomfort (including 

Nausea 

Vomiting 

Constipation and/or diarrhea

Viral infection of the digestive tract

Upper respiratory infection (cold) 

High blood sugar 

Changes in vision 

Joint pain 

Tingling in the limbs or body 

Dizziness and hypotension (low blood pressure) 

Flushing 

Chills 

Abnormal liver function tests 

Pruritus (itching) and rash
There is an increased risk of infection in subjects with weakened immune systems. If you have a weakened 
immune system it means you have an increased risk of infection, whether or not you participate in this study.
You may have some side effects we do not expect because we are still learning about the study agent. 
In March of 2015, the FDA updated how the study agent should be given based on its use in patients with low 
iron levels.  The FDA recommendation is to give 510 mg over 15 minutes. In this study, your dose is calculated by 
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 8 of 15   
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your weight and will likely be less than 510 mg. For this study, you will receive 4 mg per kilogram (so a 68 
kilogram [150 pound] individual would receive 272 mg of the study agent, a 90 kilogram [200 pound] individual 
would receive 360 mg). The study agent will be divided up and given in three doses, and MR images will be 
taken in between. The time between the doses will be about 5 minutes. 
The first smaller dose will be given quickly, over about 5 seconds, and the other two doses will be given more 
slowly, over about 10-20 seconds. This first dose is less than 20% of the FDA approved 510 mg.  The first dose 
will be given faster than the FDA’s recommended rate because this allows special images, which are not possible 
when the study agent is given at a slower rate. This gives information about blood supply of the tumor and 
normal brain. The increased rate may increase your risk of adverse reactions. 
The remaining two doses will be given slowly, but not as slow as the FDA recommends because of the timing 
of the images. The FDA recommended timing may not be applicable to this study population because the total 
dose is injected in three smaller doses, which may help to decrease the risk of adverse events. 
For pregnancy/risk to fetus (for women): We do not know whether the study agent  is safe for a developing 
fetus or a nursing infant.  You should not become pregnant or nurse an infant while you are in this study. If 
you are sexually active and are at risk of getting pregnant, you and your male partner(s) must use a method of 
birth control that works well or you must not have intercourse. The investigator will talk to you about the 
types of birth control that are acceptable. You will have to use birth control or abstain from intercourse the 
whole time you are in this study. If you become pregnant during the research study, please tell the 
investigator and your doctor immediately. 
For pregnancy/risk to fetus (for men): We do not know whether the study agent can damage sperm. You 
should not father a child while in this study. If you are sexually active and are at risk of causing a pregnancy, 
you and your female partner(s) must use a method of birth control that works well or you must not have 
intercourse. The investigator will talk to you about the types of birth control that are acceptable. You will have 
to use birth control or abstain from intercourse the whole time you are in this study. If a female partner 
becomes pregnant during the research study, please tell the investigator and ask your partner to tell her 
doctor immediately. 
For potential drug interactions:  Potential drug interactions (prescription and non-prescription) when taken 
with the study agent are unknown at this time.  The investigator will carefully review all of the drugs you are 
taking before giving you the study agent.  If any other health care provider prescribes any new drug(s) for you 
while you are in this study, please tell the investigator before you take the new drug. You could also have that 
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 9 of 15   
OHSU Knight Template Form Version: 01/04/2016
provider talk to the investigator before prescribing the new drug.  Do not take any new over-the-counter 
drugs while you are in this study unless you first check with the investigator.
There are data to show that people with multiple drug allergies may be at higher risk for anaphylaxis (a severe, 
whole body allergic reaction) following administration of the study agent.
For blood draw:  We will draw blood from your arm.  You may feel some pain when your blood is drawn.  
There is a small chance the needle will cause bleeding, a bruise, or an infection.
For MR: The magnetic resonance (MR) machine is a powerful magnet.  This magnet may cause any metal in 
your body to move.  If you know of any metal in your body, you will need to tell the investigator right away.  
Otherwise, there are no known risks of MR.  Some individuals with claustrophobia (fear of closed spaces) may 
find the MR equipment too confining.  In that case, you can request to be removed from the scanner and this 
will be done immediately.  The MR scanner makes a loud beeping sound.  You will be asked to wear protective 
earplugs during scanning.  
The standard dye (gadolinium) that is injected into your IV for the scan is generally well tolerated.  Some 
people feel dizzy or queasy or get a headache with it or notice a cold feeling near the injection site.  There is a 
rare chance of having an allergic reaction to the dye that very rarely can be serious and life threatening. 
However, if you have kidney problems or your kidneys don't work, there is chance the dye could cause a 
disease known as Nephrogenic Systemic Fibrosis (NSF). NSF causes your skin to harden due to formation of too 
much scar tissue.  This can lead to your joints not being able to move.  In some people with NSF this scaring 
can affect the internal organs and will lead to death.  Currently there is no treatment for NSF.  Blood work will 
be done prior to the MR to check your kidney function.  Multiple exposures to GBCA might increase the risk of 
developing nephrogenic systemic fibrosis, especially in patients with kidney problems.
The study coordinator will discuss with you if you need to have any medication to help you better tolerate the 
MR.  The medication would be given to help you relax and is not intended to cause you to go to sleep or 
sedate you. These medications are often given prior to an MR and may include lorazepam (Ativan) or 
diazepam (Valium) or even an anti-histamine such as diphenhydramine (Benadryl).  All of these medications 
will make you drowsy and for this reason you would need to have someone available after the MRI to drive 
you home. The risk of taking these types of medications is that they can cause problems with your breathing 
or heart function, for this reason, the MR technician will be talking with you throughout the MR and you will 
be visually monitored also.  
Let your investigator know of any questions you have about possible side effects. You can ask the investigator 
questions about side effects at any time.
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
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OHSU Knight Template Form Version: 01/04/2016
BENEFITS
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN THIS STUDY?
You may or may not personally benefit from being in this study.  However, by serving as a subject, you may 
help us learn how to benefit patients in the future.
PRIVACY
WHO WILL SEE MY MEDICAL INFORMATION? 
We will take steps to keep your personal information confidential, but we cannot guarantee total privacy. 
We will create and collect health information about you as described in the WHY IS THIS STUDY BEING DONE 
and the WHAT TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS STUDY sections of this form. 
Health information is private and is protected under federal law and Oregon law. By agreeing to be in this 
study, you are giving permission (also called authorization) for us to use and disclose your health information 
as described in this form.
The investigators, study staff and others at OHSU may use the information we collect and create about you in 
order to conduct and oversee this research study. We may release this information to others outside of OHSU 
who are involved in conducting or overseeing this research, including:

The funder of this study, The Walter S. and Lucienne Driskill Foundation, and the funder’s 
representatives

The Food and Drug Administration (FDA) 

The Office of Human Research Protections (OHRP), a federal agency that oversees research in humans

The National Cancer Institute (NCI)

AMAG, the manufacturer of the study drug
We will not release information about you to others not listed above, unless required or permitted by law. We 
will not use your name or your identity for publication or publicity purposes, unless we have your special 
permission.
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 11 of 15   
OHSU Knight Template Form Version: 01/04/2016
When we send specimens or information outside of OHSU, they may no longer be protected under federal or 
Oregon law. In this case, your specimens or information could be used and re-released without your 
permission. 
We may continue to use and disclose your information as described above indefinitely. Some of the 
information collected and created in this study may be placed in your OHSU medical record. While the 
research is in progress, you may or may not have access to this information. After the study is complete, you 
will be able to access any study information that was added to your OHSU medical record. Ask the investigator 
if you have questions about what study information you will be able to access, and when it will be available.
PARTICIPATION
CAN I STOP TAKING PART IN THIS STUDY?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the 
investigator know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let 
the investigator continue to provide your medical information to the organization running the study.
The investigator will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
The investigator may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules

If the study is stopped by the IRB or FDA.
WHAT ARE MY RIGHTS IN THIS STUDY?
Your participation in this study is voluntary. No matter what decision you make, and even if your decision 
changes, there will be no penalty to you. You will not lose medical care or any legal rights. If you have any 
questions, concerns, or complaints regarding this study now or in the future, contact the principal investigator 
listed at the beginning of the form.
This research is being overseen by an Institutional Review Board (“IRB”). You may talk to the IRB at (503) 494-
7887 or irb@ohsu.edu if:

Your questions, concerns, or complaints are not being answered by the research team

You want to talk to someone besides the research team
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 12 of 15   
OHSU Knight Template Form Version: 01/04/2016

You have questions about your rights as a research subject

You want to get more information or provide input about this research.
You may also submit a report to the OHSU Integrity Hotline online at 
https://secure.ethicspoint.com/domain/media/en/gui/18915/index.html or by calling toll-free (877) 733-8313 
(anonymous and available 24 hours a day, seven days a week).
You do not have to join this or any research study. You do not have to allow the use and disclosure of your 
health information in the study, but if you do not, you cannot be in the study.
If you do join the study and later change your mind, you have the right to quit at any time. This includes the 
right to withdraw your authorization to use and disclose your health information. If you choose not to join any 
or all parts of this study, or if you withdraw early from any or all parts of the study, there will be no penalty or 
loss of benefits to which you are otherwise entitled, including being able to receive health care services or 
insurance coverage for services. Talk to the investigator if you want to withdraw from the study.
If you no longer want your health information to be used and disclosed as described in this form, you must 
send a written request or email stating that you are revoking your authorization to: 
Knight Clinical Trials Office, ATTN: KCTO Manager
3303 SW Bond Ave, CH15R, Portland, OR 97239
trials@ohsu.edu
Your request will be effective as of the date we receive it. However, health information collected before your 
request is received may continue to be used and disclosed to the extent that we have already taken action 
based on your authorization.  
Your health care provider may be one of the investigators of this research study and, as an investigator, is 
interested in both your clinical welfare and in the conduct of this study. Before entering this study or at any 
time during the research, you may ask for a second opinion about your care from another doctor who is in no 
way involved in this project. You do not have to be in any research study offered by your physician.  
You will be told of any new information that might make you want to change your mind about continuing to 
be in the study.  
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 13 of 15   
OHSU Knight Template Form Version: 01/04/2016
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
You will not be billed for the cost of any procedures solely related to the study.  This includes the MR scans 
without or with contrast agents (gadolinium and the study agent) and the blood tests to check your kidney 
function. You or your insurance company will be billed for the outpatient clinic visits which are medically 
related to your treatment.  The screening for the study will always be done during a clinically indicated visit 
with your doctor and therefore will be billed to you or your insurance.  You are not offered any payment for 
taking part in this study.  
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I TOOK PART IN THIS STUDY?
If you believe you have been injured or harmed while participating in this research and require immediate 
treatment, contact Dr. Edward Neuwelt at 503-494-5626.
If you are injured or harmed by the study agent, you will be treated.  OHSU, the Walter S. and Lucienne Driskill 
Foundation and AMAG Pharmaceuticals, Inc. do not offer any financial compensation or payment for the cost 
of treatment if you are injured or harmed as a result of participating in this research.  Therefore, any medical 
treatment you need may be billed to you or your insurance.  However, you are not prevented from seeking to 
collect compensation for injury related to negligence on the part of those involved in the research.  Oregon 
law (Oregon Tort Claims Act (ORS 30.260 through 30.300)) may limit the dollar amount that you may recover 
from OHSU or its caregivers and researchers for a claim relating to care or research at OHSU, and the time you 
have to bring a claim.
If you have questions on this subject, please call the OHSU Research Integrity Office at (503) 494-7887.
WHAT IS COMMERCIAL DEVELOPMENT AND HOW DOES IT AFFECT ME?
Samples and information about you or obtained from you in this research may be used for commercial 
purposes, such as making a discovery that could, in the future, be patented or licensed to a company, which 
could result in a possible financial benefit to that company, OHSU, and its researchers. There are no plans to 
pay you if this happens. You will not have any property rights or ownership or financial interest in or arising 
from products or data that may result from your participation in this study. Further, you will have no 
responsibility or liability for any use that may be made of your samples or information.
WHERE CAN I GET MORE INFORMATION?
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same information 
at: 1-800-4-CANCER (1-800-422-6237).
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 14 of 15   
OHSU Knight Template Form Version: 01/04/2016
If you want more information about this study, ask your investigator.
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY?
You can talk to the investigator about any questions or concerns you have about this study or to report side 
effects or injuries. Outside of regular clinic hours, you can speak with the neuro-oncologist on-call. Refer to the 
beginning of this consent form for contact names and phone numbers. 
SIGNATURE  
MY SIGNATURE AGREEING TO TAKE PART IN THE MAIN STUDY
Your signature below indicates that you have read this entire form and that you agree to be in this study
We will give you a copy of this signed form.
OREGON HEALTH & SCIENCE UNIVERSITY
INSTITUTIONAL REVIEW BOARD
PHONE NUMBER (503) 494-7887
CONSENT/AUTHORIZATION FORM 
APPROVAL DATE
APR. 7, 2016
Do not sign this form after the
expiration date of:   APR. 06, 2017
Participant Printed Name
Participant Signature
Date
Person(s) Obtaining Consent Printed Name
Person(s) Obtaining Consent Signature
Date
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017               


IRB#: 2864  
MED. REC. NO._______________
NAME_______________________
BIRTHDATE__________________
IRB #: 2864
Page 15 of 15   
OHSU Knight Template Form Version: 01/04/2016
Use of an Interpreter: Complete if the participant is not fluent in English and an interpreter was used to obtain 
consent.  Participants who do not read or understand English must not sign this full consent form, but instead 
sign the short form translated into their native language. This form should be signed by the investigator and 
interpreter only.  If the interpreter is affiliated with the study team, the signature of an impartial witness is 
also required.
Print name of interpreter: 
 
Signature of interpreter: 
  Date: 
An oral translation of this document was administered to the participant in ____________________ (state 
language) by an individual proficient in English and ____________________ (state language). 
    Approval Expires:  3/27/2018          
    IRB Approved:  6/30/2017